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The mechanisms by which any upper respiratory virus, including SARS-CoV-2, impairs chemosensory function are not known. COVID-19 is frequently associated with olfactory dysfunction after viral infection, which provides a research opportunity to evaluate the natural course of this neurological finding. Clinical trials and prospective and histological studies of new-onset post-viral olfactory dysfunction have been limited by small sample sizes and a paucity of advanced neuroimaging data and neuropathological samples. Although data from neuropathological specimens are now available, neuroimaging of the olfactory system during the acute phase of infection is still rare due to infection control concerns and critical illness and represents a substantial gap in knowledge. The active replication of SARS-CoV-2 within the brain parenchyma (ie, in neurons and glia) has not been proven. Nevertheless, post-viral olfactory dysfunction can be viewed as a focal neurological deficit in patients with COVID-19. Evidence is also sparse for a direct causal relation between SARS-CoV-2 infection and abnormal brain findings at autopsy, and for trans-synaptic spread of the virus from the olfactory epithelium to the olfactory bulb. Taken together, clinical, radiological, histological, ultrastructural, and molecular data implicate inflammation, with or without infection, in either the olfactory epithelium, the olfactory bulb, or both. This inflammation leads to persistent olfactory deficits in a subset of people who have recovered from COVID-19. Neuroimaging has revealed localised inflammation in intracranial olfactory structures. To date, histopathological, ultrastructural, and molecular evidence does not suggest that SARS-CoV-2 is an obligate neuropathogen. The prevalence of CNS and olfactory bulb pathosis in patients with COVID-19 is not known. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term. An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions might accelerate pathological processes and symptomatic progression of neurodegenerative disease. Persistent olfactory impairment with or without perceptual distortions (ie, parosmias or phantosmias) after SARS-CoV-2 infection could, therefore, serve as a marker to identify people with an increased long-term risk of neurological disease.

The vast increase in Alzheimer disease (AD) worldwide has grave implications for individuals, family support systems and the health-care systems that will attempt to cope with the disease. Early markers of the disease are essential for efficient selection of clinical trial participants for drug development and for timely treatment once an intervention becomes available. There is avid interest in noninvasive, inexpensive markers that have the potential to identify prodromal AD. This Review considers sensory impairments that have the potential to serve as early indicators of AD, with a focus on olfaction, hearing and vision. Current evidence regarding the potential markers of AD in each modality is examined, with a particular emphasis on olfaction and current findings that olfactory function is associated with prodromal AD. Research suggests that olfactory impairment is associated with other markers that signal the emergence of prodromal AD. Auditory impairment is associated with dementia in epidemiological studies and visual system deficits have been reported in AD; however, the emergence of these deficits in prodromal AD is unclear. Further research is necessary to address the relative sensitivity and specificity of olfactory, auditory and visual measures for the detection of prodromal AD.

After contracting COVID-19, a substantial number of individuals develop a Post-COVID-Condition, marked by neurologic symptoms such as cognitive deficits, olfactory dysfunction, and fatigue. Despite this, biomarkers and pathophysiological understandings of this condition remain limited. Employing magnetic resonance imaging, we conduct a comparative analysis of cerebral microstructure among patients with Post-COVID-Condition, healthy controls, and individuals that contracted COVID-19 without long-term symptoms. We reveal widespread alterations in cerebral microstructure, attributed to a shift in volume from neuronal compartments to free fluid, associated with the severity of the initial infection. Correlating these alterations with cognition, olfaction, and fatigue unveils distinct affected networks, which are in close anatomical-functional relationship with the respective symptoms. After contracting COVID-19, a substantial number of individuals develop a Post-COVID-Condition with neurological symptoms. Here, the authors show symptom-specific brain microstructure alterations in these patients, providing insights into the underlying pathophysiology.

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.

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.

Memory decline is a central cognitive symptom in Parkinson’s Disease (PD). While task-fMRI studies link hippocampal activity (AHA) to poorer memory and olfactory performance, this relationship during rest remains understudied. The objectives of this study are to examine differences in resting-state hippocampal networks, explore the occurrence of reduced AHA within these networks, and investigate its impact on memory and olfaction in PD. Thirty-nine PD patients awaiting evaluation for device-aided Parkinson therapy and 46 healthy controls (HC) underwent resting-state fMRI (rs-fMRI). PD patients also completed a memory and olfactory assessment. Co-activation pattern (CAP) analysis was performed on the rs-fMRI data. Our results demonstrated reduced activity in two hippocampal networks in PD: Network 1, incorporating the visual cortex, cerebellum, superior parietal lobule, and precuneus, and Network 5, incorporating parts of the central executive network. PD subgroups with reduced AHA in Network 1 and 5 performed significantly worse on tests of auditory-verbal short-term, long-term and recognition memory, as well as odor identification. In conclusion, within specific resting-state hippocampal networks, reduced AHA in PD is linked to poorer auditory-verbal memory and odor identification.

ABSTRACT 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.

Introduction Patients with Parkinson’s Disease (PD) commonly experience Olfactory Dysfunction (OD). Our exploratory study examined hippocampal volumetric and resting-state functional magnetic resonance imaging (rs-fMRI) variations in a Healthy Control (HC) group versus a cognitively normal PD group, further categorized into PD with No/Mild Hyposmia (PD-N/MH) and PD with Severe Hyposmia (PD-SH). Methods We calculated participants’ relative Total Hippocampal Volume (rTHV) and performed Spearman’s partial correlations, controlled for age and gender, to examine the correlation between rTHV and olfactory performance assessed by the Odor Stick Identification Test for the Japanese (OSIT-J) score. Mann-Whitney U tests assessed rTHV differences across groups and subgroups, rejecting the null hypothesis for p  < 0.05. Furthermore, a seed-based rs-fMRI analysis compared hippocampal connectivity differences using a one-way ANCOVA covariate model with controls for age and gender. Results Spearman’s partial correlations indicated a moderate positive correlation between rTHV and OSIT-J in the whole study population (ρ = 0.406; p  = 0.007), PD group (ρ = 0.493; p  = 0.008), and PD-N/MH subgroup (ρ = 0.617; p  = 0.025). Mann-Whitney U tests demonstrated lower rTHV in PD-SH subgroup compared to both HC group ( p  = 0.013) and PD-N/MH subgroup ( p  = 0.029). Seed-to-voxel rsfMRI analysis revealed reduced hippocampal connectivity in PD-SH subjects compared to HC subjects with a single cluster of voxels. Conclusions Although the design of the study do not allow to make firm conclusions, it is reasonable to speculate that the progressive involvement of the hippocampus in PD patients is associated with the progression of OD.

Brain structural features of healthy individuals are associated with olfactory functions. However, due to the pathophysiological differences, congenital and acquired anosmia may exhibit different structural characteristics. A systematic review was undertaken to compare brain structural features between patients with congenital and acquired anosmia. A systematic search was conducted using PubMed/MEDLINE and Scopus electronic databases to identify eligible reports on anosmia and structural changes and reported according to PRISMA guidelines. Reports were extracted for information on demographics, psychophysical evaluation, and structural changes. Then, the report was systematically reviewed based on various aetiologies of anosmia in relation to (1) olfactory bulb, (2) olfactory sulcus, (3) grey matter (GM), and white matter (WM) changes. Twenty-eight published studies were identified. All studies reported consistent findings with strong associations between olfactory bulb volume and olfactory function across etiologies. However, the association of olfactory function with olfactory sulcus depth was inconsistent. The present study observed morphological variations in GM and WM volume in congenital and acquired anosmia. In acquired anosmia, reduced olfactory function is associated with reduced volumes and thickness involving the gyrus rectus, medial orbitofrontal cortex, anterior cingulate cortex, and cerebellum. These findings contrast to those observed in congenital anosmia, where a reduced olfactory function is associated with a larger volume and higher thickness in parts of the olfactory network, including the piriform cortex, orbitofrontal cortex, and insula. The present review proposes that the structural characteristics in congenital and acquired anosmia are altered differently. The mechanisms behind these changes are likely to be multifactorial and involve the interaction with the environment.

Background and objective Despite olfactory disorders being among the most common neurological complications of coronavirus disease 2019 (COVID-19), their pathogenesis has not been fully elucidated yet. Brain MR imaging is a consolidated method for evaluating olfactory system’s morphological modification, but a few quantitative studies have been published so far. The aim of the study was to provide MRI evidence of olfactory system alterations in patients with COVID-19 and neurological symptoms, including olfactory dysfunction. Methods 196 COVID-19 patients (median age: 53 years, 56% females) and 39 controls (median age 55 years, 49% females) were included in this cross-sectional observational study; 78 of the patients reported olfactory loss as the only neurological symptom. MRI processing was performed by ad-hoc semi-automatic processing procedures. Olfactory bulb (OB) volume was measured on T2-weighted MRI based on manual tracing and normalized to the brain volume. Olfactory tract (OT) median signal intensity was quantified on fluid attenuated inversion recovery (FLAIR) sequences, after preliminary intensity normalization. Results COVID-19 patients showed significantly lower left, right and total OB volumes than controls ( p  < 0.05). Age-related OB atrophy was found in the control but not in the patient population. No significant difference was found between patients with olfactory disorders and other neurological symptoms. Several outliers with abnormally high OT FLAIR signal intensity were found in the patient group. Conclusions Brain MRI findings demonstrated OB damage in COVID-19 patients with neurological complications. Future longitudinal studies are needed to clarify the transient or permanent nature of OB atrophy in COVID-19 pathology. Graphical abstract