**7. Drugs**

*Sino-Nasal and Olfactory System Disorders*

pathology [64] as well as prodromal symptom of AD [65].

**5. Parkinson's disease and olfactory impairment**

the progression of neurodegenerative pathology of PD [78].

**6. Mood and communication disorders**

diagnostic accuracy for PD distinguishing it from PD mimics [80].

Dementia associated with PD, known as Parkinson's disease dementia (PDD), is one of the most debilitating symptoms of PD and is difficult to predict during early stages of the disease. A research study using OSIT-J (odor stick identification test for Japanese) shows over 18 fold increase in risk of dementia for PD patients with severe hyposmia [79]. Indeed OI has emerged as a reliable tool for providing excellent

In addition to aging, neurodegenerative and psychiatric conditions, olfactory deficits including low OI appear as characteristic feature of mild to severe major

than in a younger control group, and AD patients had even reduced OI compared to their age matched control group [27]. At the cellular level, a characteristic neuropathological feature of AD is the appearance of neurofibrillary tangles consisting of hyperphosphorylated tau protein [63]. In relation to olfactory dysfunction, the two key hallmarks of AD neuropathology are the detection of amyloid-beta (Aβ) and hyperphosphorylated tau protein in the olfactory system; both have been detected together with impaired olfaction much before a clinical presentation of the disease [57]. An analysis assessing OI as indicator of presymptomatic AD pathogenesis in cognitively normal aged individuals shows an association of reduced OI with lower cognitive score and older age as well as increased ratio of total tau protein to phosphorylated tau protein in cerebrospinal fluid [64]. Therefore, at the behavioral level, diminished OI has emerged as a practical and affordable biomarker of AD

A major factor leading to neurodegenerative PD pathology is the loss of dopaminergic neurons from the substantia nigra, resulting in slow but substantial loss of dopamine that eventually leads to many clinical motor symptoms such as bradykinesia, rigidity, tremor, instability of posture and decline of cognitive function [66]. The olfactory system is a severely affected non-motor system in PD patients with early appearance of olfactory dysfunction that remains independent of progressive PD symptoms, their duration and treatment [67]. Additional research studies have indicated association of olfactory dysfunction with PD for over three decades [25, 68]. Olfactory dysfunction, including hyposmia and decline in olfactory acuity, has been established as one of the earliest features of PD. These are detectable in approximately 90% of early stage PD patients, where they may precede the onset of the motor symptoms by a margin of years [69–73]. Hyposmia and progressive olfactory decline in PD patients have been attributed to central olfactory processing, since the olfactory epithelium biopsy samples of PD patients were normal [74]. Subsequent MRI studies indicate a varying degree of reduction in olfactory bulb volume and depth of olfactory sulcus in PD patients than in normal control individuals. These studies indicate an association of anatomical changes with altered olfaction in PD patients [75]. Lewy bodies and Lewy neurites comprised of α-synuclein are histological hallmarks of neurodegenerative pathology in PD [76]. The olfactory bulb and lower brainstem have been considered as the induction site for the onset of histopathological features comprising of both Lew bodies and Lewy neurites [73, 77]. Along with the peripheral nervous system, such histological aberrations also begin to appear in gut nerve plexa and the olfactory bulb, thereby indicating participation of olfactory bulb cell layers in

**102**

The regenerative ability of olfactory epithelium has made it an attractive target for exploring and evaluating therapeutic strategies to distinguish and treat drug induced olfactory disorders [96]. More than 86% of cancer patients of wide age range display smell and taste disorders that persist even after completion of chemotherapy for cancer [97]. However, not every therapeutic chemotherapy drugs has negative impact on olfactory acuity (personal communication). *Bacopa monnieri* extracts administration reverses bulbectomy induced neurochemical and histological alterations in mouse model of depression; cognition dysfunction is reversed through a mechanism that enhances synaptic plasticity related signaling, BDNF transcription and protection of cholinergic systems [98].

The flavonoid Naringenin functions as antidepressant by restoring serotonin and noradrenaline levels in brain tissue [99]. In bulbectomized mice, two weeks of Naringenin treatment ameliorated depression like behavioral alterations, decreased elevated pro-inflammatory cytokines and increased levels of BDNF and serotonin in hippocampus and cortex [100].

Depression with psychomotor agitation (PMA) is a putative psychiatric disorder associated with substance dependence, specifically, opioids. It remains unaffected by drug induced major depressive episodes indicating complex interplay of therapeutic drugs in treating depression [101].

The AON, a key area of the olfactory system, shows accumulation of characteristic neuropathological markers such as hyperphosphorylated tau, α-synuclein and β-amyloid proteins at the earliest stages of AD in a Somatostatin (SST) expressing subpopulation of interneurons. In the limbic system, the same accumulation is evident in same subpopulation of interneurons [102]. However, SST is unequally involved in two predominant neurodegenerative disorders with a very strong involvement in AD pathology but quite weaker participation in PD. In early stages of AD, SST is reduced in olfactory areas whereas it is preserved in non-demented PD cases [102]. Further analysis of SST related olfactory deficiencies will pave the way of SST based therapeutic approaches.

Olfactory dysfunctions unrelated to blocked nasal passages are present in a significant percentage of Covid-19 patients [103–105]. Altered expression of SARS-CoV-2 entry genes in supporting cells of the olfactory epithelium has been proposed as a mechanism underlying COVID-19-associated anosmia [106, 107].

## **8. Discussion and conclusions**

The mammalian olfactory bulb has been termed the "brain inside the brain", due to the presence of sensory inputs, neuronal lamination and contribution of new neural elements throughout the lifetime [108]. It plays a pivotal role in olfactory processing [8, 109]. In addition to AD, PD, MCI and depressive disorders, inadequate and/or improper olfactory function together with impaired olfactory processing exist in many other neurodegenerative and neuropsychiatric disorders. For instance, in the case of multiple sclerosis (MS), prevalence of olfactory dysfunction ranges from 20 to 45% of the MS population. However, the mechanism of loss of olfaction remains unknown, except for decreased olfactory bulb and brain volume [110, 111]. In patients with a diagnosis of a behavioral FTD variant, OI and odor discrimination did not show any difference from control cases, but there was a significant difference in the odor association test. It has been attributed to impaired olfactory processing [112]. Within the healthy population, impulsive tendencies exhibit some link to olfactory defects [113]. Narcolepsy is associated with hypocretin deficiency of the limbic system. Despite genetic predisposition, it has been postulated to increase by environmental substances that may access the olfactory bulb, triggering neuroinflammation and induce neurodegeneration [114].

Single cell transcriptome analysis during mouse olfactory neurogenesis in early development reveals that expression of olfactory receptor (OR) genes becomes progressively restricted to one gene per neuron in each mature neuron instead of several receptor genes that express in immature neurons [115, 116]. Expression of a single OR allele in olfactory sensory neurons is the outcome of coalescence of multiple intergenic enhancers to a multi-chromosomal hub that allows the expression of a single OR allele while the remaining OR genes converge into few heterochromatic compartments leading to effective transcriptional silencing [117]. Age associated chromosomal breakage and DNA damage lead to an increase in markers of genome instability [118] and requires many layers of regulatory functions such as inducing senescence [48], reducing accumulation of DNA damage and enhancing DNA repair pathways [119]. Genome protection from DNA damage to minimize

**105**

USA

**Author details**

approaches [122].

**Acknowledgements**

**Conflict of interest**

tion of this chapter.

Naina Bhatia-Dey and Thomas Heinbockel\*

provided the original work is properly cited.

\*Address all correspondence to: theinbockel@howard.edu

Department of Anatomy, Howard University College of Medicine, Washington, DC,

© 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,

*Neurological and Neuropsychiatric Disorders in Relation to Olfactory Dysfunction*

OI, olfactory dysfunction and onset of neurodegenerative pathology.

aging effects is also an effective strategy to minimize risk factor for neurodegeneration [119]. This is likely to retain olfactory acuity and ability based on the model

Single cell RNA sequencing reveals differentially regulated and expressed genes as neuronal markers specific to adult born interneurons that may serve as molecular markers for synapse formation, synapse maintenance, and neural plasticity of adult brain circuits [120]. Research studies analyzing functional mechanisms of these markers and their regulation are likely to facilitate the understanding of decreased

Olfactory ensheathing glial cells help olfactory bulb neurons to connect with both the peripheral and central nervous system, and, therefore, they have been widely used as therapeutic tools for neural repair and olfactory/neural regeneration for injuries and neurodegenerative pathological conditions [121]. Indeed, the olfactory bulb has emerged as an attractive target for many novel therapeutic

Another fast growing research topic addresses the role of microRNAs in regulating genes that participate in cognition and neurodegeneration [123–125] and olfactory acuity. Such findings would also add to a better understanding of the relationship between olfactory dysfunction and neurodegenerative pathologies. Targeting synaptic deficits in AD patients and aging individuals by improving synaptic plasticity though alteration of structural deficits in dendritic spines through microRNA mediated regulatory pathways could be an effective and novel therapeutic strategy for AD as well as other neurodegenerative disorders [126].

This work was supported in part by grants from the National Science Foundation

The authors declare that there is no conflict of interests regarding the publica-

(NSF IOS-1355034) and the **Charles and Mary** Latham Trust Fund.

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

proposed by Bashkirova and Lomvardas [117].

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

aging effects is also an effective strategy to minimize risk factor for neurodegeneration [119]. This is likely to retain olfactory acuity and ability based on the model proposed by Bashkirova and Lomvardas [117].

Single cell RNA sequencing reveals differentially regulated and expressed genes as neuronal markers specific to adult born interneurons that may serve as molecular markers for synapse formation, synapse maintenance, and neural plasticity of adult brain circuits [120]. Research studies analyzing functional mechanisms of these markers and their regulation are likely to facilitate the understanding of decreased OI, olfactory dysfunction and onset of neurodegenerative pathology.

Olfactory ensheathing glial cells help olfactory bulb neurons to connect with both the peripheral and central nervous system, and, therefore, they have been widely used as therapeutic tools for neural repair and olfactory/neural regeneration for injuries and neurodegenerative pathological conditions [121]. Indeed, the olfactory bulb has emerged as an attractive target for many novel therapeutic approaches [122].

Another fast growing research topic addresses the role of microRNAs in regulating genes that participate in cognition and neurodegeneration [123–125] and olfactory acuity. Such findings would also add to a better understanding of the relationship between olfactory dysfunction and neurodegenerative pathologies.

Targeting synaptic deficits in AD patients and aging individuals by improving synaptic plasticity though alteration of structural deficits in dendritic spines through microRNA mediated regulatory pathways could be an effective and novel therapeutic strategy for AD as well as other neurodegenerative disorders [126].
