**3. Aging effects in the olfactory system**

Age-associated impairment in the sense of olfaction has been well documented [19–23]. Akin to neurodegenerative pathology, a decline in olfactory acuity and olfactory dysfunction are common features of the normal aging process [24–27] detectable in over 50% individuals ranging in age from 65 to 80 years and almost in 75% of those above 80 years [24, 28–30]. This decline in olfactory function is detected using different kinds of tests such as psychophysical, psychophysiological and electrophysiological tests that determine odor detection, identification and discrimination, odor related physiological changes in cardiac and respiratory system as well as odor-event related potentials [29]. However, studies analyzing the mechanism of non-pathological, normal chronological age-related decline of olfactory acuity and impaired olfactory function are limited, despite the fact that deficits in the olfactory sense are considered as important symptom for early and differential diagnosis of neurodegenerative disorders [28]. At the anatomical level, the sense of olfaction is affected by age-associated ossification and closure of foramina of the cribriform plate [29, 31]. There is evidence of a quantitative reduction in the olfactory epithelium and its replacement by respiratory epithelium in normal subjects of the aging population which is evident in biopsies of the upper nasal septum [32]. It is now clearly evident that in the course of normal aging, suboptimal olfaction and olfactory dysfunction are associated with a number of anatomical and physiological features such as age-associated thinning of the olfactory neuroepithelium, altered cellular patterns and regional distribution of nuclei of olfactory sensory and sustentacular cells [29], reduction of mucosal metabolizing enzymes and sensory loss of olfactory sensory cells to various odorants along with a cumulative effect of environmental exposure to the olfactory epithelium [30]. An additional causative factor is the parallel loss of olfactory function in direct correlation with a clear age-associated decline in the volume of the olfactory bulb in adults of both genders [33–35]. Other than the olfactory bulb, a reduction in volume of AON, amygdala, hippocampus and piriform cortex in the limbic system contribute to a loss of olfaction due to their pivotal role in olfactory processing [36]. Testing the sensitivity and response of isolated sensory neurons to odorant mixtures indicates a loss of olfactory sensitivity and specificity in neurons derived from older subjects [37]. In older individuals, there is evidence of decreased beta-event related synchronization in response to certain pleasant odorants and, therefore, these individuals rated such odorants as less pleasant, thereby, denoting a decline in olfactory processing [38]. A change in olfactory perception represents subtle olfactory dysfunction that appears to precede a number neurodegenerative disorders and is presumed due to loss of synaptic function [39, 40]. Subsequent studies have shown that loss in olfactory sensitivity and perception is heterogeneous and appears to be more specific to heavier molecules [41]. Inherent allelic variations of brain

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*Neurological and Neuropsychiatric Disorders in Relation to Olfactory Dysfunction*

initial symptoms of neurological and neuropsychiatric disorders.

**4. Alzheimer's disease, dementia and olfactory deficits**

Olfactory deficiencies are evident in a number of neurodegenerative disorders such as AD, dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), MCI, PD and Huntington disease [40, 51, 56–59]. In an extensive two year study with six-monthly follow up, all MCI patients with lower range of olfaction score but no subjective smelling loss detected by standard UPSIT (University of Pennsylvania Smell Identification Test) developed AD. In contrast, in a control group of higher olfaction score, AD occurrence was nil [60]. A similar association of lower olfaction score with development of AD pathology was evident in a multiethnic community cohort with UPSIT test [61]. In a comparative OI analysis of FTD and AD patients with normal age matched control individuals, OI score of FTD patients differed significantly with control group, however, there was a close resemblance in OI pattern of FTD patients with OI in AD patients [62]. An analysis using Pocket Small Test as indicator of OI performance in AD patients and healthy young and age matched control group of individuals detected reduced OI in an older control group

derived neurotrophic factor (BDNF) also affect and add to age-dependent olfactory decline [29, 42]. A comparative research study quantifying heritability of odor identification and cognition detected a role of common genes in both olfaction and cognition. However, heritability of odor identification was lower in contrast to that of cognition [43]. Quantitative analysis of olfaction using odor identification (OI) scale in community dwelling subjects of age group 70–79 years reveals association of higher risk of dementia with poor OI score [44] and reduction in OI has been linked to advanced physiological brain aging as well as with a number of neurodegenerative diseases [45]. An aging cortical synapse in limbic structures has been considered as a hallmark of age-associated decline in cognition [46]. However, such studies are still preliminary for the olfactory bulb, despite evidence of growth factor dependent induction of synaptic strength in olfactory bulb cell layers during odor-dependent social transmission of food preference [47]. Chronological age adds to the impact of environmental exposure through living and working conditions on all physiological systems and their functions [48]. Experimental analysis indicates age-dependent accumulation of somatic mutations using both proliferative and non-proliferative cell types from human brain tissue [49]. It further indicates the probability of mutation accumulation in neurons. Genome-wide single somatic nucleotide variant analysis on DNA of 159 single neurons of 15 normal individuals with a wide age range (4 months to 82 years) and 9 individuals diagnosed with early onset of neurodegeneration revealed linear increase in both sets, indicating age-dependent accumulation of somatic mutations as significant factor affecting neurodegeneration [50]. Research studies of classical neurodegenerative disorders have proposed that the observed variability of olfactory dysfunction in diverse neurological and neuropsychiatric diseases could aid in early differential diagnosis of Alzheimer's disease (AD), Parkinson's disease (PD), mild cognitive impairment (MCI), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration known as FTLD-TDP43 [51–54]. A cell biology oriented experimental approach to detect the presence of neurodegenerationassociated proteins used nasal brushing to collect olfactory neurons from olfactory mucosa of normal subjects and detected four different characteristic proteins involved in neurodegenerative pathology: α-synuclein, transactive response DNA-binding protein 43 (TDP-43), hyperphosphorylated tau and β-amyloid proteins [55]. These findings have prompted an analysis of the parallel progression of loss of olfaction with onset of neurodegenerative pathology and/or decline in cognitive abilities as

*DOI: http://dx.doi.org/10.5772/intechopen.93888*

### *Neurological and Neuropsychiatric Disorders in Relation to Olfactory Dysfunction DOI: http://dx.doi.org/10.5772/intechopen.93888*

derived neurotrophic factor (BDNF) also affect and add to age-dependent olfactory decline [29, 42]. A comparative research study quantifying heritability of odor identification and cognition detected a role of common genes in both olfaction and cognition. However, heritability of odor identification was lower in contrast to that of cognition [43]. Quantitative analysis of olfaction using odor identification (OI) scale in community dwelling subjects of age group 70–79 years reveals association of higher risk of dementia with poor OI score [44] and reduction in OI has been linked to advanced physiological brain aging as well as with a number of neurodegenerative diseases [45]. An aging cortical synapse in limbic structures has been considered as a hallmark of age-associated decline in cognition [46]. However, such studies are still preliminary for the olfactory bulb, despite evidence of growth factor dependent induction of synaptic strength in olfactory bulb cell layers during odor-dependent social transmission of food preference [47]. Chronological age adds to the impact of environmental exposure through living and working conditions on all physiological systems and their functions [48]. Experimental analysis indicates age-dependent accumulation of somatic mutations using both proliferative and non-proliferative cell types from human brain tissue [49]. It further indicates the probability of mutation accumulation in neurons. Genome-wide single somatic nucleotide variant analysis on DNA of 159 single neurons of 15 normal individuals with a wide age range (4 months to 82 years) and 9 individuals diagnosed with early onset of neurodegeneration revealed linear increase in both sets, indicating age-dependent accumulation of somatic mutations as significant factor affecting neurodegeneration [50]. Research studies of classical neurodegenerative disorders have proposed that the observed variability of olfactory dysfunction in diverse neurological and neuropsychiatric diseases could aid in early differential diagnosis of Alzheimer's disease (AD), Parkinson's disease (PD), mild cognitive impairment (MCI), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration known as FTLD-TDP43 [51–54]. A cell biology oriented experimental approach to detect the presence of neurodegenerationassociated proteins used nasal brushing to collect olfactory neurons from olfactory mucosa of normal subjects and detected four different characteristic proteins involved in neurodegenerative pathology: α-synuclein, transactive response DNA-binding protein 43 (TDP-43), hyperphosphorylated tau and β-amyloid proteins [55]. These findings have prompted an analysis of the parallel progression of loss of olfaction with onset of neurodegenerative pathology and/or decline in cognitive abilities as initial symptoms of neurological and neuropsychiatric disorders.
