**2. Traumatic brain injury, neuroinflammation, and its link with Alzheimer's disease**

Postmortem studies in human populations have shown microglia activation many years after TBI. Innate activation of microglia generally leads to amyloidogenic APP processing and the generation of Aβ plaques. Aβ plaques formed during the initial weeks after injury may regress with time. In this case, a continuously

**137**

**Table 1.**

*Neuropathology of Traumatic Brain Injury and Its Role in the Development of Alzheimer's Disease*

Compelling epidemiological evidence indicates that moderate and severe TBI is associated with increased risk of development of progressive disorders of cognitive impairment leading to dementia or AD [15, 26–28]. Therefore, TBI is considered as a strong epigenetic risk factor for AD [29, 30]. Aβ plaques, a hallmark of AD, are found in 30% of patients who do not survive TBI [13]. A history of TBI is a strong risk factor for AD, although there remains a lack of clear consensus around this topic since a few epidemiological studies have not uncovered such an association [31]. However, there exists strong evidence linking TBI to AD-related pathologies [32, 33]. Moderate and severe head injury increased the risk of AD for 2.3 and 4.5 times, respectively [30]. Although there is clinical evidence linking TBI and AD pathologies, there is an important lack of knowledge specific to the mechanisms

In follow up studies, an increased incidence of head trauma in those with AD has been found only in males, not in females, and the risk of developing AD after TBI focused on injury severity [4, 25]. In studies where these criteria are more broadly defined, we can analyze the relative risk from head trauma of differing severity; it has been suggested [8] that a prior history of TBI accelerates the onset of AD and that the higher the incidence of severe the injury, the higher the risk of developing AD. Roberts et al. provided one of the first studies to closely examine Aβ deposition after TBI [34] (**Table 1**). Data from subsequent studies have suggested that even a single moderate to severe TBI event is a significant risk factor for the later onset of

However, it remains unknown whether patients with prior brain damage instead develop a distinct clinical phenotype of dementia, different from that of the typical AD. Examination of human brain samples confirmed that TBI

16 Severe TBI 38% Aβ deposits, diffuse plaques 18 days

20% (under 40) Aβ plaques

30% Aβ diffuse deposits

tau (PHF-1) axons

Tau-positive astrocytes

18 TBI Aβ42 peptide, axonal damage, APP deposits,

18 Severe TBI 33% Aβ deposits, Aβ42 peptide, diffuse plaques

70% (60–80 age) Aβ plaques (50% controls)

80% neuronal/glial intracellular Aβ peptides

neurofilament, β-secretase, g-secretase

11 TBI Tau-positive oligodendrocytes 2 h [107]

**Pathology associated, postmortem tissue Time** 

**after injury**

of TBI

Several times

Several times

4 h–5 days

2–19 h [36]

**References**

[34]

[96]

[97]

[22]

renewed store of Aβ in degenerating axons can be kept in check through degeneration by endogenous mediators or anti-inflammatory phagocytic microglia, or macrophages. A deficiency in microglia clearance of Aβ could possibly account for this balance shift, especially since aging microglia are known to have a reduction in phagocytic capacity and this is also observed in AD, the most common age-related

*DOI: http://dx.doi.org/10.5772/intechopen.81945*

dementia [13].

driving this link.

dementia or AD [35, 36].

**Category of TBI**

152 Severe TBI 30% Aβ diffuse deposits

7 TBI Aβ42 peptide

*Patients with TBI and associated AD pathology.*

**Patients (N)**

*Neuropathology of Traumatic Brain Injury and Its Role in the Development of Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.81945*

renewed store of Aβ in degenerating axons can be kept in check through degeneration by endogenous mediators or anti-inflammatory phagocytic microglia, or macrophages. A deficiency in microglia clearance of Aβ could possibly account for this balance shift, especially since aging microglia are known to have a reduction in phagocytic capacity and this is also observed in AD, the most common age-related dementia [13].

Compelling epidemiological evidence indicates that moderate and severe TBI is associated with increased risk of development of progressive disorders of cognitive impairment leading to dementia or AD [15, 26–28]. Therefore, TBI is considered as a strong epigenetic risk factor for AD [29, 30]. Aβ plaques, a hallmark of AD, are found in 30% of patients who do not survive TBI [13]. A history of TBI is a strong risk factor for AD, although there remains a lack of clear consensus around this topic since a few epidemiological studies have not uncovered such an association [31]. However, there exists strong evidence linking TBI to AD-related pathologies [32, 33]. Moderate and severe head injury increased the risk of AD for 2.3 and 4.5 times, respectively [30]. Although there is clinical evidence linking TBI and AD pathologies, there is an important lack of knowledge specific to the mechanisms driving this link.

In follow up studies, an increased incidence of head trauma in those with AD has been found only in males, not in females, and the risk of developing AD after TBI focused on injury severity [4, 25]. In studies where these criteria are more broadly defined, we can analyze the relative risk from head trauma of differing severity; it has been suggested [8] that a prior history of TBI accelerates the onset of AD and that the higher the incidence of severe the injury, the higher the risk of developing AD. Roberts et al. provided one of the first studies to closely examine Aβ deposition after TBI [34] (**Table 1**). Data from subsequent studies have suggested that even a single moderate to severe TBI event is a significant risk factor for the later onset of dementia or AD [35, 36].

However, it remains unknown whether patients with prior brain damage instead develop a distinct clinical phenotype of dementia, different from that of the typical AD. Examination of human brain samples confirmed that TBI


**Table 1.**

*Patients with TBI and associated AD pathology.*

*Amyloid Diseases*

cians to treat patients with TBI are minimal*.*

both TBI survivors and animal models of brain injury.

to induce dementia [18].

factors [23–25].

animal models and human studies.

**Alzheimer's disease**

Functional deficits caused by TBI result from an initial impact and secondary damage that continue to develop over time and provide a therapeutic window for treatment to prevent or ameliorate many of the damaging consequences of injury [6]. While single compounds have been reported to be effective for short periods in standardized rodent models of TBI, therapeutic tools currently available to clini-

The neuroinflammatory cascade following TBI contributes to neurodegeneration and death through the cumulative action of multiple damaging processes [7]. TBI is one of the most consistent candidates for initiating the molecular cascades that result in neurodegenerative diseases, such as Parkinson's disease (PD) or amyotrophic lateral sclerosis (ALS) [8–11]. Notably, there exists a strong epidemiological relationship between the occurrence of TBI and the development of Alzheimer's disease (AD) later in life [12–15]. The link between TBI and AD is strengthened through the identification of acute and chronic AD-like pathologies in the brain in

AD is a progressive neurodegenerative disease, which can only be fully diagnosed at autopsy. It is characterized, histologically, by the presence of amyloid plaques and intracellular neurofibrillary tangles (NFT) in the brain [16]. The amyloid plaques consist of aggregated proteinaceous material, a significant component of amyloid β (Aβ). The tangles are composed of paired helical filaments (PHF) of the microtubule-associated phosphoprotein tau [16, 17]. In this chapter, I will describe the main pathological similarities, and differences, between TBI and AD. Although the evidence suggests that TBI is a risk factor for dementia, very little is known about what type, frequency, or severity of trauma is necessary

A chronic disease process is initiated after TBI, known as the secondary injury cascade, and as part of this process, neuroinflammation, neuronal loss, or the production, aggregation and clearance of Aβ peptides occurs [19]. Several of these pathophysiological features have been characterized in patients with AD with similar neuropathology. Furthermore, epidemiological studies have shown how repetitive injury, or a single mild, moderate, or severe TBI, can cause a wide range of proteinopathies [20], and likely contribute to the later onset of debilitating neurodegenerative diseases. Indeed, the human pathology of survival from TBI is best described as a "polypathology", featuring Aβ, tau, and TDP-43 pathologies, together with white matter degradation, neuronal loss, and neuroinflammation [21]. There exist many pathological features common to both acute brain injury and AD, including Aβ deposition, tau phosphorylation, neurite degeneration, synapse loss and microgliosis [22]. Besides, the susceptibility of the patient may be predetermined by multiple factors such as age, sex and the interplay of several genetic

The purpose of this chapter is to discuss the neuropathology and genetic risk factors associated with TBI that may collectively shed some light on the risk of developing dementia or AD following head trauma, as well as possible treatments in

Postmortem studies in human populations have shown microglia activation many years after TBI. Innate activation of microglia generally leads to amyloidogenic APP processing and the generation of Aβ plaques. Aβ plaques formed during the initial weeks after injury may regress with time. In this case, a continuously

**2. Traumatic brain injury, neuroinflammation, and its link with** 

**136**


**139**

**Table 2.**

*Neuropathology of Traumatic Brain Injury and Its Role in the Development of Alzheimer's Disease*

**Time postinjury**

1, 3 and 21 days

1 h, 2 h, 48 h, 1 week, or 2 weeks

2 days–1 year

months

6 h–10 days

Increase cleaved Tau 6–168 h Cortex [116]

3–10 days

3h, 3 days, 6 months

2–24 h Interstitial fluid

3 months Hippocampus [100]

11 days Cortex [113]

Cortex and thalamus

Cortex, striatum, cingulum, and hippocampus

White matter, cortex and thalamus

White matter, cortex

White matter and cortex

Subcortical white matter

White matter [44]

**Brain regions References**

[112]

[94]

[95]

[114]

[115]

[117]

[65]

**Pathology associated** 

Increase Aβ baseline in transgenic and decrease Aβ after injury

56% apoE4:PDAPP: increase Aβ deposition and amyloid plaques 20% apoE3:PDAPP: increase Aβ deposition and amyloid plaques

ApoE4 Die or poorer outcomes than apoE3

APP accumulation in damaged axons No accumulating Aβ observed intracellularly

APP accumulation in damaged axons No accumulating Aβ observed intracellularly

or in plaques

or in plaques

Reduction of Aβ accumulated in damage axons according with severity of injury

Increase pTau 6

APP and Aβ identified in damaged axons No Aβ plaques observed

APP and Aβ accumulation Diffuse Aβ plaques Increase total Tau

Aβ, APP, BACE and presenilin-1 accumulation in damaged axons Diffuse Aβ plaques

**to AD**

processes were the principal driver of accumulation of Aβ peptides in swollen axons shortly after TBI, which persisted for years following the initial trauma [13]. In addition to such clinical studies, there exist multiple types of brain injuries in different animal models of AD. These animal models have been used to examine the formation, aggregation, and accumulation of Aβ after injury; almost

all of these are demonstrated an elevation in Aβ levels after TBI (**Table 2**).

*DOI: http://dx.doi.org/10.5772/intechopen.81945*

**injury model**

Controlled cortical impact

Controlled cortical impact

Closed head injury

Weight drop (open skull)

Lateral fluid percussion

Lateral fluid percussion

Lateral fluid percussion

Weight drop (open skull)

Controlled cortical impact

acceleration (model of DAI)

Rotational acceleration (model of DAI)

*Animal studies on TBI and associated AD pathology.*

Swine Rotational

**Animals Animal** 

Mouse (PDAPP) and Tg2576

Mouse (PDAPP) crossed with apoE3 and apoE4

Mouse (ApoE3/ ApoE4), or ApoE null mice

Rat (Sprague Dawley)


*Neuropathology of Traumatic Brain Injury and Its Role in the Development of Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.81945*

#### **Table 2.**

*Amyloid Diseases*

Mouse (Tg2576)

Mouse (wild-type)

Mouse (3xTg-AD)

Mouse (3xTg-AD)

Mouse (h-Tau)

Mouse (APP-YAC)

Mouse (APPNLh/ NLh)

Mouse (BACE knock-out)

Mouse (PDAPP)

**Animals Animal** 

**injury model**

Controlled cortical impact

Controlled cortical impact

Repetitive mild TBI

Controlled cortical impact

Repetitive mTBI

Controlled cortical impact

Controlled cortical impact

Controlled cortical impact

Controlled cortical impact

Controlled cortical impact

Controlled cortical impact

Controlled cortical impact

Controlled cortical impact

**Pathology associated** 

Increase Aβ40 and Aβ42

Increase Aβ40 oligomers and Aβ42 levels Increase pTau

Increase Aβ40 levels Increase total Tau and

Decrease Aβ40 levels, but not Aβ42

Decrease of caspase-3 by administration of a pan-caspase inhibitor Reduction of caspasecleaved APP, Aβ40 and

Improved histological

Administration of simvastatin resulted in decreased Aβ levels Decreased hippocampal

Behavioural outcome

Increase Aβ40 and Aβ42

Decrease in Aβ plaques 2, 5

Increase neuronal death and memory impairment No Aβ plaques

levels

**Time postinjury**

9–16 weeks

Increase pTau 1 day Fimbria [93]

1–24 h and 7 days

Increase pTau 21 d Cortex [77]

24 h 14 days **Brain regions References**

Cortex [92]

Cortex [76, 108]

Cortex [43]

3 days Hippocampus [37]

1 week Cortex [109]

3 h Hippocampus [110]

hippocampus

Cortex and hippocampus

Cortex and Hippocampus [19]

[90]

[91]

1–7 days Cortex and

Increase Aβ40 23 days Hippocampus [111]

2 h–2 months

and 8 months

Decrease in Aβ plaques 16 weeks Hippocampus [103]

**to AD**

levels

pTau

Aβ40

outcome

tissue loss

improved

Increase Aβ40 Improved histological, behavioural outcomes following injury Administration of a γ-secretase inhibitor (DAPT) in non-transgenic mice improved outcomes

**138**

*Animal studies on TBI and associated AD pathology.*

processes were the principal driver of accumulation of Aβ peptides in swollen axons shortly after TBI, which persisted for years following the initial trauma [13]. In addition to such clinical studies, there exist multiple types of brain injuries in different animal models of AD. These animal models have been used to examine the formation, aggregation, and accumulation of Aβ after injury; almost all of these are demonstrated an elevation in Aβ levels after TBI (**Table 2**).
