Neurology

Background: The Western Aphasia Battery-Revised (WAB-R) Aphasia Quotient is the most widely used standardized post-stroke aphasia measure; its conventional 93.8 cutoff has limited sensitivity to mild residual impairment. Beyond the cutoff, it offers limited objective discourse assessment, no action-naming assessment, and naming tests limited to very common objects. Aims: We sought short tests capturing subtle aphasia in patients recovered above the WAB-R threshold, then its demographic and lesion correlates. Methods & Procedures: Sixty-seven patients with acute left-hemisphere ischemic stroke completed acute structural MRI and a 12-month language battery comprising the WAB-R, Boston Naming Test (BNT), Hopkins Action Naming Assessment (HANA), and Modern Cookie Theft (MCT) picture description. Hierarchical logistic (binary deficit) and linear (control-referenced composite z-score) regressions evaluated acute aphasia history, sex, education, age, acute depression (PHQ-9), and residualized regional lesion load. Outcomes & Results: Of 67 participants, 45 (67%) recovered above the WAB-R threshold. Of these, 18 (40%) had residual deficits on at least one supplemental test ("subtle aphasia"). BNT plus MCT content-unit count captured all 18 (100%); HANA added none beyond these two. The binary model discriminated deficit from no-deficit at AUC = 0.80 (95% CI [0.70, 1.00]); higher education significantly lowered deficit odds (OR = 0.80/year, 95% CI [0.64, 1.00], p = .049). On the continuous composite, acute PHQ-9 independently predicted 12-month outcome ({beta} = -0.13 per point, 95% CI [-0.22, -0.04], p = .006, cumulative R-squared = 0.38). Applying the Senthilkumar et al. (2026) stricter cutoff (WAB-AQ [≥] 96.7) reclassified 12 of 45 (27%) out of recovery, capturing 8 of 18 (44%) subtle-aphasia patients. Composite residualized lesion load did not differentiate the groups when adjusted. Conclusions: Above the WAB-R recovery threshold, subtle aphasia is present on the BNT or MCT in ~40%, with higher education associated with lower odds at 12 months; acute depression emerged as a candidate correlate but did not survive removal of a single high-influence observation, warranting replication in larger samples. Regional lesion variables informative at greater stroke severity contribute little as large lesions cluster in the persistently aphasic group, reducing lesion variance within the recovered subgroup and its discrimination of subtle deficits. This adds to evidence that clinicians should not infer complete language recovery from the WAB-AQ alone, and that identifying residual deficits may require greater investment in behavioral assessment and consideration of alternative WAB-AQ cutoffs. Structural anatomical information, by contrast, appears to add little discriminative value at the upper performance range.

Importance: As new treatments increase quality and length of life in people with multiple sclerosis (MS), effective prevention and management of common comorbidities, including Diabetes Mellitus (DM), is increasingly important. Objective: To compare incidence of DM and its associations with hospitalisation and mortality in adults with MS and matched controls. Design: Using English primary care data from the Clinical Practice Research Datalink (CPRD), linked to Hospital Episode Statistics and national mortality records, we matched adults with MS diagnosed between 2000 and 2023, with up to ten controls without MS by age, sex, and practice. We excluded individuals with preexisting DM, defined using diagnostic and management codes. Outcomes included all-cause hospitalisation (number and duration) and mortality. We used Poisson, negative binomial, linear, and Cox proportional hazards models, adjusting for demographic and socioeconomic factors, adding interaction terms to examine if ethnicity, deprivation, and urbanity were associated with outcomes. Results: We included 9,010 individuals with MS and 78,121 matched controls. Over a mean follow-up of 13.2 years, people with MS had over twice the incidence of DM compared with controls (adjusted incidence rate ratio [aIRR]=2.26, 95% CI: 1.96 to 2.61, p<0.001). Among people with MS, incident DM was associated with higher hospitalisation rates (aIRR=1.82, 95%CI: 1.47 to 2.28, p<0.001), longer hospitalisation duration (median 18 vs 4 days, adjusted beta;=0.53, 95%CI: 0.41 to 0.65, p<0.001), and increased all-cause mortality when incident DM was modelled as a time-varying exposure (adjusted hazard ratio=1.46, 95%CI: 1.17 to 1.82, p<0.001), compared to those who did not develop DM. Similar patterns were observed among controls (hospitalisation rates: aIRR = 2.96, 95% CI 2.63 to 3.23, p<0.001; hospitalisation duration: adjusted {beta} = 0.93, 95% CI: 0.86 to 0.99, p<0.001; mortality [time-varying]: HR = 1.50, 95% CI: 1.27 to 1.77, p<0.001). The relationship between DM and increased hospitalisation was stronger in rural areas among those with MS and stronger in White groups among controls. Conclusions: People with MS are more likely to be diagnosed with DM, resulting in greater all-cause hospitalisation and all-cause mortality. This highlights the importance of equitable screening, prevention, and management of DM in people living with MS, with particular attention to geographical health inequalities.

Abstract Background: Lacunes are 3-15 mm cavities originating from small perforating artery disease and are a hallmark of cerebral small vessel disease (cSVD). Prior prevalence studies relied on manual rating, which is prone to inter-rater variability and cannot quantify volume. We applied deep learning to quantify lacunes in a diverse community-based cohort. Methods: In this cross-sectional analysis of 1,038 Multi-Ethnic Study of Atherosclerosis (MESA) participants, with longitudinal cognitive follow-up, we quantified lacunes, confirmed them with a trained rater, and classified them as deep or lobar. Regression models examined associations of lacunes with cardiovascular risk factors, other small vessel disease lesions, brain atrophy, and cognition. Structural equation modeling evaluated whether deep lacune burden mediated associations of age or Framingham All-Cardiovascular Disease (CVD) Risk Score with atrophy and cognition. Results: Overall, 182 participants (17.5%) had at least one lacune (deep: 9.2%; lobar: 9.6%). Hispanic participants had lower lacune burden than White participants. Age, Framingham All-CVD Risk Score, PREVENT 10-year Total CVD Risk Score, and hypertension were associated with overall and deep lacunes, while lobar lacunes showed no associations. Deep lacunes were associated with white matter hyperintensities, enlarged perivascular spaces, and cerebral microbleeds, as well as SPARE-BA, SPARE-AD, and cortical and hippocampal atrophy. Deep lacunes were cross-sectionally associated with decreased global cognition and language/semantic performance, and longitudinally with accelerated executive function decline independent of count. Deep lacune burden significantly mediated associations of age and Framingham All-CVD Risk Score with SPARE-AD, SPARE-BA, and global cognition. Conclusions: In this multi-ethnic community-based cohort, deep lacune burden demonstrated stronger associations with vascular risk, other cerebral small vessel disease markers, brain atrophy, and longitudinal executive function decline than lobar burden. By providing a continuous measure of lesion volume, automated quantification captured information beyond lacune count.

Background and Objectives. Prion disease is an untreatable, typically rapidly progressive dementia. New drug candidates designed to lower prion protein are now entering clinical trials. To support future pivotal trials, we sought to assemble and analyze a public dataset of natural history data characterizing the symptomatic course of prion disease in order to provide a quantitative basis for modelling and rational trial design. Methods. We extracted data from medical publications between 2000 and 2024 reporting on n[&ge;]5 prion disease patients. Information about demographics, ascertainment, and clinical milestones, such as time from onset to death, akinetic mutism, diagnostic testing and outcomes, were extracted for aggregate cohorts of [&ge;]2 patients and individual patient-level data (PLD). We computed summary statistics of cohorts and PLD, visualized survival through forest plots and Kaplan-Meier curves, analyzed covariates regarding survival, and identified biases and heterogeneity within the literature. Results. From 245 included publications we extracted 418 aggregate cohort medians and 1,400 rows of individual PLD. 90% of cohorts and 91% of individual patients had symptom-to-death milestones, while only 7% and 11% had a time interval from a clinical presentation milestone to death, respectively. Symptom-to-death intervals varied as much as 3.2-fold even between cohorts of the same histopathologic subtype, and akinetic mutism occurred 73% sooner than death when both endpoints were reported (N=53). Indicators of disease severity, such as a cognitive test, were rarely present in either aggregate data (11%) or PLD (6%). Discussion. Data routinely reported in publications can quantify diagnostic delay and covariates affecting survival time, but are limited in ability to inform pivotal trial design because most such data are aggregated, cross-sectional, lack indicators of disease severity, and present timelines beginning with onset rather than more relevant clinical milestones, such as diagnosis, that may better reflect the moment of potential for trial enrollment. There is a need for clinical data to report milestones such as intervals from diagnosis to death, for longitudinal cognitive and functional scores, and for deposition of publicly accessible PLD.

Objectives: Poor sleep quality is a risk factor for Alzheimer's disease (AD). Older African Americans experience disproportionately high rates of sleep disturbance and AD. Medial temporal lobe (MTL) flexibility reflects dynamic neural reorganization and may be a marker of generalization performance. This study examined whether sleep quality moderates the association between MTL flexibility and memory generalization. Methods: Fifty older African Americans (MeanAge=69.7{+/-}6.21 years; 80% women) underwent rs-fMRI to quantify MTL flexibility, Rutgers Acquired Equivalence Task for memory generalization, and Pittsburgh Sleep Quality Index for sleep quality. Results: Greater MTL flexibility was associated with better generalization (r=0.367, p=.017). Good sleepers showed higher MTL flexibility (F(1,44)=8.11, p2=.156, p=.007) and superior generalization (F(1,46)= 12.33, p2=.211, p=.001). Sleep quality significantly moderated the MTL flexibility and generalization relationship ({beta}=-1.519, p=.012). Conclusions: Preserved MTL flexibility may confer generalization only in good sleepers, suggesting that sleep disturbance may disrupt the MTL neural resilience among older African Americans.

A major obstacle for clinical trials is the lack of objective, sensitive, and reliable measures that can detect modest changes in disease progression. Here, we determine whether acoustic and linguistic digital speech measures automatically obtained during a functionally relevant passage-reading task capture multiple dimensions of disease in ataxia, including functional communication impairment, subclinical cerebellar dysfunction and disease progression. A total of 157 individuals with ataxia and 84 controls contributed cross-sectional data, and 54 individuals with ataxia and 43 controls contributed longitudinal data within the ongoing Neurobooth natural history study. Participants completed standardized speech recordings, patient-reported outcome measures (PROMs) and neurologist-rated clinical evaluations. A novel speech processing pipeline was developed to automatically transcribe audio recordings, identify word boundaries and extract a predefined set of linguistic and within-word acoustic features. Individuals with ataxia exhibited marked disruption of speech timing, coordination and articulatory control, including slowed speech (d=1.23), prolonged inter-word pauses (d=-0.91), higher/more variable vocal intensity (|d|=0.43-0.51) and altered spectral content (|d|=0.43-0.79) compared to healthy controls. Linguistic features (e.g. speaking rate and within-word pause duration) showed strong associations with clinician-rated severity and PROMs (|r|=0.23-68), indicating alignment with functional communication impairment and patient-perceived disease burden. In contrast, acoustic features derived from cepstral measures captured subtle abnormalities in speech motor control, differentiating not only individuals with ataxia (d=0.65) but also pre-ataxic individuals (d=0.56), and those without clinically evident dysarthria (d=0.45), from controls. These findings indicate that acoustic features reflect subclinical cerebellar motor dysfunction involving impaired temporal coordination and vocal control before overt clinical speech impairment emerges. Longitudinally, several acoustic measures were sensitive to disease progression (MSDR=0.19-0.68), even in cases where clinical scales showed no detectable change. Speech-derived changes correlated with changes in clinical scales and PROMs. Both acoustic and linguistic features exhibited strong intra-session reliability. During passage reading, acoustic and linguistic measures provide complementary but different clinical information in ataxias. Linguistic measures primarily reflect downstream functional consequences of ataxic dysarthria, whereas acoustic measures provide sensitive indicators of subclinical cerebellar motor dysfunction and progression. These findings demonstrate that natural speech analysis can produce digital measures for detecting subclinical disease, quantifying functional impairment, monitoring progression in ataxia, with strong potential for application in clinical trials and remote monitoring.

Importance: Older adults (65 years and older) are the largest and fastest growing population of traumatic brain injury (TBI) victims. However, real-world evidence of 6-month functional outcomes is limited. Objective: To describe 6-month functional outcomes in older adults after mild TBI (mTBI; presenting Glasgow Coma Scale score 13-15), by age group and preinjury cognitive status. To evaluate the performance of the Glasgow Outcome Scale - Extended (GOSE) as a geriatric mTBI clinical trial endpoint. Design: Prospective cohort study; single-center pilot enrollment February 2018-April 2019; two-center enrollment October 2020-March 2025. Setting: Two U.S. level I trauma centers. Participants: Older adults presenting within 72 hours of mTBI who received head CT, and their co-enrolled study-partner informants. Data curation and analysis were performed January 2023-November 2025. Exposure: mTBI. Main outcome and measures: GOSE was assessed at 2 weeks and 6 months post-injury and weighted using inverse probability weighting to mitigate attrition bias. Reliable change index was used to estimate the proportions of GOSE improvement or deterioration from 2 weeks to 6 months versus a 9-item Activities of Daily Living survey (ADL, Supplemental Methods) and Functional Activities Questionnaire (FAQ). Results: Among 253 participants with mTBI, mean (SD) age was 77.3 (8.3) years, 129 (51%) were female, 68 (34%) had pre-injury mild cognitive impairment and 28 (15%) had pre-injury dementia (58 had unknown preinjury cognitive status). At 6 months, 14% died, 73% achieved home independence (GOSE 5+), and 17% achieved complete recovery (GOSE 8). Younger-old and persons without preinjury cognitive impairment had substantially better recovery (mortality 6-11%, home independence 84-86%, complete recovery 21-22%) versus oldest-old and those with pre-injury dementia (mortality 29-32%, home independence 23-52%, complete recovery 5-10%). GOSE detected the greatest proportion of reliable improvement or deterioration compared to ADL and FAQ, though low agreement reflects their complementary domains. Conclusions and Relevance: Most younger and cognitively-unimpaired older adults achieved favorable functional outcomes, however, more vulnerable older adults may suffer chronic disability after mTBI. GOSE effectively captures meaningful change in this population, while ADL and FAQ provide important complementary information. Findings underscore the need for age-appropriate prognostication and more inclusive geriatric TBI research and clinical trial design.

Background. Post-stroke anxiety and depression frequently co-occur, and whether each is independently associated with cognitive impairment remains unclear because most studies model one without adjusting for the other variable. In a five-year cohort, we tested whether anxiety and depression have distinct cognitive correlates and whether early affective status predicted subsequent cognitive recovery. Methods. Patients from the STROKDEM cohort were assessed at 6, 12, 36, and 60 months post-stroke for anxiety, depression, and five cognitive domains (memory, executive functioning, attention, visuospatial functioning, and language). Two symmetric random-intercept linear mixed models regressed each affective score on the cognitive domains while adjusting for other scores. Repeated-measures correlations, multiple imputations for attrition, and exploratory trajectory and prognostic models were also used. Results. After mutual adjustment and correction, depression was independently associated with executive and visuospatial function, whereas anxiety showed no independent cognitive correlation. Repeated-measures correlation confirmed this dissociation. The anxiety findings were stable across the sensitivity analyses and multiple imputations. Attrition was selective for baseline cognition, and exploratory associations between early affect and cognitive recovery did not survive multiple imputations and were inconclusive. Limitations. Attrition was substantial and selective on baseline cognition; the persistent anxiety subgroup was small, limiting the power for trajectory analyses; and psychiatric history, psychotropic medication, and cognitive reserve beyond education were unavailable. Conclusions. The cognitive burden of post-stroke affective disorders is carried by depression, rather than anxiety. Because anxiety-related cognitive impairment largely reflects comorbid depression, screening for depression rather than anxiety alone may better identify stroke survivors at risk of cognitive impairment.

INTRODUCTION: We integrate visual and quantitative metrics in white matter and medial temporal lobe to examine relationships with neuropathology in a community cohort. METHODS: Postmortem in situ MRI (T1, T2, DWI) was performed in 25 human brains, followed by visual ratings (Fazekas, MTA, ERICA, Koedam). Neuropathology included ADNC, LATE-NC, hippocampal sclerosis, PART, ARTAG, Lewy pathology, and CAA. RESULTS: Increased Fazekas score was linked to aging, lower education, hypertension, higher basilar artery wall thickness, and greater Braak NFT stage. WMH volume also correlated with lacunes, Thal phase, and CERAD score that was not observed using Fazekas. Hippocampal volumes were lower in elderly, less educated people and were associated with higher atrophy scores and higher Braak NFT stage. Higher amygdala volume was only associated with higher CERAD score. DISCUSSION: Quantitative MRI may detect neuropathologic associations more sensitively than visual ratings. Tau pathology is a key predictor of WMH burden and hippocampal atrophy.

Background: The Progressive Supranuclear Palsy Clinical Deficits Scale (PSP-CDS) is a brief rating scale of clinical severity in PSP. However, its longitudinal performance has not been evaluated. We aimed to assess the ability of the PSP-CDS to track disease progression over time and to compare progression across PSP phenotypes in a real-world Asian cohort. Methods: Patients who met the Movement Disorder Society PSP diagnostic criteria and underwent at least 2 PSP-CDS assessments were recruited from movement disorders clinics in Malaysia. Longitudinal progression was evaluated using linear mixed-effects models. Domain-specific progression and subtype-specific trajectories were also analyzed. Associations between annualized changes in PSP-CDS and Barthel Index (BI) scores were examined. Results: 104 patients (including 59 with PSP-Richardson's syndrome [PSP-RS], 28 with predominant parkinsonism [PSP-P], and 14 with progressive gait freezing [PSP-PGF]) contributed 394 PSP-CDS assessments over a median follow-up of 33.2 months (range, 8.7-73.1 months). PSP-CDS scores increased significantly over time ({beta}=0.126 points/month), corresponding to estimated increases of 1.13 points over 9 months and 2.27 points over 18 months. Subtype-specific analyses demonstrated the fastest progression in PSP-RS (0.156 points/month), followed by PSP-PGF (0.081 points/month) and PSP-P (0.077 points/month). Exploratory domain-level analyses showed that finger dexterity, communication, and dysphagia were the most rapidly worsening domains. Annualized PSP-CDS progression correlated significantly with annualized decline in BI scores (Spearman's {rho}=-0.474, P<0.001). Conclusions: The PSP-CDS is sensitive to longitudinal disease progression in PSP and captures clinically-meaningful functional decline. Its brevity and ability to distinguish differential progression across PSP phenotypes support its utility as a pragmatic outcome measure for routine clinical practice and research.

Background Optic pathway hypothalamic glioma (OPHG) can cause irreversible visual impairment. Radiotherapy and radiosurgery are used for progressive, recurrent, or treatment-refractory disease, but their effects on visual outcomes remain incompletely defined. Objective To synthesize visual outcomes following radiotherapy or radiosurgery for OPHG, with visual preservation as the primary outcome. Methods This prospectively registered systematic review and meta-analysis (PROSPERO CRD420261440136) followed the PRISMA 2020 statement. PubMed, Scopus, Web of Science, Embase, the Cochrane Library, Google Scholar, and ClinicalTrials.gov were searched from inception to 1 June 2026. Eligible studies included patients with OPHG or related optic pathway or hypothalamic gliomas treated with radiotherapy or radiosurgery and reporting extractable visual outcomes. Visual preservation was defined as stable or improved vision. Random-effects meta-analyses of logit-transformed proportions were performed. Results Forty-nine studies were included in the systematic review, of which 19 contributed 494 visual outcome observations to the meta-analysis. The pooled visual preservation rate was 75.6% (95% CI 65.1% to 83.7%; I2 = 71.6%). Pooled rates of visual improvement, stability, and worsening were 24.7% (95% CI 19.5% to 30.8%), 46.7% (95% CI 37.0% to 56.6%), and 20.6% (95% CI 12.7% to 31.6%), respectively. Preservation was higher in pure radiotherapy or radiosurgery cohorts than in mixed-treatment cohorts (85% vs 66%; subgroup p = 0.0104), although differences in cohort composition and treatment attribution may have influenced this finding. Conclusion Radiotherapy and radiosurgery were associated with preservation of vision in approximately three-quarters of evaluable outcomes, predominantly through visual stability rather than recovery. Standardized visual outcome definitions are needed to improve future comparisons and treatment evaluation.

Background and Objectives: Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods: This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results: Variant carriers (n=147) and familial non-carriers (n=113) did not differ in age (mean{+/-}SD, 25.9{+/-}3.2 years), sex (53% female), or number of visits (2.1{+/-}1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years (b=-982.8mm3, SE=317.0, p=0.0046, f2=0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines (b=64.4mm3, SE=29.9, p=0.035, f2=0.07). For MAPT and GRN, there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion: C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

Background: Plasma phosphorylated tau-217 (ptau217) has demonstrated accuracy exceeding 90% for Alzheimers disease (AD) diagnosis. While its diagnostic validity has been established, its real-world clinical utility in altering or corroborating clinician diagnoses remains less understood. This study evaluates the impact of plasma ptau217 on diagnostic reclassification in a memory disorders clinic. Methods: We conducted a retrospective chart review of 100 patients evaluated for memory impairment who subsequently underwent plasma biomarker testing. Initial clinical diagnoses were established using the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer Disease and Related Disorders Association criteria, neuropsychological testing, and brain magnetic resonance imaging without knowledge of plasma biomarker results. Follow-up diagnoses were assigned after the availability of plasma ptau217 or Precivity AD2 results. Diagnostic reclassification was evaluated under two p-tau217 classification schemes to determine the AD etiology: a binary cutoff with lower threshold (AD = ptau217 > 0.18) and a three-level cutoff incorporating a higher threshold (AD = ptau217 > 0.325). Reclassification matrices and McNemar's tests were used to assess changes in diagnosis. Subgroup analyses were conducted according to apolipoprotein E (APOE) {epsilon}4 carrier status. Results: The overall diagnosis reclassification rates were 37.8% (chi-square (1) = 10.81, p = 0.001) and 46.9% (chi-square (1) = 29.76; p < 0.001) using lower and higher threshold analyses, respectively. With the higher threshold (ptau217 > 0.325), reclassification among APOE {epsilon}4 carriers occurred in both directions at similar frequencies, without evidence of a net shift toward AD or non-AD (42% from AD to non-AD, 43% from non-AD to AD, chi-square (1) = 2.77 p = 0.096). Among {epsilon}4 non-carriers, reclassification was significantly asymmetric toward non-AD (66% from AD to non-AD, 14% from non-AD to AD, chi-square (1) = 16.41, p < 0.001), suggesting ptau217 may be identifying diagnostically heterogeneous cases in which the clinical presentation resembles AD but instead reflects an alternative or co-morbid etiologies. Conclusion: Plasma ptau217 meaningfully influences diagnostic decisions in a memory clinic setting and may be particularly valuable among APOE {epsilon}4 non-carriers, where biomarker-informed evaluation frequently shifted diagnoses away from AD.

Background: Blood-brain barrier (BBB) dysfunction is increasingly recognized as a feature of cerebral amyloid angiopathy (CAA) and has been linked to hemorrhagic imaging manifestations such as cortical superficial siderosis. However, it remains unclear whether neurovascular barrier dysfunction can be captured by routinely available fluid biomarkers and whether such markers identify clinically relevant hemorrhage-prone CAA phenotypes. The CSF/serum albumin quotient (QAlb) is an established marker of neurovascular barrier dysfunction. We investigated QAlb levels in CAA and their association with imaging markers of disease severity. Methods: We included 225 participants (115 with CAA, 72 with Alzheimers disease [AD], 38 healthy controls) with CSF biomarkers and standardized MRI evaluation. Pathologic QAlb levels were identified via the age-corrected Reiber-formula. Group differences and determinants of pathological QAlb were assessed using uni- and multivariable regression analyses. The diagnostic relevance was assessed by receiver operating characteristic analysis. Results: QAlb levels were higher in CAA than in controls (ratio of means [RoM] 1.43, 95% CI 1.28-1.58) and patients with AD (RoM 1.22, 95% CI 1.10-1.35; both p<0.001). Pathological QAlb was independently associated with CAA compared with controls (OR 12.16, 95% CI 2.56-57.86) and AD (OR 2.14, 95% CI 1.07-4.28). Despite these associations, QAlb showed only moderate discrimination between CAA and controls (AUC 0.75, 95% CI 0.67-0.82) and low discrimination between CAA and AD (AUC 0.63, 95% CI 0.55-0.71). Within the CAA cohort, pathological QAlb was independently associated with disseminated cortical superficial siderosis (OR 3.92, 95% CI 1.31-11.72; p=0.014), a marker of advanced hemorrhage-prone disease. Conclusion: QAlb is elevated in patients with CAA and is associated with disseminated cortical superficial siderosis, the strongest predictor of future intracerebral hemorrhage. These findings support an association between neurovascular barrier dysfunction and the hemorrhage-prone phenotype of CAA.

Importance: Apolipoprotein E (APOE) {varepsilon}4 is the strongest genetic risk factor for sporadic dementia, yet whether the benefits of intensive systolic blood pressure (SBP) control differ by APOE {varepsilon}4 carrier status remains unknown. This is among the first randomized evaluations of intensive SBP control on all-cause dementia by APOE {varepsilon}4 status in US adults without diabetes. Objective: To compare effects of intensive vs standard SBP control on incident all-cause probable dementia between APOE {varepsilon}4 carriers and non-carriers. Design, Setting, and Participants: Secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), a multicenter randomized trial of adults [&ge;]50 years with hypertension and increased cardiovascular risk, but without diabetes, prior stroke, or dementia. Primary cognitive follow-up ended July 2018. Participants were further followed with telephone-based outcome assessment from 2019 through 2023. Interventions: Intensive SBP control (goal <120 mm Hg) vs standard SBP control (goal <140 mm Hg). Main Outcomes and Measures: The primary outcome was all-cause probable dementia. Secondary outcomes were mild cognitive impairment (MCI); MCI or dementia; MCI, dementia, or death; and all-cause mortality. APOE {varepsilon}4 status was the primary effect modifier. Results: Of 9,361 randomized participants, 8,390 (89.6%) had APOE genotyping (29% {varepsilon}4 carriers); 7,733 (82.6%) had both genotype and outcome data (mean age, 68 years; 36% female; 28% Non-Hispanic Black). Over a median follow-up of 5.1 years, dementia rates (intensive vs standard) were 9.7 vs 13.2 per 1,000 person-years among {varepsilon}4 carriers (hazard ratio [HR], 0.73; 95% CI, 0.51-1.04) and 6.1 vs 6.7 among non-carriers (HR, 0.91; 95% CI, 0.67-1.23; P-interaction = .35). Four-year risk differences were -1.7% (95% CI, -3.4% to 0%; number needed to treat, 59) among carriers and 0.2% (95% CI, -0.6% to 1%) among non-carriers (P-interaction = .045). Patterns were similar for the composite of MCI or dementia; effects on MCI were similar between APOE {varepsilon}4 subgroups. Conclusions and Relevance: Among US adults at high cardiovascular risk, intensive SBP control yielded larger absolute risk reduction in dementia among APOE {varepsilon}4 carriers than non-carriers; relative effects were similar. These findings may inform APOE {varepsilon}4-stratified blood pressure management for dementia prevention.

Background: Post-stroke dysphagia (PSD) contributes to aspiration, pneumonia, malnutrition, prolonged hospitalization and mortality. We evaluated the discrimination, validity and readiness of machine learning and data-driven prediction models for PSD-related outcomes. Methods: Following a prospectively registered protocol (PROSPERO CRD420261419259), we searched PubMed/MEDLINE, Embase, Web of Science Core Collection, CINAHL and CENTRAL from inception through June 7, 2026. Eligible studies developed or validated multivariable prediction models for PSD-related outcomes in adults with stroke. We used PROBAST and PROBAST+AI to assess risk of bias and applicability and TRIPOD+AI to evaluate reporting. Area under the curve (AUC) estimates were pooled on the logit scale with random-effects models. Results: Twenty-four studies were included and ten contributed to meta-analysis. Four studies predicting early or incident PSD yielded a pooled AUC of 0.94 (95% CI 0.60-0.99; I2 = 95.6%). Pooled AUCs were 0.84 (95% CI 0.71-0.92) for aspiration or penetration-aspiration and 0.89 (95% CI 0.24-1.00) for severe dysphagia. The exploratory analysis of all ten risk-prediction models produced an AUC of 0.90 (95% CI 0.80-0.95), but heterogeneity was substantial (I2 = 90.3%) and the prediction interval was 0.51-0.99. Every study had high risk of bias because of analysis-domain concerns; calibration and external validation were uncommon. Conclusions: Reported discrimination was often high, but the evidence does not establish reliable performance in care. Independent validation, calibration, complete model reporting and clinical-impact studies are needed before these models guide post-stroke swallowing care. Keywords: Post-stroke dysphagia; Stroke; Deglutition disorders; Machine learning; Clinical prediction model; Area under the curve; Meta-analysis

Background: Alzheimer's disease and related dementias (ADRD) affect over 7.2 million Americans aged 65 and older, with the APOE-4 allele representing the strongest known genetic risk factor. Physical activity (PA) has been associated with reduced dementia risk, but its interaction with APOE genotype remains poorly characterized in large, genomically informed cohorts. Methods: We conducted a retrospective cohort analysis using linked genomic, survey, and longitudinal electronic health record data from the VA Million Veteran Program (MVP). Veterans aged <65 at enrollment with available APOE genotype data, at least 10 years of prior VA medical history, and a completed Lifestyle Survey were included. Individuals with a pre-existing ADRD diagnosis were excluded, yielding a final cohort of 137,593 veterans. Self-reported vigorous physical activity (PA) was ascertained from the MVP Lifestyle Survey and coded as both a four-level ordinal variable and a binary active/inactive classification. The primary composite outcome was incident ADRD or all-cause mortality. Cox proportional hazards models were fitted adjusting for age, sex, race/ethnicity, and baseline comorbidities. A multiplicative interaction term between APOE {varepsilon}4 allele count and PA level was included to formally test for effect modification. Results: Over a median follow-up of 84 months, 65,628 participants (47.7%) experienced the composite outcome. Each additional APOE-4 allele was associated with a 19% increase in risk (aHR = 1.19, 95% CI 1.17-1.21), while active individuals had a 33% lower risk compared to inactive individuals (aHR = 0.67, 95% CI 0.66-0.68). A statistically significant interaction between APOE-4 burden and PA was identified (p < 0.005). Stratified analyses demonstrated that the protective association of PA was present across all genotype groups, with homozygotes demonstrating a 22% risk reduction among active individuals. Conclusions: In this large veteran cohort, vigorous PA was independently and significantly associated with reduced risk of incident ADRD or death across all APOE genotype groups, with the greatest absolute benefit observed among individuals at highest genetic risk. These findings support the prioritization of PA as a targeted preventive strategy, particularly for APOE-4 carriers.

Background: The Boston Criteria v2.0 represent the gold standard for diagnosing Cerebral Amyloid Angiopathy (CAA), but their application is currently precluded in mixed small vessel disease (SVD), where deep and lobar hemorrhages coexist. The aims of this study are: (i) to determine which cerebrospinal fluid (CSF) biomarker (A{beta}42, A{beta}40, A{beta}42/40 ratio) is the best candidate to support the CAA diagnosis; (ii) to define a data-driven cut-off, and (iii) to explore if a biomarker-integrated classification significantly improves the phenotypical concordance with the suspected predominant SVD (CAA vs. arteriosclerosis). Methods: We analyzed data from a retrospective multicenter cohort of patients with suspected CAA, defined as probable CAA (Boston criteria v2.0) but allowing deep hemorrhagic lesions, and with available CSF biomarkers. We visually quantified MRI-visible SVD markers (e.g., cerebral microbleeds [CMB], cortical superficial siderosis [cSS], lacunes) and their association with MRI-visible SVD features. We employed a Gaussian Mixture Model (GMM) to identify a data-driven threshold for amyloid positivity (A+). Then, we compared the prevalence of MRI-visible manifestations of SVD between subgroups applying different frameworks, namely the current MRI-based classification (probable CAA vs. mixed SVD) and a CSF biomarker-integrated classification (A+ vs. A-). Results: We enrolled 121 patients (age: 72 [66-77] years; 60% probable CAA, 40% mixed SVD with suspected CAA). The CSF A{beta}42/40 ratio showed a bimodal distribution and consistent associations with all CAA-specific radiological features. The CSF biomarker-integrated reclassification, particularly using the GMM cut-off, significantly improved the distinction between subgroups regarding CAA- and arteriosclerosis-related MRI features (e.g., cSS presence: probable CAA vs. mixed SVD: aOR=2.84 [95%CI 1.27-6.39], p=0.011; A+ vs. A-: aOR=12.68 [95%CI 4.31-37.32], p<0.001; deep lacunes presence: probable CAA vs. mixed SVD: aOR=0.20 [95%CI 0.08-0.50], p<0.001; A+ vs. A-: aOR=0.04 [95%CI 0.01-0.11], p<0.001). Notably, patients classified as A+ never demonstrated more than four deep CMBs. Discussion: A CSF biomarker-integrated classification may improve the classification of CAA compared with the current MRI-based framework. These findings are cohort-specific and would benefit from further validation, especially with a neuropathological reference. Still, these results support a future transition toward an integrated biological-radiological framework, which may refine in vivo CAA diagnosis, particularly in mixed SVD.

Background: Therapy development in ultra-rare, progressive and fatal diseases like vanishing white matter (VWM) is hampered by very low patient numbers and ethical constraints regarding placebo-controlled studies. Under such conditions, standard randomized controlled trials may not be feasible. The use of historical control information could be part of a solution, but would require extra considerations regarding selection of patients and choice of endpoints. We used the VWM registry as a case study to outline key methodological considerations for informing trial design in ultra-rare disease. Methods: The study included 462 patients, available in the VWM registry. Prospective clinical data were collected since 2004 using VWM-specific questionnaire and Health Utility Index (HUI) assessments, while retrospective data from clinical charts were available from 1988 on. We evaluated methodological aspects relevant to trial design, including patient selection, drift in the disease course over time, endpoint selection, and clinically relevant stratification into subgroups. Results: Regarding patient selection, patients with comorbidities impacting disease course, and pre-symptomatic individuals without clinical onset were considered not suitable as historical controls. After excluding patients before 1991, we found no evidence of drift in the disease course from 1991 onwards. Regarding choice of endpoints, episodes of rapid decline were relatively infrequent and occurred mostly at disease onset, limiting their usefulness as trial endpoint. Multi-state modelling and clinical evaluation showed ambulation as preferable endpoint over survival. For longitudinal HUI multiscores, baseline imputation allowed modelling of early disease. The scores showed a distinct ordering, reflecting the association between multi-domain function and disease progression. Regarding stratification, the combination of data-driven analyses and clinical expertise informed revised age of onset groups. Females showed later onset and milder disease; adjustment for age of onset eliminated the effect of sex. Conclusion: This case study provides key considerations for evaluating registry data as historical control and demonstrates how these considerations can inform clinical trial design in ultra-rare diseases.

The photic sneeze reflex (PSR), in which exposure to bright light triggers sneezing, is widely recognised but inconsistently defined and measured. We conducted the first systematic review and meta-analysis of PSR prevalence to synthesise the epidemiological evidence, assess methodological quality, and identify priorities for future research. We included 18 articles comprising 31 study groups and extracted prevalence estimates, study characteristics, ascertainment methods, and epidemiological information. Fifteen eligible study groups classified as healthy were included in the primary meta-analysis. The pooled prevalence was 22% (95% CI, 15%-29%), with extreme between-study heterogeneity (I2 = 99.3%). Reported prevalence estimates and associations with participant characteristics varied widely, and nearly all studies were judged to be at high risk of bias. The pooled estimate should therefore be interpreted as a descriptive summary of the available evidence rather than a precise estimate of population prevalence. Future studies require a standardised operational definition, representative sampling, transparent reporting, and reproducible methods for assessing light-triggered sneezing.