Abstract Objectives Cognitive and behavioral phenomena define behavioral variant frontotemporal dementia (bvFTD), but neuropsychiatric symptoms (NPS) outside the core criteria are common throughout the illness. Identifying how NPS cluster in bvFTD may clarify the underlying neurobiology of bvFTD-related NPS and guide development of therapies. Methodology Participants (N=354) with sporadic and genetic bvFTD were enrolled in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium. Dementia stage was defined as early (CDR® plus NACC FTLD ≤ 1) or advanced (CDR® plus NACC FTLD ≥ 1). Baseline and annual follow-up visit data were analyzed to compare NPS across stages of bvFTD. Psychiatric states were captured using the Neuropsychiatric Inventory-Questionnaire and Clinician Judgement of Symptoms. Polychoric cluster analysis was used to describe NPS clusters. Results NPS were highly prevalent (≥ 90%) in early and late bvFTD. Four NPS clusters were identified based on magnitude of factor loadings: affective, disinhibited, compulsive, and psychosis. Neuropsychiatric symptoms fluctuated across visits. In the affective cluster, depression and anxiety showed the least visit-to-visit stability. In the disinhibited cluster, elation showed the least stability. Symptoms in the psychosis and compulsive clusters (hallucinations, delusions, obsessions/compulsions, and hyperorality) were largely stable, persisting from visit-to-visit in more than 50% of cases. Conclusion NPS in bvFTD are frequent and cluster into four discrete groups in bvFTD. These clusters may result from specific neural network disruptions that could serve as targets for future interventions. The fluctuating nature of NPS in bvFTD suggests that they are not reliable markers of disease progression or stage.
Traumatic brain injury has been associated with short-term olfactory dysfunction, but the association of number of prior head injuries and head injury severity with both subjective and objective long-term olfactory function is less clear.To investigate the associations of prior head injury, number of prior head injuries, and head injury severity with subjective and psychophysical (objective) olfactory function in older adults and to examine concordance between subjective and objective olfactory function among individuals with and without head injury.This prospective cohort study included 5951 participants who attended Atherosclerosis Risk in Communities (ARIC) Study visit 5 (2011 through 2013). Data analysis was performed between November 2021 and May 2022.Head injury was defined by self-report and International Classification of Diseases codes.Self-reported subjective olfactory dysfunction was assessed by the question, "Do you suffer from smell loss or a significantly decreased sense of smell?" Objective olfactory performance was assessed using the 12-item Sniffin' Sticks odor identification test.Overall, the 5951 participants were a mean (SD) age of 75.6 (5.2) years, 3501 (58.8%) were female, 1356 (22.8%) were of Black race, and 1666 (28.0%) had a history of head injury. Participants with prior head injury were more likely than individuals without prior head injury to report subjective olfactory dysfunction (24% vs 20%; difference, 4%; 95% CI, 1% to 6%) and have objective anosmia (15% vs 13%; difference, 2%; 95% CI, 0.1% to 4%) but had lower concordance between subjective and objective assessment (72% vs 77%; difference, -5%; 95% CI, -8% to -3%). In logistic regression models adjusted for sociodemographics and medical comorbidities including cognitive status, participants with a history of prior head injury, particularly individuals with 2 or more prior head injuries and more severe head injuries, were more likely to self-report subjective olfactory dysfunction and were more likely to be found to have objective anosmia compared with participants with no history of head injury.Findings of this cohort study provide evidence supporting the association between head injury and olfactory dysfunction, particularly among individuals who experienced multiple prior head injuries and among individuals with more severe head injury. The findings also suggest that individuals with prior head injury were more likely to both under-self-report and over-self-report deficits compared with objective olfactory testing; therefore, it may be important to consider objective olfactory testing in this patient population.
Objective: 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. Participants and Methods: 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. Results: 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). Conclusions: 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.
Abstract Smell deficits and neurobiological changes in the olfactory bulb (OB) and olfactory epithelium (OE) have been observed in schizophrenia and related disorders. The OE is the most peripheral olfactory system located outside the cranium, and is connected with the brain via direct neuronal projections to the OB. Nevertheless, it is unknown whether and how a disturbance of the OE affects the OB in schizophrenia and related disorders. Addressing this gap would be the first step in studying the impact of OE pathology in the disease pathophysiology in the brain. In this cross-species study, we observed that chronic, local OE inflammation with a set of upregulated genes in an inducible olfactory inflammation (IOI) mouse model led to a volume reduction, layer structure changes, and alterations of neuron functionality in the OB. Furthermore, IOI model also displayed behavioral deficits relevant to negative symptoms (avolition) in parallel to smell deficits. In first episode psychosis (FEP) patients, we observed a significant alteration in immune/inflammation-related molecular signatures in olfactory neuronal cells (ONCs) enriched from biopsied OE and a significant reduction in the OB volume, compared with those of healthy controls (HC). The increased expression of immune/inflammation-related molecules in ONCs was significantly correlated to the OB volume reduction in FEP patients, but no correlation was found in HCs. Moreover, the increased expression of human orthologues of the IOI genes in ONCs was significantly correlated with the OB volume reduction in FEP, but not in HCs. Together, our study implies a potential mechanism of the OE-OB pathology in patients with psychotic disorders (schizophrenia and related disorders). We hope that this mechanism may have a cross-disease implication, including COVID-19-elicited mental conditions that include smell deficits.
Decreased olfactory function is very common in the older population, being present in over half of those between the ages of 65 and 80 years and in over three quarters of those over the age of 80 years. Such dysfunction significantly influences physical well-being and quality of life, nutrition, the enjoyment of food, as well as everyday safety. Indeed a disproportionate number of the elderly die in accident gas poisonings each year. As described in this review, multiple factors contribute to such age-related loss, including altered nasal engorgement, increased propensity for nasal disease, cumulative damage to the olfactory epithelium from viral and other environmental insults, decrements in mucosal metabolizing enzymes, ossification of cribriform plate foramina, loss of selectivity of receptor cells to odorants, changes in neurotransmitter and neuromodulator systems, and neuronal expression of aberrant proteins associated with neurodegenerative disease. It is now well established that decreased smell loss can be an early sign of such neurodegenerative diseases as Alzheimer's disease and idiopathic Parkinson's disease. In this review we provide an overview of the anatomy and physiology of the aging olfactory system, how this system is clinically evaluated, and the multiple pathophysiological factors that are associated with its dysfunction.
Abstract Objective Olfactory dysfunction has been well documented in individuals with temporal lobe epilepsy, but its use in presurgical planning has yet to be examined. We assessed the role of preoperative odor identification in mesial onset seizure localization utilizing stereoelectroencephalography (S‐EEG) and magnetic resonance–guided laser interstitial thermal therapy (MRgLiTT) outcome. Methods We identified 30 patients who had typical seizures captured during S‐EEG monitoring or MRgLiTT of mesial temporal structures (n = 17 S‐EEG, n = 13 MRgLiTT); seizure onset zone was classified as unilateral mesial seizure onset, or multifocal with unilateral mesial onset and nonmesial onset. Odor identification ability was assessed using the Sniffin’ Sticks Odor Identification Test (SSOIT). Patients also completed measures of confrontation naming and auditory‐verbal learning/memory using the Boston Naming Test and Hopkins Verbal Learning Test–Revised, respectively. Results Overall, patients with intractable focal epilepsy exhibited poor olfactory performance (median [M] = 10.4, interquartile range [IQR] = 9.4‐11.8). Of 19 patients who underwent MRgLiTT, 10 patients (52.6%) were seizure‐free at last follow‐up (M = 13 months, IQR =10‐18). Patients who were seizure‐free after MRgLiTT (n = 10) had poorer odor identification scores (M = 9, IQR = 7‐13) compared to patients with seizure reoccurrence (M = 13, IQR = 12.5‐15). Odor identification score was inversely associated with seizure freedom, with odds ratio = 0.60 (95% confidence interval [CI] = 0.38‐0.95, P = .03). Receiver operating characteristic analysis revealed that an SSOIT score of 12 was the ideal cutoff for predicting favorable seizure outcome (area under the curve = 0.84, 95% CI = 0.64‐1.0). Sensitivity was 88.9% and specificity was 78.9%, with a likelihood ratio of 2.9 of seizure failure in patients who had an odor identification score ≥ 12. Significance Interictal olfactory dysfunction is commonly seen in patients with intractable focal epilepsy. Odor identification is a novel, noninvasive presurgical biomarker to distinguish who may or may not benefit from MRgLiTT of mesial temporal structures.
