Biology subjects

Joseph, T.

Publications and source records attributed to Joseph, T..

16 recordsLinked to original sources

bioRxiv2026

Long-term voluntary exercise reveals limited translation of hippocampal molecular responses into neuroprotection in 5xFAD mice

Physical exercise promotes systemic and neural adaptations that support healthy brain aging and may mitigate Alzheimers disease (AD) progression. However, the capacity of the AD-afflicted brain to mount and translate exercise-responsive molecular adaptations into neuroprotection remains unclear. Here, we examined the effects of long-term voluntary wheel running (VWR) on molecular, neuropathological, and behavioral outcomes in independently studied male and female 5xFAD mice. VWR elicited expected metabolic and transcriptional remodeling of inguinal white adipose tissue, confirming engagement of exercise-responsive peripheral biology. In contrast, hippocampal transcriptional responses were modest, with few differentially expressed genes and coordinated changes emerging primarily at the pathway level. These responses involved synaptic, neuroimmune, mitochondrial, neurotrophic, and monoaminergic processes and differed qualitatively between the two groups. Several components of the canonical hippocampal exercise response also failed to converge into coordinated cellular adaptations: synaptic protein abundance changed without altering synapse density, while neurotrophic, neurogenic, and vascular responses showed little correspondence across molecular and cellular measures. VWR also produced little change in hippocampal amyloid pathology or behavioral function despite sustained exercise engagement. Together, these findings demonstrate that the 5xFAD brain retains modest molecular responsiveness to prolonged voluntary exercise but may be unable to mount a sufficiently robust or coordinated response to produce broad neuroprotective effects. These findings highlight disease context as an important determinant of the efficacy of exercise-based interventions in neurodegenerative disease.

neuroscience↗

bioRxiv2026

Single-nuclei RNA-sequencing uncovers sexually divergent exercise signatures partially mimicked by TFEB overexpression in mouse skeletal muscle

Exercise induces extensive, cell-type-specific transcriptional remodeling in skeletal muscle to support metabolic flexibility and adaptation. However, the regulatory mechanisms underlying these transcriptional programs, and the extent to which they differ between sexes, remain poorly defined. We previously reported that lifelong, muscle-specific overexpression of human Transcription Factor E-B (cTFEB;HSACre transgenic mice) recapitulates many adaptive features of endurance training in both sexes, leading to profound geroprotective effects during aging even in the absence of exercise. Here, we profile transcriptional adaptations to voluntary wheel running (VWR) and TFEB-overexpression at single-nucleus resolution in young male and female mouse tibialis anterior muscle. This represents, to our knowledge, the first integrated analysis of exercise and TFEB signaling using sex as a biological variable. Using robust bioinformatic and single-nuclei RNA-sequencing approaches, we profiled six muscle-resident cell populations and uncover previously unrecognized, sex-dependent signaling nodes governing exercise-associated metabolic plasticity. TFEB activation and endurance training by VWR elicit strongly correlated transcriptional programs enriched for lipid metabolism, mitochondrial remodeling, and immune modulation, establishing TFEB-overexpression as a partial exercise mimetic. In general, female muscle exhibited enhanced extracellular matrix and lipid-associated responses to endurance training and TFEB overexpression, whereas males preferentially engaged in angiogenic and oxidative networks, revealing distinct sex-specific, sex-dimorphic, or sex-agnostic regulatory routes to metabolic flexibility. Integration with independent multi-omics datasets from endurance-trained rats (MoTrPAC) confirms the conservation of TFEB-exercise transcriptional convergence in skeletal muscle across species and potentially muscle types. Together, these findings define TFEB as a regulator of exercise transcriptional programs and reveal sex-specific molecular frameworks that drive metabolic adaptation in skeletal muscle. Furthermore, the resulting sex-resolved, single-nucleus transcriptional atlas provides a unique resource for the field, enabling comparative, mechanistic, and hypothesis-driven exploration of exercise-responsive skeletal muscle regulatory networks across sexes.

physiology↗

bioRxiv2025

Impact of N6-methyladenosine (m6A) machinery on HIV-1 replication in primary CD4+ T cells

N6-methyladenosine (m6A) is the most prevalent internal modification of cellular and viral RNA and is critical to the regulation of its localization, stability, and translation. Previous studies on the role of m6A during HIV-1 replication have produced conflicting results. Since m6A function can vary dramatically by cell type and state, here we aimed to clarify the role of the m6A machinery during HIV-1 replication in primary CD4+ T cells. Using CRISPR-Cas9 we targeted 46 cellular genes implicated in m6A or 5-methylcytosine (m5C) regulation and measured subsequent HIV-1 replication in primary CD4+ T cells. Only knockout of the m6A writer complex auxiliary proteins VIRMA and WTAP, and the m6A reader YTHDF2 were validated as significantly decreasing HIV-1 replication. In contrast, knockout of METTL3 or METTL14, which form the catalytic core of the writer complex, resulted in only marginal changes in HIV-1 infection, despite significant decreases in total cellular m6A levels. Chemical inhibition of METTL3 led to a dose-dependent decrease in HIV-1 infection, coupled with an increase in protein levels of METTL3 and other writer complex members. Expression of writer proteins was also co-dependent, revealing complex regulatory feedback mechanisms. Overall, these results clarify the role of epitranscriptomic machinery during HIV-1 replication in primary CD4+ T cells and suggest regulation by auxiliary members of the m6A writer complex is more influential than the function of the catalytic core itself on HIV-1 infection in primary CD4+ T cells. IMPORTANCEm6A is the most common chemical modification on cellular and viral RNA and regulates its stability, localization, and translation. m6A modification and its regulation varies dramatically between cell types and cell states. In this study, we investigated the role of m6A factors during HIV-1 infection of physiologically relevant primary CD4+ T cells. Using CRISPR-Cas9 to knockout 46 cellular genes implicated in RNA modification, we found only the m6A writer complex auxiliary members WTAP and VIRMA, and the reader YTHDF2, significantly affected HIV-1 replication in these cells. In contrast, knockout of METTL3 or METTL14, which form the catalytic core of the writer complex, resulted in marginal changes in HIV-1 infection, despite larger reductions in total cellular m6A levels. Our findings suggest regulation by auxiliary members of the m6A writer complex is more influential than the function of the catalytic core itself on HIV-1 infection in primary CD4+ T cells.

microbiology↗

bioRxiv2025

Dabigatran prevents lipopolysaccharide mediated apoptosis in zebrafish through a thrombin independent mechanism

Endotoxemia is a feature of sepsis pathogenesis and has also been found to mediate the pathophysiology of multiple inflammatory conditions. In this work, we use a lipopolysaccharide (LPS) induced endotoxemia model in zebrafish to identify novel mediators of LPS toxicity. We performed transcriptomic studies on LPS-treated larvae, followed by in silico analysis, which revealed associations between the signatures of LPS-treated embryos and those of drugs involving diverse pathways. In parallel, we performed an in vivo screen using >1,500 FDA-approved compounds and identified multiple novel small molecules that reduced inflammation and prevented LPS toxicity. We focused on the direct thrombin inhibitor dabigatran, which was identified through both the in vivo and in silico analyses. We found that dabigatran co-administration significantly reduced the expression of inflammatory cytokines and completely protected zebrafish from endotoxemic death due to LPS. Surprisingly, we found that this protection occurs in prothrombin mutant fish, proving that protection from endotoxemia occurs independently of the anticoagulant function of dabigatran. We additionally found that dabigatran administration significantly decreased nitric oxide production and apoptosis compared to LPS treatment alone, suggesting possible mechanisms by which protection from endotoxemia is achieved. In summary, we identify several novel small molecules that prevent LPS-induced endotoxemia and show that one such small molecule, dabigatran, exerts a thrombin-independent effect on nitric oxide production and apoptosis. This and the other identified small molecules warrant further exploration in inflammatory conditions including sepsis.

pharmacology and toxicology↗

bioRxiv2025

Mitosis detection in the wild using detection transformers

BackgroundIdentification of mitotic cells and its down-stream analysis, is an important parameter in understanding the pathology of cancer, predicting response to chemotherapy and overall survival. However, their reliable detection remains challenging due to morphological overlap with other cellular structures, resulting in variability and high levels of false positives. Current artificial intelligence (AI) algorithms further face limitations when confronted with tissue heterogeneity and often underperform in non-tumor, inflamed, or necrotic regions. To address these challenges, Track 1 of MIDOG 2025 challenge expands the scope of mitotic figure detection to include all tissue regions, encompassing both hotspot and non-hotspot areas, thereby promoting real-world clinical applicability. MethodsWe propose a generalized deep learning based mitotic detection model (MD model) for robust and accurate detection of mitotic figures using the MIDOG-2025 challenge dataset. Our model enables robust and accurate detection of mitotic figures and demonstrates strong generalization to domain shifts arising from diverse histological regions, variations in scanners, tumor subtypes and laboratory protocols. ResultsOur approach showed a consistent performance with an F1-score of 0.7769 with a high recall of 0.8222. Our approach outperforms the baselines and generalizes well across the tumor types on the preliminary test set. ConclusionOur approach makes the final predictions with reduced false positives and improved detection accuracy. It generalizes well to address the domain shifts caused by diverse histological regions across the different tumor types among others.

pathology↗

bioRxiv2024

Endothelial PHD2 deficiency induces apoptosis resistance and inflammation via AKT activation and AIP1 loss independent of HIF2α

BACKGROUNDIn hypoxic and pseudohypoxic rodent models of pulmonary arterial hypertension (PAH), hypoxia-inducible factor (HIF) inhibition reduces disease severity. However, HIF activation alone, due to genetic alterations or use of inhibitors of prolyl hydroxylase domain (PHD) enzymes, has not been definitively shown to cause PAH in humans, indicating the involvement of other mechanisms. METHODSPseudohypoxia was investigated in primary human lung endothelial cells by silencing PHD2, and in Tie2-Cre/Phd2 knockout mice, a rodent model of PAH. Lung vascular endothelial cells from PAH patients, and lung tissue from both SU5416/hypoxia PAH rats and PAH patients, were examined for validation. RESULTSPHD2 silencing or inhibition, while activating HIF2, induces apoptosis-resistance, hypo-proliferation, and IFN/STAT activation in endothelial cells, independent of HIF signaling. Mechanistically, PHD2 deficiency activates AKT and ERK, inhibits JNK, and reduces AIP1 (ASK1-interacting protein 1), all independent of HIF2. Like PHD2, AIP1 silencing affects these same kinase pathways and produces a similar dysfunctional endothelial cell phenotype, which can be partially reversed by AKT inhibition. These findings are corroborated in lung tissues of rodent PAH models and pulmonary vascular endothelial cells and tissues from PAH patients. CONCLUSIONSPHD2 deficiency in lung vascular endothelial cells induces an apoptosis-resistant, inflammatory, and hypo-proliferative phenotype. AKT activation and AIP1 loss, but not HIF signaling, drive these aberrant phenotypic changes. Our study suggests that HIF blockade alone may not suffice for PAH therapy; targeting PHD2, AKT, and AIP1 has the potential for developing more effective treatment. GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/578286v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1fd0a0borg.highwire.dtl.DTLVardef@19e6ba9org.highwire.dtl.DTLVardef@1ae2827org.highwire.dtl.DTLVardef@ce31ec_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPHD2 silencing in human lung vascular endothelial cells suppresses apoptosis, inhibits proliferation, and activates STAT signaling, effects that persist despite HIF2 inhibition or knockdown. C_LIO_LIPHD2 silencing activates AKT and ERK, inhibits JNK, and decreases AIP1, all independently of HIF2 C_LIO_LILike PHD2, AIP1 silencing led to similar alterations in kinase signaling and endothelial cell phenotypes, which are partially reversed by ATK inhibition. C_LIO_LIThese in vitro findings align with observations in lung vascular endothelial cells and tissues from rodent models of PAH as well as PAH patients. C_LI

cell biology↗

bioRxiv2023

Size dependent steady-state saturation limit in biomolecular transport through nuclear membranes

The nucleus preserves the genomic DNA of eukaryotic organisms and maintains the integrity of the cell by regulating the transport of molecules across the nuclear membrane. It is hitherto assumed that small molecules having a size below the passive permeability limit are allowed to diffuse freely to the nucleus while the transport of larger molecules are regulated via an active mechanism involving energy. Here we report on the kinetics of nuclear import and export of a model system of dextran molecules having a size below the passive permeability limit. The studies carried out using time-lapse confocal fluorescence microscopy show a clear deviation from the passive diffusion model. In particular, it is observed that the steady-state concentration of dextran molecules inside the nucleus is consistently less than the concentration outside, in contradiction to the predictions of the passive diffusion model. Detailed analysis and modeling of the transport show that the nuclear export rates significantly differ from the import rates and the difference in rates is dependent on the size of the molecules. The nuclear export rates are further confirmed by an independent experimental study where we observe the diffusion of dextran molecules from the nucleus directly. Our experiments and transport model would suggest that the nucleus actively rejects exogenous macromolecules even below the passive permeability limit. This result can have significant impact on biomedical research especially in areas related to targeted drug delivery and gene therapy.

biophysics↗

bioRxiv2023

NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy

Meningiomas are the most common primary intracranial tumors1-3. Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental4,5. Resistance to radiotherapy is common in high-grade meningiomas6, and the cell types and signaling mechanisms driving meningioma tumorigenesis or resistance to radiotherapy are incompletely understood. Here we report NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy and find NOTCH3+ meningioma mural cells are conserved across meningiomas from humans, dogs, and mice. NOTCH3+ cells are restricted to the perivascular niche during meningeal development and homeostasis and in low-grade meningiomas but are expressed throughout high-grade meningiomas that are resistant to radiotherapy. Integrating single-cell transcriptomics with lineage tracing and imaging approaches across mouse genetic and xenograft models, we show NOTCH3 drives tumor initiating capacity, cell proliferation, angiogenesis, and resistance to radiotherapy to increase meningioma growth and reduce survival. An antibody stabilizing the extracellular negative regulatory region of NOTCH37,8 blocks meningioma tumorigenesis and sensitizes meningiomas to radiotherapy, reducing tumor growth and improving survival in preclinical models. In summary, our results identify a conserved cell type and signaling mechanism that underlie meningioma tumorigenesis and resistance to radiotherapy, revealing a new therapeutic vulnerability to treat meningiomas that are resistant to standard interventions.

cancer biology↗

bioRxiv2023

A Robust Deep Learning Approach for Joint Nuclei Detection and Cell Classification in Pan-Cancer Histology Images

Advanced image processing methods have shown promise in computational pathology, including the extraction of crucial microscopic features from histology images. Accurate detection and classification of cell nuclei from whole-slide images (WSI) play a crucial role in capturing the molecular and morphological landscape of the tissue sample. They enable widespread downstream applications, including cancer diagnosis, prognosis, and discovery of novel markers. Robust nuclei detection and classification are challenging due to the high intra-class variability and inter-class similarity of the microscopic morphological features. This is further compounded by the domain shift arising due to the variability in tissue types, staining protocols, and image acquisition. Motivated by the ability of the recent deep learning techniques to learn complex patterns in a biasfree manner, we develop a novel and robust deep learning model TransNuc, based on vision transformers, for simultaneous detection and classification of cell nuclei from H&E stained WSI. We benchmarked TransNuc on the comprehensive Open Pan-cancer Histology Dataset (PanNuke), sampled from over 20,000 WSI, comprising 19 different tissue types and five clinically important cell classes, namely, Neoplastic, Epithelial, Inflammatory, Connective, and Dead cells. TransNuc exhibited superior performance compared to the state-of-theart, including Hover-Net and Micro-Net. TransNuc was able to learn robust feature representations and thereby perform consistently better for the abundant classes such as neoplastic, and the under-represented classes such as dead cells. Similar performance gains were also obtained for epithelial and connective classes that have a significant inter-class morphological similarity.

pathology↗

bioRxiv2023

A deep catalog of protein-coding variation in 985,830 individuals

Coding variants that have significant impact on function can provide insights into the biology of a gene but are typically rare in the population. Identifying and ascertaining the frequency of such rare variants requires very large sample sizes. Here, we present the largest catalog of human protein-coding variation to date, derived from exome sequencing of 985,830 individuals of diverse ancestry to serve as a rich resource for studying rare coding variants. Individuals of African, Admixed American, East Asian, Middle Eastern, and South Asian ancestry account for 20% of this Exome dataset. Our catalog of variants includes approximately 10.5 million missense (54% novel) and 1.1 million predicted loss-of-function (pLOF) variants (65% novel, 53% observed only once). We identified individuals with rare homozygous pLOF variants in 4,874 genes, and for 1,838 of these this work is the first to document at least one pLOF homozygote. Additional insights from the RGC-ME dataset include 1) improved estimates of selection against heterozygous loss-of-function and identification of 3,459 genes intolerant to loss-of-function, 83 of which were previously assessed as tolerant to loss-of-function and 1,241 that lack disease annotations; 2) identification of regions depleted of missense variation in 457 genes that are tolerant to loss-of-function; 3) functional interpretation for 10,708 variants of unknown or conflicting significance reported in ClinVar as cryptic splice sites using splicing score thresholds based on empirical variant deleteriousness scores derived from RGC-ME; and 4) an observation that approximately 3% of sequenced individuals carry a clinically actionable genetic variant in the ACMG SF 3.1 list of genes. We make this important resource of coding variation available to the public through a variant allele frequency browser. We anticipate that this report and the RGC-ME dataset will serve as a valuable reference for understanding rare coding variation and help advance precision medicine efforts.

genetics↗

bioRxiv2023

Joint testing of rare variant burden scores using non-negative least squares

Gene-based burden tests are a popular and powerful approach for analysis of exome-wide association studies. These approaches combine sets of variants within a gene into a single burden score that is then tested for association. Typically, a range of burden scores are calculated and tested across a range of annotation classes and frequency bins. Correlation between these tests can complicate the multiple testing correction and hamper interpretation of the results. We introduce a new method called the Sparse Burden Association Test (SBAT) that tests the joint set of burden scores under the assumption that causal burden scores act in the same effect direction. The method simultaneously assesses the significance of the model fit and selects the set of burden scores that best explain the association at the same time. Using simulated data, we show that the method is well calibrated and highlight some scenarios where the test outperforms existing gene-based tests. We apply the method to 73 quantitative traits from the UK Biobank which further illustrates the power of the method. This test is implemented in the REGENIE software.

genetics↗

bioRxiv2022

Genotyping, sequencing and analysis of 140,000 adults from the Mexico City Prospective Study

The Mexico City Prospective Study (MCPS) is a prospective cohort of over 150,000 adults recruited two decades ago from the urban districts of Coyoacan and Iztapalapa in Mexico City. We generated genotype and exome sequencing data for all individuals, and whole genome sequencing for 10,000 selected individuals. We uncovered high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Native American, European and African ancestry, with extensive admixture from indigenous groups in Central, Southern and South Eastern Mexico. Native Mexican segments of the genome had lower levels of coding variation, but an excess of homozygous loss of function variants compared with segments of African and European origin. We estimated population specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Native Mexico at exome variants, all available via a public browser. Using whole genome sequencing, we developed an imputation reference panel which outperforms existing panels at common variants in individuals with high proportions of Central, South and South Eastern Native Mexican ancestry. Our work illustrates the value of genetic studies in populations with diverse ancestry and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States where the Hispanic/Latino population is predominantly of Mexican descent.

genetics↗

bioRxiv2022

ALS sensitive spinal motor neurons enter a degenerative downward spiral of impaired splicing and proteostasis

Despite clear therapeutic potential, the mechanisms that confer differential neuronal sensitivity are not well understood. During Amyotrophic Lateral Sclerosis (ALS), sensitive spinal motor neurons (SpMN) die while a subset of rostral cranial motor neurons (CrMN) survive. In this work, we optimized a protocol to differentiate CrMNs and SpMNs from human induced pluripotent stem cells (iPSCs) by direct programming and positional patterning. Human iCrMNs are more resistant than iSpMNs to proteotoxic stress and rely on the proteasome to maintain proteostasis. iCrMNs better prevent mislocalization of TDP43 from the nucleus, a hallmark of ALS progression. iSpMNs contain more splicing defects than iCrMNs in response to ALS-related stress with genes involved in splicing and proteostasis maintenance. Therefore, iCrMNs resist ALS at two levels, preventing protein accumulation and reducing splicing defects in response to TDP43 nuclear depletion. Thus, ALS-sensitive iSpMNs appear to enter a downward spiral compromising their ability to maintain proteostasis and splicing.

neuroscience↗

bioRxiv2022

First whole-genome sequence of Cervid atadenovirus A outside of the United States from an Adenoviral hemorrhagic disease epizootic of black-tailed deer in Canada

A complete 30,616 nucleotide Cervid atadenovirus A genome was determined from tissues of a black-tailed deer that died in 2020 in British Columbia, Canada. Unique, non-synonymous SNPs in the E1B, Iva2 and E4.3 coding regions, and deletions totalling 74 nucleotides not observed in moose and red deer isolates were present.

genomics↗

bioRxiv2019

Rapid response to the Alpha-1 Adrenergic Agent Phenylephrine in the Perioperative Period is Impacted by Genomics and Ancestry

BackgroundThe emergence of genomic data in biobanks and health systems offers new ways to derive medically important phenotypes, including acute phenotypes that occur during in-patient clinical care. We hypothesized that there is a genetic underpinning to the magnitude of the response to phenylephrine, an 1-adrenergic receptor agonist commonly used to treat hypotension during anesthesia and surgery.\n\nMethodsWe quantified the response to phenylephrine by determining the delta between the minimum blood pressure (BP) within five minutes before and the maximum BP within five minutes after bolus administration. We then performed a genome-wide association study (GWAS) adjusted for genetic ancestry, demographics, and relevant clinical covariates to investigate genetic factors underlying individual differences systolic BP response to phenylephrine ({Delta}SBP), as well as mean arterial pressure ({Delta}MAP) and diastolic BP ({Delta}DBP), for both the entire study cohort as well as for each of 3 ancestry sub-cohorts; European American(EA), African American(AA), and Hispanic American(HA).\n\nResults4,317 patients met inclusion criteria, of which 3,699 were genotyped. Average {Delta}BP values over the entire cohort were {Delta}SBP=17(+-25) mmHg, {Delta}MAP=14(+-18) mmHg, {Delta}DBP=11(+-14) mmHg. The largest difference between populations was observed for {Delta}SBP ({Delta}SBPEA=20(+-24) mmHg; {Delta}SBPHA=16(+-25) mmHg; {Delta}SBPAA=15(+-25) mmHg). The differences remained after adjusting for clinical covariates and ancestry (EA vs. HA: {Delta}SBP, p<0.032;{Delta}MAP, p<0.021;{Delta}DBP,p<0.008);(EA vs. AA:{Delta}SBP,p<5.13x10-5;{Delta}MAP,p<2.1x10-4;{Delta}DBP,p<3.3x10-4). GWAS revealed significant associations between loci and BP response in 5 different genome regions (p<5x10-8) in the entire cohort, and suggestive associations in 2 different regions in EAs (p<6x10-8,p<7x10-8). We observed non-random enrichment in association with SBP drug response in 165 loci previously reported to be associated with systolic blood pressure. Finally, we discovered rare variants, rs188427942 and rs147664194 present at [~]1% in EAs and rs146535276 present at [~]1% in AAs respectively, where patients carrying one copy of these variants show no response to phenylephrine.\n\nConclusionsIt is possible to derive a quantitative phenotype suited for comparative statistics and genome-wide association studies from routinely collected perioperative data. There are population differences in rapid response to phenylephrine, large effect alleles and novel genes affecting pharmaceutical response, and phenylephrine non-responders, with implications for personalized treatment during surgery.

genomics↗

bioRxiv2018

Screening performance of abbreviated versions of the UPSIT smell test

BackgroundHyposmia features in several neurodegenerative conditions, including Parkinsons disease (PD). The University of Pennsylvania Smell Identification Test (UPSIT) is a widely used screening tool for detecting hyposmia, but is time-consuming and expensive when used on a large scale.\n\nMethodsWe assessed shorter subsets of UPSIT items for their ability to detect hyposmia in 891 healthy participants from the PREDICT-PD study. Established shorter tests included Versions A and B of both the 4-item Pocket Smell Test (PST) and 12-item Brief Smell Identification Test (BSIT). Using a data-driven approach, we evaluated screening performances of 23,231,378 combinations of 1-7 smell items from the full UPSIT.\n\nResultsPST Versions A and B achieved sensitivity/specificity of 76.8%/64.9% and 86.6%/45.9% respectively, whilst BSIT Versions A and B achieved 83.1%/79.5% and 96.5%/51.8% for detecting hyposmia defined by the longer UPSIT. From the data-driven analysis, two optimised sets of 7 smells surpassed the screening performance of the 12 item BSITs (with validation sensitivity/specificities of 88.2%/85.4% and 100%/53.5%). A set of 4 smells (Menthol, Clove, Gingerbread and Orange) had higher sensitivity for hyposmia than PST-A, -B and even BSIT-A (with validation sensitivity 91.2%). The same 4 smells also featured amongst those most commonly misidentified by 44 individuals with PD compared to 891 PREDICT-PD controls and a screening test using these 4 smells would have identified all hyposmic patients with PD.\n\nConclusionUsing abbreviated smell tests could provide a cost-effective means of screening for hyposmia in large cohorts, allowing more targeted administration of the UPSIT or similar smell tests.

neuroscience↗