Brain and Its Neurodegeneration

**3**

**Figure 1.**

*The location and connections of cerebellum.*

**Chapter 1**

*Rajani Singh*

**1. Introduction**

**Abstract**

Cerebellum: Its Anatomy,

Cerebellum is the largest part of the hindbrain and weighs about 150 g. It is enshrined in posterior cranial fossa behind the pons and medulla oblongata and separated from these structures by cavity of fourth ventricle. It is connected to brainstem by three fibre tracts known as cerebellar peduncles. Cerebellum controls the same side of body. It precisely coordinates skilled voluntary movements by controlling strength, duration and force of contraction, so that they are smooth, balanced and accurate. It is also responsible for maintaining equilibrium, muscle tone and posture of the body. This is achieved through the use of somatic sensory information in modulating the motor output from the cerebrum and brainstem. Sherrington regarded cerebellum as the head ganglion of the proprioceptive system. Dysfunction of cerebellum along with degenerative diseases of cerebellum such as spinocerebellar ataxia, multiple sclerosis, malignant tumours, etc. may culminate into disequilibrium, hypotonia, difficulty in talking, sleeping, maintaining muscular coordination and dyssynergia which at times may be life threatening. Hence, knowledge of anatomy of cerebellum is imperative for neuroanatomists and neurosurgeons.

**Keywords:** cerebellum, pons, medulla, equilibrium, voluntary movements

Cerebellum is a Latin word meaning little brain. It is the largest part of the hind brain and weighs about 150 g. It is enshrined in posterior cranial fossa beneath the

Functions and Diseases

#### **Chapter 1**

### Cerebellum: Its Anatomy, Functions and Diseases

*Rajani Singh*

#### **Abstract**

Cerebellum is the largest part of the hindbrain and weighs about 150 g. It is enshrined in posterior cranial fossa behind the pons and medulla oblongata and separated from these structures by cavity of fourth ventricle. It is connected to brainstem by three fibre tracts known as cerebellar peduncles. Cerebellum controls the same side of body. It precisely coordinates skilled voluntary movements by controlling strength, duration and force of contraction, so that they are smooth, balanced and accurate. It is also responsible for maintaining equilibrium, muscle tone and posture of the body. This is achieved through the use of somatic sensory information in modulating the motor output from the cerebrum and brainstem. Sherrington regarded cerebellum as the head ganglion of the proprioceptive system. Dysfunction of cerebellum along with degenerative diseases of cerebellum such as spinocerebellar ataxia, multiple sclerosis, malignant tumours, etc. may culminate into disequilibrium, hypotonia, difficulty in talking, sleeping, maintaining muscular coordination and dyssynergia which at times may be life threatening. Hence, knowledge of anatomy of cerebellum is imperative for neuroanatomists and neurosurgeons.

**Keywords:** cerebellum, pons, medulla, equilibrium, voluntary movements

#### **1. Introduction**

Cerebellum is a Latin word meaning little brain. It is the largest part of the hind brain and weighs about 150 g. It is enshrined in posterior cranial fossa beneath the

**Figure 1.** *The location and connections of cerebellum.*

#### *Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

tentorium cerebelli behind the pons and medulla oblongata. Cerebellum is separated from the pons and medulla by the cavity of fourth ventricle (**Figure 1**).

Cerebellum is connected to brainstem by three large bundles of fibres called cerebellar peduncles. Superior peduncle connects cerebellum with mid brain, middle with pons and inferior with medulla oblongata [1].

#### **2. Gross anatomy**

Grossly cerebellum comprises of three parts: two surfaces, two notches and three well demarcated fissures (**Figure 2A** and **B**).

#### **2.1 Parts**

Cerebellum consists of two large bilateral lobes called cerebellar hemispheres. These two lobes are united to each other by a median worm like portion, vermis. Superior and inferior aspect of vermis are known as superior and inferior vermis, respectively. Superior vermis is continuous with the hemispheres but the inferior vermis is separated from hemispheres by deep furrow, the vallecular [2, 3].

#### **2.2 Surfaces**

Superior surface of the cerebellum is convex, and two cerebellar hemispheres are continuous with each other on this surface. Inferior surface presents deep furrow known as vallecular which separates two cerebellar hemispheres. The floor of the vallecular is occupied by inferior vermis.

#### **2.3 Notches**

There is a wide shallow gap known as anterior cerebellar notch on the anterior aspect of cerebellum. The anterior cerebellar notch lodges pons and medulla. Similarly, posteriorly there is posterior cerebellar notch which lodges falx cerebelli.

#### **2.4 Fissures**

Three fissures are related to cerebellum viz. horizontal, postero-lateral and primary fissures.

#### **Figure 2.**

*(A) Schematic diagram showing superior surface of the cerebellum; (B) schematic diagram showing subdivisions of the cerebellum on the inferior surface. N = nodule, U = uvula, P = pyramid, T = tuber, BI = biventral lobule, ISL = inferior semilunar lobule.*

**5**

**Table 1.**

*Cerebellum: Its Anatomy, Functions and Diseases DOI: http://dx.doi.org/10.5772/intechopen.93064*

cerebelli into anterior and posterior (middle) lobes.

**3. Subdivisions of cerebellum**

connected to the nodule by peduncles.

**4. Morphological subdivisions**

*Subdivisions of vermis and cerebellar hemispheres.*

Paleocerebellum and Neocerebellum.

and posture of trunk muscles.

inferior surface consists of tuber, pyramid and uvula [4, 5].

Anterior lobe Lingula No lateral extension

Posterior lobe Declive Lobulus simplex

Flocculonodular lobe Nodule Flocculus

**3.1 Anatomical subdivisions**

cerebellum.

corpus cerebelli.

posterior lobes.

Horizontal fissure is most prominent and courses along the lateral and posterior

Postero-lateral fissure is located on the inferior surface of the cerebellum and separates the flocculonodular lobe from the rest of the cerebellum also known as

Cerebellum is divided by postero-lateral fissure into flocculonodular lobe and corpus cerebelli which is further divided by primary fissure into anterior and

Flocculonodular lobe is located on the inferior surface in front of postero-lateral fissure and comprises of nodule of inferior vermis and a pair of floccule which are

Anterior lobe is situated on the superior surface anterior to primary fissure. Vermal portion of anterior lobe consists of lingual, central lobule, and culmen. Posterior lobe is located between the primary fissure on superior surface and postero-lateral fissure on inferior surface. This lobe includes both surfaces of cerebellum. Superior surface of posterior lobe consists of declive and folium while

Subdivisions of vermis and cerebellar hemispheres are described in **Table 1**.

**Lobes Subdivisions of vermis Subdivisions of cerebellar hemispheres**

Culmen Quadrangular lobule

Pyramid Biventral lobule

Uvula Tonsil

Folium Superior semilunar lobule Tuber Inferior semilunar lobule

Central lobule Ala

Phylogenetically cerebellum is divided into three subdivisions: Archicerebellum,

Archicerebellum (vestibular cerebellum): it is the oldest part of cerebellum and first to appear in aquatic vertebrates. Fishes and lower amphibians possess only this component of the cerebellum. Archicerebellum comprises of flocculonodular lobe and lingula and has mainly vestibular connections. It maintains equilibrium, tone

margins of the cerebellum. It separates the superior and inferior surfaces of the

Primary fissure is situated on the superior surface and divides the corpus

*Cerebellum: Its Anatomy, Functions and Diseases DOI: http://dx.doi.org/10.5772/intechopen.93064*

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

with pons and inferior with medulla oblongata [1].

well demarcated fissures (**Figure 2A** and **B**).

vallecular is occupied by inferior vermis.

**2. Gross anatomy**

**2.1 Parts**

**2.2 Surfaces**

**2.3 Notches**

**2.4 Fissures**

primary fissures.

tentorium cerebelli behind the pons and medulla oblongata. Cerebellum is separated from the pons and medulla by the cavity of fourth ventricle (**Figure 1**).

Cerebellum is connected to brainstem by three large bundles of fibres called cerebellar peduncles. Superior peduncle connects cerebellum with mid brain, middle

Grossly cerebellum comprises of three parts: two surfaces, two notches and three

Cerebellum consists of two large bilateral lobes called cerebellar hemispheres. These two lobes are united to each other by a median worm like portion, vermis. Superior and inferior aspect of vermis are known as superior and inferior vermis, respectively. Superior vermis is continuous with the hemispheres but the inferior vermis is separated from hemispheres by deep furrow, the vallecular [2, 3].

Superior surface of the cerebellum is convex, and two cerebellar hemispheres are continuous with each other on this surface. Inferior surface presents deep furrow known as vallecular which separates two cerebellar hemispheres. The floor of the

There is a wide shallow gap known as anterior cerebellar notch on the anterior

Three fissures are related to cerebellum viz. horizontal, postero-lateral and

aspect of cerebellum. The anterior cerebellar notch lodges pons and medulla. Similarly, posteriorly there is posterior cerebellar notch which lodges falx cerebelli.

*(A) Schematic diagram showing superior surface of the cerebellum; (B) schematic diagram showing subdivisions of the cerebellum on the inferior surface. N = nodule, U = uvula, P = pyramid, T = tuber,* 

**4**

**Figure 2.**

*BI = biventral lobule, ISL = inferior semilunar lobule.*

Horizontal fissure is most prominent and courses along the lateral and posterior margins of the cerebellum. It separates the superior and inferior surfaces of the cerebellum.

Postero-lateral fissure is located on the inferior surface of the cerebellum and separates the flocculonodular lobe from the rest of the cerebellum also known as corpus cerebelli.

Primary fissure is situated on the superior surface and divides the corpus cerebelli into anterior and posterior (middle) lobes.

#### **3. Subdivisions of cerebellum**

#### **3.1 Anatomical subdivisions**

Cerebellum is divided by postero-lateral fissure into flocculonodular lobe and corpus cerebelli which is further divided by primary fissure into anterior and posterior lobes.

Flocculonodular lobe is located on the inferior surface in front of postero-lateral fissure and comprises of nodule of inferior vermis and a pair of floccule which are connected to the nodule by peduncles.

Anterior lobe is situated on the superior surface anterior to primary fissure. Vermal portion of anterior lobe consists of lingual, central lobule, and culmen.

Posterior lobe is located between the primary fissure on superior surface and postero-lateral fissure on inferior surface. This lobe includes both surfaces of cerebellum. Superior surface of posterior lobe consists of declive and folium while inferior surface consists of tuber, pyramid and uvula [4, 5].


Subdivisions of vermis and cerebellar hemispheres are described in **Table 1**.

**Table 1.**

*Subdivisions of vermis and cerebellar hemispheres.*

#### **4. Morphological subdivisions**

Phylogenetically cerebellum is divided into three subdivisions: Archicerebellum, Paleocerebellum and Neocerebellum.

Archicerebellum (vestibular cerebellum): it is the oldest part of cerebellum and first to appear in aquatic vertebrates. Fishes and lower amphibians possess only this component of the cerebellum. Archicerebellum comprises of flocculonodular lobe and lingula and has mainly vestibular connections. It maintains equilibrium, tone and posture of trunk muscles.

Paleocerebellum (spinal cerebellum) appears next in terrestrial vertebrates with the appearance of limbs. It includes anterior lobe except lingula and pyramid and uvula. It is concerned with spinocerebellar connections and responsible for tone, posture and crude movements of the limbs.

Neocerebellum (cerebral cerebellum) is the most recent part of cerebellum to develop. It develops in primates and associated with the enlargement of telencephalone and cerebral cortex. It is very prominent in higher mammals. Neocerebellum includes posterior lobe except pyramid and uvula. It is mainly cortico-ponto-cerebellar connections and is concerned with smooth performance of skilled voluntary movements [4, 5].

#### **5. Cytoarchitecture of cerebellum**

Cerebellum consists of outer layer of grey matter, the cerebellar cortex and inner layer of white matter. Masses of grey matter, intracerebellar nuclei lie embedded in the white matter. Cerebellar cortex is folded to form narrow leaf like bands called folia. Each folium consists of central core of white matter surrounded by thin layer of grey matter. Central core of white matter is arranged in the form of the branching tree so called arbor vitae cerebelli.

#### **5.1 Grey matter**

Main features of grey matter are (a) cerebellar cortex and (b) intracebellar nuclei.

#### **5.2 Structure of cerebellar**

Cerebellar cortex composed of three distinct layers: (a) outer molecular layer, (b) intermediate Purkinje cell layer, and (c) inner granular layer cortex (**Figure 3**).

#### **5.3 Molecular (plexiform) layer**

This layer consists of unmyelinated nerve fibres derived from axons of granule, stellate and basket cells, dendrites of Purkinje and Golgi cells. It also contains

**7**

**Figure 4.**

*Intracerebellar nuclei.*

*Cerebellum: Its Anatomy, Functions and Diseases DOI: http://dx.doi.org/10.5772/intechopen.93064*

with dendrites of Purkinje cells.

**5.4 Purkinje cell layer**

these nuclei.

**5.5 Granular layer**

**6. Intracerebellar nuclei**

grey matter embedded in white matter.

stellate and basket cells. Stellate cells possess short process and are found scattered near the surface. The axons of these cell synapse with the dendrites of Purkinje cells. Basket cells contains little cytoplasm but have extensive processes. The axons of these cells follow transverse course parallel to the cortical surface and synapse

Purkinje cell layer consists of single layer of flask shaped Purkinje cells. Dendrites of these cells travel upwards into the molecular layer in which these cells undergo profuse branching. The dendrites of Purkinje cells synapse with collaterals of basket cells, axons of granule cells and climbing fibres. Axons of Purkinje cells travel through granular layer into white matter where they form synaptic connections with intracerebellar nuclei and exert inhibitory influence on

The inner granular layer composed of numerous granule cells and few Golgi cells. Each granule cell possesses 4–5 dendrites which synapse with mossy fibres. Axons of these cells courses into molecular layer where these bifurcates and branches pass parallel to the long axis of cerebellar folium. These fibres are known

Golgi cells are prominent but scanty, and their dendrites ramify in molecular layer. Human cerebellum contains about 30–50 billion granule cells, 30 million Purkinje

Intracerebellar nuclei (**Figure 4**) also known as central nuclei are collection of

As these are situated close to roof of IV ventricle on each side of midline hence

also referred as roof nuclei. From lateral to medial side, these are (1) Dentate nucleus, (2) Emboliform nucleus, (3) Globose nucleus, and (4) Fastigial nucleus.

cells and 100 million stellate and basket cells. Purkinje cells, granule cells, stellate cells, basket cells and Golgi cells constitute intrinsic neurons of cerebellar cortex. All intrinsic neurons except granule cells are inhibitory and such collection of inhibitory neurons is not found anywhere in the central nervous system except cerebellum [1, 2].

as parallel fibres and synapse with the dendrites of Purkinje cells.

stellate and basket cells. Stellate cells possess short process and are found scattered near the surface. The axons of these cell synapse with the dendrites of Purkinje cells. Basket cells contains little cytoplasm but have extensive processes. The axons of these cells follow transverse course parallel to the cortical surface and synapse with dendrites of Purkinje cells.

#### **5.4 Purkinje cell layer**

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

posture and crude movements of the limbs.

**5. Cytoarchitecture of cerebellum**

tree so called arbor vitae cerebelli.

**5.2 Structure of cerebellar**

**5.3 Molecular (plexiform) layer**

**5.1 Grey matter**

Paleocerebellum (spinal cerebellum) appears next in terrestrial vertebrates with the appearance of limbs. It includes anterior lobe except lingula and pyramid and uvula. It is concerned with spinocerebellar connections and responsible for tone,

Cerebellum consists of outer layer of grey matter, the cerebellar cortex and inner layer of white matter. Masses of grey matter, intracerebellar nuclei lie embedded in the white matter. Cerebellar cortex is folded to form narrow leaf like bands called folia. Each folium consists of central core of white matter surrounded by thin layer of grey matter. Central core of white matter is arranged in the form of the branching

Main features of grey matter are (a) cerebellar cortex and (b) intracebellar nuclei.

Cerebellar cortex composed of three distinct layers: (a) outer molecular layer, (b) intermediate Purkinje cell layer, and (c) inner granular layer cortex (**Figure 3**).

This layer consists of unmyelinated nerve fibres derived from axons of granule,

stellate and basket cells, dendrites of Purkinje and Golgi cells. It also contains

Neocerebellum (cerebral cerebellum) is the most recent part of cerebellum to develop. It develops in primates and associated with the enlargement of telencephalone and cerebral cortex. It is very prominent in higher mammals. Neocerebellum includes posterior lobe except pyramid and uvula. It is mainly cortico-ponto-cerebellar connections and is concerned with smooth performance of skilled voluntary movements [4, 5].

**6**

**Figure 3.**

*Structure of cerebellar cortex along with intrinsic neurons and their processes.*

Purkinje cell layer consists of single layer of flask shaped Purkinje cells. Dendrites of these cells travel upwards into the molecular layer in which these cells undergo profuse branching. The dendrites of Purkinje cells synapse with collaterals of basket cells, axons of granule cells and climbing fibres. Axons of Purkinje cells travel through granular layer into white matter where they form synaptic connections with intracerebellar nuclei and exert inhibitory influence on these nuclei.

#### **5.5 Granular layer**

The inner granular layer composed of numerous granule cells and few Golgi cells. Each granule cell possesses 4–5 dendrites which synapse with mossy fibres. Axons of these cells courses into molecular layer where these bifurcates and branches pass parallel to the long axis of cerebellar folium. These fibres are known as parallel fibres and synapse with the dendrites of Purkinje cells.

Golgi cells are prominent but scanty, and their dendrites ramify in molecular layer. Human cerebellum contains about 30–50 billion granule cells, 30 million Purkinje cells and 100 million stellate and basket cells. Purkinje cells, granule cells, stellate cells, basket cells and Golgi cells constitute intrinsic neurons of cerebellar cortex. All

intrinsic neurons except granule cells are inhibitory and such collection of inhibitory neurons is not found anywhere in the central nervous system except cerebellum [1, 2].

#### **6. Intracerebellar nuclei**

Intracerebellar nuclei (**Figure 4**) also known as central nuclei are collection of grey matter embedded in white matter.

As these are situated close to roof of IV ventricle on each side of midline hence also referred as roof nuclei. From lateral to medial side, these are (1) Dentate nucleus, (2) Emboliform nucleus, (3) Globose nucleus, and (4) Fastigial nucleus.

**Figure 4.** *Intracerebellar nuclei.*

#### **6.1 Dentate nucleus**

It is the most prominent cerebellar nucleus and largest in primates including human beings. It belongs to neocerebellum and receives afferent from it. Its shape is like crumpled purse with hilum directed ventro-medially and its interior is filled with white matter consisting of efferent fibres forming most of the superior cerebellar peduncle.

#### **6.2 Emboliform nucleus**

It is oval shaped and located medial to dentate nucleus. It belongs to paleocerebellum, and this nucleus receives fibres from paleocerebellum and gives fibres to red nucleus via superior cerebellar peduncle.

#### **6.3 Globose nucleus**

It is rounded in shape and situated between emboliform and fastigial nuclei. It has similar connections as emboliform nucleus. Emboliform and globose nuclei together are known as nucleus interpositus.

#### **6.4 Fastigial nucleus**

This nucleus is situated in the midline in the vermis and smaller than dentate nucleus but larger than nucleus interpositus. It belongs to archicerebellum receiving afferents from it conveying efferents to vestibular and reticular nuclei.

#### **7. White matter**

White matter of cerebellum composed of three types of fibres viz. intrinsic, afferent and efferent. Intrinsic fibres are limited to cerebellum and connect different regions of cerebellum either of same hemispheres or of the two cerebellar hemispheres. Afferents and efferents connect cerebellum to other parts of central nervous system.

#### **8. Connections of cerebellum**

#### **8.1 Afferent fibres**

Cerebellum acquires information from cerebral cortex, spinal cord, vestibular apparatus, red nucleus and tectum of midbrain through afferent fibres. Cerebellum accrues input from cerebral cortex through cortico-ponto-cerebellar, cerebro-olivocerebellar and cerebro-reticulo-cerebellar pathways. Cerebellum receives information from spinal cord through anterior spinocerebellar, posterior spinocerebellar and cuneocerebellar tracts and that from vestibular apparatus either directly or after relaying in the vestibular nuclei [4, 5].

Afferent fibres reach the cerebellum through middle and inferior cerebellar peduncle and are of two types: (a) climbing fibres and (b) mossy fibres.

Climbing fibres arises in the inferior olivary nucleus and each fibre after giving a collateral to the intracerebellar nuclei synapses with the Purkinje cell. Mossy fibres are the main afferent fibres of cerebellum, and each mossy divides into 30–40

**9**

and vestibular nuclei.

*Cerebellum: Its Anatomy, Functions and Diseases DOI: http://dx.doi.org/10.5772/intechopen.93064*

excitatory effect on Purkinje cells.

**9. Intrinsic cerebellar circuitry**

**10. Cerebellar peduncles**

and inferior to the medulla oblongata.

from the cerebellum arising in dentate nucleus.

part of the pons and cerebellar hemispheres.

inferior.

**8.2 Efferent fibres**

cerebellar peduncle.

shape surrounded by a capsule of neuroglial cells.

and vermis directly end in lateral vestibular nuclei.

terminal swellings known as rosette which synapses with dendrites of granule cells and axons of Golgi cells. The structure formed by the rosette along with its synapses with granule and Golgi cells is known as cerebellar glomerulus which is spherical in

One climbing fibre synapses with single Purkinje cell; however, one mossy fibre synapses with many granule cells, and each granule cell synapses with thousands of Purkinje cells. Thus, one climbing fibre influences one Purkinje cells while one mossy fibres multitude of Purkinje cells. Both climbing and mossy fibres have

Cerebellum provides output to red nucleus, thalamus, vestibular nuclei and reticular formation through efferent fibres via Purkinje cells. Majority of axons of Purkinje cells synapse with neurons of intracerebellar nuclei which in turn project to other parts of nervous system but few Purkinje cells from flocculonodular lobe

Efferent fibres from dentate, emboliform and globose nuclei travel through superior cerebellar peduncle and those from fastigial nucleus through inferior

All the afferent fibres to the cerebellum viz. climbing and mossy fibres are excitatory to the cells of cerebral cortex, and their collaterals are also excitatory to the intracerebellar nuclei. The climbing fibres excite the Purkinje cells directly but mossy fibres excite the Purkinje cells through granule cells which in turn excite basket and stellate cells but basket and stellate cells inhibit the Purkinje cells. Mossy

Purkinje cells inhibit intracerebellar nuclei which in turn control muscular activ-

The afferent and efferent fibres of the cerebellum together form three bundles,

Superior cerebellum connects cerebellum to the midbrain, middle to the pons

Superior cerebellar peduncle (brachium conjunctivum) ascends upward from the anterior cerebellar notch to the tectum of the midbrain. These peduncles form the supero-lateral boundary of the fourth ventricle. It conveys mainly efferent fibres

Middle cerebellar peduncle (brachium pontis) is the largest of three peduncles and consists principally of afferent fibres to the cerebellum. It bridges the basilar

Inferior cerebellar peduncle (restiform body) connects dorso-lateral part of medulla oblongata and cerebellar hemispheres and composed of afferent fibres to the cerebellum from spinal cord, olivary nucleus, reticular formation of the medulla

cerebellar peduncles on each side. These peduncles are superior, middle and

fibres in addition also excite Golgi cells which in turn inhibit granule cells.

ity through motor areas of brainstem and cerebral cortex.

*Cerebellum: Its Anatomy, Functions and Diseases DOI: http://dx.doi.org/10.5772/intechopen.93064*

terminal swellings known as rosette which synapses with dendrites of granule cells and axons of Golgi cells. The structure formed by the rosette along with its synapses with granule and Golgi cells is known as cerebellar glomerulus which is spherical in shape surrounded by a capsule of neuroglial cells.

One climbing fibre synapses with single Purkinje cell; however, one mossy fibre synapses with many granule cells, and each granule cell synapses with thousands of Purkinje cells. Thus, one climbing fibre influences one Purkinje cells while one mossy fibres multitude of Purkinje cells. Both climbing and mossy fibres have excitatory effect on Purkinje cells.

#### **8.2 Efferent fibres**

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

It is the most prominent cerebellar nucleus and largest in primates including human beings. It belongs to neocerebellum and receives afferent from it. Its shape is like crumpled purse with hilum directed ventro-medially and its interior is filled with white matter consisting of efferent fibres forming most of the superior

It is oval shaped and located medial to dentate nucleus. It belongs to paleocerebellum, and this nucleus receives fibres from paleocerebellum and gives fibres to

It is rounded in shape and situated between emboliform and fastigial nuclei. It has similar connections as emboliform nucleus. Emboliform and globose nuclei

This nucleus is situated in the midline in the vermis and smaller than dentate nucleus but larger than nucleus interpositus. It belongs to archicerebellum receiving

White matter of cerebellum composed of three types of fibres viz. intrinsic, afferent and efferent. Intrinsic fibres are limited to cerebellum and connect different regions of cerebellum either of same hemispheres or of the two cerebellar hemispheres. Afferents and efferents connect cerebellum to other parts of central

Cerebellum acquires information from cerebral cortex, spinal cord, vestibular apparatus, red nucleus and tectum of midbrain through afferent fibres. Cerebellum accrues input from cerebral cortex through cortico-ponto-cerebellar, cerebro-olivocerebellar and cerebro-reticulo-cerebellar pathways. Cerebellum receives information from spinal cord through anterior spinocerebellar, posterior spinocerebellar and cuneocerebellar tracts and that from vestibular apparatus either directly or

Afferent fibres reach the cerebellum through middle and inferior cerebellar

Climbing fibres arises in the inferior olivary nucleus and each fibre after giving a collateral to the intracerebellar nuclei synapses with the Purkinje cell. Mossy fibres are the main afferent fibres of cerebellum, and each mossy divides into 30–40

peduncle and are of two types: (a) climbing fibres and (b) mossy fibres.

afferents from it conveying efferents to vestibular and reticular nuclei.

**6.1 Dentate nucleus**

cerebellar peduncle.

**6.3 Globose nucleus**

**6.4 Fastigial nucleus**

**7. White matter**

nervous system.

**8.1 Afferent fibres**

**8. Connections of cerebellum**

after relaying in the vestibular nuclei [4, 5].

**6.2 Emboliform nucleus**

red nucleus via superior cerebellar peduncle.

together are known as nucleus interpositus.

**8**

Cerebellum provides output to red nucleus, thalamus, vestibular nuclei and reticular formation through efferent fibres via Purkinje cells. Majority of axons of Purkinje cells synapse with neurons of intracerebellar nuclei which in turn project to other parts of nervous system but few Purkinje cells from flocculonodular lobe and vermis directly end in lateral vestibular nuclei.

Efferent fibres from dentate, emboliform and globose nuclei travel through superior cerebellar peduncle and those from fastigial nucleus through inferior cerebellar peduncle.

#### **9. Intrinsic cerebellar circuitry**

All the afferent fibres to the cerebellum viz. climbing and mossy fibres are excitatory to the cells of cerebral cortex, and their collaterals are also excitatory to the intracerebellar nuclei. The climbing fibres excite the Purkinje cells directly but mossy fibres excite the Purkinje cells through granule cells which in turn excite basket and stellate cells but basket and stellate cells inhibit the Purkinje cells. Mossy fibres in addition also excite Golgi cells which in turn inhibit granule cells.

Purkinje cells inhibit intracerebellar nuclei which in turn control muscular activity through motor areas of brainstem and cerebral cortex.

#### **10. Cerebellar peduncles**

The afferent and efferent fibres of the cerebellum together form three bundles, cerebellar peduncles on each side. These peduncles are superior, middle and inferior.

Superior cerebellum connects cerebellum to the midbrain, middle to the pons and inferior to the medulla oblongata.

Superior cerebellar peduncle (brachium conjunctivum) ascends upward from the anterior cerebellar notch to the tectum of the midbrain. These peduncles form the supero-lateral boundary of the fourth ventricle. It conveys mainly efferent fibres from the cerebellum arising in dentate nucleus.

Middle cerebellar peduncle (brachium pontis) is the largest of three peduncles and consists principally of afferent fibres to the cerebellum. It bridges the basilar part of the pons and cerebellar hemispheres.

Inferior cerebellar peduncle (restiform body) connects dorso-lateral part of medulla oblongata and cerebellar hemispheres and composed of afferent fibres to the cerebellum from spinal cord, olivary nucleus, reticular formation of the medulla and vestibular nuclei.

### **11. Fibres transmitted by cerebellar peduncles**

#### **11.1 Superior cerebellar peduncle**

This peduncle conveys both afferent and efferent fibres.

#### *11.1.1 Afferent fibres*


#### *11.1.2 Efferent fibres*


#### **11.2 Middle cerebellar peduncle**

#### *11.2.1 Afferent fibres*


**11**

*Cerebellum: Its Anatomy, Functions and Diseases DOI: http://dx.doi.org/10.5772/intechopen.93064*

**11.3 Inferior cerebellar peduncle**

pyramid of vermis.

in fastigial nuclei.

*11.3.2 Efferent fibres*

projected to vestibular nuclei

inferior olivary nucleus.

**12. Functions of cerebellum**

nuclei form hook bundle of russel.

tween agonist and antagonist muscles.

lower limb to paleocerebellum.

and project into the neocerebellum.

and project on to the contralateral neocerebellum.

the medulla oblongata and project on to the neocerebellum.

No efferent fibres pass through this peduncle.

1.Posterior spino-cerebellar tract arises from thoracic nucleus (Clarke's column) of the spinal cord conveying proprioceptive and exteroceptive impulses from

2.Cuneo-cerebellar tract (posterior external arcuate fibres) arise from ipsilateral accessory cuneate nucleus of medulla transmitting proprioceptive and exteroceptive impulses from upper limb and upper trunk and project on culmen and

3.Anterior external arcuate fibres originate from arcuate nucleus of both sides

4.Vestibulo-cerebellar tract primarily arise from vestibular nerve and secondary from medial and inferior vestibular nuclei forming juxta-restiform body and projecting to ipsilateral flocculonodular lobe, uvula and lingual. Few fibres end

5.Olivo-cerebellar tract sprout from contralateral inferior olivary nucleus and project into the neocerebellum but few fibres terminate into deep nuclei.

6.Parolivo-cerebellar tract arise from medial and dorsal accessory olivary nuclei

7.Reticulo-cerebellar tract buds from lateral and paramedian reticular nuclei of

1.Cerebello-vestibular fibres sprout from ipsilateral flocculonodular and fastigial nuclei of both sides. These fibres travel through juxta-restiform body and

2.Cerebello-reticular fibres arise from fastigial nuclei of both sides and reaches the pontine and reticular formation. Fibres arising from contralateral fastigial

3.Cerebello-olivary fibre's origin is unknown and connect cerebellum with the

1.Cerebellum maintains equilibrium, muscle tone, posture and coordinates skilled voluntary movements by regulating the grade of muscle tension be-

*11.2.2 Efferent fibres*

*11.3.1 Afferent fibres*

*Cerebellum: Its Anatomy, Functions and Diseases DOI: http://dx.doi.org/10.5772/intechopen.93064*

#### *11.2.2 Efferent fibres*

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

1.Anterior spino-cerebellar tract arise from the cells of laminae V-VII of the spinal cord. This tract convey proprioceptive and exteroceptive impulses from lower limb and lower part of the body and maintenance of posture and move-

2.Tecto-cerebellar tract originate from the superior and inferior colliculi of the midbrain tectum and are projected to the vermal and paravermal regions of declive, folium, tuber and pyramid and carry information from visual and

3.Trigemino-cerebellar fibres arise from superior sensory and spinal nucleus of

4.Ceruleo-cerebellar is nor-adrenergic fibres arising from locus ceruleus and

1.Dentato-thalamic fibres arise from dentate nucleus and projected to area 4 and

2.Cerebello-rubral fibres erupt from nucleus interpositus and end in contralat-

3.Cerebello-olivary fibres bud from dentate nucleus and terminate in inferior

4.Cerebello-reticular fibres originate from fastigial nucleus and end in reticular

1.Ponto-cerebellar fibres originate from pontine nuclei of basilar part of the pons and projected partly to contralateral neocerebellum and partly to contralateral paleocerebellum. Pontine nuclei receive fibres from cerebral cortex forming

2.Reticulo-cerebellar tract arise from reticular formation of brainstem and are

3.Some serotonergic fibres from raphe nuclei of the pons reach the cerebellum

the trigeminal nerve and are projected to the culmen and declive.

5.Hypothalamo-cerebellar fibres are cholinergic fibres originating from

6 of the motor cortex regulating motor functions.

**11. Fibres transmitted by cerebellar peduncles**

This peduncle conveys both afferent and efferent fibres.

**11.1 Superior cerebellar peduncle**

ment of lower limb.

auditory system.

hypothalamus.

eral red nucleus.

olivary nucleus.

**11.2 Middle cerebellar peduncle**

cerebro-ponto-cerebellar tract.

through this peduncle.

projected to the vermal region of the cerebellum.

nuclei.

*11.2.1 Afferent fibres*

*11.1.2 Efferent fibres*

inhibiting Purkinje cells.

*11.1.1 Afferent fibres*

**10**

No efferent fibres pass through this peduncle.

#### **11.3 Inferior cerebellar peduncle**

#### *11.3.1 Afferent fibres*


#### *11.3.2 Efferent fibres*


#### **12. Functions of cerebellum**

1.Cerebellum maintains equilibrium, muscle tone, posture and coordinates skilled voluntary movements by regulating the grade of muscle tension between agonist and antagonist muscles.


### **13. Arterial supply of the cerebellum**

The cerebellum is irrigated by three pairs of cerebellar arteries.


#### **14. Applied anatomy**

Cerebellar lesions may occur due to trauma, vascular occlusion, tumour or other pathologies producing cerebellar syndrome. Cerebellar syndrome is grouped in three types viz. Archicerebellar, paleocerebellar and neocerebellar syndromes.

#### **14.1 Archicerebellar syndrome**

In this syndrome, predominantly flocculonodular is affected by tumour, medulloblastoma. The patient is unable to maintain equilibrium while standing and falls on closing the eyes. This is called positive Romberg's sign. In addition to this, the patient walks on a wide base with legs well apart and sways from side to side.

#### **14.2 Paleocerebellum syndrome**

Lesion of this part of cerebellum produces hypotonia (decreased muscle tone) of limb muscles manifesting as:

**13**

*Cerebellum: Its Anatomy, Functions and Diseases DOI: http://dx.doi.org/10.5772/intechopen.93064*

**14.3 Neocerebellum syndrome**

tremor which manifests in form of:

or walk on a broad base.

pushing act immediately.

Cerebellar degenerative diseases:

a.**Spinocerebellar ataxia**

b.**Multiple sclerosis**

wrong places.

muscles.

b.Abnormal tendon reflex, for example, oscillating movements of leg are pro-

Lesion in this part of cerebellum leads to incoordination known as asynergia and

a.Ataxia due to incoordination of muscles of trunk, pectoral and pelvic girdles. The patient tends to fall on the side of lesion and to prevent fall patient stands

b.Dysmetria culminates into past pointing where the patient is not able to measure the distance for performing intended task. This is tested by finger-nose test in which the patient is supposed to touch the tip of nose by finger but in this

c.Intention tremors appear during purposeful movements and disappear during rest. These tremors are coarse, arrhythmic and occur at the end of the movement.

d.Dysdiadochokinesis/adiadochokinesis is the inability to perform alternate

e.Rebound phenomenon occurs when the action of agonist muscle is not checked by corresponding antagonist muscle. If the patient is asked to push the palm of physician and when physician removes his hand, the hand of the patient moves back (rebounds) and hits the physician as the patient is unable to stop the

f. Dysarthria/scanning speech occurs due to incoordination of muscles responsible for speech. The speech is slurred, prolonged, explosive and with pauses at

g.Nystagmus results in oscillation of eye ball due to incoordination of extraocular

In addition to above mentioned diseases, cerebellum is affected by certain

This condition involves mutation in genes causing degenerative changes in neurons of cerebellum including brainstem and spinal cord. If a parent is affected by this disease, there is 50% chance of inheriting the disease [6]. It is hereditary progressive degenerative disease often fatal. The disease is associated with progressive incoordination of gait, hand, speech and eye. No treatment is available only

In this condition, both genetic and environmental factors influence the outcome of diseases [7]. The myelin sheath enveloping the neurons is damaged resulting in delayed and interrupted impulses from and to the cerebellum [8]. It is incurable condition.

neurodegenerative diseases which are elaborated below:

symptomatic relief can be provided to affected individuals.

disorder the patient either over or under shoots the tip of nose.

movements with rapidity such as supination and pronation.

duced when patellar tendon is tapped (Pendular knee jerk).

c.Unable to maintain equilibrium while walking exhibiting ataxic gait.

a.Instability of joints resulting in flail joints.


#### **14.3 Neocerebellum syndrome**

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

reticular formation.

force and direction.

the cerebellum.

**14. Applied anatomy**

**14.1 Archicerebellar syndrome**

**14.2 Paleocerebellum syndrome**

a.Instability of joints resulting in flail joints.

limb muscles manifesting as:

**13. Arterial supply of the cerebellum**

part of inferior surface of cerebellum.

rior part of inferior surface of cerebellum.

The cerebellum is irrigated by three pairs of cerebellar arteries.

a.Superior cerebellar artery, branch of basilar artery irrigates superior surface of

b.Anterior inferior cerebellar artery, branch of basilar artery supplies anterior

c.Posterior inferior cerebellar artery, branch of vertebral artery irrigates poste-

Cerebellar lesions may occur due to trauma, vascular occlusion, tumour or other

In this syndrome, predominantly flocculonodular is affected by tumour, medulloblastoma. The patient is unable to maintain equilibrium while standing and falls on closing the eyes. This is called positive Romberg's sign. In addition to this, the patient walks on a wide base with legs well apart and sways from side to side.

Lesion of this part of cerebellum produces hypotonia (decreased muscle tone) of

pathologies producing cerebellar syndrome. Cerebellar syndrome is grouped in three types viz. Archicerebellar, paleocerebellar and neocerebellar syndromes.

2.Sherrington named cerebellum as the head ganglion of the proprioceptive system as various sensory inputs from the vestibular, visual and auditory systems, stretch receptors of muscle spindle and Golgi tendon organ, tactile and pressure receptors of head and body are relayed in the cerebellum. The sensory impulses are processed in the intrinsic cerebellar circuitry and integrated into the motor system by cerebral motor cortex, red nucleus, vestibular nuclei and

3.If the movement is to be carried out, cerebral cortex sends information to anterior horn cells of spinal cord to initiate movement, and it also sends impulses to cerebellum about the movement to be executed. Cerebellum also receives proprioceptive information from the muscles and joints about the actual movement occurring. The cerebellum compares both these information about movement and if any difference is noted in information concerning intended and actual movement, the cerebellum sends the information to cerebral cortex and anterior horn cells of the spinal cord to correct the discrepancy so that movement carried out is accurate in time, rate, range,

**12**

Lesion in this part of cerebellum leads to incoordination known as asynergia and tremor which manifests in form of:


In addition to above mentioned diseases, cerebellum is affected by certain neurodegenerative diseases which are elaborated below:

Cerebellar degenerative diseases:

#### a.**Spinocerebellar ataxia**

This condition involves mutation in genes causing degenerative changes in neurons of cerebellum including brainstem and spinal cord. If a parent is affected by this disease, there is 50% chance of inheriting the disease [6]. It is hereditary progressive degenerative disease often fatal. The disease is associated with progressive incoordination of gait, hand, speech and eye. No treatment is available only symptomatic relief can be provided to affected individuals.

#### b.**Multiple sclerosis**

In this condition, both genetic and environmental factors influence the outcome of diseases [7]. The myelin sheath enveloping the neurons is damaged resulting in delayed and interrupted impulses from and to the cerebellum [8]. It is incurable condition.

#### c.**Paraneoplastic disorders**

In this disorder, the person's autoimmune system especially T-cells become active in response to malignant tumours resulting in degeneration of neurons of cerebellum causing impaired ability to talk, walk, sleep, maintain balance and coordinate muscle activity [9]. This disorder is more common in middle aged individuals with lung, ovarian and breast cancer [10].

#### d.**Chronic alcohol abuse**

This condition is more prevalent in men than women. Chronic alcohol intake reduces vitamin B1 absorption and utilisation leading to degeneration of cerebellar neurons [11]. It is most common cause of nutritional spinocerebellar ataxia.

#### e.**Parkinson's disease**

Lesions of basal ganglion and cerebellum produce abnormal movements or changes in tone. Tremors occur both with the lesions of basal ganglion and cerebellum. However, tremors in cerebellar lesions occur only during movement, hence also known as intention tremors, while in basal ganglion diseases, like Parkinson's disease, tremors are observed during resting state. In addition to this, other signs of Parkinson's disease like mask face, clasp knife rigidity, lead pipe rigidity and hypokinesia/akinesia are not observed in cerebellar neurodegenerative diseases.

#### f. **Alzheimer's disease**

This chronic neurodegenerative disease is characterised by gradual onset of dementia. Alzheimer's disease is the cause of dementia in 60–70% cases. Most common early symptom is difficulty in remembering recent events [12]. Later on other symptoms like problems with language, disorientation and mood swings appear slowly. Though the causes of this disease can be various, the risk attributed to genetics is estimated to be around 70% [13]. In this disease, there is degeneration and loss of neurons and synapses in various parts of brain resulting in atrophy (reduction in size) of related regions. Amyloid plaques and neurofibrillary tangles are found deposited in the neurons of the brain [14].

#### g.**Huntington's disease**

Huntington's disease is also known as Huntington's chorea. It is an inherited disorder caused by mutation in the huntingtin gene which codes for huntingtin protein. Mutant huntingtin gene produces mutant and defective protein which is toxic to neurons of brain causing degenerative changes in brain. This causes problem with mood and mental abilities associated with lack of coordination and unsteady gait. Gradually coordinated movements become difficult and person is unable to talk [15]. There is as no treatment for the disease except for the supportive treatment.

#### **15. Conclusion**

Normally, cerebellum maintains equilibrium, muscle tone, posture and coordinates skilled voluntary movements which are very essential to carry out day to day activities. However, lesions of cerebellum may disrupt these actions which may cause various types of inconveniences and discomforts to the patients.

Dysfunction of cerebellum may culminate into disequilibrium, hypotonia and dyssynergia, which at times may be life threatening. In addition to the degenerative diseases of cerebellum described above, it causes difficulty in talking eating, sleeping coordination of muscular activity and other neurological complications. Hence, knowledge of the anatomy of the cerebellum is imperative for neuroanatomists and neurosurgeons.

**15**

**Author details**

Department of Anatomy, UP University of Medical Sciences Saifai Etawah, UP,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: nani\_sahayal@rediffmail.com

provided the original work is properly cited.

Rajani Singh

India

*Cerebellum: Its Anatomy, Functions and Diseases DOI: http://dx.doi.org/10.5772/intechopen.93064*

*Cerebellum: Its Anatomy, Functions and Diseases DOI: http://dx.doi.org/10.5772/intechopen.93064*

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

In this disorder, the person's autoimmune system especially T-cells become active in response to malignant tumours resulting in degeneration of neurons of cerebellum causing impaired ability to talk, walk, sleep, maintain balance and coordinate muscle activity [9]. This disorder is more common in middle aged individuals with

This condition is more prevalent in men than women. Chronic alcohol intake reduces vitamin B1 absorption and utilisation leading to degeneration of cerebellar

Lesions of basal ganglion and cerebellum produce abnormal movements or changes in tone. Tremors occur both with the lesions of basal ganglion and cerebellum. However, tremors in cerebellar lesions occur only during movement, hence also known as intention tremors, while in basal ganglion diseases, like Parkinson's disease, tremors are observed during resting state. In addition to this, other signs of Parkinson's disease like mask face, clasp knife rigidity, lead pipe rigidity and hypokinesia/akinesia are not observed in cerebellar neurodegenerative diseases.

This chronic neurodegenerative disease is characterised by gradual onset of dementia. Alzheimer's disease is the cause of dementia in 60–70% cases. Most common early symptom is difficulty in remembering recent events [12]. Later on other symptoms like problems with language, disorientation and mood swings appear slowly. Though the causes of this disease can be various, the risk attributed to genetics is estimated to be around 70% [13]. In this disease, there is degeneration and loss of neurons and synapses in various parts of brain resulting in atrophy (reduction in size) of related regions. Amyloid plaques and neurofibrillary tangles

Huntington's disease is also known as Huntington's chorea. It is an inherited disorder caused by mutation in the huntingtin gene which codes for huntingtin protein. Mutant huntingtin gene produces mutant and defective protein which is toxic to neurons of brain causing degenerative changes in brain. This causes problem with mood and mental abilities associated with lack of coordination and unsteady gait. Gradually coordinated movements become difficult and person is unable to talk [15].

Normally, cerebellum maintains equilibrium, muscle tone, posture and coordinates skilled voluntary movements which are very essential to carry out day to day activities. However, lesions of cerebellum may disrupt these actions which may

Dysfunction of cerebellum may culminate into disequilibrium, hypotonia and dyssynergia, which at times may be life threatening. In addition to the degenerative diseases of cerebellum described above, it causes difficulty in talking eating, sleeping coordination of muscular activity and other neurological complications. Hence, knowledge of the anatomy of the cerebellum is imperative for neuroanatomists and

There is as no treatment for the disease except for the supportive treatment.

cause various types of inconveniences and discomforts to the patients.

neurons [11]. It is most common cause of nutritional spinocerebellar ataxia.

c.**Paraneoplastic disorders**

lung, ovarian and breast cancer [10].

d.**Chronic alcohol abuse**

e.**Parkinson's disease**

f. **Alzheimer's disease**

g.**Huntington's disease**

**15. Conclusion**

neurosurgeons.

are found deposited in the neurons of the brain [14].

**14**

### **Author details**

Rajani Singh Department of Anatomy, UP University of Medical Sciences Saifai Etawah, UP, India

\*Address all correspondence to: nani\_sahayal@rediffmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **References**

[1] Standring S. Gray's Anatomy Chapter-the Cerebellum. 39th ed. Edinberg: Churchill Livinstone; 2005. pp. 353-368

[2] Datta AK. Essentials of Human Anatomy-Neuroanatomy, Chapter- the Cerebellum. 4th ed. India (Kolkata): Current Books International; 2013. pp. 166-181

[3] Singh V. Textbook of Clinical Neurotomy Chapter-the Cerebellum. 2nd ed. India (New Delhi): Elsevier; 2011. pp. 111-119

[4] Chaurasia BD. Human Anatomy (Head Neck and Brain) Chapter-Cerebellum. 4th ed. India (New Delhi): CBS Publishers and distributors; 2009. pp. 389-394

[5] Kulkarni NV. Clinical Anatomy Chapter-Cerebellum. 2nd ed. India (New Delhi): Jaypee Brothers. 2012. pp. 532-535

[6] Ataxias and Cerebellar or Spinocerebellar Degeneration Information Page. National Institute of Neurological Disorders and Stroke. Available from: https://www.ninds.nih. gov/Disorders/All-Disorders/Ataxiasand-Cerebellar-or-Spinocerebellar-Degeneration-Information-Page

[7] Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology. 2013;**83**(3):278-286

[8] Biologydictionary.net Editors. "Myelin Sheath." Biology Dictionary, Biologydictionary.net. 2017. Available from: https://biologydictionary.net/ myelin-sheath/

[9] Paraneoplastic syndromes of the nervous system - Symptoms and causes. Mayo Clinic. 2020. [Accessed: 5th May 2020]

[10] NINDS Paraneoplastic Syndromes Information Page. National Institute of Neurological Disorders and Stroke Website. 2009. Available from: https:// www.ninds.nih.gov/Disorders/All-Disorders/Paraneoplastic-Syndromes-Information-Page [Accessed: 5th May 2020]

[11] Shanmugarajah PD, Hoggard N, Currie S, Aeschlimann DP, Aeschlimann PC, Gleeson DC, et al. Alcohol-related cerebellar degeneration: Not all down to toxicity? Cerebellum & Ataxias. 2016;**3**(1):17

[12] Burns A, Iliffe S. Alzheimer's disease. BMJ. 2009;**338**:b158. DOI: 10.1136/bmj.b158

[13] Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet. 2011;**377**(9770):1019-1031

[14] Wenk GL. Neuropathologic changes in Alzheimer's disease. The Journal of Clinical Psychiatry. 2003;**64**(Suppl 9):7-10

[15] Dayalu P, Albin RL. Huntington disease: Pathogenesis and treatment. Neurologic Clinics. 2015;**33**(1):101-114. DOI: 10.1016/j.ncl.2014.09.003

**17**

**Chapter 2**

**Abstract**

disorder.

The Brain Stress System in the

Neurobiology of the "Dark Side"

of Addiction and Its Relation to

*Maria Uscinska, Nicolo' Gagliano and Frank Ho-Yin Lai*

**Keywords:** addiction, stress, neurobiology, corticotropin-releasing factor,

DSM-5 defines addiction as an evolving and chronically relapsing disorder, characterized by a compulsion to take drugs, the development of dependence and a motivational withdrawal syndrome with a negative emotional state when access to the drug is prevented [1, 2]. The profound malaise and anxiety during withdrawal, protracted abstinence syndrome marked by a low-level anxiety/dysphoria, and a high vulnerability to relapse upon exposure to an acute stressor is aptly termed 'the dark side' of addiction. It is the common element of the disorder, although all addictions to different drugs are characterized by distinct patterns with emphasis

The disorder typically progresses in a cyclical manner through three stages, namely preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect (see **Figure 1**). The early stages of the cycle are characterized by impulsivity,

hypothalamic-pituitary-adrenal (HPA) axis

on different stages of the addiction cycle.

**1. Conceptual framework**

Addiction is a chronically relapsing disorder characterized by a compulsion to seek and take a substance of abuse, the development of dependence, and a negative emotional state when intake is stopped. Compelling evidence argues that dysregulation of the brain stress system is a key constituent of the addiction process. Through mechanisms of negative reinforcement, the stress system is posited to induce negative emotional state referred to as the 'dark side of addiction' as it becomes the powerful motivation for drug-seeking associated with compulsive use. Therein, the neuropharmacological actions of corticotropin-releasing factor (CRF) is posited to play a key role in the anxiety/stress-like effects of acute withdrawal, anxiety/ stress-like effects of abstinence, and relapse to drug taking. In this view, the present chapter sheds a critical light on latest research developments implicating this largely neglected component of substance abuse to give insight into the neuropathology of the 'dark side' of addiction. Moreover, the chapter provides insight into individual vulnerability to addiction and proposes a novel treatment candidate for the

Neurodegeneration

#### **Chapter 2**

## The Brain Stress System in the Neurobiology of the "Dark Side" of Addiction and Its Relation to Neurodegeneration

*Maria Uscinska, Nicolo' Gagliano and Frank Ho-Yin Lai*

#### **Abstract**

Addiction is a chronically relapsing disorder characterized by a compulsion to seek and take a substance of abuse, the development of dependence, and a negative emotional state when intake is stopped. Compelling evidence argues that dysregulation of the brain stress system is a key constituent of the addiction process. Through mechanisms of negative reinforcement, the stress system is posited to induce negative emotional state referred to as the 'dark side of addiction' as it becomes the powerful motivation for drug-seeking associated with compulsive use. Therein, the neuropharmacological actions of corticotropin-releasing factor (CRF) is posited to play a key role in the anxiety/stress-like effects of acute withdrawal, anxiety/ stress-like effects of abstinence, and relapse to drug taking. In this view, the present chapter sheds a critical light on latest research developments implicating this largely neglected component of substance abuse to give insight into the neuropathology of the 'dark side' of addiction. Moreover, the chapter provides insight into individual vulnerability to addiction and proposes a novel treatment candidate for the disorder.

**Keywords:** addiction, stress, neurobiology, corticotropin-releasing factor, hypothalamic-pituitary-adrenal (HPA) axis

#### **1. Conceptual framework**

DSM-5 defines addiction as an evolving and chronically relapsing disorder, characterized by a compulsion to take drugs, the development of dependence and a motivational withdrawal syndrome with a negative emotional state when access to the drug is prevented [1, 2]. The profound malaise and anxiety during withdrawal, protracted abstinence syndrome marked by a low-level anxiety/dysphoria, and a high vulnerability to relapse upon exposure to an acute stressor is aptly termed 'the dark side' of addiction. It is the common element of the disorder, although all addictions to different drugs are characterized by distinct patterns with emphasis on different stages of the addiction cycle.

The disorder typically progresses in a cyclical manner through three stages, namely preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect (see **Figure 1**). The early stages of the cycle are characterized by impulsivity,

**16**

2020]

myelin-sheath/

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

2020]

[10] NINDS Paraneoplastic Syndromes Information Page. National Institute of Neurological Disorders and Stroke Website. 2009. Available from: https:// www.ninds.nih.gov/Disorders/All-Disorders/Paraneoplastic-Syndromes-Information-Page [Accessed: 5th May

[11] Shanmugarajah PD, Hoggard N,

Aeschlimann PC, Gleeson DC, et al. Alcohol-related cerebellar degeneration: Not all down to toxicity? Cerebellum &

[12] Burns A, Iliffe S. Alzheimer's disease. BMJ. 2009;**338**:b158. DOI:

[13] Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet. 2011;**377**(9770):1019-1031

[14] Wenk GL. Neuropathologic changes in Alzheimer's disease. The Journal of Clinical Psychiatry.

[15] Dayalu P, Albin RL. Huntington disease: Pathogenesis and treatment. Neurologic Clinics. 2015;**33**(1):101-114.

DOI: 10.1016/j.ncl.2014.09.003

2003;**64**(Suppl 9):7-10

Currie S, Aeschlimann DP,

Ataxias. 2016;**3**(1):17

10.1136/bmj.b158

[1] Standring S. Gray's Anatomy Chapter-the Cerebellum. 39th ed. Edinberg: Churchill Livinstone; 2005.

[2] Datta AK. Essentials of Human Anatomy-Neuroanatomy, Chapter- the Cerebellum. 4th ed. India (Kolkata): Current Books International; 2013.

[3] Singh V. Textbook of Clinical Neurotomy Chapter-the Cerebellum. 2nd ed. India (New Delhi): Elsevier;

[4] Chaurasia BD. Human Anatomy (Head Neck and Brain) Chapter-Cerebellum. 4th ed. India (New Delhi): CBS Publishers and distributors; 2009.

[5] Kulkarni NV. Clinical Anatomy Chapter-Cerebellum. 2nd ed. India (New Delhi): Jaypee Brothers. 2012.

[7] Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology. 2013;**83**(3):278-286

[8] Biologydictionary.net Editors. "Myelin Sheath." Biology Dictionary, Biologydictionary.net. 2017. Available from: https://biologydictionary.net/

[9] Paraneoplastic syndromes of the nervous system - Symptoms and causes. Mayo Clinic. 2020. [Accessed: 5th May

[6] Ataxias and Cerebellar or Spinocerebellar Degeneration Information Page. National Institute of Neurological Disorders and Stroke. Available from: https://www.ninds.nih. gov/Disorders/All-Disorders/Ataxiasand-Cerebellar-or-Spinocerebellar-Degeneration-Information-Page

pp. 353-368

**References**

pp. 166-181

2011. pp. 111-119

pp. 389-394

pp. 532-535

**Figure 1.**

*The progression of alcohol dependence over time marked by a shift in underlying motivational mechanisms. From initial, positively reinforcing, pleasurable drug effects, the addictive process progresses over time to being driven by negatively reinforcing relief from a negative emotional state.*

whereas terminal stages are dominated by compulsivity. The former refers to rapid reactions to internal and external factors with no concern about negative outcomes whilst the latter to perseveration in actions despite adverse consequences or in the face of incorrect responses in choice situations. As the cycle of drug taking and withdrawal continues, the different components of the addiction cycle become more intense, and progressively evolve into a more severe pathology [1]. This process is accompanied by changes in the motivational behavioral mechanism that maintains addiction. Inasmuch as removal of negative emotional state associated with drug withdrawal becomes the mechanism driving the dependence-induced drug intake, there is a shift from positive to negative reinforcement maintaining the motivated behavior [3].

#### **2. The dark side of addiction**

In relation to the dark side of addiction, a wealth of data supports that symptoms of acute withdrawal from chronic drugs of abuse tend to be affective in nature, persist beyond the acute phase to protracted abstinence, and precede relapse to drug-seeking [4, 5]. Tension, fatigue and anxiety related to alcohol withdrawal have been shown to last from 5 to 9 months post-withdrawal [6, 7]. Furthermore, negative affective symptoms appear to be the leading precipitant of relapse [8, 9]. By way of example, the association between relapse and a subclinical negative affective state was shown to be particularly strong in patients with alcohol dependence, who underwent a 12-week clinical trial [10]. Animal data further shows that a history of dependence lowers the "dependence threshold" and makes the subsequent addiction more severe, relative to subjects receiving alcohol for the first time [11–14]. Moreover, the former category evidenced a prolonged elevation in ethanol self-administration after acute withdrawal and detoxification [15–18], and this was accompanied by increased overt responsivity to stressors and increased responsivity to antagonists of the brain CRF systems [19–21]. Finally, evidence exists to support that a history of prior dependence increases sensitivity to stress-induced reinstatement upon exposure to variety of stressors such as footshock, social stress, or pharmacological stress (e.g., yohimbine) [22]. Notably,

**19**

*The Brain Stress System in the Neurobiology of the "Dark Side" of Addiction and Its Relation…*

the neural mechanism of stress-induced reinstatement overlaps with that of acute motivational withdrawal [23]. In what follows, next sections of the chapter provide

In neural terms, the "dark side" of addiction is posited to be mediated by activation of brain stress system that interacts with hormonal stress systems. Emerging evidence have highlighted that dysregulation of brain arousal/stress systems plays a key role in pathophysiology of drug addiction [2]. More relevant to this chapter, the negative emotional state associated with the dark side of addiction has been linked to a cycle of increasing dysregulation of brain reward/anti-reward mechanisms. Therein, corticotropin releasing factor (CRF) appears to be the prominent component of the negative reinforcement processes that drive the compulsivity of

CRF is a 41-amino acid polypeptide that mobilizes the body's hormonal, autonomic, and behavioral responses to stressors (for a review of the biology of CRF systems see [24, 25]). It has a wide distribution across the brain with particularly high concentrations of cell bodies in the paraventricular nucleus of the hypothalamus, the basal forebrain, and the brainstem [26]. Therein, majority of stress-like effects are mediated by the brain and pituitary CRF1 receptors [25]. The urocortin/ CRF2 systems have been less explored, with some data pointing to neuroadaptation associated with chronic drug use, also in opposition to the effects of the CRF1

Initial drug use at the binge/intoxication stage of addiction cycle activates the hypothalamic pituitary-adrenal (HPA) axis, which initiates acquisition of drugseeking behavior through activity in the brain motivational circuits [27–30]. HPA axis activity is characterized by a cascade of physiological changes within the paraventricular nucleus of the hypothalamus, the anterior lobe of the pituitary

The CRF is synthesized by neurosecretory neurons in the medial parvocellular subdivision of the paraventricular nucleus and released into the portal blood vessels of the anterior pituitary gland. Therein it binds to the CRF1 receptor on pituitary corticotropes triggering the release of adreno-corticotropin hormone (ACTH) into the systemic circulation, which induces glucocorticoid synthesis and secretion from

Once drug-seeking behavior is initiated, the transition from acute to chronic administration of drugs of abuse is mediated by progressive changes in the HPA axis that can lead to subsequent activation of extrahypothalamic brain stress systems characterizing the withdrawal/negative affect stage [32–34]. The HPA axis is regulated via negative feedback from circulating glucocorticoids that act on glucocorticoid receptors in the paraventricular nucleus and the hippocampus. Although high levels of glucocorticoids can feedback to shut off the HPA axis, they can also sensibilize CRF systems in the central nucleus of the amygdala and basolateral amygdala involved in behavioral responses to stressors [35–39]. This observation lends support

to the thesis that CRF has a key role in the dark side of the addiction process.

As the cycle of drug taking and withdrawal continues, the different components of the addiction cycle become more intense, changes also the motivational

gland, and the adrenal gland (for review, see Ref. [31]).

*DOI: http://dx.doi.org/10.5772/intechopen.93152*

**3. Brain stress systems and addiction**

addiction [2].

receptor.

the adrenal cortex.

**4. Allostatic model of addiction**

a conceptual framework linking addiction to stress systems.

the neural mechanism of stress-induced reinstatement overlaps with that of acute motivational withdrawal [23]. In what follows, next sections of the chapter provide a conceptual framework linking addiction to stress systems.

#### **3. Brain stress systems and addiction**

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

whereas terminal stages are dominated by compulsivity. The former refers to rapid reactions to internal and external factors with no concern about negative outcomes whilst the latter to perseveration in actions despite adverse consequences or in the face of incorrect responses in choice situations. As the cycle of drug taking and withdrawal continues, the different components of the addiction cycle become more intense, and progressively evolve into a more severe pathology [1]. This process is accompanied by changes in the motivational behavioral mechanism that maintains addiction. Inasmuch as removal of negative emotional state associated with drug withdrawal becomes the mechanism driving the dependence-induced drug intake, there is a shift from positive to negative reinforcement maintaining the

*The progression of alcohol dependence over time marked by a shift in underlying motivational mechanisms. From initial, positively reinforcing, pleasurable drug effects, the addictive process progresses over time to being* 

*driven by negatively reinforcing relief from a negative emotional state.*

In relation to the dark side of addiction, a wealth of data supports that symptoms of acute withdrawal from chronic drugs of abuse tend to be affective in nature, persist beyond the acute phase to protracted abstinence, and precede relapse to drug-seeking [4, 5]. Tension, fatigue and anxiety related to alcohol withdrawal have been shown to last from 5 to 9 months post-withdrawal [6, 7]. Furthermore, negative affective symptoms appear to be the leading precipitant of relapse [8, 9]. By way of example, the association between relapse and a subclinical negative affective state was shown to be particularly strong in patients with alcohol dependence, who underwent a 12-week clinical trial [10]. Animal data further shows that a history of dependence lowers the "dependence threshold" and makes the subsequent addiction more severe, relative to subjects receiving alcohol for the first time [11–14]. Moreover, the former category evidenced a prolonged elevation in ethanol self-administration after acute withdrawal and detoxification [15–18], and this was accompanied by increased overt responsivity to stressors and increased responsivity to antagonists of the brain CRF systems [19–21]. Finally, evidence exists to support that a history of prior dependence increases sensitivity to stress-induced reinstatement upon exposure to variety of stressors such as footshock, social stress, or pharmacological stress (e.g., yohimbine) [22]. Notably,

**18**

motivated behavior [3].

**Figure 1.**

**2. The dark side of addiction**

In neural terms, the "dark side" of addiction is posited to be mediated by activation of brain stress system that interacts with hormonal stress systems. Emerging evidence have highlighted that dysregulation of brain arousal/stress systems plays a key role in pathophysiology of drug addiction [2]. More relevant to this chapter, the negative emotional state associated with the dark side of addiction has been linked to a cycle of increasing dysregulation of brain reward/anti-reward mechanisms. Therein, corticotropin releasing factor (CRF) appears to be the prominent component of the negative reinforcement processes that drive the compulsivity of addiction [2].

CRF is a 41-amino acid polypeptide that mobilizes the body's hormonal, autonomic, and behavioral responses to stressors (for a review of the biology of CRF systems see [24, 25]). It has a wide distribution across the brain with particularly high concentrations of cell bodies in the paraventricular nucleus of the hypothalamus, the basal forebrain, and the brainstem [26]. Therein, majority of stress-like effects are mediated by the brain and pituitary CRF1 receptors [25]. The urocortin/ CRF2 systems have been less explored, with some data pointing to neuroadaptation associated with chronic drug use, also in opposition to the effects of the CRF1 receptor.

Initial drug use at the binge/intoxication stage of addiction cycle activates the hypothalamic pituitary-adrenal (HPA) axis, which initiates acquisition of drugseeking behavior through activity in the brain motivational circuits [27–30]. HPA axis activity is characterized by a cascade of physiological changes within the paraventricular nucleus of the hypothalamus, the anterior lobe of the pituitary gland, and the adrenal gland (for review, see Ref. [31]).

The CRF is synthesized by neurosecretory neurons in the medial parvocellular subdivision of the paraventricular nucleus and released into the portal blood vessels of the anterior pituitary gland. Therein it binds to the CRF1 receptor on pituitary corticotropes triggering the release of adreno-corticotropin hormone (ACTH) into the systemic circulation, which induces glucocorticoid synthesis and secretion from the adrenal cortex.

Once drug-seeking behavior is initiated, the transition from acute to chronic administration of drugs of abuse is mediated by progressive changes in the HPA axis that can lead to subsequent activation of extrahypothalamic brain stress systems characterizing the withdrawal/negative affect stage [32–34]. The HPA axis is regulated via negative feedback from circulating glucocorticoids that act on glucocorticoid receptors in the paraventricular nucleus and the hippocampus. Although high levels of glucocorticoids can feedback to shut off the HPA axis, they can also sensibilize CRF systems in the central nucleus of the amygdala and basolateral amygdala involved in behavioral responses to stressors [35–39]. This observation lends support to the thesis that CRF has a key role in the dark side of the addiction process.

#### **4. Allostatic model of addiction**

As the cycle of drug taking and withdrawal continues, the different components of the addiction cycle become more intense, changes also the motivational behavioral mechanism that maintains addiction. The shift from positive to negative reinforcement behind motivation in compulsive drug use might be explained by allostatic model of the brain motivational systems. It defines addiction as a failure of counteradaptive processes of optimal homeostatic reward functioning to return to their normal range [2, 40]. Therein, the posited mechanism of pathology is mediated by within-system neuroadaptations (changes in reward pathways) and between-system neuroadaptations (brain stress systems) [1, 41].

The body's response to stress related to addiction is controlled by CRF in the paraventricular nucleus of the hypothalamus. It maintains homeostasis by orchestrating rapid and sustained responses to anticipated challenges to normal operating level of the regulatory system. Upon exposure to an environmental challenge, a feed-forward mechanism continuously re-evaluates the environmental demand for adaption, and accordingly readjusts all parameters toward new set points to mobilize resources quickly. However, it might become the engine for pathology if insufficient resources are available to shut off the response. This leads to an allostatic state, defined as a stability with an altered set point [42]. In this view, CRF becomes the key contributor to allostasis and it is hypothesized to mediate the compulsivity and relapse to drug-seeking and drug-taking in addiction [43].

More relevant to this treatise, repeated administration of drugs of abuse leads to an alteration in psychological homeostatic processes, characterized by overactivation of normal arousal or emotional systems in the body [44]. Given that addiction shares some common characteristic with chronic physiological disorders, it allows to speculate that it represents a chronic deviation of the regulatory system from its normal operating level, rather than mere homeostatic dysregulation of emotional function.

Just like any chronic physiological disorder, addiction is subject to significant environmental stressors, deteriorates with time, and is marked by a residual neural trace for rapid re-addiction even after years of abstinence. In response to excessive drug use the brain attempts to maintain homeostatic stability through molecular, cellular, and neurocircuitry changes that occur at the cost of allostatic state. Allostasis represents a chronic deviation from optimal brain emotional regulation marked by decreased function of reward circuits, strengthened stimulus–response associations, loss of executive control and recruitment of the brain stress systems. These neurobiological changes underpin the chronic elevation of reward threshold associated with negative emotional state, thereby contributing to the compulsive drug use [45]. In this view, the cycle of increasing dysregulation of brain reward/ anti-reward mechanisms constitutes the posited mechanism of the negative emotions in addiction and compulsive drug use.

#### **5. CRF in the dark side of addiction**

All drugs of abuse activate the HPA axis during acquisition of drug-taking and acute withdrawal from the drug by releasing CRF in the paraventricular nucleus of the hypothalamus. Activation of the axis during acute administration facilitates activity in the brain motivational circuits of drug reward, thereby promoting acquisition of drug-seeking behavior [27–30]. Repeated administration dysregulates these acute changes beyond HPA axis to affect the brain extrahypothalamic stress system [46–49]. Therein the repeated exposure to high levels of glucorticoids may have profound effects on the extrahypothalamic brain stress systems, contributing to the persistence and relapse to cycles of addiction to drugs of abuse [32]. Repeated addiction cycles not only blunt the HPA axis response but also sensitize the response of the extrahypothalamic CRF stress system in the amygdala [34]. Whilst initially

**21**

*The Brain Stress System in the Neurobiology of the "Dark Side" of Addiction and Its Relation…*

the presence of glucocorticoids enhances response to novelty and reward, sensitization of CRF systems in the extended amygdala may contribute to a stress component of the shift from homeostasis to pathophysiology of drug addiction. The stress component is posited to constitute an opponent anti-reward process response to

Compelling evidence exist to support the thesis that the neuroanatomical substrates for many of the motivational effects associated with the dark side of addiction constitute a common neural circuitry within the basal forebrain, termed the "extended amygdala" [50]. It represents a macrostructure comprising the bed nucleus of the stria terminalis, central medial amygdala, and a transition zone in the posterior part of the medial nucleus accumbens (i.e., posterior shell) [51, 52]. Importantly, the extended amygdala includes dopamine and opioid peptides associated with the positive reinforcing effects of drugs of abuse, and major components of the extrahypothalamic CRF systems associated with negative reinforcement mechanisms [33]. It receives afferent connections from limbic cortices, the hippocampus, basolateral amygdala, midbrain, and lateral hypothalamus and efferent connections to the posterior medial ventral pallidum, ventral tegmental area, various brainstem projections, and to the lateral hypothalamus [52]. The arousal/ stress brain systems in the extended amygdala may play a key role in the negative emotional states that maintains addiction to drugs of abuse and may overlap with

Stress might exert either ameliorating or detrimental effects on physiological processes. In the short term it might be beneficial to an organism however in the long-term it plays a major role in various pathophysiology related to neurodegenerative diseases and mood disorders. Upon exposure to stress the body enters the 'fight or flight' stage, after which it builds resistance to the stress in the adaptation stage, and finally due to 'wear and tear' it reaches exhaustion [53]. In the adaptation stage, cortisol typically exerts a negative feedback effect to shut down the stress response.

Given the inhibitory control of the hippocampus over the HPA-axis, damage to this structure is posited to be causally involved in disinhibition of the HPA axis activity thereby accounting for the age-related accumulation of hippocampal damage in Alzheimer's disease (AD) and depression. This thesis is furthered by evidence of increased cortisol plasma levels in early stage of AD associated with cognitive decline [57], and a correlation of salivary cortisol levels with the severity of the disease [58]. Accordingly, neuronal atrophy was evidenced in the hippocampus of stressed or corticosteroid-treated rodents and primates [59]. Elevated CRH and cortisol levels were also shown to contribute to the symptoms of depression in a large subpopulation of depressed subjects [56]. This is corroborated by the normalizing effect of antidepressants on the synthesis of CRH by stimulation and/or upregulation of

Multiple brain regions related to cognition are actively involved in feedback regulation including the hippocampus, amygdala, the brain stem and prefrontal cortex [54]. Accordingly, stimulation by corticosteroids induced at the level of the amygdala, the prefrontal cortex and the locus coeruleus was found to interfere with HPA activity and memory [55]. A deficient cortisol feedback effect caused by glucocorticoid resistance increases the activity of the HPA-axis have been found to be associated with neurodegenerative diseases, obesity, heart disease, depression, and a variety of other health issues [56]. Therein the vasopressin neurons of the central nervous system inhibit the regulatory influence of CRH neurons in the PVN

resulting in a disproportionally high activity of the HPA system.

the negative emotional constituent of other psychopathologies.

**6. Brain stress and neurodegeneration**

*DOI: http://dx.doi.org/10.5772/intechopen.93152*

excessive activation of reward systems [2].

*The Brain Stress System in the Neurobiology of the "Dark Side" of Addiction and Its Relation… DOI: http://dx.doi.org/10.5772/intechopen.93152*

the presence of glucocorticoids enhances response to novelty and reward, sensitization of CRF systems in the extended amygdala may contribute to a stress component of the shift from homeostasis to pathophysiology of drug addiction. The stress component is posited to constitute an opponent anti-reward process response to excessive activation of reward systems [2].

Compelling evidence exist to support the thesis that the neuroanatomical substrates for many of the motivational effects associated with the dark side of addiction constitute a common neural circuitry within the basal forebrain, termed the "extended amygdala" [50]. It represents a macrostructure comprising the bed nucleus of the stria terminalis, central medial amygdala, and a transition zone in the posterior part of the medial nucleus accumbens (i.e., posterior shell) [51, 52]. Importantly, the extended amygdala includes dopamine and opioid peptides associated with the positive reinforcing effects of drugs of abuse, and major components of the extrahypothalamic CRF systems associated with negative reinforcement mechanisms [33]. It receives afferent connections from limbic cortices, the hippocampus, basolateral amygdala, midbrain, and lateral hypothalamus and efferent connections to the posterior medial ventral pallidum, ventral tegmental area, various brainstem projections, and to the lateral hypothalamus [52]. The arousal/ stress brain systems in the extended amygdala may play a key role in the negative emotional states that maintains addiction to drugs of abuse and may overlap with the negative emotional constituent of other psychopathologies.

#### **6. Brain stress and neurodegeneration**

Stress might exert either ameliorating or detrimental effects on physiological processes. In the short term it might be beneficial to an organism however in the long-term it plays a major role in various pathophysiology related to neurodegenerative diseases and mood disorders. Upon exposure to stress the body enters the 'fight or flight' stage, after which it builds resistance to the stress in the adaptation stage, and finally due to 'wear and tear' it reaches exhaustion [53]. In the adaptation stage, cortisol typically exerts a negative feedback effect to shut down the stress response. Multiple brain regions related to cognition are actively involved in feedback regulation including the hippocampus, amygdala, the brain stem and prefrontal cortex [54]. Accordingly, stimulation by corticosteroids induced at the level of the amygdala, the prefrontal cortex and the locus coeruleus was found to interfere with HPA activity and memory [55]. A deficient cortisol feedback effect caused by glucocorticoid resistance increases the activity of the HPA-axis have been found to be associated with neurodegenerative diseases, obesity, heart disease, depression, and a variety of other health issues [56]. Therein the vasopressin neurons of the central nervous system inhibit the regulatory influence of CRH neurons in the PVN resulting in a disproportionally high activity of the HPA system.

Given the inhibitory control of the hippocampus over the HPA-axis, damage to this structure is posited to be causally involved in disinhibition of the HPA axis activity thereby accounting for the age-related accumulation of hippocampal damage in Alzheimer's disease (AD) and depression. This thesis is furthered by evidence of increased cortisol plasma levels in early stage of AD associated with cognitive decline [57], and a correlation of salivary cortisol levels with the severity of the disease [58]. Accordingly, neuronal atrophy was evidenced in the hippocampus of stressed or corticosteroid-treated rodents and primates [59]. Elevated CRH and cortisol levels were also shown to contribute to the symptoms of depression in a large subpopulation of depressed subjects [56]. This is corroborated by the normalizing effect of antidepressants on the synthesis of CRH by stimulation and/or upregulation of

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

between-system neuroadaptations (brain stress systems) [1, 41].

and relapse to drug-seeking and drug-taking in addiction [43].

tions in addiction and compulsive drug use.

**5. CRF in the dark side of addiction**

behavioral mechanism that maintains addiction. The shift from positive to negative reinforcement behind motivation in compulsive drug use might be explained by allostatic model of the brain motivational systems. It defines addiction as a failure of counteradaptive processes of optimal homeostatic reward functioning to return to their normal range [2, 40]. Therein, the posited mechanism of pathology is mediated by within-system neuroadaptations (changes in reward pathways) and

The body's response to stress related to addiction is controlled by CRF in the paraventricular nucleus of the hypothalamus. It maintains homeostasis by orchestrating rapid and sustained responses to anticipated challenges to normal operating level of the regulatory system. Upon exposure to an environmental challenge, a feed-forward mechanism continuously re-evaluates the environmental demand for adaption, and accordingly readjusts all parameters toward new set points to mobilize resources quickly. However, it might become the engine for pathology if insufficient resources are available to shut off the response. This leads to an allostatic state, defined as a stability with an altered set point [42]. In this view, CRF becomes the key contributor to allostasis and it is hypothesized to mediate the compulsivity

More relevant to this treatise, repeated administration of drugs of abuse leads to an alteration in psychological homeostatic processes, characterized by overactivation of normal arousal or emotional systems in the body [44]. Given that addiction shares some common characteristic with chronic physiological disorders, it allows to speculate that it represents a chronic deviation of the regulatory system from its normal operating level, rather than mere homeostatic dysregulation of emotional

Just like any chronic physiological disorder, addiction is subject to significant environmental stressors, deteriorates with time, and is marked by a residual neural trace for rapid re-addiction even after years of abstinence. In response to excessive drug use the brain attempts to maintain homeostatic stability through molecular, cellular, and neurocircuitry changes that occur at the cost of allostatic state. Allostasis represents a chronic deviation from optimal brain emotional regulation marked by decreased function of reward circuits, strengthened stimulus–response associations, loss of executive control and recruitment of the brain stress systems. These neurobiological changes underpin the chronic elevation of reward threshold associated with negative emotional state, thereby contributing to the compulsive drug use [45]. In this view, the cycle of increasing dysregulation of brain reward/ anti-reward mechanisms constitutes the posited mechanism of the negative emo-

All drugs of abuse activate the HPA axis during acquisition of drug-taking and acute withdrawal from the drug by releasing CRF in the paraventricular nucleus of the hypothalamus. Activation of the axis during acute administration facilitates activity in the brain motivational circuits of drug reward, thereby promoting acquisition of drug-seeking behavior [27–30]. Repeated administration dysregulates these acute changes beyond HPA axis to affect the brain extrahypothalamic stress system [46–49]. Therein the repeated exposure to high levels of glucorticoids may have profound effects on the extrahypothalamic brain stress systems, contributing to the persistence and relapse to cycles of addiction to drugs of abuse [32]. Repeated addiction cycles not only blunt the HPA axis response but also sensitize the response of the extrahypothalamic CRF stress system in the amygdala [34]. Whilst initially

**20**

function.

corticosteroid receptor expression, and reversal the clinical symptoms [60]. In light of these evidence, the 'glucocorticoid cascade hypothesis' is posited to be the dominant pathogenetic mechanism in human neurodegenerative diseases marked by HPA-axis alterations including depression and AD [61].

Although CRH and cortisol seem to be etiologically involved in the development of depression, conclusive arguments cannot be drawn due to no evidence for any major damage in the human hippocampus in the disorder. Moreover, reduced hippocampal volume does not necessarily translate in cell death and might alternatively be explained by changes is water content or the structure in glial cells.

#### **7. Summary and conclusions**

Addiction to all drugs of abuse involves activation of the HPA axis. Pathophysiology of drug addiction involves dysregulation of the brain emotional system posited to be a key constituent of the negative emotional state produced by dependence that maintains drug-seeking through the mechanism of negative reinforcement. More specifically, the action of CRF in extra hypothalamic systems in the extended amygdala is considered a neural substrate of the pathophysiology of the disorder and plays a key role in maintaining the addiction cycle once it is initiated. It comprises the central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition area in the shell of the nucleus accumbens. Beyond providing insight into the neurobiology of the dark side of addiction, better characterization of the CRF systems in addiction hold promise for new targets for identifying vulnerability to addiction and novel treatments for the disorder.

#### **Conflict of interest**

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

**23**

**Author details**

Maria Uscinska1

Disorders, Turin, Italy

\*, Nicolo' Gagliano2

\*Address all correspondence to: actapsy@gmail.com

2 Humanitas Research Hospital, Milan, Italy

provided the original work is properly cited.

and Frank Ho-Yin Lai3

1 Department of Neurosciences, University of Turin, Centre for Personality

3 Rehabilitation Sciences, Hong Kong Polytechnic University, Hong Kong

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*The Brain Stress System in the Neurobiology of the "Dark Side" of Addiction and Its Relation…*

*DOI: http://dx.doi.org/10.5772/intechopen.93152*

*The Brain Stress System in the Neurobiology of the "Dark Side" of Addiction and Its Relation… DOI: http://dx.doi.org/10.5772/intechopen.93152*

#### **Author details**

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

corticosteroid receptor expression, and reversal the clinical symptoms [60]. In light of these evidence, the 'glucocorticoid cascade hypothesis' is posited to be the dominant pathogenetic mechanism in human neurodegenerative diseases marked by

be explained by changes is water content or the structure in glial cells.

Addiction to all drugs of abuse involves activation of the HPA axis.

vulnerability to addiction and novel treatments for the disorder.

Pathophysiology of drug addiction involves dysregulation of the brain emotional system posited to be a key constituent of the negative emotional state produced by dependence that maintains drug-seeking through the mechanism of negative reinforcement. More specifically, the action of CRF in extra hypothalamic systems in the extended amygdala is considered a neural substrate of the pathophysiology of the disorder and plays a key role in maintaining the addiction cycle once it is initiated. It comprises the central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition area in the shell of the nucleus accumbens. Beyond providing insight into the neurobiology of the dark side of addiction, better characterization of the CRF systems in addiction hold promise for new targets for identifying

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the

Although CRH and cortisol seem to be etiologically involved in the development of depression, conclusive arguments cannot be drawn due to no evidence for any major damage in the human hippocampus in the disorder. Moreover, reduced hippocampal volume does not necessarily translate in cell death and might alternatively

HPA-axis alterations including depression and AD [61].

**7. Summary and conclusions**

**Conflict of interest**

production of this manuscript.

**22**

Maria Uscinska1 \*, Nicolo' Gagliano2 and Frank Ho-Yin Lai3

1 Department of Neurosciences, University of Turin, Centre for Personality Disorders, Turin, Italy

2 Humanitas Research Hospital, Milan, Italy

3 Rehabilitation Sciences, Hong Kong Polytechnic University, Hong Kong

\*Address all correspondence to: actapsy@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[47] Goeders NE. Stress and cocaine addiction. The Journal of Pharmacology

[48] Sharp BM, Matta SG. Detection by in vivo microdialysis of nicotineinduced norepinephrine secretion from the hypothalamic paraventricular nucleus of freely moving rats: Dosedependency and desensitization. Endocrinology. 1993;**133**:11-19. DOI: 10.1007/978-3-0348-7445-8\_20

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*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

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[36] Makino S, Gold PW, Schulkin J. Corticosterone effects on corticotropinreleasing hormone mRNA in the central nucleus of the amygdala and the parvocellular region of the paraventricular nucleus of the hypothalamus. Brain Research. 1994;**640**:105-112. DOI: 10.1016/0006-8993(94)91862-7

[37] Swanson LW, Simmons DM.

study in the rat. The Journal of

Differential steroid hormone and neural influences on peptide mRNA levels in CRH cells of the paraventricular nucleus: A hybridization histochemical

Comparative Neurology. 1989;**285**:413- 435. DOI: 10.1002/cne.902850402

[38] Schulkin J, McEwen BS, Gold PW. Allostasis, amygdala, and anticipatory angst. Neuroscience and Biobehavioral Reviews. 1994;**18**:385-396. DOI: 10.1016/0149-7634(94)90051-5

[39] Shepard JD, Barron KW, Myers DA. Corticosterone delivery to the amygdala increases corticotropin-releasing factor mRNA in the central amygdaloid nucleus and anxiety-like behavior. Brain Research. 2000;**861**:288-295. DOI:

10.1016/s0006-8993(00)02019-9

[40] Koob GF, Le Moal M. Drug

2001;**24**:97-129. DOI: 10.1016/ S0893-133X(00)00195-0

[41] Koob GF, Bloom FE. Cellular and molecular mechanisms of drug dependence. Science. 1988;**242**:715-723.

[42] Sterling P, Eyer J. Allostasis: A new paradigm to explain arousal pathology. In: Fisher S, Reason J, editors. Handbook

DOI: 10.1126/science.2903550

addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology.

PMCID: PMC6575358

for sensation-seeking behaviors. Proceedings of the National Academy of Sciences of the United States of America. 1993;**90**:11738-11742. DOI:

10.1073/pnas.90.24.11738

[28] Piazza PV, Le Moal M.

of reward: Physiological and

Glucocorticoids as a biological substrate

pathophysiological implications. Brain Research Reviews. 1997;**25**:359-372. DOI: 10.1016/s0165-0173(97)00025-8

[29] Goeders NE. A neuroendocrine role in cocaine reinforcement. Psychoneuroendocrinology. 1997;**22**:237-259. DOI: 10.1016/ s0306-4530(97)00027-9

[30] Fahlke C, Hard E, Hansen S. Facilitation of ethanol consumption by intracerebroventricular infusions of corticosterone. Psychopharmacology. 1996;**127**:133-139. DOI: 10.1007/

[31] Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues in Clinical Neuroscience. 2006;**8**:383-395. PMCID: PMC3181830

[32] Kreek MJ, Koob GF. Drug

dependence: Stress and dysregulation of brain reward pathways. Drug and Alcohol Dependence. 1998;**51**:23-47. DOI: 10.1016/s0376-8716(98)00064-7

[33] Koob GF, Le Moal M. Plasticity of reward neurocircuitry and the 'dark side' of drug addiction. Nature Neuroscience. 2005;**8**:1442-1444. DOI:

[34] Koob GF, Kreek MJ. Stress,

American Journal of Physics. 2007;**17**:24-49. DOI: 10.1176/appi.

[35] Imaki T, Nahan JL, Rivier C, Sawchenko PE, Vale W. Differential

dysregulation of drug reward pathways, and the transition to drug dependence.

10.1038/nn1105-1442

ajp.2007.05030503

BF02805986

**26**

[43] Koob GF. Brain stress systems in the amygdala in addiction. Brain Research. 2009;**1293**:61-75. DOI: 10.1016/j. brainres.2009.03.038

[44] Hennessy JW, Levine S. Stress, arousal, and the pituitary-adrenal system: A psychoendocrine hypothesis. In: Sprague JM, Epstein AN, editors. Progress in Psychobiology and Physiological Psychology. 8th ed. New York: Academic Press; 1979. pp. 133-178

[45] Pfaff D. Brain Arousal and Information Theory: Neural and Genetic Mechanisms. Cambridge, MA: Harvard University Press; 2006

[46] Rasmussen DD, Boldt BM, Bryant CA, Mitton DR, Larsen SA, Wilkinson CW. Chronic daily ethanol and withdrawal: 1. Long-term changes in the hypothalamo-pituitaryadrenal axis. Alcoholism, Clinical and Experimental Research. 2000;**24**:1836-1849. DOI: 10.1016/j. alcohol.2006.06.007

[47] Goeders NE. Stress and cocaine addiction. The Journal of Pharmacology and Experimental Therapeutics. 2002;**301**:785-789. DOI: 10.1124/ jpet.301.3.785

[48] Sharp BM, Matta SG. Detection by in vivo microdialysis of nicotineinduced norepinephrine secretion from the hypothalamic paraventricular nucleus of freely moving rats: Dosedependency and desensitization. Endocrinology. 1993;**133**:11-19. DOI: 10.1007/978-3-0348-7445-8\_20

[49] Semba J, Wakuta M, Maeda J, Suhara T. Nicotine withdrawal induces subsensitivity of hypothalamicpituitary-adrenal axis to stress in rats: Implications for precipitation of depression during smoking

cessation. Psychoneuroendocrinology. 2004;**29**:215-226. DOI: 10.1016/ s0306-4530(03)00024-6

[50] Alheid GF, Heimer L. New perspectives in basal forebrain organization of special relevance for neuropsychiatric disorders: The striatopallidal, amygdaloid, and corticopetal components of substantia innominata. Neuroscience. 1988;**27**:1- 39. DOI: 10.1016/0306-4522(88)90217-5

[51] Johnston JB. Further contributions to the study of the evolution of the forebrain. Journal of Comparative Neurology. 1923;**35**:337-481. DOI: 10.1002/cne.900350502

[52] Heimer L, Alheid G. Piecing together the puzzle of basal forebrain anatomy. In: Napier TC, Kalivas PW, Hanin I, editors. The Basal Forebrain: Anatomy to Function. Advances in Experimental Medicine and Biology. Vol. 295. New York: Plenum Press; 1991. pp. 1-42

[53] Selye H. A syndrome produced by diverse nocuous agents. The Journal of Neuropsychiatry and Clinical Neurosciences. 1998;**10**:230-231

[54] Reul JM, de Kloet ER. Two receptor systems for corticosterone in rat brain: Microdistribution and differential occupation. Endocrinology. 1985;**117**:2505-2511

[55] Fuchs E, Czeh B, Kole MH, Michaelis T, Lucassen PJ. Alterations of neuroplasticity in depression: The hippocampus and beyond. European Neuropsychopharmacology. 2004;**14**(Suppl 5):S481-S490

[56] Swaab DF, Bao AM, Lucassen PJ. The stress system in the human brain in depression and neurodegeneration. Ageing Research Reviews. 2005;**4**:141-194

[57] Rasmuson S, Nasman B, Carlstrom K, Olsson T. Increased levels

**29**

injury, head injury

**1. Introduction**

vention" [1].

**Chapter 3**

**Abstract**

*Anoop T. Chakrapani*

Biomarkers of Diseases: Their Role

Biomarkers have been playing an increasingly significant role in clinical decision making processes worldwide. Numerous studies are being undertaken across the globe in the elusive search for the ideal biomarker for each clinical condition. In the emergency department, where rapid diagnosis of various diseases like acute coronary syndromes, pulmonary embolism, heart failure, sepsis, acute renal failure etc. is of utmost importance, specific biomarkers can expedite the time to diagnosis and treatment. To enumerate, the following biomarkers have proved their worth within the setting of emergency departments across the world. The role of cardiac troponins and CK-MB has been well established in the clinical algorithms to detect myocardial infarction. Newer markers like Heart Fatty Acid Binding Protein (H-FABP), BNP, Pro BNP as well as Ischemia modified albumin (IMA) are coming into the fray in the detection of cardiovascular emergencies, especially in the detection of heart failure. Novel biomarkers like Mid-region Proadrenomedullin (MR-proADM) are found to be useful in sepsis along with Tumour necrosis factor-alpha (TNF-alpha), Interleukins and Presepsin in burns patients. Human neutrophil gelatinase-associated lipocalin (NGAL) levels can detect renal failure much earlier than conventional methods. S100 calcium binding protein B (S100B) has been found to be useful in detection of CNS injury and hence can be used to avoid unnecessary radiation to patients in the form of CT scans. Point of care testing of many of these biomarkers in the Emergency department itself paves way for a revolutionary step in faster

in Emergency Medicine

emergency care delivery and better patient outcomes.

**Keywords:** biomarker, emergency medicine, troponin, sepsis, burns, acute kidney

According to the National Institute of Health (NIH) Biomarkers Working Group, a biological marker (biomarker) is defined as "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic inter-

Worldwide, biomarkers have been primarily studied specifically in the setting of diseases. Even so, it is imperative to understand the concept that a biomarker in the human milieu can be present as a result of normal physiological functioning and need not be the result of a pathological process always. Analysis of various biomarkers, both quantitatively and qualitatively have resulted in better understanding of physiological as well as pathological processes of the human body. An ideal

of adrenocortical and gonadal hormones in mild to moderate Alzheimer's disease. Dementia and Geriatric Cognitive Disorders. 2002;**13**:74-79

[58] Giubilei F, Patacchioli FR, Antonini G, Sepe Monti M, Tisei P, Bastianello S, et al. Altered circadian cortisol secretion in Alzheimer's disease: Clinical and neuroradiological aspects. Journal of Neuroscience Research. 2001;**66**:262-265

[59] Sapolsky RM. Glucocorticoid toxicity in the hippocampus: Temporal aspects of neuronal vulnerability. Brain Research. 1985;**359**:300-305

[60] Belanoff JK, Rothschild AJ, Cassidy F, DeBattista C, Baulieu EE, Schold C, et al. An open label trial of C-1073 (mifepristone) for psychotic major depression. Biological Psychiatry. 2002;**52**:386-392

[61] Sapolsky RM, Krey LC, McEwen BS. The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis. Endocrine Reviews. 1986;**7**:284-301

#### **Chapter 3**

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

of adrenocortical and gonadal hormones in mild to moderate Alzheimer's disease. Dementia and Geriatric Cognitive

Disorders. 2002;**13**:74-79

2001;**66**:262-265

2002;**52**:386-392

1986;**7**:284-301

[58] Giubilei F, Patacchioli FR, Antonini G, Sepe Monti M, Tisei P, Bastianello S, et al. Altered circadian cortisol secretion in Alzheimer's disease: Clinical and neuroradiological aspects. Journal of Neuroscience Research.

[59] Sapolsky RM. Glucocorticoid toxicity in the hippocampus: Temporal aspects of neuronal vulnerability. Brain

Research. 1985;**359**:300-305

[60] Belanoff JK, Rothschild AJ, Cassidy F, DeBattista C, Baulieu EE, Schold C, et al. An open label trial of C-1073 (mifepristone) for psychotic major depression. Biological Psychiatry.

[61] Sapolsky RM, Krey LC, McEwen BS. The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis. Endocrine Reviews.

**28**

## Biomarkers of Diseases: Their Role in Emergency Medicine

*Anoop T. Chakrapani*

#### **Abstract**

Biomarkers have been playing an increasingly significant role in clinical decision making processes worldwide. Numerous studies are being undertaken across the globe in the elusive search for the ideal biomarker for each clinical condition. In the emergency department, where rapid diagnosis of various diseases like acute coronary syndromes, pulmonary embolism, heart failure, sepsis, acute renal failure etc. is of utmost importance, specific biomarkers can expedite the time to diagnosis and treatment. To enumerate, the following biomarkers have proved their worth within the setting of emergency departments across the world. The role of cardiac troponins and CK-MB has been well established in the clinical algorithms to detect myocardial infarction. Newer markers like Heart Fatty Acid Binding Protein (H-FABP), BNP, Pro BNP as well as Ischemia modified albumin (IMA) are coming into the fray in the detection of cardiovascular emergencies, especially in the detection of heart failure. Novel biomarkers like Mid-region Proadrenomedullin (MR-proADM) are found to be useful in sepsis along with Tumour necrosis factor-alpha (TNF-alpha), Interleukins and Presepsin in burns patients. Human neutrophil gelatinase-associated lipocalin (NGAL) levels can detect renal failure much earlier than conventional methods. S100 calcium binding protein B (S100B) has been found to be useful in detection of CNS injury and hence can be used to avoid unnecessary radiation to patients in the form of CT scans. Point of care testing of many of these biomarkers in the Emergency department itself paves way for a revolutionary step in faster emergency care delivery and better patient outcomes.

**Keywords:** biomarker, emergency medicine, troponin, sepsis, burns, acute kidney injury, head injury

#### **1. Introduction**

According to the National Institute of Health (NIH) Biomarkers Working Group, a biological marker (biomarker) is defined as "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention" [1].

Worldwide, biomarkers have been primarily studied specifically in the setting of diseases. Even so, it is imperative to understand the concept that a biomarker in the human milieu can be present as a result of normal physiological functioning and need not be the result of a pathological process always. Analysis of various biomarkers, both quantitatively and qualitatively have resulted in better understanding of physiological as well as pathological processes of the human body. An ideal

biomarker should aid in early diagnosis, help in risk stratification, be able to monitor response to treatment modalities and predict outcomes better than the clinical processes and investigations existing in medical practice at that point of time [2].

In medical practice, biomarkers can be of diagnostic or prognostic value. In the setting of practicing Emergency medicine, diagnostic biomarkers assume greater significance. In the Emergency department, where time is of the essence, diagnostic biomarkers help in quick clinical decision making as well as patient disposition. A biomarker that is able to make a clinical differentiation between two similar disease conditions is highly valuable for an emergency physician. This helps in rapid diagnosis, which leads to faster treatment initiation. Faster the treatment can be initiated, faster the patient movement. A faster TAT (turnaround time) for patients in the ED translates to lesser waiting times in the ED. An ideal biomarker in the Emergency department should have the following characteristics—High diagnostic accuracy which involves a high degree of sensitivity with reasonable specificity, should be reproducible across platforms and should be cost effective to the patient and the clinician.

Numerous biomarkers have been extensively studied for the purpose of clinical utility, but only a few handfuls have proved their mettle in clinical practice. The abundance of biomarker tests available, pose a not so friendly dilemma to the clinician of the present. Understandably, there is still a long way to traverse from the laboratory table to the patient bedside. Numerous trials and research activities are underway across the world in the field of biomarkers. Most of them are still in various phases of preclinical trials and are expected to be available by the patient's bedside in a few years' time.

In modern clinical practice, biomarkers are being used more and more for clinical decision making. The current gamut of biomarkers available in the clinical realm have changed the way we practice medicine. The increase in the use of biomarkers for clinical decision making has expedited the patient disposition to a great extent. Having said that, there is also the other side of the coin which is the increase in the health care cost. The over dependence of clinicians on biomarkers should be viewed with caution as this escalates the overall cost of treatment and the patients will have to bear that burden. The decision to make use of biomarkers in the clinical context should be individualised and targeted to prevent its overuse or abuse [3]. This will put a strain on the already scarce resources in the health care sector. It is always pertinent to remember that—A biomarker should always be evaluated in the clinical context and should never be used as a standalone tool for clinical decision making.

In Emergency medical practice, majority of the biomarker work has been focussed in the field of cardiology, renal failure and sepsis, as early detection and prompt interventions in the early phases of the diseases can significantly alter the natural course of the disease and improve the patient morbidity and mortality. Other areas of focus are hepatic diseases, traumatic brain injury, venous thromboembolism etc., where biomarkers are increasingly being tested for their clinical utility. Therefore, the chapter focuses in detail on these clinically significant biomarkers.

#### **2. Acute coronary syndromes**

Acute coronary syndromes have been in the forefront of novel biomarker evaluation research due to its widespread prevalence as well as the need for detection in a time sensitive manner. Almost 20 million patients with symptoms of acute coronary syndromes present to emergency departments in North America and Europe annually [4, 5]. Numerous studies have been performed on various biomarkers, the conventional markers as well as high sensitive variants, and also with respect to

**31**

**2.2 Cardiac troponins**

*Biomarkers of Diseases: Their Role in Emergency Medicine*

different time frames. In the Emergency department, making a rapid diagnosis of acute myocardial infarction is of utmost importance, as *'time is muscle'*. The earlier a diagnosis of ACS can be made, the earlier revascularisation can be initiated. Early treatment can decrease the morbidity and mortality to a significant extent in case of ACS. At the same time, it is also important to make sure deserving patients are disposed of from the ED as soon as possible in a time dependent manner once ACS is ruled out. This assumes more significance in EDs that receive a high volume of patients and need patients to be either admitted for further workup or discharged in a timely manner. At the same time, discharging patients from the ED always has a risk of patients ending up in an adverse cardiac event. Institutional protocols that include serial biomarker evaluation help in minimising these risks to a great extent. Historically, biomarkers like LDH (lactate dehydrogenase) and AST (aspartate

aminotransferase) were tried in the detection of an acute coronary syndrome especially towards the end of 20th century. Their clinical significance slowly began to decline with the advent of better alternatives as well as lack of specificity. The next in line were the markers with better specificity and sensitivity, namely—the troponins and creatine kinase. As the 21st century is taking its foothold, the scientific community is focussing its attention on these biomarkers for detection of acute coronary events, a leading cause of death worldwide. The research was primarily focussed on Creatine Kinase – MB fraction, which used to be the gold standard of evaluation of ACS. But, that has given way to the newer biomarkers—Troponin I and Troponin T – both conventional and high sensitive, which are being studied

Creatine Kinase is an intracellular enzyme with a dimeric molecule which has 3 isoforms—CK-MM (muscle), CK-BB (brain) and CK-MB (myocardium), based on the organ of origin. CK-MB is the isoenzyme fraction which is predominantly seen in cardiac muscle and hence the utility in detecting cardiac muscle damage. This marker is leaked into the systemic circulation from the cellular cytosol due to disruption of the cell membrane as a result of myocardial injury. This marker can be assayed by a clinician to help in the diagnosis of myocardial infarction. CK-MB isoenzyme can be detected in the bloodstream about 4–6 hours after the onset of chest pain. It peaks by 12–24 hrs and returns to baseline by 12–48 hours. This short time window of rise and fall of CK MB is especially useful in detecting reinfarction or infarct extension in a patient in whom the troponin values might be already elevated as a result of an infarct. It is also helpful in identifying complications in patients who have undergone revascularization procedures in the cardiac care unit. The reference values for CK-MB are as follows—males: ≤ 7.7 ng/mL and females: ≤ 4.3 ng/mL. CK MB assay should always be viewed with a pinch of salt since it is a subunit of the total CK in the system. Abnormal elevations of CK MB can be detected along with an increased level of total CK in cases of traumatic muscle injuries, rhabdomyolysis, myopathies etc. It is worthwhile to note that the normally CK-MB fraction accounts for only 3–5% of the total CK in the body and any increase beyond 30–50% of the total CK should prompt suspicion of abnormal beta subunit synthesis. But, over the past few years, the burden of diagnosis of acute myocardial

Troponin is a complex protein molecule comprising of three regulatory proteins

playing an integral role in the contraction of cardiac and skeletal muscle. These

injury has been shifted on to the shoulders of troponins [6].

*DOI: http://dx.doi.org/10.5772/intechopen.94509*

extensively across the globe.

**2.1 Creatine kinase: MB**

#### *Biomarkers of Diseases: Their Role in Emergency Medicine DOI: http://dx.doi.org/10.5772/intechopen.94509*

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

across platforms and should be cost effective to the patient and the clinician.

Numerous biomarkers have been extensively studied for the purpose of clinical utility, but only a few handfuls have proved their mettle in clinical practice. The abundance of biomarker tests available, pose a not so friendly dilemma to the clinician of the present. Understandably, there is still a long way to traverse from the laboratory table to the patient bedside. Numerous trials and research activities are underway across the world in the field of biomarkers. Most of them are still in various phases of preclinical trials and are expected to be available by the patient's bedside in

In modern clinical practice, biomarkers are being used more and more for clinical

Acute coronary syndromes have been in the forefront of novel biomarker evaluation research due to its widespread prevalence as well as the need for detection in a time sensitive manner. Almost 20 million patients with symptoms of acute coronary syndromes present to emergency departments in North America and Europe annually [4, 5]. Numerous studies have been performed on various biomarkers, the conventional markers as well as high sensitive variants, and also with respect to

decision making. The current gamut of biomarkers available in the clinical realm have changed the way we practice medicine. The increase in the use of biomarkers for clinical decision making has expedited the patient disposition to a great extent. Having said that, there is also the other side of the coin which is the increase in the health care cost. The over dependence of clinicians on biomarkers should be viewed with caution as this escalates the overall cost of treatment and the patients will have to bear that burden. The decision to make use of biomarkers in the clinical context should be individualised and targeted to prevent its overuse or abuse [3]. This will put a strain on the already scarce resources in the health care sector. It is always pertinent to remember that—A biomarker should always be evaluated in the clinical context and should never be used as a standalone tool for clinical decision making. In Emergency medical practice, majority of the biomarker work has been focussed in the field of cardiology, renal failure and sepsis, as early detection and prompt interventions in the early phases of the diseases can significantly alter the natural course of the disease and improve the patient morbidity and mortality. Other areas of focus are hepatic diseases, traumatic brain injury, venous thromboembolism etc., where biomarkers are increasingly being tested for their clinical utility. Therefore, the chapter focuses in detail on these clinically significant

biomarker should aid in early diagnosis, help in risk stratification, be able to monitor response to treatment modalities and predict outcomes better than the clinical processes and investigations existing in medical practice at that point of time [2]. In medical practice, biomarkers can be of diagnostic or prognostic value. In the setting of practicing Emergency medicine, diagnostic biomarkers assume greater significance. In the Emergency department, where time is of the essence, diagnostic biomarkers help in quick clinical decision making as well as patient disposition. A biomarker that is able to make a clinical differentiation between two similar disease conditions is highly valuable for an emergency physician. This helps in rapid diagnosis, which leads to faster treatment initiation. Faster the treatment can be initiated, faster the patient movement. A faster TAT (turnaround time) for patients in the ED translates to lesser waiting times in the ED. An ideal biomarker in the Emergency department should have the following characteristics—High diagnostic accuracy which involves a high degree of sensitivity with reasonable specificity, should be reproducible

**30**

biomarkers.

**2. Acute coronary syndromes**

a few years' time.

different time frames. In the Emergency department, making a rapid diagnosis of acute myocardial infarction is of utmost importance, as *'time is muscle'*. The earlier a diagnosis of ACS can be made, the earlier revascularisation can be initiated. Early treatment can decrease the morbidity and mortality to a significant extent in case of ACS. At the same time, it is also important to make sure deserving patients are disposed of from the ED as soon as possible in a time dependent manner once ACS is ruled out. This assumes more significance in EDs that receive a high volume of patients and need patients to be either admitted for further workup or discharged in a timely manner. At the same time, discharging patients from the ED always has a risk of patients ending up in an adverse cardiac event. Institutional protocols that include serial biomarker evaluation help in minimising these risks to a great extent.

Historically, biomarkers like LDH (lactate dehydrogenase) and AST (aspartate aminotransferase) were tried in the detection of an acute coronary syndrome especially towards the end of 20th century. Their clinical significance slowly began to decline with the advent of better alternatives as well as lack of specificity. The next in line were the markers with better specificity and sensitivity, namely—the troponins and creatine kinase. As the 21st century is taking its foothold, the scientific community is focussing its attention on these biomarkers for detection of acute coronary events, a leading cause of death worldwide. The research was primarily focussed on Creatine Kinase – MB fraction, which used to be the gold standard of evaluation of ACS. But, that has given way to the newer biomarkers—Troponin I and Troponin T – both conventional and high sensitive, which are being studied extensively across the globe.

#### **2.1 Creatine kinase: MB**

Creatine Kinase is an intracellular enzyme with a dimeric molecule which has 3 isoforms—CK-MM (muscle), CK-BB (brain) and CK-MB (myocardium), based on the organ of origin. CK-MB is the isoenzyme fraction which is predominantly seen in cardiac muscle and hence the utility in detecting cardiac muscle damage. This marker is leaked into the systemic circulation from the cellular cytosol due to disruption of the cell membrane as a result of myocardial injury. This marker can be assayed by a clinician to help in the diagnosis of myocardial infarction. CK-MB isoenzyme can be detected in the bloodstream about 4–6 hours after the onset of chest pain. It peaks by 12–24 hrs and returns to baseline by 12–48 hours. This short time window of rise and fall of CK MB is especially useful in detecting reinfarction or infarct extension in a patient in whom the troponin values might be already elevated as a result of an infarct. It is also helpful in identifying complications in patients who have undergone revascularization procedures in the cardiac care unit. The reference values for CK-MB are as follows—males: ≤ 7.7 ng/mL and females: ≤ 4.3 ng/mL. CK MB assay should always be viewed with a pinch of salt since it is a subunit of the total CK in the system. Abnormal elevations of CK MB can be detected along with an increased level of total CK in cases of traumatic muscle injuries, rhabdomyolysis, myopathies etc. It is worthwhile to note that the normally CK-MB fraction accounts for only 3–5% of the total CK in the body and any increase beyond 30–50% of the total CK should prompt suspicion of abnormal beta subunit synthesis. But, over the past few years, the burden of diagnosis of acute myocardial injury has been shifted on to the shoulders of troponins [6].

#### **2.2 Cardiac troponins**

Troponin is a complex protein molecule comprising of three regulatory proteins playing an integral role in the contraction of cardiac and skeletal muscle. These

three subunits are namely—Troponin I (TnI), Troponin T (TnT) and Troponin C (TnC). Each subunit has a unique function. Troponin T binds to the troponin components of Tropomyosin, troponin I inhibits the interaction of myosin with actin and troponin C has the sites for binding of calcium ions to initiate muscle contraction.

Similar to creatine kinase, any cellular injury leads to leakage of the troponins into the systemic circulation thereby providing a window for diagnosis of acute myocardial infarction. Troponins have much higher specificity and sensitivity than creatine kinase. The utility of cardiac troponins especially – Troponin T and Troponin I has been validated in various studies across the world and hence has been incorporated into the diagnostic guidelines of acute myocardial infarction.

Normally troponins are not detectable in the bloodstream due to the minute quantities in open circulation, which is <0.01 ng/mL for Troponin T and ≤ 0.04 ng/mL for Troponin I. After a myocardial injury, elevated troponin levels in the bloodstream can be detected within a period of 4–6 hours, by conventional methods. The reason for this delay in detection has been attributed to the molecular weight and size (21–37 kDa). This can cause clinically significant delay in the diagnosis of myocardial infarction especially in the setting of nonspecific ECG changes. This has led to the advent of high sensitive assays which can detect troponins at much lower levels (at the levels of ng/L) and that too, much earlier than conventional methods. Troponins can be detected as early as 2 hours after the ischemic event by high sensitive troponin assays currently in clinical practice. This also has a caveat, that is, troponin levels can be detected in the circulation even without myocardial injury [4, 5]. Hence a troponin value above the 99th percentile is taken as a diagnostic cut-off for detection of myocardial ischemia. A 20% rise or fall from the baseline within a period of 3–6 hours can confirm the diagnosis of an acute myocardial infarction according to the National Academy of Clinical Biochemistry [6]. It has been recommended by the American college of Cardiology (ACC) that serial values of troponin be considered at 6–9 hr. intervals to rule out NSTEMI [7]. European Society of Cardiology has also reiterated the importance of doing serial assessments of troponins rather than making a clinical decision based on a single value [8]. In a recent large multicentre evaluation in patients with suspected ACS who presented within 8 hours of symptom onset, it was found that it was possible to diagnose ACS with 3-hour marker samples rather than the conventional method of doing serial markers at 6 hour intervals, without losing out on the diagnostic accuracy [9]. Along with clinical evidence of MI, an elevation of troponin level more than 5 times the upper limit compared to the baseline is needed to diagnose a PCI-related MI and more than 10 times the upper limit to diagnose a CABG-related MI [10]. Multiple studies have shown that there is correlation between the levels of troponins and development of adverse cardiac events [11, 12].

Elevated troponin levels may not always indicate myocardial injury [13, 14]. It can also be elevated in non-ischemic conditions as well. A rise/fall in troponin levels are needed to detect acute MI in patients in whom troponins will be elevated otherwise, like renal failure. Even though sensitivity is increased, specificity has come down which may indicate an underlying disease than an acute coronary event. Various causes of nonischemic elevation of troponins are detailed in the below table (**Table 1**). The troponin levels have to be interpreted only in the appropriate clinical setting, failing which the physician may be misled to an alternate diagnosis [15].

#### **2.3 Other contenders**

Numerous other biomarkers have piqued the interest of the scientific community to identify acute coronary events more early as well as more precisely. Very few have actually stood on their own when compared to troponin studies. The most

**33**

*Biomarkers of Diseases: Their Role in Emergency Medicine*

**Cardiac Non Cardiac**

• Myocarditis • Renal failure • Pericarditis • Sepsis • Infiltrative diseases • Stroke

• Congestive cardiac failure • Pulmonary Embolism

• Blunt chest trauma

common drawback being the cost of the investigation as well as availability. Some of

Myoglobin (Mb) peaks within minutes of cardiac ischemia. With the recent advancements for detection of hs-troponin levels, the utility of Mb has come down in the diagnostic algorithm [16]. A few examples of other novel biomarkers of myocardial ischemia/injury that have undergone clinical trials are given below in **Table 2**. They include cardiac intracellular proteins, markers of neurohormonal activation, markers for haemostatic activity, vascular inflammation markers etc. [17]. In this study, the assessment of H-FABP within the first 4 h of symptoms was found to be superior to cTnT for detection of MI. But the reduced specificity of H-FABP is presently limiting its usefulness in clinical practice. Soluble CD40 ligand and choline which are biomarkers signalling the instability of atherosclerotic plaque formation, have been studied, but did not show add any prognostic or diagnostic value to the existing ones in practice. But the other biomarkers they studied along with this, did not show any favour-

Cardiac failure is a complex process involving a multitude of pathophysiological processes. As a result of this, various biomarkers have been identified which correlate with specific aspects of heart failure. The marker which has made its mark in a clinically significant manner are the natriuretic peptides-B type natriuretic peptide

*DOI: http://dx.doi.org/10.5772/intechopen.94509*

*Examples of non ACS-causes of elevated troponin levels:*

• Heart Fatty Acid Binding Protein (H-FABP) • Glycogen Phosphorylase-BB (GP-BB)

• NT-Pro-Brain Natriuretic Peptide (NT-ProBNP)

• High Sensitivity C-Reactive Protein (HsCRP)

• Pregnancy Associated Plasma Protein-A (PAPP-A)

• Matrix Metalloproteinase-9 (MMP-9)

• Soluble CD40 Ligand (SCD40L)

*Newer biomarkers for cardiac ischemia.*

**Table 1.**

• Myoglobin (Mb) P

• Myeloperoxidase (MPO)

• D-Dimer

**Table 2.**

the examples are discussed below.

able clinical significance.

**3. Cardiac failure**

(BNP) and NT pro BNP.


#### **Table 1.**

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

three subunits are namely—Troponin I (TnI), Troponin T (TnT) and Troponin C (TnC). Each subunit has a unique function. Troponin T binds to the troponin components of Tropomyosin, troponin I inhibits the interaction of myosin with actin and troponin C has the sites for binding of calcium ions to initiate muscle

Similar to creatine kinase, any cellular injury leads to leakage of the troponins into the systemic circulation thereby providing a window for diagnosis of acute myocardial infarction. Troponins have much higher specificity and sensitivity than creatine kinase. The utility of cardiac troponins especially – Troponin T and Troponin I has been validated in various studies across the world and hence has been incorporated into the diagnostic guidelines of acute myocardial infarction. Normally troponins are not detectable in the bloodstream due to the minute quantities in open circulation, which is <0.01 ng/mL for Troponin T and ≤ 0.04 ng/mL for Troponin I. After a myocardial injury, elevated troponin levels in the bloodstream can be detected within a period of 4–6 hours, by conventional methods. The reason for this delay in detection has been attributed to the molecular weight and size (21–37 kDa). This can cause clinically significant delay in the diagnosis of myocardial infarction especially in the setting of nonspecific ECG changes. This has led to the advent of high sensitive assays which can detect troponins at much lower levels (at the levels of ng/L) and that too, much earlier than conventional methods. Troponins can be detected as early as 2 hours after the ischemic event by high sensitive troponin assays currently in clinical practice. This also has a caveat, that is, troponin levels can be detected in the circulation even without myocardial injury [4, 5]. Hence a troponin value above the 99th percentile is taken as a diagnostic cut-off for detection of myocardial ischemia. A 20% rise or fall from the baseline within a period of 3–6 hours can confirm the diagnosis of an acute myocardial infarction according to the National Academy of Clinical Biochemistry [6]. It has been recommended by the American college of Cardiology (ACC) that serial values of troponin be considered at 6–9 hr. intervals to rule out NSTEMI [7]. European Society of Cardiology has also reiterated the importance of doing serial assessments of troponins rather than making a clinical decision based on a single value [8]. In a recent large multicentre evaluation in patients with suspected ACS who presented within 8 hours of symptom onset, it was found that it was possible to diagnose ACS with 3-hour marker samples rather than the conventional method of doing serial markers at 6 hour intervals, without losing out on the diagnostic accuracy [9]. Along with clinical evidence of MI, an elevation of troponin level more than 5 times the upper limit compared to the baseline is needed to diagnose a PCI-related MI and more than 10 times the upper limit to diagnose a CABG-related MI [10]. Multiple studies have shown that there is correlation between the levels of troponins and

**32**

**2.3 Other contenders**

development of adverse cardiac events [11, 12].

Elevated troponin levels may not always indicate myocardial injury [13, 14]. It can also be elevated in non-ischemic conditions as well. A rise/fall in troponin levels are needed to detect acute MI in patients in whom troponins will be elevated otherwise, like renal failure. Even though sensitivity is increased, specificity has come down which may indicate an underlying disease than an acute coronary event. Various causes of nonischemic elevation of troponins are detailed in the below table (**Table 1**). The troponin levels have to be interpreted only in the appropriate clinical setting, failing which the physician may be misled to an alternate diagnosis [15].

Numerous other biomarkers have piqued the interest of the scientific community to identify acute coronary events more early as well as more precisely. Very few have actually stood on their own when compared to troponin studies. The most

contraction.

*Examples of non ACS-causes of elevated troponin levels:*


#### **Table 2.**

*Newer biomarkers for cardiac ischemia.*

common drawback being the cost of the investigation as well as availability. Some of the examples are discussed below.

Myoglobin (Mb) peaks within minutes of cardiac ischemia. With the recent advancements for detection of hs-troponin levels, the utility of Mb has come down in the diagnostic algorithm [16]. A few examples of other novel biomarkers of myocardial ischemia/injury that have undergone clinical trials are given below in **Table 2**. They include cardiac intracellular proteins, markers of neurohormonal activation, markers for haemostatic activity, vascular inflammation markers etc. [17]. In this study, the assessment of H-FABP within the first 4 h of symptoms was found to be superior to cTnT for detection of MI. But the reduced specificity of H-FABP is presently limiting its usefulness in clinical practice. Soluble CD40 ligand and choline which are biomarkers signalling the instability of atherosclerotic plaque formation, have been studied, but did not show add any prognostic or diagnostic value to the existing ones in practice. But the other biomarkers they studied along with this, did not show any favourable clinical significance.

#### **3. Cardiac failure**

Cardiac failure is a complex process involving a multitude of pathophysiological processes. As a result of this, various biomarkers have been identified which correlate with specific aspects of heart failure. The marker which has made its mark in a clinically significant manner are the natriuretic peptides-B type natriuretic peptide (BNP) and NT pro BNP.

#### **3.1 B type natriuretic peptide (BNP) & NT pro BNP**

BNP is secreted from the ventricles as a result of neurohormonal activation due to volume overload and resultant stretching of the myocardial muscle fibres. In patients with left ventricular dysfunction/failure, high plasma levels of BNP and NT pro BNP are specific for elevated filling pressures in the cardiac chambers. This can be used in the clinical context for the diagnosis as well as prognostication of cardiac failure. ProBNP is a 108-amino acid polypeptide precursor which is stored in secretory granules in both ventricles and, to a lesser extent, in the atria. After proBNP is secreted, it is cleaved to the 76-peptide, biologically inert N-terminal fragment NT-proBNP and the 32-peptide, biologically active hormone BNP. BNP is rapidly cleared from the circulation; the plasma half-life being approximately 20 min. No receptor-mediated clearance of NT-proBNP is known to occur, because of which NT-proBNP has a prolonged half-life of 60–120 min. The reference values for NT-proBNP varies widely with age and gender, which can be tricky for the clinician while assessing patients, especially in the elderly population (**Table 3**).

In the multicentre Breathing Not Properly Study [18], using plasma BNP level of 100 pg/mL as cut off, gave a sensitivity of 90%, specificity of 76% and a diagnostic accuracy of 81% which was superior to clinical assessment alone in a series of 1586 patients who presented to the ED with acute dyspnoea. A BNP level < 100 pg/ml or an NT-proBNP level < 300 pg/ml can essentially rule out Acute HF in most cases. When using N-terminal proBNP for the diagnosis of acute CHF, a value of 900 pg/mL has high specificity and sensitivity.

Apart from left ventricular failure, these biomarkers can be elevated in numerous other conditions which can cause myocardial stretch. Patients with right ventricular failure secondary to pulmonary embolism or pulmonary hypertension, valvular heart disease, arrhythmias such as atrial fibrillation, renal failure and advanced age may also have elevated levels of BNP or NT-proBNP [19]. In severe renal failure, the NT-pro BNP value of >1200 pg/mL is needed to make a diagnosis of cardiac failure. A common clinical scenario in which the patient is obese, the pro-BNP values can be falsely lower which can mask cardiac failure and lead to misdiagnosis.

The European Society of Cardiology Task Force has recommended that the algorithm for HF diagnosis should include an NP assay as the first step along with electrocardiography (ECG) and chest X-ray [20]. Biomarkers are not just useful in the diagnostic algorithm, but also in guiding treatment. In a meta-analysis [21] of 2686 patients in 12 randomised trials, the researchers found that the use of cardiac peptides to guide pharmacologic therapy significantly reduces mortality and HF related hospitalisation in patients with chronic HF.

As discussed in the previous section, Troponin I (TnI) also plays an important role in the pathophysiological profile of cardiac failure. Newer markers that have potential to be significance in the future for diagnosis and prognosis in heart failure include high-sensitivity C-reactive protein (hsCRP), uric acid and


**35**

mortality [30].

*Biomarkers of Diseases: Their Role in Emergency Medicine*

myeloperoxidase (MPO), soluble toll-like receptor-2 (ST2) and soluble fms-like tyrosine kinase receptor-1 (sFlt-1). Recently, a study in which the amount of exhaled acetone is measured has shown promise as a newer non-invasive modality for cardiac failure assessment [22]. A recent study attempted to evaluate the predictive utility of these biomarkers with a multimarker score which included BNP, troponin I and creatinine apart from the above markers. They concluded that a multimarker score significantly improves prediction of adverse events in ambulatory patients with chronic heart failure [23]. But, NACB's practice guidelines on cardiac biomarker testing specifically recommends against routine use of biomarker testing only for risk stratification [24]. The newer entries into this field include galectin-3 [25], MR-proANP (midregion pro–atrial natriuretic peptide) [26], MR-proADM (mid regional pro-adrenomedullin), co-peptin, adiponectin, pentraxin-3, soluble ICAM-1(intercellular adhesion molecule-1), PAPP-A (preg-

In a case of suspected pulmonary embolism, laboratory evaluation by biomarker levels is primarily helpful in ruling out the diagnosis in low probability scenarios, rather than ruling in a confirmation of a diagnosis. D-dimer has been in clinical use extensively since the past few decades and the other markers which are increasingly

D-dimer is a degradation product produced by plasmin during fibrinolysis. The reference value of D-dimer is ≤500 ng/mL Fibrinogen equivalent Units (FEU). It has very low specificity, but a high sensitivity. Due to the low specificity, a clinical diagnosis of pulmonary embolism requires a strong clinical suspicion. In order to help the clinician in this regard, various scoring systems to assess the probability of making a diagnosis of PE have been devised. Well's criteria and its modified version are among the most commonly used. These scoring systems assist the clinician in assessing the probability of a diagnosis of PE along with the blood levels of the biomarker used. In patients with a low pretest probability of PE as assessed by well's criteria and a negative d-dimer value, the diagnosis of pulmonary embolism can be essentially ruled out

Ischemia modified albumin (IMA) is a newer marker that has shown potential as a substitute for D-dimer as it has been found to be better than the latter in a few studies due to its better positive predictive value [29]. The reference value for IMA is ≤0.540 ABSU. In patients with pulmonary embolism, more so in those who develop RV dysfunction, other biomarkers like troponins and BNP are also found to be elevated. This occurs due to the increased pulmonary vascular resistance, pulmonary artery pressure and resultant RV afterload. The elevated troponin levels can pose a dilemma for a clinician who wants to rule out ACS as well in the clinical setting as the symptoms of both the conditions may overlap significantly. The elevated levels of BNP/NT pro-BNP in patients with pulmonary embolism have been found to be associated with increase in risk for complications and 30-day

used are troponins, BNP and Ischemia modified albumin (IMA).

without any probability of adverse events happening later [27, 28].

**4.2 Ischemia modified albumin (IMA)**

*DOI: http://dx.doi.org/10.5772/intechopen.94509*

nancy associated plasma protein A) etc.

**4. Pulmonary embolism**

**4.1 D-dimer**

**Table 3.** *Reference values for NT-ProBNP:* myeloperoxidase (MPO), soluble toll-like receptor-2 (ST2) and soluble fms-like tyrosine kinase receptor-1 (sFlt-1). Recently, a study in which the amount of exhaled acetone is measured has shown promise as a newer non-invasive modality for cardiac failure assessment [22]. A recent study attempted to evaluate the predictive utility of these biomarkers with a multimarker score which included BNP, troponin I and creatinine apart from the above markers. They concluded that a multimarker score significantly improves prediction of adverse events in ambulatory patients with chronic heart failure [23]. But, NACB's practice guidelines on cardiac biomarker testing specifically recommends against routine use of biomarker testing only for risk stratification [24]. The newer entries into this field include galectin-3 [25], MR-proANP (midregion pro–atrial natriuretic peptide) [26], MR-proADM (mid regional pro-adrenomedullin), co-peptin, adiponectin, pentraxin-3, soluble ICAM-1(intercellular adhesion molecule-1), PAPP-A (pregnancy associated plasma protein A) etc.

#### **4. Pulmonary embolism**

In a case of suspected pulmonary embolism, laboratory evaluation by biomarker levels is primarily helpful in ruling out the diagnosis in low probability scenarios, rather than ruling in a confirmation of a diagnosis. D-dimer has been in clinical use extensively since the past few decades and the other markers which are increasingly used are troponins, BNP and Ischemia modified albumin (IMA).

#### **4.1 D-dimer**

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

while assessing patients, especially in the elderly population (**Table 3**).

In the multicentre Breathing Not Properly Study [18], using plasma BNP level of 100 pg/mL as cut off, gave a sensitivity of 90%, specificity of 76% and a diagnostic accuracy of 81% which was superior to clinical assessment alone in a series of 1586 patients who presented to the ED with acute dyspnoea. A BNP level < 100 pg/ml or an NT-proBNP level < 300 pg/ml can essentially rule out Acute HF in most cases. When using N-terminal proBNP for the diagnosis of acute CHF, a value of 900 pg/mL has

Apart from left ventricular failure, these biomarkers can be elevated in numer-

The European Society of Cardiology Task Force has recommended that the algorithm for HF diagnosis should include an NP assay as the first step along with electrocardiography (ECG) and chest X-ray [20]. Biomarkers are not just useful in the diagnostic algorithm, but also in guiding treatment. In a meta-analysis [21] of 2686 patients in 12 randomised trials, the researchers found that the use of cardiac peptides to guide pharmacologic therapy significantly reduces mortality and HF

As discussed in the previous section, Troponin I (TnI) also plays an important

role in the pathophysiological profile of cardiac failure. Newer markers that have potential to be significance in the future for diagnosis and prognosis in heart failure include high-sensitivity C-reactive protein (hsCRP), uric acid and

**Age Males Females** ≤45 yrs 10–51 pg/mL 10–140 pg/mL 45–70 yrs 10–100 pg/mL 10–206 pg/mL ≥70 yrs 10–138 pg/mL 10–1263 pg/mL

related hospitalisation in patients with chronic HF.

ous other conditions which can cause myocardial stretch. Patients with right ventricular failure secondary to pulmonary embolism or pulmonary hypertension, valvular heart disease, arrhythmias such as atrial fibrillation, renal failure and advanced age may also have elevated levels of BNP or NT-proBNP [19]. In severe renal failure, the NT-pro BNP value of >1200 pg/mL is needed to make a diagnosis of cardiac failure. A common clinical scenario in which the patient is obese, the pro-BNP values can be falsely lower which can mask cardiac failure and lead to

BNP is secreted from the ventricles as a result of neurohormonal activation due to volume overload and resultant stretching of the myocardial muscle fibres. In patients with left ventricular dysfunction/failure, high plasma levels of BNP and NT pro BNP are specific for elevated filling pressures in the cardiac chambers. This can be used in the clinical context for the diagnosis as well as prognostication of cardiac failure. ProBNP is a 108-amino acid polypeptide precursor which is stored in secretory granules in both ventricles and, to a lesser extent, in the atria. After proBNP is secreted, it is cleaved to the 76-peptide, biologically inert N-terminal fragment NT-proBNP and the 32-peptide, biologically active hormone BNP. BNP is rapidly cleared from the circulation; the plasma half-life being approximately 20 min. No receptor-mediated clearance of NT-proBNP is known to occur, because of which NT-proBNP has a prolonged half-life of 60–120 min. The reference values for NT-proBNP varies widely with age and gender, which can be tricky for the clinician

**3.1 B type natriuretic peptide (BNP) & NT pro BNP**

high specificity and sensitivity.

misdiagnosis.

**34**

**Table 3.**

*Reference values for NT-ProBNP:*

D-dimer is a degradation product produced by plasmin during fibrinolysis. The reference value of D-dimer is ≤500 ng/mL Fibrinogen equivalent Units (FEU). It has very low specificity, but a high sensitivity. Due to the low specificity, a clinical diagnosis of pulmonary embolism requires a strong clinical suspicion. In order to help the clinician in this regard, various scoring systems to assess the probability of making a diagnosis of PE have been devised. Well's criteria and its modified version are among the most commonly used. These scoring systems assist the clinician in assessing the probability of a diagnosis of PE along with the blood levels of the biomarker used. In patients with a low pretest probability of PE as assessed by well's criteria and a negative d-dimer value, the diagnosis of pulmonary embolism can be essentially ruled out without any probability of adverse events happening later [27, 28].

#### **4.2 Ischemia modified albumin (IMA)**

Ischemia modified albumin (IMA) is a newer marker that has shown potential as a substitute for D-dimer as it has been found to be better than the latter in a few studies due to its better positive predictive value [29]. The reference value for IMA is ≤0.540 ABSU. In patients with pulmonary embolism, more so in those who develop RV dysfunction, other biomarkers like troponins and BNP are also found to be elevated. This occurs due to the increased pulmonary vascular resistance, pulmonary artery pressure and resultant RV afterload. The elevated troponin levels can pose a dilemma for a clinician who wants to rule out ACS as well in the clinical setting as the symptoms of both the conditions may overlap significantly. The elevated levels of BNP/NT pro-BNP in patients with pulmonary embolism have been found to be associated with increase in risk for complications and 30-day mortality [30].

#### **5. Sepsis**

Sepsis is a complex process that stems from a combination of features of a systemic inflammatory response to a known or presumed infection. It is associated with a very high mortality rate around 30% not to mention the significant economic impact on the healthcare system [31]. Sepsis can be viewed as a chain of events in the body as a response to an inciting agent through an inflammatory pathway. This provides clinicians the opportunity to diagnose sepsis early by either picking up the inciting agent or the inflammatory response to the agent. More than 170 biomarkers have been identified as useful for evaluating sepsis [32], which itself points to the fact that none of them can be used as a single marker for accurate diagnosis or prognosis. C-reactive protein, procalcitonin and serum lactate are among the prominent ones used extensively worldwide at present.

#### **5.1 C-reactive protein**

C-Reactive protein, one of the most commonly used markers for sepsis, is synthesised in the liver as an acute phase reactant. The normal levels in a healthy adult individual tends to be below 10 mg/L. Depending on the severity, any stress or stimulus can cause an elevation in the CRP levels, even manifold up to 500 mg/L. The levels peak around 36–48 hrs and the plasma half-life is approx. 19 hrs. Although very commonly used as an inflammatory marker, it lacks specificity as it is found to be elevated in numerous conditions like post-operative patients, burns, myocardial infarction and inflammatory/rheumatic diseases as well [33]. It can be elevated even in normal individuals especially in elderly as well as pregnancy. Moreover, even a viral infection can cause a mild increase in the serum levels of CRP, contrary to popular belief. The sensitivity and specificity of CRP as a marker for bacterial infections are 68–92% and 40–67%, respectively [34, 35]. CRP plasma levels have shown to correlate with the severity of infection [36] which makes it a useful marker to assess the response to pharmacological treatment.

#### **5.2 Procalcitonin (PCT)**

It is a 116-amino acid polypeptide which is the prohormone of calcitonin. It has a short half-life (25–30 hours), and is encoded by the *CALC-1* gene. PCT is normally produced by neuroendocrine cells, mainly in the thyroid (C-cells), from which calcitonin is derived which is responsible for regulation of calcium metabolism in the body. It is also produced in low amounts in other neuroendocrine cells in the intestine and lungs. The *CALC-1* gene is normally suppressed in non-endocrine tissues. Bacterial infection stimulates *CALC-1*gene transcription in non-endocrine cells [37], leading to increased PCT production which can be detected in the circulation making it a marker for diagnosis of bacterial infection and sepsis. PCT is released from various organs including lung, liver, kidney, pancreas, spleen, colon, and even adipose tissues in infectious conditions. In healthy individuals, the serum PCT levels are <0.1 ng/ml, which increases in response to an infective stimulus. Serum PCT levels begin to rise around 4 hrs after the insult and peaks by 24 hrs. The half-life of PCT is approx. 24 hrs and after the infectious process has started resolving, PCT levels decrease by almost 50% every day [38]. In a systematic review and meta-analysis, PCT with a cut-off median value of 1.1 ng/mL was found to be more specific (specificity - 81%) than CRP (67%) for differentiating bacterial infection among hospitalised patients [39]. PCT also has a sensitivity of 77% which makes it a useful marker for early diagnosis of sepsis [40]. These features make PCT a favourable biomarker to be used for guidance of antibiotic stewardship as well to reduce the ever increasing inappropriate use/abuse of antibiotics [41].

**37**

**6. Burns**

<0.5 nmol/L.

**5.5 Other markers of sepsis**

*Biomarkers of Diseases: Their Role in Emergency Medicine*

Lactate is produced in the body even normally, which gets cleared off rapidly in healthy individuals. But, in cases of sepsis and resultant hypoperfusion, the levels of lactic acid increase when anaerobic metabolism increases in the body. Lactate clearance has been shown in a prominent light in the 'Early goal directed therapy' of septic patients. This indicates that, more than a diagnostic marker, lactate has prognostic significance in patients with sepsis. Recent studies have shown that patients with even a milder increase in serum levels in the range of 2–4 mmol/L were at an increased risk of morbidity and mortality [42]. In a study conducted in an urban academic centre which included 1278 patients with infections, those with lactate levels above 4 mmol/L had higher in-hospital mortality rates than patients with lactate levels less than 2.5 mmol/L (28.4% vs. 4.9%) [43]. The bottom line is,

Adrenomedullin (ADM) is a 52-amino acid ringed peptide produced from endothelial cells in cardiovascular, renal, pulmonary, cerebrovascular and endocrine tissues. It is a potent endogenous vasodilator in the human body. ADM is not easily measurable due to its very short half-life of 22 minutes in the circulation, its rapid degradation by proteases, and the formation of complexes with circulating complement factor H [45]. The prohormone of ADM - ProADM can be used as a surrogate marker for this purpose as it is more easily quantifiable, and the tools required for this are available commercially. The mid-regional fragment of proadrenomedullin (MR-proADM) is a marker of endothelial dysfunction/inflammation and therefore can be seen in elevated levels in numerous disease conditions. Pro-ADM has been found to be an independent predictor for adverse outcomes in patients with COPD [46]. It has also been studied in the context of burns, in which it was found to have utility in early recognition of onset of sepsis in burns victims [47]. It is still early days for MR-proADM in routine clinical practice as many studies [48] have failed to demonstrate any added utility with respect to other less expensive parameters presently available. For healthy individuals, the reference values for MR pro ADM is

Cytokines like TNF, IL-1β and IL-6 are the predominant inflammatory mediators responsible for the initial inflammatory response and the levels correlate with the organ damage and mortality [49]. Similarly, High-mobility group box 1 protein (HMGB1) and Macrophage migration inhibitory factor (MIF) are also found to increase in patients with severe sepsis and septic shock and is correlated with the degree of organ failure [50, 51]. Lipopolysaccharide-binding protein (LBS) is an acute phase protein which increases in sepsis and makes it useful as a diagnostic tool as well as a marker for severity of the disease [52, 53]. Other biomarkers like serum amyloid A, eosinophil count, mannan and antimannan, and IFN-γ-inducible

In patients who are hospitalised with burns, sepsis is considered as one of the most important causes for mortality. Biomarkers which can help pick up the onset of sepsis in burn patients in the early phase itself will be useful in the proactive

protein 10 also show potential to be of use in the future.

the better the lactate clearance, better the outcome of the patient [44].

*DOI: http://dx.doi.org/10.5772/intechopen.94509*

**5.4 Proadrenomedullin (MR-proADM)**

**5.3 Serum lactate**

#### **5.3 Serum lactate**

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

Sepsis is a complex process that stems from a combination of features of a systemic inflammatory response to a known or presumed infection. It is associated with a very high mortality rate around 30% not to mention the significant economic impact on the healthcare system [31]. Sepsis can be viewed as a chain of events in the body as a response to an inciting agent through an inflammatory pathway. This provides clinicians the opportunity to diagnose sepsis early by either picking up the inciting agent or the inflammatory response to the agent. More than 170 biomarkers have been identified as useful for evaluating sepsis [32], which itself points to the fact that none of them can be used as a single marker for accurate diagnosis or prognosis. C-reactive protein, procalcitonin and serum lactate are among the prominent

C-Reactive protein, one of the most commonly used markers for sepsis, is synthesised in the liver as an acute phase reactant. The normal levels in a healthy adult individual tends to be below 10 mg/L. Depending on the severity, any stress or stimulus can cause an elevation in the CRP levels, even manifold up to 500 mg/L.

The levels peak around 36–48 hrs and the plasma half-life is approx. 19 hrs. Although very commonly used as an inflammatory marker, it lacks specificity as it is found to be elevated in numerous conditions like post-operative patients, burns, myocardial infarction and inflammatory/rheumatic diseases as well [33]. It can be elevated even in normal individuals especially in elderly as well as pregnancy. Moreover, even a viral infection can cause a mild increase in the serum levels of CRP, contrary to popular belief. The sensitivity and specificity of CRP as a marker for bacterial infections are 68–92% and 40–67%, respectively [34, 35]. CRP plasma levels have shown to correlate with the severity of infection [36] which makes it a

useful marker to assess the response to pharmacological treatment.

the ever increasing inappropriate use/abuse of antibiotics [41].

It is a 116-amino acid polypeptide which is the prohormone of calcitonin. It has a short half-life (25–30 hours), and is encoded by the *CALC-1* gene. PCT is normally produced by neuroendocrine cells, mainly in the thyroid (C-cells), from which calcitonin is derived which is responsible for regulation of calcium metabolism in the body. It is also produced in low amounts in other neuroendocrine cells in the intestine and lungs. The *CALC-1* gene is normally suppressed in non-endocrine tissues. Bacterial infection stimulates *CALC-1*gene transcription in non-endocrine cells [37], leading to increased PCT production which can be detected in the

circulation making it a marker for diagnosis of bacterial infection and sepsis. PCT is released from various organs including lung, liver, kidney, pancreas, spleen, colon, and even adipose tissues in infectious conditions. In healthy individuals, the serum PCT levels are <0.1 ng/ml, which increases in response to an infective stimulus. Serum PCT levels begin to rise around 4 hrs after the insult and peaks by 24 hrs. The half-life of PCT is approx. 24 hrs and after the infectious process has started resolving, PCT levels decrease by almost 50% every day [38]. In a systematic review and meta-analysis, PCT with a cut-off median value of 1.1 ng/mL was found to be more specific (specificity - 81%) than CRP (67%) for differentiating bacterial infection among hospitalised patients [39]. PCT also has a sensitivity of 77% which makes it a useful marker for early diagnosis of sepsis [40]. These features make PCT a favourable biomarker to be used for guidance of antibiotic stewardship as well to reduce

**36**

**5. Sepsis**

ones used extensively worldwide at present.

**5.1 C-reactive protein**

**5.2 Procalcitonin (PCT)**

Lactate is produced in the body even normally, which gets cleared off rapidly in healthy individuals. But, in cases of sepsis and resultant hypoperfusion, the levels of lactic acid increase when anaerobic metabolism increases in the body. Lactate clearance has been shown in a prominent light in the 'Early goal directed therapy' of septic patients. This indicates that, more than a diagnostic marker, lactate has prognostic significance in patients with sepsis. Recent studies have shown that patients with even a milder increase in serum levels in the range of 2–4 mmol/L were at an increased risk of morbidity and mortality [42]. In a study conducted in an urban academic centre which included 1278 patients with infections, those with lactate levels above 4 mmol/L had higher in-hospital mortality rates than patients with lactate levels less than 2.5 mmol/L (28.4% vs. 4.9%) [43]. The bottom line is, the better the lactate clearance, better the outcome of the patient [44].

#### **5.4 Proadrenomedullin (MR-proADM)**

Adrenomedullin (ADM) is a 52-amino acid ringed peptide produced from endothelial cells in cardiovascular, renal, pulmonary, cerebrovascular and endocrine tissues. It is a potent endogenous vasodilator in the human body. ADM is not easily measurable due to its very short half-life of 22 minutes in the circulation, its rapid degradation by proteases, and the formation of complexes with circulating complement factor H [45]. The prohormone of ADM - ProADM can be used as a surrogate marker for this purpose as it is more easily quantifiable, and the tools required for this are available commercially. The mid-regional fragment of proadrenomedullin (MR-proADM) is a marker of endothelial dysfunction/inflammation and therefore can be seen in elevated levels in numerous disease conditions. Pro-ADM has been found to be an independent predictor for adverse outcomes in patients with COPD [46]. It has also been studied in the context of burns, in which it was found to have utility in early recognition of onset of sepsis in burns victims [47]. It is still early days for MR-proADM in routine clinical practice as many studies [48] have failed to demonstrate any added utility with respect to other less expensive parameters presently available. For healthy individuals, the reference values for MR pro ADM is <0.5 nmol/L.

#### **5.5 Other markers of sepsis**

Cytokines like TNF, IL-1β and IL-6 are the predominant inflammatory mediators responsible for the initial inflammatory response and the levels correlate with the organ damage and mortality [49]. Similarly, High-mobility group box 1 protein (HMGB1) and Macrophage migration inhibitory factor (MIF) are also found to increase in patients with severe sepsis and septic shock and is correlated with the degree of organ failure [50, 51]. Lipopolysaccharide-binding protein (LBS) is an acute phase protein which increases in sepsis and makes it useful as a diagnostic tool as well as a marker for severity of the disease [52, 53]. Other biomarkers like serum amyloid A, eosinophil count, mannan and antimannan, and IFN-γ-inducible protein 10 also show potential to be of use in the future.

#### **6. Burns**

In patients who are hospitalised with burns, sepsis is considered as one of the most important causes for mortality. Biomarkers which can help pick up the onset of sepsis in burn patients in the early phase itself will be useful in the proactive

management of complications. Procalcitonin, Tumour necrosis factor-alpha (TNF-alpha), MR Pro-ADM, Interleukins 6, 8 & 10, Presepsin are among the major ones studied in this context in addition to assessment of single-nucleotide polymorphisms (SNPs) and leukocyte transcriptomes [54].

#### **6.1 Procalcitonin**

PCT has been extensively studied in the context of sepsis, but literature regarding studies in burns are much lesser in comparison to other critical conditions. Serum levels of PCT were found to be elevated in patients who developed infections after burns in one of the initial studies done in 1993 which had 9 burns patients included among the 79 general patients enrolled in the study [55]. In a recent metaanalysis of around 12 studies in burns patients led the investigators to believe that PCT has a strong ability to differentiate between patients with sepsis and without sepsis [56]. The study proposed that a PCT value >1.47 ng/mL can prompt the clinicians to initiate early antibiotic therapy to counter the development of sepsis and improve patient outcomes.

#### **6.2 Tumour necrosis factor-alpha (TNF-alpha)**

It is a proinflammatory cytokine and has been researched worldwide in various disease conditions among the host of numerous inflammatory mediators. It is produced ubiquitously in the body in response to various stimuli which can be infectious or ischemic in nature. They include endotoxins, complement system activation, hypoxia, ischemia as well as reperfusion [57]. TNF-alpha has been found to be elevated in burns and the values are seen to be higher in patients found to be in sepsis [58]. It has also been shown to have a prognostic value in burns victims. In burns patients who were treated with GM-CSF, the values of TNF alpha were shown to come down gradually as the treatment progressed [59], hence proving its role as a prognostic indicator. Reference value: ≤ 2.8 pg/mL.

#### **6.3 Interleukins**

The interleukins (ILs) are a large class of cytokines that promote cell-to-cell interactions and the stimulation of humoral or cell-mediated immune responses. They were initially thought to be produced only by the leukocytes, but have been found to be produced from numerous sources since then. The IL family consists of a huge number of members of which IL-6, IL-8 and IL-10 have been shown to be associated with evaluation of sepsis in burns patients. IL-6 has been found to be elevated in burns patients with sepsis [60]. It not only helps in the early diagnosis, but also has prognostic significance regarding the mortality as the levels have been found to be correlating with the size of the burns [61]. Recently, a meta-analysis of studies done on critically ill patients regarding markers of sepsis found IL-6 to have a high specificity, hence making it a suitable marker to confirm an infectious process [62]. Similarly, studies have found that IL-8 levels in burns patients correlate with the development of sepsis and multi-organ failure resulting in mortality [63]. The authors of the study opined that it can be used as a biomarker for monitoring the morbidity and mortality of burn patients developing sepsis. IL-10, similar to its counterparts, have been shown to have a correlation to development of sepsis in burn patients. Normally, the serum levels increase after the injury and decline later. But a failure to decline over time and being persistently elevated should point towards the development of an infective process and may increase the chances of mortality [64], hence making it a prognostic indicator in burn patients.

**39**

early [70, 71].

*Biomarkers of Diseases: Their Role in Emergency Medicine*

Some of the other notable markers pertaining to burns patients are - **Presepsin** which is the soluble form of cluster of differentiation 14 (CD14), a glycoprotein that functions as receptor for endotoxin complexes triggering signal transduction pathways implicated in systemic inflammation. In a study conducted on burns patients, Presepsin elevation preceded the elevation of CRP and PCT by 1 day as a marker of sepsis [65]. Several individual studies have reported the diagnostic accuracy of presepsin (sCD14-ST) for sepsis, but the results are inconsistent. Presepsin is an effective adjunct biomarker for the diagnosis of sepsis, but is insufficient to detect or rule out sepsis when used alone [66]. **Single-nucleotide polymorphisms (SNPs)** which are variations in a nucleotide at a specific chromosome location and has been linked to sepsis susceptibility and differences in prognosis in burns patients [67]. Gene-expression patterns like the **leukocyte transcriptome** shifts towards increased expression of genes involved in innate immunity and the inflammatory response and has been noted in burns patients [68]. But, most of these markers are not useful in day to day practice and have been limited to research settings at present. Nonetheless, the possibility of these markers making way into the clinical

Conventionally, renal function tests which include serum levels of creatinine, urea and assessment of glomerular filtration rate are the methods used to quantify renal diseases. But, these conventional methods have a huge drawback. There is an unacceptable high time lag between the onset of tissue injury and derangement of these biochemical values. This hinders any active reno-protective interventions that may be initiated promptly. Moreover, the serum levels of these markers vary widely even in healthy individuals as it depends on various physical factors like age, gender, muscle mass etc. This has led the medical community to look for alternatives. Human neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), interleukin-18 (IL-18), cystatin C, clusterin, fatty acid binding protein, and osteopontin are the prominent ones that have been studied and NGAL has been

**Neutrophil Gelatinase-associated Lipocalin (NGAL)** is a protein that is expressed in neutrophils and has a role in innate immune response as well as repair and reepithelialisation in the kidney. In patients with acute kidney injury, ischemic or nonischemic type, plasma/urine levels of NGAL have been found to be elevated. (>50 μg/L)[69]. Both urinary and plasma levels of NGAL were found to increase by more than 10-fold within 2–6 hours of cardiac surgery in patients who later developed acute kidney injury. Urinary NGAL has been studied more extensively in paediatric population and has been found to be useful in detecting kidney injury following transplantation, cardiac surgery as well as contrast induced nephropathy

Other markers that are being studied for their utility in kidney injury are Interleukin-18, Kidney injury molecule 1 (KIM-1), Cystatin – C, Sodium/Hydrogen Exchanger Isoform 3(NHE3) and Liver-type fatty acid binding protein (L-FABP). Kidney injury molecule 1 (KIM-1) and Interleukin-18 are found to be elevated in case of ischemic Acute Tubular Necrosis [72, 73]. Cystatin-C has been found to be better at estimating the GFR than the conventional method using creatinine [74]. Sodium/Hydrogen Exchanger Isoform 3(NHE3), which is found in the urine

*DOI: http://dx.doi.org/10.5772/intechopen.94509*

domain in the future cannot be ruled out.

**7. Acute kidney injury**

the most prominent one of the lot.

**7.1 Neutrophil gelatinase-associated lipocalin (NGAL)**

*Biomarkers of Diseases: Their Role in Emergency Medicine DOI: http://dx.doi.org/10.5772/intechopen.94509*

Some of the other notable markers pertaining to burns patients are - **Presepsin** which is the soluble form of cluster of differentiation 14 (CD14), a glycoprotein that functions as receptor for endotoxin complexes triggering signal transduction pathways implicated in systemic inflammation. In a study conducted on burns patients, Presepsin elevation preceded the elevation of CRP and PCT by 1 day as a marker of sepsis [65]. Several individual studies have reported the diagnostic accuracy of presepsin (sCD14-ST) for sepsis, but the results are inconsistent. Presepsin is an effective adjunct biomarker for the diagnosis of sepsis, but is insufficient to detect or rule out sepsis when used alone [66]. **Single-nucleotide polymorphisms (SNPs)** which are variations in a nucleotide at a specific chromosome location and has been linked to sepsis susceptibility and differences in prognosis in burns patients [67]. Gene-expression patterns like the **leukocyte transcriptome** shifts towards increased expression of genes involved in innate immunity and the inflammatory response and has been noted in burns patients [68]. But, most of these markers are not useful in day to day practice and have been limited to research settings at present. Nonetheless, the possibility of these markers making way into the clinical domain in the future cannot be ruled out.

#### **7. Acute kidney injury**

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

management of complications. Procalcitonin, Tumour necrosis factor-alpha (TNF-alpha), MR Pro-ADM, Interleukins 6, 8 & 10, Presepsin are among the major ones studied in this context in addition to assessment of single-nucleotide polymor-

PCT has been extensively studied in the context of sepsis, but literature regarding studies in burns are much lesser in comparison to other critical conditions. Serum levels of PCT were found to be elevated in patients who developed infections after burns in one of the initial studies done in 1993 which had 9 burns patients included among the 79 general patients enrolled in the study [55]. In a recent metaanalysis of around 12 studies in burns patients led the investigators to believe that PCT has a strong ability to differentiate between patients with sepsis and without sepsis [56]. The study proposed that a PCT value >1.47 ng/mL can prompt the clinicians to initiate early antibiotic therapy to counter the development of sepsis and

It is a proinflammatory cytokine and has been researched worldwide in various disease conditions among the host of numerous inflammatory mediators. It is produced ubiquitously in the body in response to various stimuli which can be infectious or ischemic in nature. They include endotoxins, complement system activation, hypoxia, ischemia as well as reperfusion [57]. TNF-alpha has been found to be elevated in burns and the values are seen to be higher in patients found to be in sepsis [58]. It has also been shown to have a prognostic value in burns victims. In burns patients who were treated with GM-CSF, the values of TNF alpha were shown to come down gradually as the treatment progressed [59], hence proving its role as a

The interleukins (ILs) are a large class of cytokines that promote cell-to-cell interactions and the stimulation of humoral or cell-mediated immune responses. They were initially thought to be produced only by the leukocytes, but have been found to be produced from numerous sources since then. The IL family consists of a huge number of members of which IL-6, IL-8 and IL-10 have been shown to be associated with evaluation of sepsis in burns patients. IL-6 has been found to be elevated in burns patients with sepsis [60]. It not only helps in the early diagnosis, but also has prognostic significance regarding the mortality as the levels have been found to be correlating with the size of the burns [61]. Recently, a meta-analysis of studies done on critically ill patients regarding markers of sepsis found IL-6 to have a high specificity, hence making it a suitable marker to confirm an infectious process [62]. Similarly, studies have found that IL-8 levels in burns patients correlate with the development of sepsis and multi-organ failure resulting in mortality [63]. The authors of the study opined that it can be used as a biomarker for monitoring the morbidity and mortality of burn patients developing sepsis. IL-10, similar to its counterparts, have been shown to have a correlation to development of sepsis in burn patients. Normally, the serum levels increase after the injury and decline later. But a failure to decline over time and being persistently elevated should point towards the development of an infective process and may increase the chances of

mortality [64], hence making it a prognostic indicator in burn patients.

phisms (SNPs) and leukocyte transcriptomes [54].

**6.2 Tumour necrosis factor-alpha (TNF-alpha)**

prognostic indicator. Reference value: ≤ 2.8 pg/mL.

**6.1 Procalcitonin**

improve patient outcomes.

**6.3 Interleukins**

**38**

Conventionally, renal function tests which include serum levels of creatinine, urea and assessment of glomerular filtration rate are the methods used to quantify renal diseases. But, these conventional methods have a huge drawback. There is an unacceptable high time lag between the onset of tissue injury and derangement of these biochemical values. This hinders any active reno-protective interventions that may be initiated promptly. Moreover, the serum levels of these markers vary widely even in healthy individuals as it depends on various physical factors like age, gender, muscle mass etc. This has led the medical community to look for alternatives. Human neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), interleukin-18 (IL-18), cystatin C, clusterin, fatty acid binding protein, and osteopontin are the prominent ones that have been studied and NGAL has been the most prominent one of the lot.

#### **7.1 Neutrophil gelatinase-associated lipocalin (NGAL)**

**Neutrophil Gelatinase-associated Lipocalin (NGAL)** is a protein that is expressed in neutrophils and has a role in innate immune response as well as repair and reepithelialisation in the kidney. In patients with acute kidney injury, ischemic or nonischemic type, plasma/urine levels of NGAL have been found to be elevated. (>50 μg/L)[69]. Both urinary and plasma levels of NGAL were found to increase by more than 10-fold within 2–6 hours of cardiac surgery in patients who later developed acute kidney injury. Urinary NGAL has been studied more extensively in paediatric population and has been found to be useful in detecting kidney injury following transplantation, cardiac surgery as well as contrast induced nephropathy early [70, 71].

Other markers that are being studied for their utility in kidney injury are Interleukin-18, Kidney injury molecule 1 (KIM-1), Cystatin – C, Sodium/Hydrogen Exchanger Isoform 3(NHE3) and Liver-type fatty acid binding protein (L-FABP). Kidney injury molecule 1 (KIM-1) and Interleukin-18 are found to be elevated in case of ischemic Acute Tubular Necrosis [72, 73]. Cystatin-C has been found to be better at estimating the GFR than the conventional method using creatinine [74]. Sodium/Hydrogen Exchanger Isoform 3(NHE3), which is found in the urine

following tubular injury, has been found to be better than fractional excretion of sodium in differentiating between pre renal and intrinsic renal causes for renal failure [75]. Liver-type fatty acid binding protein (L-FABP) has also shown promise in animal studies for early detection of AKI and is being adapted as a possible biomarker for AKI [76].

#### **8. Traumatic brain injury**

#### **8.1 Traumatic brain injury—acute injury**

Traumatic brain injury is a major cause of morbidity and mortality across the world [77]. The reasons are several, but the lion's share of the incidents can be attributed to the high speed motor vehicle collisions. In addition to that, there are other contributing factors like falls as well as injuries due to contact sports. The acute injuries can be devastating and even fatal, but a huge number of those patients also develop chronic neurological sequelae which can be debilitating [78]. Given the complexity of the situation, the understanding of the mechanisms and pathophysiology of these chronic conditions are much less understood compared to their acute counterparts [79].

Traumatic Brain Injury (TBI) can be classified into acute or chronic based on the acuity of the event. Acute traumatic events as a result of MVA (motor vehicle accidents), falls or sporting events mostly result in immediate clinical symptoms or signs that are often diagnosed with the help of neuroimaging immediately by the clinician. A concussion as a result of contact sports or accidents can result in clinical features which can range from mild dizziness to complete unconsciousness. But, it will exhibit no discernible defects in neuroimaging of the patient [80]. Therefore it becomes a clinical diagnosis rather than a radiological diagnosis. Many patients, especially sportspersons who are part of contact sports like boxing have exhibited persistent symptoms for hours to days to months after the insult [81]. The shearing forces in an acceleration/deceleration injury causes axonal damage which is often responsible for the clinical manifestations. The acute event leads to a primary insult to the central nervous system which can manifest as cerebral oedema or even intracranial haemorrhage. This in turn leads to increase in the intracranial pressure which in turn causes cerebral hypoperfusion and resultant tissue hypoxia [82].

Traumatic head injury is not an area which usually requires a biomarker evaluation from the Neurosurgeon's point of view for the purpose of acute care. Clinical decision making is often dependent on neuroimaging, which is a CT scan usually. But, recently, the role of biomarkers has become important in the decision making process of getting a neuroimaging. This is done with a view of reducing the radiation exposure to patients with mild head injury. These biomarkers are not usually present in the circulation and their presence generally indicates a breach of Blood– brain barrier. Some of the important biomarkers described in the recent literature are Glial fibrillary acidic protein (GFAP), calcium binding protein S100B, and tau protein [83]. The most important one in the horizon is S100 calcium binding protein B (S100B), which is a glial-specific protein which is primarily expressed by a subtype of mature astrocytes. It is elevated in neuronal damage which makes it a potential marker for CNS insults. In a study done on 512 adult patients with mild head injury (GCS 14–15, loss of consciousness and/or amnesia and no additional risk factors), the researchers used protein S100B levels as a clinical tool to determine whether the patient needed a CT scan [84]. They found that adult patients with mild head injury, without additional risk factors and with S100B levels of <0.10 mcg/L within 3 hours of injury, can safely be discharged from the hospital without

**41**

*Biomarkers of Diseases: Their Role in Emergency Medicine*

neuroimaging. A recent study done in Sweden tries to shed light on the utility of biomarkers like total tau, protein S100B and neuron-specific enolase in assessing

Once the primary insult is over, the brain can suffer from secondary injury as a result of sequelae from the initial insult. This can occur after days, weeks, months or years after the initial event. This results from biochemical cascades that are triggered by the primary event. These secondary events are mediated by free radicals and reactive oxygen species that are generated as a result of tissue hypoxia, reperfusion injury and neuroinflammation [86]. The change in membrane permeability which results from the initial injury causes increase in the calcium uptake or activation of NMDA and AMPA receptors by glutamate can cause mitochondrial dysfunction [87]. Thus the inflammatory response leads to further cellular disruption and the vicious cycle continues to damage the nervous homeostasis. These inflammatory insults in the nervous system give rise to various inflammatory markers which can be detected in the system. These biomarkers have been extensively studied and their usefulness in the clinical environment hotly debated. Even though many of these markers many of them show enough promise within the confines of the laboratory, they are yet to come to the bedside to be used by the clinician in daily practice. Many animal studies have demonstrated an increase in biochemical markers even after a single day after the insult and these can persist even after a month [88]. Acrolein, a post-traumatic neurotoxin can be quantified in brain tissue and can be elevated depending on the insult. A sustained upregulation has been demonstrated after brain injury, which suggests that it is a potential marker for neuronal injury

Proton Magnetic Resonance Spectroscopy (1H-MRS) is a technique which is able to measure the neurochemicals in the nervous system. This helps in detecting the neurotransmitters and metabolites, thereby quantifying the markers in various clinical conditions. Using this method, animal studies have found that endogenous antioxidants glutathione and ascorbic acid may be decreased up to 2 weeks following the insult [90]. F2-isoprostane, a lipid peroxidation by-product, has been found to be elevated on chronic brain injury or Chronic Traumatic Encephalopathy (CTE)

H-MRS), there

As detected by Proton Magnetic Resonance Spectroscopy (1

have been consistent results in detection of the following neurotransmitters in children with Autism Spectrum Disorder(ASD). There has been reduced levels of N-acetylaspartate (NAA), Creatine and phosphocreatine (Cr + PCr), Glutamine, Myo-Inositol and Choline containing compounds in the subcortical areas as well as cortical white matter and grey matter in varying degrees in children with ASD [91].

Neurodegenerative diseases can be extremely debilitating and distressing to not only the patient, but also the caregivers. Once diagnosed, the pathophysiological mechanisms can seldom be reversed and hence it becomes the source of social, financial and economic drain for not only families, but for the governmental health machinery itself. The social impact is huge, but the economic impact of these condi-

Hence, it becomes imperative that the diagnosis can be made as early as possible thereby mitigating the scenario. An earlier diagnosis will help the clinician as well as the caregivers to come to a plan for further care of the patient. It is also essential

*DOI: http://dx.doi.org/10.5772/intechopen.94509*

concussion injuries in sports persons [85].

and inflammation [89].

which manifests years after the insult(s).

**8.3 Neurodegenerative diseases**

tions cannot be ignored by any means.

**8.2 Traumatic brain injury - chronic Sequelae**

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

biomarker for AKI [76].

**8. Traumatic brain injury**

their acute counterparts [79].

**8.1 Traumatic brain injury—acute injury**

following tubular injury, has been found to be better than fractional excretion of sodium in differentiating between pre renal and intrinsic renal causes for renal failure [75]. Liver-type fatty acid binding protein (L-FABP) has also shown promise in animal studies for early detection of AKI and is being adapted as a possible

Traumatic brain injury is a major cause of morbidity and mortality across the world [77]. The reasons are several, but the lion's share of the incidents can be attributed to the high speed motor vehicle collisions. In addition to that, there are other contributing factors like falls as well as injuries due to contact sports. The acute injuries can be devastating and even fatal, but a huge number of those patients also develop chronic neurological sequelae which can be debilitating [78]. Given the complexity of the situation, the understanding of the mechanisms and pathophysiology of these chronic conditions are much less understood compared to

Traumatic Brain Injury (TBI) can be classified into acute or chronic based on the acuity of the event. Acute traumatic events as a result of MVA (motor vehicle accidents), falls or sporting events mostly result in immediate clinical symptoms or signs that are often diagnosed with the help of neuroimaging immediately by the clinician. A concussion as a result of contact sports or accidents can result in clinical features which can range from mild dizziness to complete unconsciousness. But, it will exhibit no discernible defects in neuroimaging of the patient [80]. Therefore it becomes a clinical diagnosis rather than a radiological diagnosis. Many patients, especially sportspersons who are part of contact sports like boxing have exhibited persistent symptoms for hours to days to months after the insult [81]. The shearing forces in an acceleration/deceleration injury causes axonal damage which is often responsible for the clinical manifestations. The acute event leads to a primary insult to the central nervous system which can manifest as cerebral oedema or even intracranial haemorrhage. This in turn leads to increase in the intracranial pressure which in turn causes cerebral hypoperfusion and resultant tissue hypoxia [82]. Traumatic head injury is not an area which usually requires a biomarker evaluation from the Neurosurgeon's point of view for the purpose of acute care. Clinical decision making is often dependent on neuroimaging, which is a CT scan usually. But, recently, the role of biomarkers has become important in the decision making process of getting a neuroimaging. This is done with a view of reducing the radiation exposure to patients with mild head injury. These biomarkers are not usually present in the circulation and their presence generally indicates a breach of Blood– brain barrier. Some of the important biomarkers described in the recent literature are Glial fibrillary acidic protein (GFAP), calcium binding protein S100B, and tau protein [83]. The most important one in the horizon is S100 calcium binding protein B (S100B), which is a glial-specific protein which is primarily expressed by a subtype of mature astrocytes. It is elevated in neuronal damage which makes it a potential marker for CNS insults. In a study done on 512 adult patients with mild head injury (GCS 14–15, loss of consciousness and/or amnesia and no additional risk factors), the researchers used protein S100B levels as a clinical tool to determine whether the patient needed a CT scan [84]. They found that adult patients with mild head injury, without additional risk factors and with S100B levels of <0.10 mcg/L within 3 hours of injury, can safely be discharged from the hospital without

**40**

neuroimaging. A recent study done in Sweden tries to shed light on the utility of biomarkers like total tau, protein S100B and neuron-specific enolase in assessing concussion injuries in sports persons [85].

#### **8.2 Traumatic brain injury - chronic Sequelae**

Once the primary insult is over, the brain can suffer from secondary injury as a result of sequelae from the initial insult. This can occur after days, weeks, months or years after the initial event. This results from biochemical cascades that are triggered by the primary event. These secondary events are mediated by free radicals and reactive oxygen species that are generated as a result of tissue hypoxia, reperfusion injury and neuroinflammation [86]. The change in membrane permeability which results from the initial injury causes increase in the calcium uptake or activation of NMDA and AMPA receptors by glutamate can cause mitochondrial dysfunction [87]. Thus the inflammatory response leads to further cellular disruption and the vicious cycle continues to damage the nervous homeostasis. These inflammatory insults in the nervous system give rise to various inflammatory markers which can be detected in the system. These biomarkers have been extensively studied and their usefulness in the clinical environment hotly debated. Even though many of these markers many of them show enough promise within the confines of the laboratory, they are yet to come to the bedside to be used by the clinician in daily practice.

Many animal studies have demonstrated an increase in biochemical markers even after a single day after the insult and these can persist even after a month [88]. Acrolein, a post-traumatic neurotoxin can be quantified in brain tissue and can be elevated depending on the insult. A sustained upregulation has been demonstrated after brain injury, which suggests that it is a potential marker for neuronal injury and inflammation [89].

Proton Magnetic Resonance Spectroscopy (1H-MRS) is a technique which is able to measure the neurochemicals in the nervous system. This helps in detecting the neurotransmitters and metabolites, thereby quantifying the markers in various clinical conditions. Using this method, animal studies have found that endogenous antioxidants glutathione and ascorbic acid may be decreased up to 2 weeks following the insult [90]. F2-isoprostane, a lipid peroxidation by-product, has been found to be elevated on chronic brain injury or Chronic Traumatic Encephalopathy (CTE) which manifests years after the insult(s).

As detected by Proton Magnetic Resonance Spectroscopy (1 H-MRS), there have been consistent results in detection of the following neurotransmitters in children with Autism Spectrum Disorder(ASD). There has been reduced levels of N-acetylaspartate (NAA), Creatine and phosphocreatine (Cr + PCr), Glutamine, Myo-Inositol and Choline containing compounds in the subcortical areas as well as cortical white matter and grey matter in varying degrees in children with ASD [91].

#### **8.3 Neurodegenerative diseases**

Neurodegenerative diseases can be extremely debilitating and distressing to not only the patient, but also the caregivers. Once diagnosed, the pathophysiological mechanisms can seldom be reversed and hence it becomes the source of social, financial and economic drain for not only families, but for the governmental health machinery itself. The social impact is huge, but the economic impact of these conditions cannot be ignored by any means.

Hence, it becomes imperative that the diagnosis can be made as early as possible thereby mitigating the scenario. An earlier diagnosis will help the clinician as well as the caregivers to come to a plan for further care of the patient. It is also essential

to look at the therapeutic interventions which can arrest or at least slow down the progression of the disease. This is where the role of biomarkers come into picture. A biomarker can help in diagnosing a particular condition early. Even if the diagnosis cannot be confirmed, at least the possibility of the condition can be ascertained and hence be prepared against. This is where a biomarker helps in fighting the diseases which for all practical purposes, have no definitive curative measures available by the bedside.

Biomarkers in neurodegenerative conditions can be classified as fluid and radiological markers. Since radiology is an integral and essential part of assessment of the neurological system in modern medicine, many techniques have been developed which can detect the presence of markers within the brain tissue which can point towards the presence or likelihood of a particular disease condition. On the other hand, there are fluid biomarkers that can be detected in the fluid that flows all over the brain - the cerebrospinal fluid (CSF). Before we look into those markers, it needs to be kept in mind that quite a few markers have gone to the lab in the hunt for that perfect biomarker. But, none of them has been successful enough to be brought to the bedside for daily clinical practice. Among the many neurodegenerative conditions, Alzheimer's disease has been the most extensively studied, because of its prevalence and impact on the society. But the biomarkers used in Alzheimer's disease do overlap with many other conditions as well due to similarities in pathophysiology.

Biomarkers in neurodegenerative conditions can be detected in blood and cerebrospinal fluid (CSF) and are clubbed together to be called as fluid markers. The predominant ones are Amyloid β peptides/oligomers and Tau peptides. Neurofilament light chain (NfL), which is found in myelinated axons, is an important marker which indicates white matter damage and points towards neurodegeneration [92]. Serial NFL sampling in patients at risk of developing Alzheimer's Disease, can be used to predict brain atrophy rates, cognitive impairment and disease progression [93]. These can be estimated by assays in blood as well as CSF. The major disadvantage these markers face is the low specificity and that hinders its utility in clinical practice. Another set of markers or radiological distinction characteristics can be detected in MRI and PET scans and are termed as radiological biomarkers. MRI utilises the various imaging modalities available to detect white matter lesions that are present in many of the neurodegenerative diseases. These include reduction in the volume, thickness, presence of microbleeds, myelin, iron, neuromelanin within the brain tissue in specific regions. PET targets various Tau lesions and Amyloid β aggregates in various regions within the neuronal system to detect the possibility of neurodegeneration. Apart from these, there are genetic biomarkers or specific genes that can predict the possibility of a neurodegenerative disease condition (**Table 4**).


**43**

*Biomarkers of Diseases: Their Role in Emergency Medicine*

It is a proteinopathy which is characterised by accumulation of Tau neurofibrillary tangles and extracellular Amyloid β plaques. These can be assessed by radiological methods as well as by looking at the fluid biomarkers. It has a prolonged pre-clinical phase where there Tau lesions can be found in the subcortical regions even before profound clinical symptoms appear [94]. Similarly amyloid β aggregates are initially found in the neocortical regions and later subcortical and cerebellar regions [95]. Plasma levels of Aβ42 has been found to be decreased compared to controls in a study [96]. The National Institute on Ageing and Alzheimer's Association Research Framework has defined AD by its underlying pathologic processes that can be documented by post-mortem examination or in vivo by biomarkers [97]. The biomarkers are classified into the 3 major groups- β amyloid deposition, pathologic tau, and neurodegeneration - AT(N). As and when newer biomarkers are discovered, they may be added into these categories. When it comes to therapeutics targeted based on these markers, there is still a long way to go to get these implemented in clinical practice. This may be due to the lack of direct correlation between the marker load with the clinical deterioration [98] as well as lack of

It is the most common presentation of synucleinopathy. The presentation can be similar to other similar conditions like Dementia with Lewy bodies. The typical feature can be aggregation of α-synuclein in the form of Lewy bodies which starts in the subcortical regions and later spread into the other regions [100]. Apart from the mutations in the genes, causality has been attributed to pesticide exposure as well as

This encompasses a spectrum of disease conditions characterised by vacuolation, gliosis and neuronal loss in the cortical regions of the frontal and temporal lobes. Features of Tau protein accumulation, TDP-43 or fused in sarcoma can be seen in this condition [102]. Since they share a similar pathophysiology, Amyotrophic lateral sclerosis (ALS) and other similar motor neuron diseases are

Huntington's disease is characterised by progressive neuronal loss and astrogliosis in the striatum along with prominent degeneration of the other cortical regions [103]. Similar to other disease conditions, there is limited data available to look at the therapeutic use of markers in HD also. Plasma levels of IL-8, TNF-α [104], and NfL may become useful in the coming years in this regard. A decrease in the uptake of phosphodiesterase-10 PET tracer in the strial region may become an important marker with regard to therapeutics in HD [105]. Diagnosis of Prion diseases like sporadic Creutzfeldt-Jakob disease (sCJD) is done by EEG, MRI or CSF based biomarkers with the use of real-time quaking-induced conversion (RT-QuIC) which

Since many of the neurodegenerative conditions present late in clinical practice, it is imperative that in order to tackle this menace, the scientific community will have to bring forth tools that can detect these early as well us much ahead of the phase of clinical presentation, even decades. It is in this regard, the biomarkers have a major role to play, whether they are radiological or fluid markers. Genetic markers are useful when we are dealing with hereditary conditions or familial variants of

*DOI: http://dx.doi.org/10.5772/intechopen.94509*

*8.3.1 Alzheimer's disease*

specificity [99].

*8.3.2 Parkinson's disease*

traumatic brain injury [101].

*8.3.3 Frontotemporal lobar degeneration*

considered to be part of the same spectrum.

is preferred over 14-3-3 protein detection [106].

#### **Table 4.**

*Genetic biomarkers for neurodegenerative diseases.*

#### *8.3.1 Alzheimer's disease*

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

to look at the therapeutic interventions which can arrest or at least slow down the progression of the disease. This is where the role of biomarkers come into picture. A biomarker can help in diagnosing a particular condition early. Even if the diagnosis cannot be confirmed, at least the possibility of the condition can be ascertained and hence be prepared against. This is where a biomarker helps in fighting the diseases which for all practical purposes, have no definitive curative measures available by

Biomarkers in neurodegenerative conditions can be classified as fluid and radiological markers. Since radiology is an integral and essential part of assessment of the neurological system in modern medicine, many techniques have been developed which can detect the presence of markers within the brain tissue which can point towards the presence or likelihood of a particular disease condition. On the other hand, there are fluid biomarkers that can be detected in the fluid that flows all over the brain - the cerebrospinal fluid (CSF). Before we look into those markers, it needs to be kept in mind that quite a few markers have gone to the lab in the hunt for that perfect biomarker. But, none of them has been successful enough to be brought to the bedside for daily clinical practice. Among the many neurodegenerative conditions, Alzheimer's disease has been the most extensively studied, because of its prevalence and impact on the society. But the biomarkers used in Alzheimer's disease do overlap with many other conditions as well due to similari-

Biomarkers in neurodegenerative conditions can be detected in blood and cerebrospinal fluid (CSF) and are clubbed together to be called as fluid markers. The predominant ones are Amyloid β peptides/oligomers and Tau peptides. Neurofilament light chain (NfL), which is found in myelinated axons, is an important marker which indicates white matter damage and points towards neurodegeneration [92]. Serial NFL sampling in patients at risk of developing Alzheimer's Disease, can be used to predict brain atrophy rates, cognitive impairment and disease progression [93]. These can be estimated by assays in blood as well as CSF. The major disadvantage these markers face is the low specificity and that hinders its utility in clinical practice. Another set of markers or radiological distinction characteristics can be detected in MRI and PET scans and are termed as radiological biomarkers. MRI utilises the various imaging modalities available to detect white matter lesions that are present in many of the neurodegenerative diseases. These include reduction in the volume, thickness, presence of microbleeds, myelin, iron, neuromelanin within the brain tissue in specific regions. PET targets various Tau lesions and Amyloid β aggregates in various regions within the neuronal system to detect the possibility of neurodegeneration. Apart from these, there are genetic biomarkers or specific genes that can predict the possibility of a neurodegenerative disease condition (**Table 4**).

**Gene(s) Disease syndrome associated**

*VCP, TARDBP, SOD1, FUS* Amyotrophic Lateral Sclerosis

*ApoE (ε4 allele), TREM2* AD- Risk factors

*HTT* Huntington's disease *SNCA, GBA* Parkinson's disease *PRNP* Prion Disease

*Genetic biomarkers for neurodegenerative diseases.*

*APP, PSEN1, PSEN2* Familial - Early-onset Alzheimer's disease

*MAPT, C9orf72, GRN* Behavioural-variant frontotemporal dementia

**42**

**Table 4.**

the bedside.

ties in pathophysiology.

It is a proteinopathy which is characterised by accumulation of Tau neurofibrillary tangles and extracellular Amyloid β plaques. These can be assessed by radiological methods as well as by looking at the fluid biomarkers. It has a prolonged pre-clinical phase where there Tau lesions can be found in the subcortical regions even before profound clinical symptoms appear [94]. Similarly amyloid β aggregates are initially found in the neocortical regions and later subcortical and cerebellar regions [95]. Plasma levels of Aβ42 has been found to be decreased compared to controls in a study [96]. The National Institute on Ageing and Alzheimer's Association Research Framework has defined AD by its underlying pathologic processes that can be documented by post-mortem examination or in vivo by biomarkers [97]. The biomarkers are classified into the 3 major groups- β amyloid deposition, pathologic tau, and neurodegeneration - AT(N). As and when newer biomarkers are discovered, they may be added into these categories. When it comes to therapeutics targeted based on these markers, there is still a long way to go to get these implemented in clinical practice. This may be due to the lack of direct correlation between the marker load with the clinical deterioration [98] as well as lack of specificity [99].

#### *8.3.2 Parkinson's disease*

It is the most common presentation of synucleinopathy. The presentation can be similar to other similar conditions like Dementia with Lewy bodies. The typical feature can be aggregation of α-synuclein in the form of Lewy bodies which starts in the subcortical regions and later spread into the other regions [100]. Apart from the mutations in the genes, causality has been attributed to pesticide exposure as well as traumatic brain injury [101].

#### *8.3.3 Frontotemporal lobar degeneration*

This encompasses a spectrum of disease conditions characterised by vacuolation, gliosis and neuronal loss in the cortical regions of the frontal and temporal lobes. Features of Tau protein accumulation, TDP-43 or fused in sarcoma can be seen in this condition [102]. Since they share a similar pathophysiology, Amyotrophic lateral sclerosis (ALS) and other similar motor neuron diseases are considered to be part of the same spectrum.

Huntington's disease is characterised by progressive neuronal loss and astrogliosis in the striatum along with prominent degeneration of the other cortical regions [103]. Similar to other disease conditions, there is limited data available to look at the therapeutic use of markers in HD also. Plasma levels of IL-8, TNF-α [104], and NfL may become useful in the coming years in this regard. A decrease in the uptake of phosphodiesterase-10 PET tracer in the strial region may become an important marker with regard to therapeutics in HD [105]. Diagnosis of Prion diseases like sporadic Creutzfeldt-Jakob disease (sCJD) is done by EEG, MRI or CSF based biomarkers with the use of real-time quaking-induced conversion (RT-QuIC) which is preferred over 14-3-3 protein detection [106].

Since many of the neurodegenerative conditions present late in clinical practice, it is imperative that in order to tackle this menace, the scientific community will have to bring forth tools that can detect these early as well us much ahead of the phase of clinical presentation, even decades. It is in this regard, the biomarkers have a major role to play, whether they are radiological or fluid markers. Genetic markers are useful when we are dealing with hereditary conditions or familial variants of

neurodegenerative conditions. Confirmation of the diagnosis is essential in determining the treatment and initiating it at the earliest for the best possible response.

#### **8.4 Newer modalities in the horizon**

Even though the field of biomarker evaluation is not very old, it is a fast changing world and newer techniques are being added to the mix quite often. A recent technique is the Multimer Detection System-Oligomeric Aβ, which looks at the tendency of plasma proteins to oligomerize [107]. Immune-infrared sensor assay to measure blood vessels for the propensity of the amyloid protein to form β-sheets has also been tried with some success as a potential biomarker [108]. Measurement of locus coeruleus, an early affected region, using special MRI techniques is also being explored as a potential target [109].

#### **9. Point of care tests (POCT)**

POCT refers to diagnostic evaluation at or near the site of patient care. A POC lab is not within the institutional central laboratory, but nearer to the patient care setting like ED or ICU. POC testing of biomarkers is increasingly becoming the norm at the moment. This has been touted as the next revolutionary step in faster healthcare delivery in the Emergency department. But, the challenge lies in transferring the resultant advantage to improvement in patient care and disposition. The benefit demonstrated on paper should be translated to better patient care by the bedside. If the results of the POC testing do not alter the course of management of the patient, it defeats the whole purpose of POCT.

#### **10. Future of biomarker use in emergency medicine**

Biomarkers are being increasingly used in the Emergency departments for faster patient disposition. Recently efforts are being undertaken to include an array of biomarkers in the triage scoring itself as a method of risk stratification of patients presenting to the ED [110]. In this study, the researchers included biomarkers from 3 distinct biological pathways for risk stratification of general medical patients presenting to the ED. The study included biomarkers of inflammation (proadrenomedullin [ProADM]), stress (copeptin) and infection (procalcitonin). They used a multi-marker approach to stratify patients and came to a conclusion that all the markers strongly predicted the risk of death, ICU admission and high initial triage priority, especially ProADM. It is a possibility that these methods may get introduced in clinical practice in the not so distant future.

#### **11. Conclusion**

Biomarkers are among the best tools in the hand of the clinicians at present. Each and every clinical condition has been tagged with a quantifiable biomarker which helps in faster clinical diagnosis as well as prognostication. Overall this would lead towards better healthcare delivery to the patient. But, the sheer vast numbers and volumes of various biomarkers in the research pipeline points towards a glaring fact. There is no single marker that can give a complete picture of the patient's clinical condition. There is no ideal biomarker. A scoring system based on multiple

**45**

*Biomarkers of Diseases: Their Role in Emergency Medicine*

markers would give a better picture than a single one. This accuracy always comes at a higher cost, which translates to more expensive healthcare delivery. There is dire requirement for better clinical validation among the various contenders in each disease process A biomarker based evaluation system, though more accurate, may not suit each and every healthcare facility, but needs to be tailored based on the adaptability and cost effectiveness suited to the society it caters to. Given the vast array of biomarker assays, clinicians should keep in mind that these should always be used as tools that compliment your clinical decision making process rather than

I would like to acknowledge the role of my wife, Aparna, who has been a pillar of support throughout the writing of this chapter just like she has been throughout our life together. I would also like to acknowledge the support given by my parents,

friends as well as colleagues in my department, who made me what I am.

*DOI: http://dx.doi.org/10.5772/intechopen.94509*

replacing the process itself.

**Acknowledgements**

**Conflict of interest**

**Abbreviations**

I have no conflict of interest to declare.

ACC American College of Cardiology ACS Acute Coronary Syndrome AST Aspartate aminotransferase BNP B type natriuretic peptide

CABG Coronary Artery Bypass Grafting

H-FABP Heart Fatty Acid Binding Protein

MR-proADM Mid-regional Proadrenomedullin

NACB National Academy of Clinical Biochemistry NGAL Neutrophil gelatinase-associated lipocalin NSTEMI Non ST Elevation Myocardial Infarction NT pro BNP N-Terminal pro B type natriuretic peptide PCI Percutaneous Coronary Intervention

IMA Ischemia modified albumin LDH Lactate dehydrogenase LVF Left Ventricular Failure MI Myocardial Infarction

COPD Chronic Obstructive Pulmonary Disease

CHF Congestive Heart Failure CNS Central Nervous System

CT Computed Tomography ECG Electrocardiogram ED Emergency Department

ICU Intensive Care Unit

POCT Point of Care Testing QC Quality Control

IL Interleukin

*Biomarkers of Diseases: Their Role in Emergency Medicine DOI: http://dx.doi.org/10.5772/intechopen.94509*

markers would give a better picture than a single one. This accuracy always comes at a higher cost, which translates to more expensive healthcare delivery. There is dire requirement for better clinical validation among the various contenders in each disease process A biomarker based evaluation system, though more accurate, may not suit each and every healthcare facility, but needs to be tailored based on the adaptability and cost effectiveness suited to the society it caters to. Given the vast array of biomarker assays, clinicians should keep in mind that these should always be used as tools that compliment your clinical decision making process rather than replacing the process itself.

#### **Acknowledgements**

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

**8.4 Newer modalities in the horizon**

explored as a potential target [109].

**9. Point of care tests (POCT)**

the patient, it defeats the whole purpose of POCT.

**10. Future of biomarker use in emergency medicine**

introduced in clinical practice in the not so distant future.

neurodegenerative conditions. Confirmation of the diagnosis is essential in determining the treatment and initiating it at the earliest for the best possible response.

Even though the field of biomarker evaluation is not very old, it is a fast changing world and newer techniques are being added to the mix quite often. A recent technique is the Multimer Detection System-Oligomeric Aβ, which looks at the tendency of plasma proteins to oligomerize [107]. Immune-infrared sensor assay to measure blood vessels for the propensity of the amyloid protein to form β-sheets has also been tried with some success as a potential biomarker [108]. Measurement of locus coeruleus, an early affected region, using special MRI techniques is also being

POCT refers to diagnostic evaluation at or near the site of patient care. A POC lab is not within the institutional central laboratory, but nearer to the patient care setting like ED or ICU. POC testing of biomarkers is increasingly becoming the norm at the moment. This has been touted as the next revolutionary step in faster healthcare delivery in the Emergency department. But, the challenge lies in transferring the resultant advantage to improvement in patient care and disposition. The benefit demonstrated on paper should be translated to better patient care by the bedside. If the results of the POC testing do not alter the course of management of

Biomarkers are being increasingly used in the Emergency departments for faster patient disposition. Recently efforts are being undertaken to include an array of biomarkers in the triage scoring itself as a method of risk stratification of patients presenting to the ED [110]. In this study, the researchers included biomarkers from 3 distinct biological pathways for risk stratification of general medical patients presenting to the ED. The study included biomarkers of inflammation (pro-

adrenomedullin [ProADM]), stress (copeptin) and infection (procalcitonin). They used a multi-marker approach to stratify patients and came to a conclusion that all the markers strongly predicted the risk of death, ICU admission and high initial triage priority, especially ProADM. It is a possibility that these methods may get

Biomarkers are among the best tools in the hand of the clinicians at present. Each and every clinical condition has been tagged with a quantifiable biomarker which helps in faster clinical diagnosis as well as prognostication. Overall this would lead towards better healthcare delivery to the patient. But, the sheer vast numbers and volumes of various biomarkers in the research pipeline points towards a glaring fact. There is no single marker that can give a complete picture of the patient's clinical condition. There is no ideal biomarker. A scoring system based on multiple

**44**

**11. Conclusion**

I would like to acknowledge the role of my wife, Aparna, who has been a pillar of support throughout the writing of this chapter just like she has been throughout our life together. I would also like to acknowledge the support given by my parents, friends as well as colleagues in my department, who made me what I am.

#### **Conflict of interest**

I have no conflict of interest to declare.

#### **Abbreviations**


STEMI ST Elevation Myocardial Infarction TNF Tumour Necrosis Factor TNF-alpha Tumour necrosis factor-alpha

#### **Author details**

Anoop T. Chakrapani Frimley Park Hospital, Frimley, United Kingdom

\*Address all correspondence to: dranooptc@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**47**

*Biomarkers of Diseases: Their Role in Emergency Medicine*

Cardiology/American Heart Association Task Force on Practice Guidelines. J Am

[8] Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, Caso P, Dudek D, Gielen S, Huber K, Ohman M, Petrie MC, Sonntag F, Uva MS, Storey RF, Wijns W, Zahger D: ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary

syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC).ESC Committee for Practice Guidelines. Eur Heart J. 2011 Dec;

32(23):2999-3054.

2012;**60**:1581-1598

[9] Diercks D.B, Peacock W.F,

Hollander J.E, Singer A.J, Birkhahn R, Shapiro N: Diagnostic accuracy of a point-of-care troponin I assay for acute myocardial infarction within 3 hours after presentation in early presenters to the emergency department with chest pain. Am Heart J 2012;163:74-80.e4

[10] Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Journal of the American College of Cardiology.

[11] Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med. Oct 19 2000;343(16):1139-1147

[12] Newby LK, Christenson RH,

Ohman EM, Armstrong PW, Thompson TD, Lee KL, et al. Value of serial troponin T measures for early and late risk stratification in patients with acute coronary syndromes. The GUSTO-IIa

Coll Cardiol. Aug 14 2007;**50**(7)

*DOI: http://dx.doi.org/10.5772/intechopen.94509*

[1] Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clinical Pharmacology and Therapeutics.

[2] Chakrapani AT. Biomarkers in emergency medicine. In: David S, editor. Clinical Pathways in Emergency Medicine. New Delhi: Springer; 2016. DOI: https://doi. org/10.1007/978-81-322-2710-6\_32

[3] Schuetz P, Aujesky D, Muller C, Muller B. Biomarker-guided

Weekly. 2015;**145**:w14079

personalised emergency medicine for all - hope for another hype? Swiss Medical

[4] Hollander JE, Than M, Mueller C. State-of-the-art evaluation of emergency department patients presenting with potential acute coronary syndromes. Circulation. *2016*;**134**:547-564. DOI: 10.1161/ CirculationAHA.116.021886

[5] Saenger AK, Beyrau R, Braun S, Cooray R, Dolci A, Freidank H, et al. Multicentre analytical evaluation of a high-sensitivity troponin T assay. Clinica Chimica Acta. 2011 Apr

11;**412**(9-10):748-754

2007;**53**:552-574

[6] Morrow DA, Cannon CP,

[7] Anderson JL, Adams CD,

Antman EM, Bridges CR, Califf RM, Casey DE Jr, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of

Jesse RL, et al. National Academy of Clinical Biochemistry Laboratory medicine practice guidelines: Clinical characteristics and utilization of biochemical markers in acute coronary syndromes. Clinical Chemistry.

**References**

2001;**69**(3):89-95

*Biomarkers of Diseases: Their Role in Emergency Medicine DOI: http://dx.doi.org/10.5772/intechopen.94509*

#### **References**

*Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches*

STEMI ST Elevation Myocardial Infarction

TNF Tumour Necrosis Factor TNF-alpha Tumour necrosis factor-alpha

**46**

**Author details**

Anoop T. Chakrapani

Frimley Park Hospital, Frimley, United Kingdom

provided the original work is properly cited.

\*Address all correspondence to: dranooptc@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

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**55**

Section 2

Alzheimer's Disease:

Molecular Mechanisms,

Biomarkers and Treatment

### Section 2
