Those at genetic risk for Alzheimer's Disease (AD) because of the ApoE ε4 allele show differences in activation during olfactory information processing and memory in areas such as MTL structures, entorhinal cortex, posterior cingulate, precuneus, and inferior parietal lobule, suggesting preclinical AD neuropathology and olfactory impairment as a biomarker for predicting later AD onset (Murphy, 2019). The effects of smoking on AD have varied, with early studies suggesting either no effect or protective effects, and recent studies suggesting smoking as a risk factor for AD but with the need for further investigation in preclinical stages. Therefore, this study focused on olfaction and smoking as risk factors for preclinical AD neuropathology by studying differences in fMRI BOLD signal changes in smokers and nonsmokers during olfactory tasks.

Archival data from 25 non-demented older adults recruited from the UCSD Alzheimer's Disease Research Center who completed an Assessment Scale-Cognitive Subscale (ADAS-Cog) and functional MRI scans at 3T, acquired during performance of an odor identification task. Odor Identification (OI) measured correct (hits) or incorrect (misses) identification of odors presented by an olfactometer to deliver the odor stimuli in short, controlled durations during fMRI scanning.

fMRI data were preprocessed using fMRIprep, smoothed at 4mm, scaled, and first level analyses were conducted using 3dDeconvolve in AFNI with time points corresponding to hits and misses as regressors. Differences between smokers and nonsmokers revealed smokers show a larger difference in BOLD signal change from hits minus misses at five significant clusters (p = 0.01 with the minimum cluster size [voxels] at 42). Peak areas of significant clusters included the right precuneus, right calcarine gyrus, left inferior parietal lobule, left superior parietal lobule, and left middle occipital gyrus. Analyses suggested a greater difference in activity between hits and misses in smokers compared to nonsmokers, with more activity during hits.

Differences in activation between smokers and nonsmokers during an olfactory identification task, with greater activity in smokers during hits, suggests greater effort to correctly identify an odor. These findings of hyperactivation in areas (such as the precuneus and inferior parietal lobule) are similar to findings of hyperactivation during odor memory observed in studies of ε4 carriers during preclinical stages. Results provide further insight into smoking as a risk factor for AD. Moreover, results suggest the risk of smoking could potentially be reflected in altered activity in olfactory information processing networks in preclinical stages of AD. The study highlights the need for research to further understand the role smoking plays in the development of AD and the use of olfaction as a biomarker to aid in disease detection, prevention, and stage-associated treatments.

Olfactory function declines during normal aging; however, accelerated olfactory decline is observed in neurodegenerative diseases, such as Alzheimer’s disease (AD). Moreover, olfactory deficits in pre-clinical AD are associated with future cognitive decline. Odor identification and memory deficits have been consistently reported in early stage AD indicating its potential sensitivity to AD pathophysiology in olfactory and limbic structures, yet few studies of olfaction have incorporated structural measures in a well-characterized cohort of older adults. In the current study we examined the association between odor identification impairment, cognition, and medial temporal lobe (MTL) sub-regions in cognitively unimpaired and impaired older adults.

We enrolled 140 participants (age=72.25±6.54, 56% female, years of education=16.30±2.63, 82% Caucasian, 15% Black/AA, 3% Multiracial) from the Penn Alzheimer’s Disease Research Center Clinical Cohort. Participants completed the Sniffin’ Sticks Odor Identification Test (SS-OIT), cognitive testing (NACC UDS2 or UDS3 and additional cognitive tests), and MRI scans (3T Siemens MAGNETOM Prisma MRI scanner). For the SS-OIT, participants were presented with 16 odorants using felt-tipped pen dispensers and asked to identify each odor from four multiple-choice options. Scores range from 0 to 16. Additionally, cognitive domains were created by averaging z-scores from tests within each domain: attention, memory, language, executive function, and visuospatial. This cohort was divided into participants with unimpaired cognition (n=96) and impaired cognition (MCI, dementia; n=44) using established normative data and consensus diagnosis. Linear regressions were performed to examine the association between SS-OIT score, each cognitive domain, and MTL measurements for unimpaired and impaired groups. For all analyses, we controlled for age, race, sex, education, smoking status, and hypertension and additionally for MOCA score and intracranial volume with MTL measurements.

In the unimpaired group, SS-OIT significantly associated with language (p<.05). In the impaired group, SS-OIT significantly associated with language and memory (p<.05). In the unimpaired group, SS-OIT significantly associated with right anterior hippocampal volume (p<.05). In the impaired group, significant associations were found between SS-OIT and right anterior hippocampal volume (p<.05) and left hippocampal mean thickness (p<.05). Additionally, SS-OIT significantly associated with left and right entorhinal cortex volume (p<.05) and mean thickness (p<.05).

This study reveals that lower odor identification performance is related to lower performance on measures of cognition and atrophy in MTL sub-regions in unimpaired and impaired older adults. Our findings support prior results demonstrating relationships between olfactory function, cognition, and MTL sub-regions. Specifically, olfactory function and episodic memory have been shown to follow similar patterns of decline in the course of AD, potentially reflecting AD pathology in shared regions of the MTL subserving episodic memory and olfactory function. Our findings demonstrate that reductions in both cortical thickness and grey matter volume of MTL regions are linked to olfactory deficits in individuals at risk for Alzheimer’s dementia. Future steps will include the analysis of longitudinal cognitive and imaging indices and the incorporation of fluid biomarker data.

One of the greatest challenges of the Alzheimer’s disease (AD) epidemic is identifying the disease prior to substantial neurological compromise. The established biomarkers of AD, such as measures of cognitive impairment, hippocampal atrophy, and CSF measures of beta amyloid and tau, used in research and drug trials are less indicative of AD pathology in preclinical, non-demented, populations. Olfactory dysfunction, a well-established sensory impairment of AD found to correlate strongly with tau burden and hippocampal volume measures, has shown to be a promising preclinical biomarker for AD progression. Several studies have found either impaired odor identification or odor memory at baseline to predict 5-year follow-up cognitive decline and conversion from MCI to AD, but less is known about how olfactory performance reflects the integrity of associated brain regions such as the hippocampus. The present analysis aims to explore the value of psychophysical olfactory assessment as biomarker measure in preclinical AD studies and drug trials by investigating its relationships with structural measures of the hippocampus.

A sample consisted of non-demented older adults (age >75), recruited from the UCSD Alzheimer’s Disease Research Center as part of a ongoing olfactory biomarker study. Participants completed the AD Assessment Scale-Cognitive Subscale-13 (ADAS-Cog-13), San Diego Odor Identification Test (SDOIT), tests of odor recognition memory (ORMem) and odor associative memory (OAM), and MRI derived hippocampal volumes and average hippocampal occupancy (Avg HOC). Left and right hippocampal volumes were adjusted for each participant’s estimated intracranial volume. Bivariate correlations were calculated for ADAS-Cog-13 and SDOIT total scores, performance scores for odor recognition and odor associative memory tests, and the three hippocampal measures (bilateral volumes and average occupancy).

ADAS-Cog-13 score did not show significant correlations with either hippocampal measure at the .05 level. SDOIT scores were significantly correlated with the measure of Avg HOC (p<.05). ORMem false positive responses were significantly correlated with Avg HOC (p<.01) and right hippocampal volume (p<.05). ORMem miss responses and OAM errors were both correlated with left (p<.05) and right (p<.01) hippocampal volumes.

These results demonstrate that psychophysical assessments of odor identification and odor memory can better reflect the integrity of the hippocampus in nondemented older adults, compared to the neuropsychological ADAS-Cog-13. This is congruent with olfactory dysfunction preceding cognitive-memory decline in AD cases and provides support for the utility of psychophysical olfactory assessment along with other established AD biomarkers in research and drug trials in preclinical populations.

Supported by NIH grant # R01AG062006-04 from the National Institute on Aging to CM. Special thank you to the staff and participants of the UCSD ADRC, especially Christina Gigliotti, and Aaron Jacobson at the UCSD Center for fMRI.

Olfaction is a critical sensory function and changes in the ability to detect smells could affect quality of life by diminishing appreciation of food, drink, and other aroma-based experiences, increase danger of hazardous exposures, and cause a loss of employment. Additionally, decrements in olfaction have been related to onset of some neurodegenerative conditions. Olfactory impairments in military populations are highly prevalent and often attributed to the long-term effects of mild traumatic brain injury (mTBI) and chronic psychiatric disorders. The main goal of this investigation was to examine olfactory function in a cohort of combat veterans using a quantitative smell test.

Participants underwent a neurological examination using a revised version of the Neurological Outcome Scale for Traumatic Brain Injury. Olfactory function was examined using a set of essential oil vials with common odors. Based on the number of correctly identified odors, the following grading system was employed: no deficit; mild; moderate; severe deficit; and absence of smell detection. All study assessments were performed prior to March of 2020 (onset of COVID-19 pandemic). In addition, participants completed performance validity testing (PVT) and screening for ongoing substance misuse using the Alcohol Use Disorders Identification Test and Drug Abuse Screening Test-10. Lifetime history of brain injury, combat-related extracranial injuries, and deployment characteristics were assessed using structured interview. All available medical records were reviewed.

Participants were 38 veterans with a deployment-related mTBI who passed the PVT and did not have ongoing substance misuse issues. Olfactory examination revealed normosmia in 20 participants and various degrees of deficit in 18 (11= mild; 4=moderate; and 3=severe). The groups did not differ in demographics, post-injury interval, or current clinical (non-psychiatric) conditions. Participants with hyposmia frequently reported being exposed to a higher number of blasts and being positioned closer to the nearest primary blast, and more often endorsed a period of loss of consciousness after the most serious mTBI. In addition, they more often reported tympanic membrane perforation, extracranial injuries, and histories of both blast and blunt force mTBI. Comorbid diagnoses of posttraumatic stress disorder (PTSD), depression, chronic headaches, and pain were more common among these participants as well.

Several blast exposure and specific injury-related characteristics increase the likelihood of long-term olfactory impairments, comorbid psychiatric conditions, and chronic pain among veterans with a history of deployment-related mTBI. Notably, none of the participants with hyposmia had a clinical diagnosis of olfactory dysfunction or were receiving service-connected disability for a loss of sense of smell at the time of their assessment. Multidisciplinary rehabilitation care provided to combat veterans with history of mTBI and/or PTSD should include olfactory examination using both quantitative and qualitative smell tests, education regarding the adversities related to loss of smell, management of current psychiatric symptoms, and follow-up assessments. The lack of a comparison group without a history of mTBI and the small sample size were the main limitations of this investigation.

Olfactory dysfunction can influence nutritional intake, the detection of environmental hazards, and quality of life. Prior research has found discordance between subjective and objective measures of olfaction. In people living with HIV (PLWH), olfactory dysfunction is widely reported; however, few studies have examined concordance between subjective olfactory self-ratings and performance on an objective psychophysical measure of olfaction and associated factors in men living with HIV (MLWH).

MLWH (n=51, mean age=54 years, 66.7% Black) completed two subjective olfaction ratings (two 5-point Likert scales), the Smell Identification Test (SIT), cognitive measures (HVLT-R, TMT), and self-report questionnaires assessing smell habits, mood, cognitive failures, and quality of life. Participants were categorized into one of four groups: true positives (TP; impaired subjective olfaction and objective olfaction dysfunction), false negatives (FN; intact subjective olfaction and objective olfaction dysfunction), false positives (FP; impaired subjective olfaction and objective normosmia), and true negatives (TN; intact subjective olfaction and normosmia). Established formulas were used to calculate the sensitivity and specificity of subjective olfaction, and t-tests and ANOVA were used to examine potential demographic, clinical, and cognitive factors contributing to discordance between subjective and objective olfaction dysfunction.

Across both subjective self-report items, 35.3% reported olfactory dysfunction, whereas 60.8% had objective olfaction dysfunction on the SIT (score < 33). Black MLWH had significantly higher rates of subjective (Black 41.2% vs. White 35.3%) and objective (Black 73.5% vs. White 35.3%) olfactory dysfunction (X2(1)=9.22, p=.002). We found discordance between subjective and objective olfaction measures, with 29.4% of the sample having objective olfaction dysfunction and not recognizing it (FN). In comparison, 3.9% with self-rated olfaction impairment had normal objective olfaction scores (FP). Additionally, there was concordance in subjective self-reports compared with objective olfaction, with 35.3% correctly identifying normal olfaction (TN) and 31.4% correctly identifying olfactory dysfunction (TP). Those unaware of olfaction dysfunction (FN) reported using less scented products in daily life on the Smell Habits Questionnaire. Although the FN group had faster TMT scores, these findings were no longer significant after the removal of three outliers in the TP group (e.g., time to complete greater than 350 seconds).

Our findings cohere with work in healthy older adults, traumatic brain injury, and Parkinson’s disease, documenting that subjective olfaction may inadequately capture the full range of a person’s olfactory status. We extend these findings to a sample of MLWH, in which discordance rates ranged from 35-61% for subjective and objective olfactory dysfunction. Unawareness of olfactory dysfunction in MLWH was associated with less daily smell habits and paradoxically faster TMT performance. A higher number of smell habits in the TP group indicate that more frequent odor exposure may increase sensitivity to olfactory declines. Future studies with larger samples will be helpful in understanding the full nature of these relationships. Lastly, given that one-third of the sample had discordance between subjective and objective olfaction, objective olfaction measures may be useful to consider in the neuropsychological assessment and standard clinical care for PLWH.

To analyse variations in the n-butanol threshold and odour identification scores of the Connecticut Chemosensory Clinical Research Centre test in various grades of olfactory dysfunction and in different nasal conditions leading to olfactory loss.

Retrospective observational study.

All grades of olfactory dysfunction were predominantly noted among males. In chronic rhinosinusitis, anosmia or severe hyposmia was seen in 87.5 per cent of patients without polyps in comparison with 68 per cent of patients with polyps. In addition, 90 per cent of patients with atrophic rhinitis and post-traumatic loss had anosmia, but only 30.7 per cent of patients with allergic rhinitis had anosmia. Pepper was the most affected smell for all the nasal diseases except atrophic rhinitis, in which asafoetida and baby powder smells were affected more.

In most inflammatory sinonasal conditions, odour identification is relatively preserved even when the threshold is maximally affected. In patients with comparable olfactory dysfunction based on the Connecticut Chemosensory Clinical Research Centre test score, a relatively preserved suprathreshold odour identification score may predict better prognosis.

The aim of this study was to identify the potential electrophysiological biomarkers of human responses by comparing the electroencephalogram brain wave changes towards lavender versus normal saline in a healthy human population.

This study included a total of 44 participants without subjective olfactory disturbances. Lavender and normal saline were used as the olfactory stimulant and control. Electroencephalogram was recorded and power spectra were analysed by the spectral analysis for each alpha, beta, delta, theta and gamma bandwidth frequency upon exposure to lavender and normal saline independently.

The oscillatory brain activities in response to the olfactory stimulant indicated that the lavender smell decreased the beta activity in the left frontal (F7 electrode) and central region (C3 electrode) with a reduction in the gamma activity in the right parietal region (P4 electrode) (p < 0.05).

Olfactory stimulants result in changes of electrical brain activities in different brain regions, as evidenced by the topographical brain map and spectra analysis of each brain wave.

To assess the effectiveness of the nasal airflow inducing manoeuvre or ‘polite yawn’ technique in improving olfaction and quality of life in laryngectomised patients.

Using a prospective study design, 42 patients scheduled to undergo laryngectomy at a tertiary care centre were subjected to olfaction testing before surgery and two weeks following the surgery. The nasal airflow inducing manoeuvre was taught, and the olfaction test was repeated with the patient performing the nasal airflow inducing manoeuvre. Quality of life was assessed using the Appetite, Hunger and Sensory Perception questionnaire with calculation of scores after the patient had learnt the nasal airflow inducing manoeuvre.

There was a significant reduction in the composite olfaction score, from a mean (standard deviation) baseline value of 4.01 (1.39) to 0.44 (0.51), two weeks after surgery (p < 0.001). After practising the nasal airflow inducing manoeuvre, the olfaction scores increased to 3.05 (1.32) (p < 0.001). Appetite, Hunger and Sensory Perception questionnaire scores ranged from 52 to 110 (normal range, 29–145), suggesting an improvement in the quality of life of patients.

The nasal airflow inducing manoeuvre, an inexpensive, simple, patient-friendly manoeuvre, can be used in the olfaction rehabilitation of patients undergoing laryngectomy.

Impaired olfaction may be a biomarker for early Lewy body disease, but its value in mild cognitive impairment with Lewy bodies (MCI-LB) is unknown. We compared olfaction in MCI-LB with MCI due to Alzheimer’s disease (MCI-AD) and healthy older adults. We hypothesized that olfactory function would be worse in probable MCI-LB than in both MCI-AD and healthy comparison subjects (HC).

Cross-sectional study assessing olfaction using Sniffin’ Sticks 16 (SS-16) in MCI-LB, MCI-AD, and HC with longitudinal follow-up. Differences were adjusted for age, and receiver operating characteristic (ROC) curves were used for discriminating MCI-LB from MCI-AD and HC.

Participants were recruited from Memory Services in the North East of England.

Thirty-eight probable MCI-LB, 33 MCI-AD, 19 possible MCI-LB, and 32HC.

Olfaction was assessed using SS-16 and a questionnaire.

Participants with probable MCI-LB had worse olfaction than both MCI-AD (age-adjusted mean difference (B) = 2.05, 95% CI: 0.62–3.49, p = 0.005) and HC (B = 3.96, 95% CI: 2.51–5.40, p < 0.001). The previously identified cutoff score for the SS-16 of ≤ 10 had 84% sensitivity for probable MCI-LB (95% CI: 69–94%), but 30% specificity versus MCI-AD. ROC analysis found a lower cutoff of ≤ 7 was better (63% sensitivity for MCI-LB, with 73% specificity vs MCI-AD and 97% vs HC). Asking about olfactory impairments was not useful in identifying them.

MCI-LB had worse olfaction than MCI-AD and normal aging. A lower cutoff score of ≤ 7 is required when using SS-16 in such patients. Olfactory testing may have value in identifying early LB disease in memory services.

Autism-spectrum disorders (ASD) are characterized by deficits in social domains, associated with abnormal socioemotional perception. Although olfaction provides access to socioemotional cues, little is known about the perception of emotional odors considering their social meaning in ASD.

To investigate the subjective responses to emotional body odors (BOs) versus non-social, common odors (COs) in ASD.

Eleven ASD and 49 typically developed (TD) adults were asked to smell negative, positive, and neutral BOs (axillary sweat from healthy individuals exposed to fearful, happy, and neutral film-clips) and COs, and to rate each odor on perceived pleasantness, intensity, familiarity and arousal. Odors were presented for 5 sec. Analyses were performed with linear mixed-effect models with fixed factors (group × odor type × valence) and covariates (e.g., age; intensity for arousal/familiarity; familiarity for pleasantness). Post-hoc comparisons were Bonferroni-corrected.

Odors were perceived as significantly more intense (p=.044) and pleasant (p<.001) in ASD than TD. Distinct response patterns were found in ASD and TD. First, positive BOs and COs were similarly arousing and pleasant in ASD (p>.05), but not in TD (p<.001). Second, positive and neutral COs were equally arousing, familiar and pleasant in ASD (p>.05), but not in TD (p<.001). No differences were observed between BOs in ASD and TD (p>.05).

ASD is associated with abnormal subjective responses to emotional odors, which could contribute to the social communication difficulties characterizing ASD. Since emotional BOs elicit psychological responses in others, analyses on subjective and automatic responses will allow a better understanding of the role of olfaction in ASD.

No significant relationships.

Severe acute respiratory syndrome coronavirus-2 is a formidable virus, responsible for coronavirus disease 2019 and endowed with marked neurotropism. The damage it causes to the nervous system is manifold. The main neurological manifestation is anosmia. Olfactory damage is often transient, but there are no data reflecting an observational period of several months.

This study evaluated the trend of anosmia in patients affected by coronavirus disease 2019 in the eight months following diagnosis.

Fifty-five subjects who presented with symptoms suggestive of coronavirus disease 2019 and who developed anosmia, between the end of February and the beginning of March 2020, were investigated. The patients were interviewed after eight months to determine functional recovery and assess the degree of recovery.

Ninety-one per cent of the population reported olfactory recovery and, of these, 53 per cent had total recovery after eight months. Females and younger age groups seem slightly advantaged in functional recovery. The elderly population appears to have excellent prospects for full functional recovery.

Anosmia represents a frequent neurological manifestation during coronavirus disease 2019. Fortunately, it is transient in most cases, and only a small percentage of patients affected by it report long-term functional deficits.

Chronic rhinosinusitis is associated with altered mucociliary clearance and olfaction. The study aimed to analyse the reversibility of impairment and endoscopic factors predicting changes in mucociliary clearance and olfactory parameters.

This prospective study included patients undergoing functional endoscopic sinus surgery for medically refractory chronic rhinosinusitis. Pre- and post-operative measurements of mucociliary clearance, olfactory thresholds, and identification scores were recorded.

Of the 96 patients, 65.6 per cent had polyposis and 80.2 per cent underwent primary surgery. Improvements in mucociliary clearance and olfaction scores were seen in all patients, with greater reversibility of impairment in patients with polyposis and in those who underwent revision surgery. The presence of polyps correlated significantly with changes in mucociliary clearance and olfaction.

The study highlights improvements in mucociliary clearance, olfactory thresholds and identification scores after functional endoscopic sinus surgery in chronic rhinosinusitis with or without nasal polyposis, as well as for primary and revision surgeries. Adequate post-operative care and prevention of polyps recurrence help to improve mucociliary clearance and olfaction scores.

It is unclear whether olfactory deficits improve after remission in depressed patients. Therefore, we aimed to assess in drug-free patients the olfactory performance of patients with major depressive episodes (MDE) and its change after antidepressant treatment.

In the DEP-ARREST-CLIN study, 69 drug-free patients with a current MDE in the context of major depressive disorder (MDD) were assessed for their olfactory performances and depression severity, before and after 1 (M1) and 3 (M3) months of venlafaxine antidepressant treatment. They were compared to 32 age- and sex-matched healthy controls (HCs). Olfaction was assessed with a psychophysical test, the Sniffin’ Sticks test (Threshold: T score; Discrimination: D score; Identification: I score; total score: T + D + I = TDI score) and Pleasantness (pleasantness score: p score; neutral score: N score; unpleasantness score: U score).

As compared to HCs, depressed patients had lower TDI olfactory scores [mean (s.d.) 30.0(4.5) v. 33.3(4.2), p < 0.001], T scores [5.6(2.6) v. 7.4(2.6), p < 0.01], p scores [7.5(3.0) v. 9.8(2.8), p < 0.001)] and higher N scores [3.5(2.6) v. 2.1(1.8), p < 0.01]. T, p and N scores at baseline were independent from depression and anhedonia severity. After venlafaxine treatment, significant increases of T scores [M1: 7.0(2.6) and M3: 6.8(3.1), p < 0.01] and p scores [M1: 8.1(3.0) and M3: 8.4(3.3), p < 0.05] were evidenced, in remitters only (T: p < 0.01; P: p < 0.01). Olfaction improvement was mediated by depression improvement.

The olfactory signature of MDE is restored after venlafaxine treatment. This olfaction improvement is mediated by depression improvement.