With the trend of population ageing, cognitive frailty in older adults is an increasingly pressing public health issue. Identifying early-stage risk factors has become a key priority for researchers with the goal of preventing disability. This study aimed to test a conceptual model and elucidate the pathways leading to cognitive frailty using Structural Equation Modelling (SEM). We conducted a cross-sectional design with data from outpatient departments within a tertiary medical centre in southern Taiwan. Participants (n = 208) were aged 65 years or older and able to communicate independently with the researchers. Demographic factors, extant health conditions, and psychosocial factors were collected. Structural Equation Modelling (SEM) was used to construct a path model. Olfactory function was significantly positively correlated with nutritional status and significantly negatively correlated with depressive symptoms, resilience, and cognitive frailty. Nutritional status was significantly negatively correlated with sarcopenia. Resilience was significantly positively correlated with social support but negatively correlated with sarcopenia. Sarcopenia was significantly positively correlated with cognitive frailty. Social support was significantly negatively correlated with cognitive frailty. Despite these associations, in this model, only one specific serial indirect pathway-via resilience and social support-demonstrated a statistically significant mediating effect between olfactory function and cognitive frailty. The findings suggest that the association between olfactory function and cognitive frailty may involve a limited, pathway-specific serial mediation through resilience and social support. Clinically, this pathway may help to inform the early identification of older adults with olfactory impairment who may benefit from targeted supportive strategies aimed at strengthening resilience and social support.

Influence of Impaired Olfaction Before Cardiac Surgery on Identifying Risk for Mortality, Perioperative Neurocognitive Dysfunction, Quality of Life, or Adverse Behavioral Outcomes.

Association of OBPIIa genetic variants with prodromal Parkinsonian phenotypes and dopaminergic biomarkers in the PPMI cohort.

Olfactory impairment is common in older adults and has been linked to weight loss and functional decline. This study aimed to examine whether olfactory impairment is associated with an accelerated decline in muscle strength among older adults. We analyzed data from 2,348 participants (aged 71-82 years; 48.0% men; 37.5% Black) in the Health, Aging, and Body Composition Study. Olfactory function was assessed using the Brief Smell Identification Test at the Year 3 clinical visit (1999-2000) and categorized as good (scores 11-12), moderate (9-10), hyposmia (7-8), or anosmia (0-6). Participants were followed for up to 7 years. Grip strength and quadriceps strength were measured at clinical visits in Years 4, 6, 8, and 10. During follow-up, participants with anosmia experienced a faster decline in grip strength than those with good olfaction. The annual difference in decline was -0.19 kg/year (95% CI: -0.37, -0.01) for men and -0.21 kg/year (95% CI: -0.37, -0.05) for women. For quadriceps strength, men with anosmia had a greater annual decline (-1.26 Nm/year; 95% CI: -2.26, -0.26), whereas no statistically significant association was observed in women. Anosmia in older adults is associated with accelerated decline in muscle strength.These findings suggest that olfactory impairment may serve as an early marker of neuromuscular aging. Further research is warranted to investigate the underlying mechanisms.

Olfactory dysfunction is a hallmark feature of COVID-19, yet the potential for recovery with long-standing COVID-19-related smell loss (CRSL) remains uncertain, particularly when treatment is initiated years later. This study evaluated olfactory outcomes in patients with CRSL compared with non-COVID-19-related smell loss (non-CRSL), with emphasis on delayed treatment initiation. This retrospective cohort study included 104 patients evaluated at a tertiary clinic between January 2023 and February 2025, comprising 47 patients with CRSL and 57 with non-CRSL. All patients completed serial Sniffin' Sticks testing (threshold, discrimination, and identification [TDI]) at ≥2 visits. Minimal clinically important difference (MCID) was defined as a ≥5.5-point increase in TDI score. All patients received olfactory training combined with twice-daily steroid nasal irrigation. Subgroup analyses examined delayed treatment initiation (>2 years), treatment adherence, and COVID-19 vaccination status. Baseline TDI scores were higher in the CRSL group than in the non-CRSL group (19.6±6.3 vs. 16.8±6.8; p<0.05). The CRSL group demonstrated significant improvement in TDI scores at follow-up (19.6±6.3 to 23.9±6.5; p<0.001), with 46% achieving MCID, whereas the non-CRSL group showed no significant change. Among CRSL patients initiating therapy >2 years after onset (n=36; mean 30.8±5.5 months), 50% achieved MCID. Treatment adherence was strongly associated with improvement, whereas COVID-19 vaccination showed a favorable but attenuated association after adjustment. Clinically meaningful olfactory recovery remains achievable with long-standing CRSL, even when treatment is initiated >2 years after onset. Prospective studies are needed to clarify causal relationships given known spontaneous recovery in post-viral olfactory dysfunction.

Anosmia and hyposmia, referring to total or partial smell loss, respectively, affect 3-20% of people. The Sniffin' Sticks Extended Test, assessing odor threshold, discrimination, and identification (TDI), is a well-validated tool widely used in European and U.S. clinics. However, its time and resource demands limit routine use. During the COVID-19 pandemic, several rapid smell tests were developed, yet their classification performance and agreement with established psychophysical measures remain underexplored. We compared four alternatives-the Visual Analogue Scale for self-rated smell ability (VAS), the smell section of the Appetite, Hunger, and Sensory Perception questionnaire (AHSP), the Global Consortium for Chemosensory Research Smell Check (GCCR-Check), and the SCENTinel rapid smell test-against TDI scores in a longitudinal cohort of 96 adults (77 female patients; age 46.6 ± 10.5 years) with post-COVID-19 smell dysfunction, assessed up to five times over 12 months. Analyses used Generalized Estimating Equations for repeated measures, Bland-Altman plots for agreement and bias, and Receiver Operating Characteristic (AUC) curves for classification. No tool dominated across all TDI-defined categories. SCENTinel showed robust performance for anosmia (0.81) with the most balanced sensitivity-specificity trade-off among rapid tests, while GCCR-Check achieved the highest AUC for anosmia (0.88) and VAS best identified normosmia (0.73). Agreement analyses revealed systematic biases in self-report and rapid psychophysical tests. Rapid tools reliably detect anosmia, while classification performance decreases near diagnostic boundaries, particularly for normosmia. Combining brief self-report and short psychophysical measures may improve accuracy while maintaining feasibility for clinical and large-scale screening.

Structural brain network alterations in schizophrenia and ultra-high risk populations: Linking olfactory dysfunction to clinical symptoms.

Temporal dynamics of olfactory training-induced neuroplasticity: an fMRI study using variable-onset hemodynamic response modelling.

Novel olfactory cleft computed tomography staging system reveals a trizone anatomic model and biphasic progression in central compartment atopic disease.

Vaccinia virus (VACV) and monkeypox virus (MPXV) are closely related members of the family Poxviridae, genus Orthopoxvirus, both capable of causing systemic infections with potential neurological complications. Although live, replication-competent VACV strains were historically used in smallpox vaccination, their clinical use was associated with rare but severe central nervous system (CNS)-related adverse events. Despite this, the mechanisms underlying VACV-induced CNS pathology, particularly olfactory dysfunction, remain poorly characterized. In this study, we found VACV-VR1354, a tissue culture-adapted derivative of the neurovirulent Western Reserve strain, can invade the CNS via the olfactory route and induce olfactory impairment. By using an intranasal infection model in two inbred mouse strains-C57BL/6N and BALB/c, we demonstrate that VACV-VR1354 efficiently disseminates from the nasal mucosa to the brain, as evidenced by a spatiotemporal gradient of viral DNA load (nasal mucosa > olfactory bulb > cerebrum > cerebellum). Evans blue extravasation assays indicated a transient increase in blood-brain barrier (BBB) permeability in the olfactory bulb, peaking at 7 days post-infection (dpi) and resolving by 14 dpi, with more pronounced effects in C57BL/6N mice. Neuroinvasion was accompanied by robust microglial and astrocytic activation, as well as injury to mature olfactory sensory neurons, particularly at 7 dpi. Transcriptomic profiling of the olfactory bulb revealed significant downregulation of olfactory receptor (OR) genes, with the downregulated genes significantly enriched in olfactory transduction pathways. Concurrently, strong upregulation of proinflammatory cytokines, chemokines, and interferon-stimulated genes (ISGs) was detected in the olfactory bulb tissue, indicative of intense neuroinflammation. Behaviorally, infected C57BL/6N mice exhibited impaired aversion to camphor odor between 14 and 49 dpi, with full functional recovery observed by 56 dpi. Collectively, our findings showed that intranasal infection of mice with VACV-VR1354 leads to a transient increase BBB permeability, neuroinflammation, and reversible olfactory/chemosensory impairment. This murine model recapitulates key features of post-viral olfactory loss and establishes a valuable platform for mechanistic studies of orthopoxvirus neuropathogenesis and therapeutic evaluation of interventions targeting viral neuroinvasion and sensory recovery.

We aimed to determine the prevalence, risk factors, patient-centered impact and health-related costs of three types of dual sensory impairment (DSI) in a multi-ethnic older Asian population. In this population-based, cross-sectional study (2017-2022) of 2048 Asian adults aged ≥ 60years, vision, hearing and olfactory impairments (VI, HI and OI) were assessed using validated clinical tests. DSI types included: VI + HI, VI + OI, and HI + OI. Age-, sex-, and ethnicity-adjusted prevalence rates (2020 Singapore Census) were calculated. Regression analyses identified associated risk factors, impacts and healthcare costs. Of the 2048 participants (mean age ± standard deviation 75.7 ± 7; 49.5% female), prevalence rates of VI + OI, VI + HI, OI + HI were 1.0%, 7.3% and 21.7%, respectively. Older age (odds ratio[OR]1.22) and multimorbidity (OR3.74) were significantly associated with VI + HI, while older age (OR1.23), males (OR3.62), living alone (OR2.37) and current smoking (OR2.51) were associated with higher odds of OI + HI. VI + HI was associated with lower HRQoL-scores (β:- 0.026), while VI + HI (OR2.39) and OI + HI (OR2.10) were associated with lower IADL status. The OI + HI group showed a trend toward higher healthcare costs compared to those without. DSI, particularly OI + HI, is relatively prevalent in older Singaporean adults. Early identification and targeted screening of at-risk groups may mitigate adverse outcomes and healthcare cost, given the global ageing population.

The olfactory nerve possesses unique anatomical features, including direct central nervous system (CNS) projection and continuous regeneration. Scientific advances have elucidated mechanisms such as combinatorial receptor coding and signal amplification. This review summarizes these foundations and examines olfactory dysfunction in COVID-19 and Parkinson's disease (PD). In COVID-19, evidence suggests that SARS-CoV-2 targets sustentacular cells rather than olfactory neurons, causing gene downregulation and parosmia attributed to incomplete peripheral filtering, while direct CNS invasion remains rare. In PD, olfactory loss is a prodromal feature. However, seed amplification assays reveal that alpha-synuclein aggregation in the nasal mucosa does not fully correlate with olfactory dysfunction, as reflected by differences between PD and Multiple System Atrophy. This, together with correlations with cardiac sympathetic denervation, challenges simple pathogen propagation hypotheses. We propose that PD-related hyposmia reflects a systemic vulnerability involving deficits in energy metabolism and neural network organization, rather than solely peripheral protein aggregation. Understanding these pathologies requires a multifaceted approach beyond anatomical lesions.

Autism spectrum disorder (ASD) is a heterogeneous developmental disconnection syndrome. Identifying circuit deficits is crucial for understanding ASD etiology, yet the involvement of multiple brain regions and genetic variations complicates this analysis. Here, using an AI-powered mapping platform, BM-auto (Brain Mapping with Auto-ROI correction), to analyze a Thy1-YFP reporter, we show that different ASD-associated mutations cause distinct circuit abnormalities but share common deficits in the piriform cortex, a region regulating olfactory discrimination and social behavior patterns. We analyzed the whole-brain distribution of the Thy1-YFP reporter in three ASD mouse models (Tbr1+/-, Nf1+/-, and Vcp+/R95G). YFP signals revealed altered axonal projections and structural connectivity. We also found that Thy1-YFP+ cell numbers varied across brain regions, revealing deficits in the differentiation or maintenance of projection neurons. While each mutation caused unique connectivity alterations, sensory regions-including the visual, somatosensory, and piriform cortices-were recurrently affected. However, effects on the visual and somatosensory cortices varied between models. The piriform cortex was the only region consistently impaired, showing reduced YFP signals and fewer Thy1-YFP+ neurons across all three models. Furthermore, all three mutants exhibited common olfactory discrimination impairments. Manipulating piriform cortex activity altered social behavior patterns, highlighting its role in ASD-linked circuit dysfunction. These findings underscore the vulnerability of sensory regions-especially the piriform cortex-to ASD-related mutations, strengthening the notion that altered sensory experiences are common in ASD.

Additive effect of free-choice olfactory training combined with pharmacotherapy: A retrospective analysis of post-viral olfactory dysfunction.

An accurate forecasting of the COVID-19 pandemic’s trajectory is crucial for informing effective prevention and control strategies. The aim of this study was to develop and compare COVID-19 forecasting models (SEIR, ARIMAX, and LSTNet) incorporating multi-symptom Google Trends signals, and to evaluate whether PCA-derived components improve out-of-sample prediction of daily confirmed cases. We conducted a correlation analysis between the confirmed cases numbers from Johns Hopkins University’s COVID-19 database and the symptomatology data from Google Trends. SEIR, ARIMAX and LSTNet model were established respectively based on this data and compared their predictive performance. Symptom-related Google Trends series were strongly correlated (e.g. taste loss vs smell loss r = 0.96, 95% compatibility interval (CI) [0.952, 0.967], p = 1.59 × 10−26; weakest pair: shortness of breath vs cough r = 0.49, CI: [0.414, 0.559], p = 4.12 × 10−27). During the Delta-predominant period, a 1-unit increase in taste-loss Google Trends was associated with 2335.57 additional daily cases CI [1738.47, 2932.67], p = 2.4 × 10−13); during the Omicron-predominant period, the estimate was 3361.13 ([2649.43, 4072.83], p = 6.06 × 10−19).It was suggested that the correlation was always strong in the epidemic periods of different SARS-COV-2 variants. Furthermore, Principal Component Analysis (PCA) was conducted, results showed the cumulative contribution rate reached at 93.04%. The Google Trends data after PCA (PCAGT) was introduced into different prediction models to improve the performance, and the results showed the SEIR model could predict the number of daily newly confirmed cases in the next 7 days with a Mean Absolute Error (MAE) of 5.30 × 103 and an RMSE of 6.60 × 103. Comparing the error of the predicted value and the actual value within 5 weeks, after incorporating PCAGT, the error of the ARIMAX model drops from 16.5% to 0.2%, and the error of the LSTNet model drops from 11.3% to 10.1%, and the improvement effect of ARIMAX was better when PCAGT was included. The ARIMAX model incorporating PCAGT had the best prediction performance with a prediction error of only 0.2% within 5 weeks. Symptom-related Google Trends were robustly associated with COVID-19 case trends across pandemic periods, and PCA-derived aggregated signals improved short-term forecasting performance, with ARIMAX+PCAGT performing best. Not applicable.

We aimed to explore the occurrence and persistence of symptoms, diagnoses and prescribing after COVID-19 among populations from earlier (wave 2) and later (wave 4) in the pandemic. With the approval of NHS England, we analysed data from English primary care using The Phoenix Partnership SystmOne through the OpenSAFELY data analytics platform. Individuals with community-diagnosed COVID-19 September 2020-January 2021 (wave 2) were matched to contemporary (2020-2021) and historical (2017-2018) comparators. Individuals with community COVID-19 December 2021-March 2022 (wave 4) were matched to contemporary comparators (last follow-up 31 March 2023). Occurrence of each of (1) long-COVID symptoms; (2) primary-care diagnoses and (3) new prescriptions was analysed at any time during 1 year after COVID-19 and at: 4-12 weeks, 12 weeks-6 months and 6 months-12 months after COVID-19 to assess persistence. 902 885 COVID-19 cases (wave 2) matched to 4 449 265 contemporary (no-COVID-19) comparators. 1 553 160 COVID-19 cases (wave 4) matched to 7 624 770 contemporary comparators. Positive wave 2 associations after COVID-19 were observed for hair loss (OR 1.57, 95% CI 1.48 to 1.66), mobility impairment (1.41, 1.35 to 1.48), fatigue (1.46, 1.42 to 1.49), cognitive impairment (1.39, 1.34 to 1.44) and loss of taste or smell (1.38, 1.31 to 1.46). At 6-12 months reporting persisted for mobility impairment, fatigue and cognitive impairment. There were small increases in new prescriptions for NSAIDs (1.24, 1.23 to 1.26), drugs to treat infections (1.24, 1.23 to 1.25) and musculoskeletal problems (1.23, 1.22 to 1.25). Wave 4 associations were generally weaker than Wave 2. Long-COVID symptoms and new prescribing generally reduce over time and are potentially less problematic following less severe illness. Fatigue/cognitive/mobility symptoms persist following COVID-19.

Aging is characterized by a decline in essential sensory functions, including olfaction, which is crucial for environmental interaction and survival. This decline is often paralleled by the cellular accumulation of dysfunctional mitochondria, particularly detrimental in post-mitotic cells, such as neurons. Mitochondrial stress triggers the mitochondrial unfolded protein response (UPRMT), a pathway that activates mitochondrial chaperones and antioxidant enzymes. Critical to the efficacy of the UPRMT is the cellular chromatin state, influenced by the methylation of lysine 9 on histone 3 (H3K9). While it has been observed that the UPRMT response can diminish with an increase in H3K9 methylation, its direct impact on age-related neurodegenerative processes, especially in the context of olfactory function, has not been clearly established. Using Drosophila, we demonstrate that an age-dependent increase in H3K9 trimethylation by the methyltransferase dSetdb1 reduces the activation capacity of the UPRMT in olfactory projection neurons, leading to neurodegeneration and loss of olfactory function. Age-related neuronal degeneration was associated with morphological alterations in mitochondria and an increase in reactive oxygen species levels. Importantly, forced demethylation of H3K9 through knockdown of dSetdb1 in olfactory projection neurons restored the UPRMT activation capacity in aged flies, and suppressed age-related mitochondrial morphological abnormalities. This, in turn, prevented age-associated neuronal degeneration and rescued age-dependent loss of olfactory function. Our findings highlight the effect of age-related epigenetic changes on the response capacity of the UPRMT, impacting neuronal integrity and function. Moreover, they suggest a potential therapeutic role for UPRMT regulators in age-related neurodegeneration and loss of olfactory function.

Olfactory dysfunction (OD) secondary to chronic rhinosinusitis (CRS) significantly impairs quality of life by hindering the detection of warning signals and reducing nutritional satisfaction. CRS, a prevalent inflammatory condition, commonly leads to diminished or complete loss of smell. A substantial component of CRS-associated OD is conductive, stemming from impaired odorant delivery to the olfactory neuroepithelium. The tools for assessing conductive OD range from clinical evaluations like endoscopy and CT scoring of the olfactory cleft to objective measures of nasal patency and advanced computational fluid dynamics modeling. The underlying conductive mechanisms are multifactorial, primarily involving two interrelated pathways: alterations in nasal airflow dynamics due to anatomical variations or obstructive lesions, and pathological changes in the physicochemical properties of olfactory cleft mucus. Obstructions from septal deviation, turbinate hypertrophy, nasal polyps, and mucosal edema within the olfactory cleft disrupt and redistribute inspiratory airflow, critically reducing odorant access. Concurrently, inflammation-driven changes in the olfactory mucus—including hypersecretion, ionic imbalance, and deficiencies in odorant-binding proteins and metabolizing enzymes—impair odorant transport, solubilization, and signal transduction. Current therapeutic strategies, such as endoscopic sinus surgery and corticosteroids, aim to relieve these conductive barriers but may offer only partial or temporary benefit, highlighting the need for precise phenotyping. A systematic, individualized assessment of both airflow patterns and mucus properties is crucial for understanding the conductive contribution and predicting outcomes. This review synthesizes current evidence on the conductive mechanisms of olfactory loss in CRS, evaluating the impact of nasal aerodynamics and mucus alterations, and discusses integrated management strategies for this debilitating condition.

Alzheimer’s Disease (AD) is a neurodegenerative condition affecting millions worldwide. Defining early pathobiological events remains challenging, in part due to inaccessibility of neural tissue. Because olfactory neurons are accessible, and olfactory loss is prevalent in AD, we evaluated olfactory brush biopsies from controls, individuals with cerebrospinal fluid (CSF) biomarker-confirmed AD, and cognitively typical individuals whose positive CSF biomarkers signal a pre-clinical AD stage. Here we show via single cell RNA-sequencing (n = 22 subjects) conserved neuroinflammatory T cell, myeloid cell, and olfactory neuron changes detectable even in pre-clinical AD subjects, and corroborate heightened CD8 T-cell activation by flow cytometry. Activated memory T cell states in the olfactory epithelium were a hallmark of pre-clinical AD, paralleling CSF T cell phenotypes seen in advanced disease, accompanied by both microglia-like inflammatory programs and evidence of olfactory neuron inflammatory injury. Together, our findings establish a platform permitting analysis of neural tissue in AD at its earliest stages.

Background: SARS-CoV-2 has evolved into multiple variants with potential differences in transmissibility, pathogenicity, and clinical presentation. Understanding variant-specific symptom profiles is essential for improving surveillance, diagnosis, and clinical management, particularly in resource-limited settings where genomic sequencing is limited. Objective: To compare the clinical characteristics associated with Alpha, Beta, Gamma, and Delta SARS-CoV-2 variants among PCR-confirmed COVID-19 cases in Khyber Pakhtunkhwa, Pakistan. Methods: A cross-sectional observational study was conducted at the Public Health Reference Laboratory, Khyber Medical University, using PCR-confirmed COVID-19 cases recorded between 2020 and 2023. SARS-CoV-2 variants were identified using mutation-specific PCR assays. Clinical and demographic data were collected through structured telephone interviews based on the World Health Organization COVID-19 case report form. Descriptive statistics and inferential analyses including chi-square and Fisher–Freeman–Halton tests were performed using SPSS version 25, with statistical significance set at p&lt;0.05. Results: Among 416 participants, the Delta variant accounted for the majority of infections (310; 74.5%), followed by Gamma (60; 14.4%), Alpha (36; 8.7%), and Beta (10; 2.4%). Delta infections were strongly associated with fever, cough, sore throat, body aches, and loss of smell and taste, each exceeding 94% prevalence. Gamma infections demonstrated high rates of fatigue, rigors, chills, rhinorrhea, and shortness of breath (&gt;90%), whereas Beta infections showed prominent gastrointestinal symptoms including nausea and vomiting (70%). Alpha infections had the highest proportion of asymptomatic cases (27.8%). Conclusion: SARS-CoV-2 variants exhibited distinct clinical phenotypes in this population, with Delta characterized by respiratory and sensory symptoms, Gamma by systemic inflammatory manifestations, and Beta by gastrointestinal involvement. Recognition of variant-specific symptom clusters may support improved clinical detection and epidemiological surveillance in settings with limited genomic sequencing capacity.