Neuropsychiatric Symptoms Mediated the Relationship Between Odor Identification and Cognition in Alzheimer's Disease Spectrum: A Structural Equation Model Analysis

Background: Odor identification dysfunction is an early predictor of the development of Alzheimer's disease (AD), but neuropsychiatric symptoms (NPS), which are common in AD and mild cognitive impairment (MCI), are also associated with odor identification dysfunction. Whether NPS affect the specificity of using odor identification dysfunction to predict cognitive decline in AD and MCI remains unclear.Methods: Patients (233 with MCI and 45 with AD) and 45 healthy controls (HCs) underwent assessments of odor identification (Sniffin' Sticks), NPS (Neuropsychiatric Inventory-12), and cognitive function (global cognition, memory, language, executive function, visual-spatial skill, and attention). Structural equation modeling (SEM) with bootstrapping estimation was conducted to explore the relationships between odor identification, NPS, and cognition.Results: Patients with NPS showed significantly worse performance in odor identification and cognition than patients without NPS and HCs. The SEM showed odor identification to be positively associated with cognition, and cognition had special indirect effects on odor identification through affective and psychosis symptoms (two factors extracted from Neuropsychiatric Inventory-12). Additionally, affective and psychosis symptoms partially mediated the effect of cognition on odor identification.Conclusion: Neuropsychiatric symptoms are associated with odor identification dysfunction in patients with AD and MCI. Studies exploring the relationship between odor identification dysfunction and cognitive decline in patients with AD and MCI should include an assessment of affective and psychosis symptoms, and adjust their confounding effects.

Smell-induced gamma oscillations in human olfactory cortex are required for accurate perception of odor identity

Studies of neuronal oscillations have contributed substantial insight into the mechanisms of visual, auditory, and somatosensory perception. However, progress in such research in the human olfactory system has lagged behind. As a result, the electrophysiological properties of the human olfactory system are poorly understood, and, in particular, whether stimulus-driven high-frequency oscillations play a role in odor processing is unknown. Here, we used direct intracranial recordings from human piriform cortex during an odor identification task to show that 3 key oscillatory rhythms are an integral part of the human olfactory cortical response to smell: Odor induces theta, beta, and gamma rhythms in human piriform cortex. We further show that these rhythms have distinct relationships with perceptual behavior. Odor-elicited gamma oscillations occur only during trials in which the odor is accurately perceived, and features of gamma oscillations predict odor identification accuracy, suggesting that they are critical for odor identity perception in humans. We also found that the amplitude of high-frequency oscillations is organized by the phase of low-frequency signals shortly following sniff onset, only when odor is present. Our findings reinforce previous work on theta oscillations, suggest that gamma oscillations in human piriform cortex are important for perception of odor identity, and constitute a robust identification of the characteristic electrophysiological response to smell in the human brain. Future work will determine whether the distinct oscillations we identified reflect distinct perceptual features of odor stimuli.

Unilateral Choanal Atresia: Indications of Long-Term Olfactory Deficits and Volumetric Brain Changes Postsurgically

<b><i>Background:</i></b> Very few studies have investigated whether unilateral choanal atresia is associated with permanent olfactory deficits. <b><i>Objective:</i></b> This study aimed to evaluate the olfactory performance of patients with unilateral choanal atresia postsurgically. <b><i>Methods:</i></b> Three patients with unilateral atresia were examined in terms of olfactory performance with the Sniffin’ Sticks test (odor identification, threshold, and discrimination), size of the olfactory bulb, and volumetric brain changes. <b><i>Results:</i></b> All patients demonstrated significantly lower olfactory performance in terms of odor threshold on the same side with the choanal atresia. Grey matter reductions were found ipsilaterally in the hippocampus. <b><i>Conclusions:</i></b> This pilot study indicates that persistent olfactory deficits and volumetric brain changes are present in patients with unilateral choanal atresia.

Olfactory Measures as Predictors of Conversion to Mild Cognitive Impairment and Alzheimer’s Disease

Background: Early biomarkers of prodromal Alzheimer’s disease (AD) are critical both to initiate interventions and to choose participants for clinical trials. Odor threshold, odor identification and odor familiarity are impaired in AD. Methods: We investigated the relative abilities of standard screening (MMSE) and olfactory measures to predict transitions from cognitively normal (CN) to mild cognitive impairment (MCI), from CN to AD, and MCI to AD. The archival sample of 497, from the UCSD ADRC, included participants who were CN, MCI, AD and converters to MCI or AD. Apoe ε4 status, a genetic risk factor, was available for 256 participants, 132 were ε4 carriers. A receiver operating characteristic curve (ROC) curve plots the trade-off between sensitivity and specificity. Area under the ROC curve (AUC) was used to determine diagnostic accuracy. Results: Different measures were better predictors at specific stages of disease risk; e.g., odor familiarity, odor identification and the combination showed higher predictive value for converting from MCI to AD in ε4 carriers than the MMSE. Combining odor familiarity and odor identification produced an AUC of 1.0 in ε4 carriers, MMSE alone was 0.58. Conclusions: Olfactory biomarkers show real promise as non-invasive indicators of prodromal AD. The results support the value of combining olfactory measures in assessment of risk for conversion to MCI and to AD.

Relationships between Cognitive Function and Odor Identification, Balance Capability, and Muscle Strength in Middle-Aged Persons with and without Type 2 Diabetes

Aim. We investigated the relationship between cognitive function and olfactory and physical functions in middle-aged persons with and without type 2 diabetes (T2D) to examine the potential of olfactory and physical functions as biomarkers for early cognitive impairment. Methods. Enrolled were 70 T2D patients (age 40 to <65 y) and 81 age-matched control participants without diabetes. Cognitive function was assessed by the Montreal Cognitive Assessment (MoCA), Trail Making Test parts A and B (TMT-A/-B), Wisconsin Card Sorting Test (WCST), Quick Inventory of Depressive Symptomatology Self-Report (QIDS), and Starkstein Apathy Scale (SAS). Multiple linear regression analyses were performed. Results. Odor identification was an independent determinant shown in the results of the TMT-A in the entire participant group and was independently associated with the MoCA and TMT-B in the T2D group. Balance capability assessed with a stabilometer was independently associated with all cognitive function tests except for QISD and SAS in the entire participant group and the T2D group and was independently associated with TMT-A in the control group. Knee extension strength was independently associated with the SAS in the entire participant group and the T2D group. Conclusions. Odor identification, balance capability, and knee extension strength were potential markers for cognitive decline in middle-aged persons with T2D.

539 - The association between olfactory dysfunction and psychiatric disorders

It is known that olfactory dysfunction occurs early in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases and frontotemporal dementia (FTD). Dementia and psychiatric disorders share a number of clinical features, such as psychosis and depression. As such, misdiagnoses across these conditions are not uncommon. A variety of studies show smell dysfunction in schizophrenia, but little is known about other psychiatric disorders. In order to verify the link between olfaction and psychiatric disorders, a medical literature search was carried out in may 2021 using PubMed, and Cochrane Library, including the terms “olfaction” and “olfactory dysfunction” combined individually with “psychiatric disorder” and “depression”. Systematic reviews and meta-analyses written in English from 1991 to 2021 were included. Even thought one review suggested that patients with depression have reduced olfactory performance when compared with healthy, results show studies with different methodology and design which makes it difficult to reach definitive conclusions as how and if olfactory functioning is related to depression. Further studies with the same methodology that examines and separates central and peripheral olfactory processing are needed. Another review showed robust olfactory deficits in schizophrenia and at-risk youths, what indicates that olfactory measures may be a useful marker of schizophrenia risk status. Finally, a systematic review compared olfactory function in FTD, depression, schizophrenia and bipolar disorder. Results revealed that odor identification but not discrimination was severely impaired in FTD, both were impaired in schizophrenia, while no olfactory impairments were observed in depression. Findings in bipolar disorder were mixed. This review showed that testing odor identification and discrimination differentiates FTD from depression and schizophrenia, but not from bipolar disorder. It is possible to conclude that olfactory dysfunction occurs in schizophrenia and dementia but not in depression.

Odor Identification and Regional Gray Matter Atrophy in Patients with Alzheimer’s Disease, Parkinson’s Disease, and the Healthy Elderly: A Cross-Sectional Structural MRI Study

Multiple associations between impaired olfactory performance and regional cortical and deep gray matter atrophy have been reported in separate studies of patients with Alzheimer’s disease (AD), Parkinson’s disease (PD), and of the healthy elderly. We aimed to evaluate such possible associations among these populations in a unified manner. Twenty AD, twenty PD patients’ and twenty healthy age- and sex-matched controls’ odor identification performance was assessed with the Lithuanian adaptation of the Sniffin’ Sticks 12 odor identification test, followed by morphometric gray matter analysis by MRI using FreeSurfer. AD patients had significantly lower cognitive performance than both PD patients and the healthy elderly, as evaluated with the Mini-Mental State Examination (MMSE). Odor identification performance was significantly worse in AD and PD patients compared with the healthy elderly; AD patients performed slightly worse than PD patients, but the difference was not statistically significant. Among patients with AD, worse odor identification performance was initially correlated with atrophy of multiple cortical and deep gray matter regions known to be involved in olfactory processing, however, only two measures—decreased thicknesses of the right medial and left lateral orbitofrontal cortices—remained significant after adjustment for possible confounders (age, MMSE score, and global cortical thickness). Among patients with PD and the healthy elderly we found no similar statistically significant correlations. Our findings support the key role of the orbitofrontal cortex in odor identification among patients with AD, and suggest that correlations between impaired odor identification performance and regional gray matter atrophy may be relatively more pronounced in AD rather than in PD.

Simple Disposable Odor Identification Tests for Predicting SARS-CoV-2 Positivity

Olfactory dysfunction (OD) is a common manifestation of COVID-19 and may be useful for screening. Survey-based olfactory evaluation tends to underestimate the prevalence of OD, while psychophysical olfactory testing during a pandemic has the disadvantage of being time consuming, expensive, and requiring standardized laboratory settings. We aimed to develop a quick, simple, affordable, and reliable test to objectively assess the prevalence and diagnostic accuracy of OD in COVID-19. The olfactory function of 64 COVID-19 inpatients and 34 controls was evaluated using a questionnaire and a simple disposable odor identification test (SDOIT) developed for this study. Four SDOIT models were assessed: 10-SDOIT, 9-SDOIT, 8-SDOIT, and 4-SDOIT, with 10, 9, 8 and 4 samples, respectively. We found a high frequency of self-reported OD in COVID-19 patients, with 32.8% and 42.2% reporting current and recent OD, respectively. Different SDOIT models revealed smell impairment in 54.7–64.1% of COVID-19 patients. The combination of either 10-SDOIT results and self-reported OD, or 8-SDOIT results and self-reported OD, were the best predictors of COVID-19, both with an AUC value of 0.87 (0.85 and 0.86 for the age-matched subjects). OD is a common symptom of COVID-19. A combination of self-reported smell deterioration and OD psychophysically evaluated using SDOIT appears to be a good predictor of COVID-19.

Symptoms of Depression Change With Olfactory Functions

Olfactory loss is associated with symptoms of depression. The present study, conducted on a large cohort of mostly dysosmic patients, aimed to investigate whether improvement in olfactory performance would correspond with a decrease in depression severity and, if so, to what extent. In 171 participants, we assessed olfactory function and severity of depression before and after an average interval of 11 months, with many patients improving in function. Separate analyses were conducted for a) the whole group of patients and b) the group of dysosmic patients in both classic and Bayesian ways. Student t-test demonstrates that the whole sample improved consistently, especially within the group of dysosmic patients in terms of odor identification, and the dysosmic group also improved in terms of odor threshold and olfactory functions in general. Pearson correlation showed that the increase in olfactory functions corresponded with the decrease in depression severity, particularly in dysosmic patients. To conclude, the present study results indicate that symptoms of depression change with olfactory functions in general and odor identification in particular.