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Abstract Decreased olfactory function is very common in the older population, being present in >50% of individuals aged between 65 and 80 years and in 62-80% of those >80 years of age. Smell dysfunction significantly influences physical well-being, quality of life, nutritional status as well as everyday safety and is associated with increased mortality. Multiple factors contribute to age-related olfactory sensory loss, including nasal engorgement, cumulative damage of the olfactory epithelium from environmental insults, a reduction in mucosal metabolizing enzymes, sensory loss of receptor cells to odorants, and changes in neurotransmitter and neuromodulator systems. In addition, structural and functional abnormalities of the olfactory epithelium, olfactory bulb, central olfactory cortex, and basic olfactory circuitry, which are related to the neuronal expression of aberrant proteins in these areas, may result in olfactory sensory impairment in aging and neurodegenerative diseases. Impaired odour identification is associated with a decrease in cognitive abilities and memory decline. A reduction in the sense of smell is considered to potentially represent an early and important warning of neurodegenerative disorders, particularly of Parkinson's disease and Alzheimer's disease, and, in mild cognitive impairment, olfactory impairment may herald progression to dementia. Further investigations of the potential role of olfactory dysfunction in the early diagnosis and treatment of neurodegenerative diseases are warranted.

The recent pandemic outbreak of coronavirus is pathogenic and a highly transmittable viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). In this time of ongoing pandemic, many emerging reports suggested that the SARS-CoV-2 has inimical effects on neurological functions, and even causes serious neurological damage. The neurological symptoms associated with COVID-19 include headache, dizziness, depression, anosmia, encephalitis, stroke, epileptic seizures, and Guillain-Barre syndrome along with many others. The involvement of the CNS may be related with poor prognosis and disease worsening. Here, we review the evidence of nervous system involvement and currently known neurological manifestations in COVID-19 infections caused by SARS-CoV-2. We prioritize the 332 human targets of SARS-CoV-2 according to their association with brain-related disease and identified 73 candidate genes. We prioritize these 73 genes according to their spatio-temporal expression in the different regions of brain and also through evolutionary intolerance analysis. The prioritized genes could be considered potential indicators of COVID-19-associated neurological symptoms and thus act as a possible therapeutic target for the prevention and treatment of CNS manifestations associated with COVID-19 patients.

Abstract Background and Hypothesis Persistent auditory verbal hallucinations (pAVHs) and olfactory identification impairment are common in schizophrenia (SCZ), but the neuroimaging mechanisms underlying both pAVHs and olfactory identification impairment are unclear. This study aimed to investigate whether pAVHs and olfactory identification impairment in SCZ patients are associated with changes in cortical thickness. Study Design In this study, cortical thickness was investigated in 78 SCZ patients with pAVHs (pAVH group), 58 SCZ patients without AVHs (non-AVH group), and 83 healthy controls (HC group) using 3T magnetic resonance imaging. The severity of pAVHs was assessed by the Auditory Hallucination Rating Scale. Olfactory identification deficits were assessed using the Odor Stick Identification Test for Japanese (OSIT-J). In addition, the relationship between the severity of pAVHs and olfactory identification disorder and cortical thickness abnormalities was determined. Study Results Significant reductions in cortical thickness were observed in the right medial orbital sulcus (olfactory sulcus) and right orbital sulcus (H-shaped sulcus) in the pAVH group compared to both the non-AVH and HC groups (P < .003, Bonferroni correction). Furthermore, the severity of pAVHs was found to be negatively correlated with the reduction in cortical thickness in the olfactory sulcus and H-shaped sulcus. Additionally, a decrease in cortical thickness in the olfactory sulcus showed a positive correlation with the OSIT-J scores (P < .05, false discovery rate correction). Conclusions Cortical thickness abnormalities in the olfactory sulcus may be a common neuroimaging mechanism for pAVHs and olfactory identification deficits in SCZ patients.

Parkinson disease (PD) is a neurodegenerative disorder characterized by massive loss of midbrain dopaminergic neurons. Whereas onset of motor impairments reflects a rather advanced stage of the disorder, hyposmia often marks the beginning of the disease. Little is known about the role of the nigro-striatal system in olfaction under physiological conditions and the anatomical basis of hyposmia in PD. Yet, the early occurrence of olfactory dysfunction implies that pathogens such as environmental toxins could incite the disease via the olfactory system. In the present study, we demonstrate a dopaminergic innervation from neurons in the substantia nigra to the olfactory bulb by axonal tracing studies. Injection of two dopaminergic neurotoxins—1-methyl-4-phenylpyridinium and 6-hydroxydopamine—into the olfactory bulb induced a decrease in the number of dopaminergic neurons in the substantia nigra. In turn, ablation of the nigral projection led to impaired olfactory perception. Hyposmia following dopaminergic deafferentation was reversed by treatment with the D1/D2/D3 dopamine receptor agonist rotigotine. Hence, we demonstrate for the first time the existence of a direct dopaminergic projection into the olfactory bulb and identify its origin in the substantia nigra in rats. These observations may provide a neuroanatomical basis for invasion of environmental toxins into the basal ganglia and for hyposmia as frequent symptom in PD.

The loss of smell is common in older age, reducing quality of life and often precedes the onset of cognitive decline and dementia. While age‐related olfactory loss has been linked to cortical thinning and volume reductions in key olfactory areas, associations between white‐matter (WM) integrity and olfaction are poorly understood. Here, we studied individuals aged 25–85 years from a population‐based cohort study with diffusion weighted imaging, together with self‐reported olfactory impairment, odor identification and odor threshold measures at baseline (N = 248) and follow‐up 5 years later (N = 192). Performance on the odor identification and threshold tests were lower in older adults and declined longitudinally. Older individuals also reported more olfaction complaints, and such complaints increased over time. Results from general linear models showed no cross‐sectional associations between WM integrity and olfaction. However, results from non‐competitive random forest models identified several tracts as significant contributors to odor identification and subjective olfactory impairment, including the fornix, cingulum and uncinate fasciculus. Moreover, longitudinal analyses showed that olfactory threshold decline was associated with decline in WM integrity in the body of corpus callosum. Taken together, the results support a link between white‐matter integrity and olfaction and provide initial evidence for its interplay with age. (A) Odor identification and threshold tests were lower in older adults and declined longitudinally. (B) Several tracts contributed significantly to odor identification and subjective olfactory impairment, including the fornix, cingulum, and uncinate fasciculus. (C) Olfactory threshold decline was associated with a decline in WM integrity in the body of the corpus callosum.

Olfactory dysfunction (OD) as a symptom of COVID-19 has received significant attention in research due to its high prevalence. While it is transient in the majority of individuals, post-COVID OD persists in a notable subset of patients even months to years after the acute infection. A deeper understanding of the underlying factors driving this phenomenon is essential. There is increasing evidence for an involvement of the central nervous system in this deficit. The objective of this study was to investigate the structural connectivity and integrity of white matter pathways in brain regions associated with olfactory processing using MRI with diffusion tensor imaging (DTI) in patients with persistent post-COVID OD. The study involved 61 patients, divided into two groups: 31 participants with post-COVID OD (PC-OlfDys) and 30 post-COVID normosmic controls (PC-N). For MRI analyses, a region of interest (ROI)-based approach and voxelwise statistical comparisons between the groups with age as a covariate was used. Fractional anisotropy (FA) in the left amygdala was higher in the PC-OlfDys than in the PC-N group, and radial diffusivity (RD) in the right amygdala was higher in the PC-OlfDys group than in PC-N. The PC-OlfDys group exhibited higher depression and anxiety scores, as measured by the eight-item Patient Health Questionnaire depression scale and the Generalized Anxiety Disorder 7 questionnaire, respectively. This study shows that post-COVID OD is associated with significant changes in the myelination or axonal diameter of olfactory-related brain regions. As the amygdala, putamen and piriform cortex (all involved in olfactory function and emotional well-being) showed associations with depression and anxiety scores, we hypothesise that post-COVID OD and depression and anxiety are interrelated, although the direction of this relationship remains to be elucidated.

Olfactory loss (OL) affects up to 20% of the general population and is related to changes in olfaction-related brain regions. This study investigated the effect of etiology and duration of OL on gray matter volume (GMV) of these regions in 257 patients. Voxel-based morphometry was applied to measure GMV in brain regions of interest to test the effects of etiology and duration on regional GMV and the relation between olfactory function and regional GMV. Etiology of OL had a significant effect on GMV in clusters representing the gyrus rectus and orbitofrontal cortex (OFC), bilaterally. Patients with congenital anosmia had reduced GMV in the gyrus rectus and an increased OFC volume compared to patients with acquired OL. There was a significant association between volume of the left OFC and olfactory function. This implies that changes in GMV in patients with acquired OL are mainly reflected in the OFC and depend on olfactory function. Morphology of olfactory areas in the brain therefore seems to relate to olfactory function and the subsequent degree of exposure to olfactory input in patients with acquired OL. Differences in GMV in congenital anosmia are most likely due to the fact that patients were never able to smell.

Loss of function of the gene SCN9A , encoding the voltage-gated sodium channel Na v 1.7, causes a congenital inability to experience pain in humans. Here we show that Na v 1.7 is not only necessary for pain sensation but is also an essential requirement for odour perception in both mice and humans. We examined human patients with loss-of-function mutations in SCN9A and show that they are unable to sense odours. To establish the essential role of Na v 1.7 in odour perception, we generated conditional null mice in which Na v 1.7 was removed from all olfactory sensory neurons. In the absence of Na v 1.7, these neurons still produce odour-evoked action potentials but fail to initiate synaptic signalling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer display vital, odour-guided behaviours such as innate odour recognition and avoidance, short-term odour learning, and maternal pup retrieval. Our study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell. No pain — no smell Humans and mice with mutations in the gene coding for the voltage-gated sodium ion channel Na v 1.7, previously shown to be insensitive to pain, are now found to be unable to perceive odours. Olfactory sensory neurons that are missing this sodium channel still produce action potentials, but their synapses fail to transmit to downstream neuronal circuits. The Na v 1.7-deficient phenotype of mice resembles that of human patients with Na v 1.7 loss-of-function mutations, indicating that elimination of this ion channel creates a mouse model of congenital general anosmia.

Traumatic Brain Injury (TBI) can be associated with partial or total smell loss. Recent studies have suggested that olfactory outcome can be positively modulated after olfactory training (OT). This study's aim was to investigate OT's potential role in smell recovery after TBI-induced olfactory loss. A prospective, randomized, and controlled study was developed. Patients with TBI-induced olfactory dysfunction (n = 42) were randomized into an experimental group with OT and a control group without (nOT). OT was performed twice daily with a six odor training set during 12 weeks. Olfactory loss was assessed using subjective olfactometry (Barcelona Smell Test [BAST] 24), a visual analogue scale (VAS), and n-butanol threshold (n-BTt) at baseline at 4, 12, and 24 weeks. Additionally, patients underwent MRI of the olfactory brain and olfactory bulbs (OB). Based on the MRI results, an overall score (0–16) was developed to associate the structural neurological damage with olfactory outcomes. The primary outcome was the change in olfactory measurements (VAS and BAST-24) between baseline and 12 weeks. The secondary outcome was the association of the MRI score with olfactory outcomes at baseline, and the impact on quality of life (QoL). After 12 weeks of training, OT patients showed a significant improvement in n-BTt (0.6 ± 1.7 OT vs. -0.6 ± 1.8 nOT, p < 0.05), but not in the smell VAS and BAST-24 scores. Olfactory outcomes (VAS, BAST-24, and n-BTt) were significantly associated with MRI structural findings (p < 0.001), but not with the OB volume or olfactory sulcus length. The present study suggests that 12 weeks of OT mildly improves the olfactory threshold in TBI, whereas the overall MRI score may be used as an imaging marker of olfactory dysfunction and disease severity in TBI patients.

Olfactory dysfunction (OD) is a common nasal disease, particularly prevalent among the elderly population, significantly impacting the affected individuals’ quality of life. This review focuses on the influence of aging and chronic inflammation on olfactory dysfunction, presenting insights from both the peripheral and central olfactory systems. By exploring the molecular mechanisms and pathological changes underlying the occurrence of olfactory dysfunction in relation to age-related diseases and chronic inflammation conditions, we aim to provide a comprehensive theoretical foundation for further research and offer valuable insights for more effective treatment of olfactory dysfunction.