Neurology

Background and objectives: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common monogenic cerebral small vessel disease. Though neuropsychiatric symptoms (NPS) of CADASIL profoundly impact function and quality of life, these symptoms remain understudied. This analysis characterizes the prevalence, severity, and profile of NPS among individuals with CADASIL-causing NOTCH3 variants and non-carrier biological family controls in the United States CADASIL Consortium (USCC). Methods: This cross-sectional analysis used multimodal baseline data from 12 enrollment sites across the country. Statistical analyses used nonparametric tests and regression models to compare clinical and neuropsychiatric outcomes across CADASIL risk tiers and controls, adjusting for age, sex, race, and education where appropriate. The primary outcome measure was the Neuropsychiatric Inventory Questionnaire (NPI-Q), an informant-reported measure which assesses 12 categories of NPS. NPI-Q item severity and distress were evaluated for individuals with confirmed cysteine-altering NOTCH3 variants and compared with controls. Results: Four hundred fifty-nine USCC participants were included in the analytic cohort: 343 cases [256 high-risk (HR); 63 medium-risk (MR); 24 low-risk (LR)]; and 116 controls. Among participants with available NPI-Q data, at least one neuropsychiatric symptom was reported by 72.6% (n = 228/314) of cases compared with 53.2% (n = 58/109) of controls. Reported symptoms were more common among CADASIL cases than controls, occurring in 75.0%, 71.2%, and 72.7% of participants in the LR, MR, and HR groups, respectively, compared with 53.2% of controls. Compared with controls, participants in the MR group and HR group had higher NPI-Q severity scores. HR participants also had higher NPI-Q distress scores than controls. Discussion: Our findings support the notion that NPS are an important clinical manifestation of CADASIL. Beyond previously reported symptoms, additional neuropsychiatric manifestations were identified. Given the higher burden and variability in the neuropsychiatric presentation of CADASIL, the relationships among neuropsychiatric, neurological, and patient-reported outcomes merit further investigation. The NPS profile may enhance the evaluation of the safety and efficacy of different treatments to target these symptoms for CADASIL patients. Trial Registration Information: The study is registered at ClinicalTrials.gov (NCT05677880, 12/12/2022).

Abstract Background and Objectives Cerebral microhaemorrhages influence eligibility and monitoring for anti-amyloid therapies. Emerging evidence and expert opinion suggest that subcortical microhaemorrhages may be less closely related to cerebral amyloidosis than lobar lesions and may therefore warrant separate consideration in anti-amyloid treatment eligibility criteria. Using longitudinal MRI data from cognitively unimpaired individuals with preclinical Alzheimer disease in the A4 study, we hypothesised that lobar and subcortical microhaemorrhages would show distinct location-specific patterns of progression and associated risk profiles. Methods We conducted a retrospective longitudinal cohort analysis of centrally assessed MRI data from A4 study participants with at least two evaluable MRI examinations. Baseline and follow-up were defined as the first and last evaluable scans, respectively. Participants were classified according to the anatomical distribution of baseline microhaemorrhages as lobar or subcortical, and subsequent location-specific lesion accumulation was examined. Multivariable logistic regression was used to assess whether baseline lobar and subcortical microhaemorrhage counts were independently associated with the development of additional lobar and subcortical microhaemorrhages. Results Among 1,146 participants followed for a mean of 4.55 years (SD = 1.78), 38 had subcortical-only and 157 had lobar-only microhaemorrhages at baseline. Subsequent lesions preferentially accumulated in the same anatomical compartment. Baseline subcortical microhaemorrhage count was associated with additional subcortical lesions (OR 3.60, 95% CI 2.00-6.47), but not with additional lobar lesions (OR 1.25, 95% CI 0.73-2.15). Conversely, baseline lobar microhaemorrhage count was associated with additional lobar lesions (OR 2.74, 95% CI 2.06-3.64), but not with additional subcortical lesions (OR 1.08, 95% CI 0.77-1.53). White matter hyperintensity burden was associated with subcortical progression, while APOE4 homozygosity and greater cerebral amyloid burden were associated with lobar progression. Systolic blood pressure was directionally positive but not associated with lobar microhaemorrhage accumulation in either analysis. Discussion Our findings support the emerging view that subcortical and lobar microhaemorrhages exhibit distinct longitudinal patterns and associated risk profiles. Longitudinal studies in patients receiving contemporary plaque-clearing therapies are needed to determine whether microhaemorrhages should be considered differently according to anatomical location in treatment eligibility and monitoring guidelines.

Background and Objectives: Vascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of dementia and a common comorbidity for reduced functional capacity in many individuals, but clinical management and clinical trial readiness are severely hindered by extreme phenotypic and mechanistic heterogeneity. This study establishes the baseline clinical, functional, and multimodal biomarker characteristics of the first United States (US) cohort of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), serving as a single-cause, monogenic small vessel disease model for sporadic VCID. Methods: Cross-sectional analysis of baseline data collected from October 2022 through January 2025 from a longitudinal cohort at 12 US enrollment sites. Adults from families with a documented NOTCH3 variant were recruited through clinical referrals, medical record review, advocacy organizations, and community outreach. Exclusion criteria included other conditions that prevented interpretation of findings and modified Rankin Scale (mRS) scores greater than 3. Central genetic characterization assigned persons with a pathogenic or likely pathogenic NOTCH3 variant to low-, medium-, or high-risk tiers based on epidermal growth factor-like repeat domains. Standardized assessments included clinical histories, exams, objective cognitive and physical assessments, self-reported, companion-reported, and clinician-rated measures, MRI, genetics, and proteomics acquired under harmonized protocols. Group comparisons used Fishers exact and Kruskal-Wallis tests. Multivariable regression used adjustment for age, sex, race, and education. Results: Of 560 participants completing baseline visits, 46 had variants of unknown significance, and 55 had pending genetic analyses. The analytic cohort included 343 persons with a CADASIL-causing NOTCH3 variant and 116 non-carrier family controls. Median age was 47.9 years (IQR 38.7-59.1), median education was 16 years (IQR 14-17), 62.5% were female, and 91.4% were White. Carriers were classified in CADASIL risk tiers: low (7.0%), medium (18.4%), or high (74.6%). Compared with controls, adjusted odds of classification into a more impaired CDR category were higher in all tiers (OR 2.55-5.08, 95% CI 1.22-11.34). Discussion: The US CADASIL Consortium has established a large, genetics-confirmed cohort spanning presymptomatic to moderate disease stages, providing a robust, harmonized platform to define early biomarker signatures and endpoints for targeted VCID therapies.

Background: Whether ethnoracial differences in cerebral small vessel disease (cSVD) appear in multimarker burden, particular MRI manifestations, or both, and how they relate to Life's Essential 8 (LE8) cardiovascular health and cognition, remain unclear. Methods: This cross-sectional study included 44,982 participants and an age- and sex-matched subsample of 1,426 with reviewed lacune and cerebral microbleed (CMB) ratings. White, South Asian, Black, Chinese and Mixed participants were compared on 0-2 (white matter hyperintensity [WMH]/enlarged perivascular space [ePVS]) and 0-4 (adding CMB and lacunes) composite scores and each marker. LE8 was related to WMH and composite burden, and cognitive means were compared by group. Models were age-, sex- and center-adjusted with false-discovery-rate correction. Results: Both composite scores differed across groups (0-2: P=0.00010; 0-4: P=0.0011), with greater burden in Black than South Asian (0-4: OR 1.66; 95% CI, 1.21-2.28) and Chinese participants (OR 2.36; 1.51-3.70), whereas Black-White contrasts were not detected. Black participants had higher WMH volume than White participants (=0.209; 0.110-0.308), robust to deprivation adjustment and segmentation method; South Asian participants had fewer ePVS (0.82; 0.72-0.93). No ethnoracial-group differences in lacune or CMB counts were detected after correction. Higher LE8 was associated with lower WMH volume (0.13 per SD; 0.17 to 0.09) and lower two-marker burden (OR 0.89 per SD; 0.87-0.91) without detected ethnoracial moderation. Black participants, who had the least favorable LE8 scores, and South Asian participants had lower global cognition than White participants (z 0.76 and 0.57 versus 0.24) despite differing WMH profiles; the pooled WMH-cognition association was null. Conclusions: Ethnoracial differences in multimarker cSVD burden were evident but marker-dependent: WMH showed the clearest Black-White difference; focal-lesion contrasts were inconclusive. Better cardiovascular health related to lower WMH and aggregate cSVD burden across groups, whereas cognitive differences did not track cSVD burden, supporting prospective prevention and cognition studies.

Background: CADASIL caused by cysteine-altering NOTCH3 variants, the most frequent hereditary cerebral small vessel disease worldwide, is characterized by marked phenotypic variability. Mutation location within the EGFr domains of the NOTCH3 receptor has emerged as a key determinant of this variability. We investigated phenotypic variability and potential modifiers of CADASIL expression by comparing individuals harbouring the same pathogenic NOTCH3 variant across distinct recruitment settings in three European countries. Methods: We compared clinical features, MRI markers, and cardiovascular risk factors among individuals harbouring the p.Arg1231Cys NOTCH3 mutation across three distinct recruitment settings: a multigenerational founder population from Cilento, Italy (CILCAD), a population-based cohort from the UK Biobank (UKB), and a clinically referred cohort from a national referral centre in Lariboisiere Hospital, Paris, France (LRB). In addition, CILCAD carriers were compared with NON-Carriers from the same population. The NOTCH3 locus was finally analysed to define the shared haplotype in CILCAD and explore potential genetic contributions to phenotypic variability. Findings: By comparing populations from three European countries, this study showed marked context-dependent phenotypic variability associated with the sole pathogenic p.Arg1231Cys NOTCH3 variant. In CILCAD, a multigenerational founder population, the haplotype carrying the NOTCH3 mutation also predisposes to decreased LDL levels, resulting in an unusually low LDL cholesterol profile in this sample. Strikingly, these very low LDL levels were associated with a higher likelihood of stroke. Interpretation: In European carriers of NOTCH3 p.Arg1231Cys, factors beyond mutation location, including genetic background, may substantially shape disease expression, while exceptionally low LDL levels could paradoxically be associated with greater disease severity.

Background: Stroke risk is increased in cancer patients, but variations by stroke type, cancer characteristics, and treatment timing remain incompletely characterized. We investigated stroke incidence after cancer diagnosis and temporal patterns of ischemic stroke around treatments. Methods: We conducted a retrospective multicenter cohort study using linked cancer registry and administrative data from 68 cancer hospitals in Osaka, Japan. Patients diagnosed between 2019 and 2022 were followed for up to 1 year. In diagnosis-based analyses, standardized incidence ratios (SIRs) compared stroke incidence with the general population. In treatment-based analyses, ischemic stroke incidence rates and adjusted incidence rate ratios (IRRs) were estimated from 14 days before through 365 days after cancer treatments (surgery, chemotherapy, or radiotherapy). Results: Among 190,471 patients, 1660 strokes occurred: 1296 (78.0%) ischemic strokes, 315 (19.0%) intracerebral hemorrhages, and 49 (3.0%) subarachnoid hemorrhages. In diagnosis-based analyses, the overall stroke SIR was 2.13 (95% CI, 2.03?2.24), with a 1.01% 1-year cumulative incidence. SIRs were 2.37 (95% CI, 2.24?2.50), 1.72 (95% CI, 1.53?1.92), and 1.22 (95% CI, 0.91?1.62) for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage, respectively. SIRs peaked immediately after diagnosis and declined thereafter. Excess risk persisted through 180 days for ischemic stroke, 30 days for intracerebral hemorrhage, and 7 days for subarachnoid hemorrhage. In treatment-based analyses, ischemic stroke incidence increased transiently around treatments. After surgery, the adjusted IRR peaked during days 0?7 (12.27 [95% CI, 8.50?17.71]) and remained elevated through days 31?90 versus days 181?365. A postoperative increase was observed even in early-stage disease. For chemotherapy, incidence was relatively high before treatment initiation. Conclusions: Stroke risk after cancer diagnosis varied by stroke type, cancer characteristics, and time since diagnosis. Ischemic stroke incidence increased transiently around cancer treatment, including an early postoperative increase in patients with early-stage disease. These findings identify periods and patient groups that may warrant heightened clinical vigilance.

Background and Objective: For their acceptance as endpoints in clinical trials, biomarkers and clinical outcome assessment (COA) measures should show reliability by being reproducible (precise) and responsive to change. We evaluated precision and responsiveness of MRI-derived brain volume metrics and various COAs in ceroid-lipofuscinosis, neuronal-3 (CLN3) disease. Methods: This longitudinal observational study (NCT03307304) included 44 individuals with CLN3-related disease (ages 0.5-29.1 years, 48% female). Brain volumetric measures were computed using SynthSeg-v2.0 from T1-weighted 3D MPRAGE images acquired at 3T (Median [Q1, Q3] total MRI follow-up duration from baseline: 2.04 [0.00, 3.69] years). Compartmental tissue volumes were normalized to a model-adjusted total intracranial volume and scaled to the tissue-specific volume fraction expected in healthy adolescent brains to extract measures of brain atrophy. COAs included the Vineland Adaptive Behavior Scales, verbal IQ, and the Unified Batten Disease Rating Scale (UBDRS). Analysis of linear mixed-effects models included only CLN3 participants with syndromic presentation, having three or more visits per measurement to estimate slope, its relative standard error (RSE), and the minimum inter-visit interval (Tmin) for statistically significant progression for each participant. Tmin to detect progression in 75% of the population (Tmin,75%) was computed for each metric. Results: Among brain volumetric measures, brain parenchyma volume (BPV) and gray matter volume (GMV) were the most precise and responsive metrics. BPV showed an overall intra-individual decline with age of -1.32%/year (95% CI: -1.64% to -0.99%), low RSE of 12.5%, and short Tmin,75% of 0.85 years (95% CI: 0.47-1.24). Amongst COAs, the UBDRS Clinical Global Impression (CGI) score was the most precise and responsive with an overall intra-individual increase of 1.26 units/year (95% CI: 1.03-1.49), RSE of 24.10%, and Tmin,75% of 2.56 years (95% CI: 1.73-3.46), though with lower precision (RSE higher) and lower responsiveness (Tmin,75% longer) than BPV. Discussion: MRI-derived metrics, in particular BPV and GMV, detected change in brain atrophy with high precision and responsiveness suggesting that they would be informative for evaluating potential neuroprotective therapies in CLN3 disease. These findings support incorporating MRI-derived volumetric measurements alongside clinical assessments in future clinical trials in CLN3.

Abstract Background: Despite the high stroke burden in the elderly, their thrombolysis utilization is suboptimal partly due to heightened hemorrhagic risk. Observational data suggest that low-dose thrombolysis may offer comparable efficacy to standard-dose with a trend toward reduced symptomatic intracranial hemorrhage (sICH), yet high-level evidence for low-dose thrombolysis in this broad population remains absent. Objective: To evaluate the safety and efficacy of low-dose intravenous tenecteplase thrombolysis in elderly stroke patients within 4.5 hours of ischaemic stroke onset. Methods and design: The DATE-AGING trial is a multicenter, prospective, randomized, open-label, blinded-end point (PROBE) non-inferiority study. Eligible participants are elderly patients (aged [≥]70 years)with acute ischemic stroke who meet current guideline recommendations for intravenous thrombolysis within 4.5 hours of symptom onset will be randomly assigned to Low-dose Tenecteplase group (0.175 mg/kg, max 17.5 mg) or Standard-dose Tenecteplase group (0.25 mg/kg, max 25 mg). The primary outcome was excellent functional outcome, defined as a mRS 0-1 assessed at 90-day post-randomization. Safety outcomes included sICH within 36 hours and mortality at 90 days. Discussions: The DATE-AGING trial is intended to provide high-quality evidence for low-dose tenecteplase intravenous thrombolysis in elderly patients with acute ischemic stroke. Trial registry number: NCT07294209(https://clinicaltrials.gov/study/07294209). Keywords: elderly patients, acute ischemic stroke, intravenous thrombolysis, low-dose tenecteplase

White matter hyperintensities on brain magnetic resonance imaging are established markers of cerebral small vessel disease and typically associate inversely with brain volume in the general population, reflecting irreversible tissue loss. In Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, a monogenic small vessel disease caused by NOTCH3 cysteine-altering mutations, white matter hyperintensities may instead reflect tissue water accumulation and perivascular space dilation rather than net structural damage. Whether this distinct pathophysiological relationship is detectable at population level among carriers of NOTCH3 cysteine-altering variants without clinically manifest disease remains unknown. We conducted a cross-sectional neuroimaging study using UK Biobank data acquired between 2014 and 2023. Among 44,943 participants with complete brain magnetic resonance imaging data (mean age 64 years +/- 8 years), 96 carried heterozygous NOTCH3 cysteine-altering variants within epidermal growth factor-like repeat domains 7 to 34 and 44,847 were non-carriers. White matter hyperintensity volume was automatically quantified and normalized to total intracranial volume. Brain parenchymal fraction was defined as combined gray and white matter volumes divided by total intracranial volume. Lacunes were manually assessed in all carriers. Linear regression and generalized additive models examined the association between white matter hyperintensity volume and brain parenchymal fraction stratified by genotype, adjusting for age, sex, lacune count, and vascular risk factors. NOTCH3 variant carriers showed markedly higher normalized white matter hyperintensity volume than non-carriers (0.83% versus 0.36%; P<10^-8) but only marginally higher brain parenchymal fraction (81.1% versus 80.5%; P=0.03). In non-carriers, white matter hyperintensity volume was inversely associated with brain parenchymal fraction (beta=-0.116% per 1% increase; P=3.10^-6). In contrast, NOTCH3 variant carriers demonstrated a positive association (beta=+0.51%; P=0.019), strengthened after adjusting for lacune count (beta=+0.61%; P=0.006). A significant genotype-specific interaction confirmed this divergence (P=0.036), persisting across age groups and after vascular risk factor adjustment. NOTCH3 cysteine-altering variant carriers identified at population level exhibit a fundamentally distinct white matter hyperintensity-brain volume relationship compared with non-carriers, consistent with lesions reflecting tissue water accumulation rather than irreversible structural loss at this early, predominantly preclinical disease stage. These findings establish that genetic context modifies neuroimaging biomarker interpretation in cerebral small vessel disease and underscore the need for genotype-aware approaches when evaluating white matter hyperintensities as markers of disease severity or progression.

INTRODUCTION: Plasma p-tau217 is associated with Alzheimer's disease pathology and memory performance, but its implications for memory may depend on fibrillar tau topography. We examined whether tau-PET subtype modified the association between plasma p-tau217 and memory. METHODS: We analyzed 396 amyloid-positive, tau-positive participants spanning cognitively unimpaired, mild cognitive impairment, and dementia stages from six cohorts with tau-PET and plasma p-tau217; 301 had harmonized memory data. Tau-PET subtypes were derived using data-driven disease progression modelling. Primary cross-sectional models tested subtypexp-tau217 interactions for memory, adjusting for age, sex, education, APOE {epsilon}4 status, and cohort. Secondary and exploratory analyses examined latent global cognition, non-memory measures, and longitudinal cognitive change. RESULTS: Three tau-PET subtypes were retained: limbic-predominant, medial temporal lobe (MTL)-sparing, and posterior-predominant. Cross-sectionally, MTL-sparing participants had lower plasma p-tau217 than the other subtypes. The association between higher plasma p-tau217 and worse memory differed by subtype (interaction p=0.002) and was stronger in MTL-sparing (B=-0.191, p<0.001) than in limbic-predominant (B=-0.07, p=0.002) and posterior-predominant participants (B=-0.07, p<0.001). The interaction remained significant after additional adjustment for diagnostic group (p=0.015). This pattern also persisted after additional adjustment for PET tau burden, amyloid Centiloids, or plasma A{beta}42/40 none of these biomarkers showed comparable subtype modification. Subtype modification was also observed for a global cognitive composite (interaction p=0.004) and subsequent memory decline in an exploratory analysis conditioned on baseline memory (interaction p=0.016). DISCUSSION: Tau-PET subtype modified the p-tau217-memory association, suggesting that the cognitive implications of plasma p-tau217 may vary with tau topography.

Vascular dementia (VaD) is a leading cause of cognitive decline with no disease-modifying therapies. It remains unclear whether diabetes drug targets causally influence VaD risk. We applied two-sample, drug target Mendelian randomisation (MR) to test whether modulation of eight antidiabetic drug targets may alter VaD risk. MR models used variants within genes encoding antidiabetic drug targets, selected according to their effects on circulating glycated haemoglobin (HbA1c, N = 437,749) in primary analyses, and cortex-specific cis-eQTLs (N = 2,683) in secondary analyses. Outcomes were clinically diagnosed VaD (N = 7,009 cases/899,672 controls) and neuroimaging markers of cerebrovascular disease: white matter hyperintensity volume (WMH; N = 50,970), inverse fractional anisotropy (iFA; N = 31,125), and mean diffusivity (MD; N = 31,147). Type-2 diabetes mellitus (T2DM; N= 62,892 cases/596,424 controls) served as a positive control outcome. Genetic instruments were available for seven of the relevant targets using both HbA1c and cortex cis-eQTL data. In primary HbA1c-scaled analyses, no antidiabetic drug target showed evidence of association with VaD risk or cerebrovascular neuroimaging markers, although DPP4 inhibition demonstrated a suggestive protective association for VaD (OR = 0.68, 95% CI = 0.46 - 1.02, p = 0.063), though the confidence interval (CI) included the null. Secondary cortex cis-eQTL analyses were similarly null, except for PPARG modulation, which was predicted to reduce iFA ({beta} = -0.50, 95% CI -0.99 to -0.02, p = 0.04). Overall, these findings provide little genetic evidence supporting currently licensed antidiabetic drugs as candidates for vascular dementia prevention, although DPP4 inhibition warrants further investigation in larger datasets.

Importance: Phosphorylated tau at threonine 217 (p-tau217) and brain-derived tau (BD-tau) are increasingly used as blood biomarkers of Alzheimer's disease (AD) and related neurological disorders. However, the distributions and biological correlates of elevated plasma p-tau217 and BD-tau in plasma from individuals eligible for blood donation remain unclear. Objective: To estimate the proportions of plasma p-tau217 and BD-tau exceeding exploratory study-specific thresholds, and examine associated inflammatory and transcriptomic features. Design: Cross-sectional study. Setting: Hospital blood bank. Participants: 257 de-identified donor samples were obtained between September 2025 and June 2026. Plasma samples from 30 population reference participants and 20 AD patients were used to derive study-specific thresholds. Complementary transcriptomic analyses were performed in 29 fresh whole blood samples. Main Outcomes and Measures: The primary outcome was the proportion of donor samples exceeding the study-specific ROC-derived Youden threshold. The proportion exceeding the prespecified published p-tau217 threshold was the secondary outcome. Other measures included plasma concentrations of BD-tau, tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6); correlations among plasma p-tau217, BD-tau and inflammatory cytokines; and associated transcriptomic alterations. Results: Plasma p-tau217 concentrations exceeded the study-specific ROC-derived Youden threshold in 53 of 256 donor samples (21%; 95% CI, 16%-26%) and the published threshold, used for a secondary comparison, in 99 of 256 samples (39%; 95% CI, 33%-45%). Plasma BD-tau concentrations exceeded the study-specific threshold in 89 of 257 samples (35%; 95% CI, 29%-41%). Plasma p-tau217 concentrations were positively associated with plasma TNF-alpha (Kendall's tau = 0.339; P < .001) and IL-6 (Kendall's tau = 0.310; P < .001) concentrations. Exploratory transcriptomic analyses identified gene expression patterns associated with p-tau217 concentrations. Measurement using a second p-tau217 antibody showed the similar findings. Conclusions and Relevance: Plasma p-tau217 and BD-tau concentrations exceeded exploratory study-specific thresholds in a subset of blood-donor samples, and higher p-tau217 concentrations were associated with inflammatory biomarkers and exploratory transcriptomic differences. These findings raise the possibility of elevated circulating tau species in some blood donors, but their clinical significance requires confirmation. Whether elevated circulating p-tau217 in donated blood has biological consequences for transfusion recipients is unknown, but deserves investigation.

BackgroundMinor ischemic stroke is heterogeneous, and low NIHSS does not reliably identify patients at risk of deterioration or disability. We investigated whether integrating CT perfusion and angiographic vessel status identifies prognostically distinct phenotypes in a consecutive stroke-code cohort. MethodsWe analyzed consecutive adults with ischemic stroke, baseline NIHSS 0-5, prestroke modified Rankin Scale (mRS) [&le;]2, presentation within 24 hours of symptom onset or last known well, and emergency multiparametric CT. Patients were classified as no perfusion deficit/no vessel occlusion (PF-/VO-), perfusion deficit without visible occlusion (PF+/VO-), or perfusion deficit with vessel occlusion (PF+/VO+). The primary outcome was mRS [&ge;]3 at 90 days; early neurological deterioration (END), defined as an NIHSS increase [&ge;]2 points by 24 hours, was secondary. Multivariable logistic regression adjusted for prespecified covariates and additional variables associated with each outcome in univariable analysis. ResultsOf 2211 patients evaluated through the stroke-code pathway, 534 met inclusion criteria; 391 (73.2%) were PF-/VO-, 61 (11.4%) PF+/VO-, and 82 (15.4%) PF+/VO+. END occurred in 8.1% and mRS [&ge;]3 at 90 days in 17.6%. END occurred in 6.6%, 4.9%, and 17.1% of PF-/VO-, PF+/VO-, and PF+/VO+ patients, respectively (P=0.004), whereas mRS [&ge;]3 occurred in 13.3%, 34.4%, and 25.6%, respectively (P<0.001). Compared with PF-/VO-, PF+/VO+ was independently associated with END (adjusted odds ratio [aOR], 2.50 [95% CI, 1.03-6.06]), whereas PF+/VO- was independently associated with mRS [&ge;]3 at 90 days (aOR, 3.36 [95% CI, 1.67-6.73]). Findings were consistent across definitions of disabling versus nondisabling stroke and after exclusion of lacunar stroke. ConclusionsMultiparametric CT identified distinct risk phenotypes in minor ischemic stroke. Perfusion deficit without visible vessel occlusion was associated with 90-day disability, whereas combined perfusion deficit and vessel occlusion identified patients at increased risk of END. Tissue perfusion and vessel status may provide complementary information for acute risk stratification and future trial enrichment.

INTRODUCTION: Stroke, dementia, and late-life depression share overlapping vascular pathophysiology, yet simple markers of shared neurological vulnerability across these conditions remain limited. Most gait research has relied on usual walking speed (UWS) alone, leaving it unclear whether quick walking speed (QWS) and gait adaptability (QWS minus UWS), relate to these conditions in the same way. METHODS: We examined associations of UWS, QWS, and gait adaptability with executive function, verbal memory, depressive symptoms, and incident stroke and dementia in the Framingham Heart Study Offspring cohort. A larger sample (n=2,308; mean age 61.5 years [SD 9.2]; 54% women) was used for cross-sectional and stroke analyses, and a dementia-free sample of 1,148 participants aged 60 years or older (mean age 68.5 years [SD 5.8]; 53% women) was used for analyses of incident dementia. We estimated associations per SD slower walking or smaller adaptability using linear, logistic, and Cox regression (10-year follow-up), overall and in women and men. RESULTS: Slower QWS and UWS were each associated with worse executive function, higher odds of high depressive symptoms (QWS OR 1.24, 95% CI 1.07-1.45; UWS OR 1.26, 95% CI 1.09-1.46), and greater hazard of incident stroke (QWS HR 1.30, 95% CI 1.03-1.64; UWS HR 1.36, 95% CI 1.11-1.65). Executive function and stroke associations were observed primarily in men (stroke QWS HR 1.55, 95% CI 1.11-2.17). For incident dementia, slower QWS reached significance (HR 1.34, 95% CI 1.10-1.63), while UWS did not (HR 1.20, 95% CI 0.98-1.46). Lower gait adaptability was associated with worse executive function overall and in women and men, and with incident dementia in women (HR 1.35, 95% CI 1.04-1.76), but not with depressive symptoms or stroke. No gait measure was associated with delayed recall. CONCLUSION: Slower QWS was associated with incident dementia; UWS was not. Adding a brief quick walking trial to routine gait assessment may identify risk that habitual-pace screening overlooks.

Background/Aims: Pre-stroke depression has been shown to be associated with worse functional outcomes and depression after stroke. However, it is not currently well understood whether pre-stroke mood disorders (e.g., depression, anxiety, mood and psychotic disorders, substance use disorder) are associated with withdrawal of life-sustaining treatment (WOLST) after a severe stroke. Methods: This was a retrospective cohort study within the Tufts Vascular Neurology Registry of patients hospitalized with severe acute ischemic stroke (AIS, defined as NIHSS [&ge;]10) or severe nontraumatic intracerebral hemorrhage (ICH, defined as ICH score [&ge;]2) between 2018 and 2022. Multivariate logistic regression was performed to identify predictors of WOLST. Results: This study included 405 patients with severe stroke. Patients who opted for WOLST were more likely to be older, female, have AIS, and experience more severe strokes. In an adjusted analysis (basic demographics, stroke type), a pre-stroke mood disorder was associated with WOLST (OR 2.15, 95% CI 1.11-4.15). In models stratified by stroke type (AIS vs. ICH) and adjusted for stroke severity, WOLST was associated with age in both groups and with mood disorder in patients with ICH. The WOLST event rate was higher in the ICH group (19% vs 11%). Conclusion: Pre-stroke mood disorder was associated with increased rates of withdrawal of care after severe stroke in this patient population. Opportunities to actively treat depression may be useful to include in goals of care discussions to mitigate the potential impact of this factor in decision-making. Consistent with prior studies, we observed a higher proportion of WOLST in older, female, and ICH patients. Future studies regarding the quality and content of goals of care discussions may help elucidate the differing effects of pre-stroke mood disorders on WOLST by stroke type seen in this study.

Objective To examine whether prospectively recorded maternal BMI in early pregnancy is associated with offspring multiple sclerosis (MS) risk, including childhood-onset and adult-onset MS. Design Nationwide population-based cohort study. Setting Swedish national health and demographic registers. Participants 1,524,863 singleton children born in Sweden from 1992 to 2007 and followed through 2025. Exposures Maternal BMI recorded at the first antenatal visit, categorised as underweight (<18.5), normal weight (18.5-24.9), overweight (25.0-29.9), and obesity ([&ge;]30.0), and also modelled continuously. Main outcome measures MS in offspring, identified as at least three ICD-10 G35 codes recorded on separate dates. Cox models estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) adjusting for confounders. Results During follow-up, 1539 offspring (0.1%) were diagnosed with MS at a median age of 24 years (interquartile range, 20-27 years). MS incidence rates by maternal BMI category were 0.37 per 10,000 person-years for both underweight, and normal weight, 0.42 for overweight, and 0.45 for obesity. Compared with normal weight women, maternal overweight and obesity were associated with higher hazards of offspring MS, with adjusted HRs of 1.20 (95% CI, 1.05 to 1.37) and 1.35 (95% CI, 1.11 to 1.64), respectively. Onset-specific analyses showed similar findings for adult-onset MS and less precise but directionally consistent estimates for paediatric-onset MS. Each 1-unit increase in maternal BMI was associated with a 3%, 4%, and 3% higher hazard of overall, paediatric-onset, and adult-onset offspring MS, respectively. Conclusions In this population-based cohort study, higher maternal BMI were associated with an increased rate of MS in offspring. The findings provide large-scale prospective evidence that maternal adiposity may be related to offspring MS risk and support further investigation of the prenatal metabolic environment in the early-life origins of MS.

Progressive multiple sclerosis (PMS) lacks blood-based biomarkers of the neurodegenerative processes driving disability. We measured synaptopodin, a postsynaptic protein, in neuronal-enriched extracellular vesicles (NEVs) across two independent cohorts: the SPRINT-MS trial (n=184) and a real-world validation cohort (n=268). A one SD increase in baseline synaptopodin was associated with ~32% lower risk of confirmed disability progression in PMS (p=0.011), with the strongest effect in secondary PMS (SPMS) (~57% lower odds, p=0.019). This SPMS association was replicated in the validation cohort (~60% lower odds, p=0.009). Higher baseline synaptopodin was associated with future slower whole-brain atrophy and preserved microstructural integrity across MRI metrics (p=0.007-0.013). Longitudinal changes in NEV synaptopodin were associated with disability worsening (p=0.007) and paralleled MRI microstructural changes. NEV synaptopodin, but not NfL, was associated with confirmed disability progression in PMS participants with both biomarkers measured (HR 0.71 vs 1.12, p=0.007 vs 0.22 for NEV synaptopodin and NfL, respectively) and SPMS (HR 0.58 vs 1.10, p=0.003 vs 0.50). Adding synaptopodin, but not NfL, to a base model improved discrimination for disability progression in SPMS in both cohorts (e.g. validation AUC 0.755 to 0.838, p=0.005). These findings identify NEV synaptopodin as a prognostic and longitudinal, blood biomarker of synaptic integrity in PMS, particularly SPMS, complementing NfL.

Objective: To identify demographic and daily cognitive, affective, and contextual predictors of headache-related interference with activity and concentration in a smartphone-based migraine cohort, using statistical models appropriate to the ordinal structure of patient-reported interference. Background: Migraine burden extends beyond headache to encompass cognitive and affective disturbance, yet most disability instruments summarize functioning retrospectively and cannot capture day-to-day variability in interference. Ecological momentary assessment addresses this limitation, yet few studies have examined cognitive and affective correlates of interference independent of pain intensity or have modeled interference using methods that respect its ordinal, non-equal-interval structure. Methods: From May 2025 to April 2026, adult participants were enrolled in this prospective, decentralized observational study via specialty clinics and social media campaigns. Eligibility required fulfilling ICHD-3 diagnostic criteria for migraine using a validated electronic survey and experiencing between 3 and 20 monthly headache days. Enrolled individuals recorded daily smartphone diary entries and performed three brief cognitive tests over a 30-day monitoring period. Daily interference with activities and concentration were captured on 5-point ordinal scales and analyzed via cumulative link mixed-effects models incorporating participant-specific random intercepts. Predictor selection across nested specifications relied on likelihood ratio testing and Akaike Information Criterion (AIC) metrics, prioritizing the more parsimonious model when goodness-of-fit was comparable. Results: The analytic sample comprised 1,267 headache-day observations from 143 participants. In the final models, brain fog (OR = 2.49 for activity, 3.19 for concentration), forgetfulness (OR = 1.48, 1.65), and mood disturbance (OR = 1.19, 1.31) were each independently associated with both outcomes (all p < 0.01), while age, sex, and employment status showed no significant association with either. Sleep quality (OR = 0.86) and anticipated next-day enjoyment (OR = 0.81) provided additional explanatory value for activity interference (p < 0.05) but not for concentration interference, for which the three-predictor model of brain fog, forgetfulness, and mood alone was retained as the most parsimonious final model. Conclusions: Cognitive and affective symptoms, rather than demographic or socioeconomic characteristics, are the primary correlates of headache-related functional interference in this cohort. Activity and concentration interference are explained by partially distinct sets of daily influences, supporting the clinical value of assessing cognitive and affective symptoms alongside conventional pain-focused evaluation.

Background: Immunothrombosis is increasingly recognized in large-vessel-occlusion acute ischemic stroke (LVO-AIS), yet most biomarker studies infer thrombus biology from circulating neutrophil extracellular trap (NET) markers or from pre-defined thrombus subtypes. We prospectively studied 160 patients with anterior-circulation LVO-AIS treated with mechanical thrombectomy to determine whether intrathrombus NETosis markers identify thrombus phenotypes with distinct clinical trajectories, and whether plasma NETosis biomarkers reflect the molecular composition of thrombi. Methods: Thrombi underwent quantitative histopathology and immunohistochemistry for citrullinated histone H3 (CitH3), neutrophil elastase (NE) and CD61. Thrombi were analyzed without prior etiological or histological stratification, and intrathrombus markers were dichotomized at cohort medians (CitH3 6.62%, NE 3.95%, CD61 23.09%) to define internally standardized candidate phenotypes. Associations with thrombus composition, collateral circulation (Tan 2-3), 3-month functional independence (modified Rankin Scale 2 or less) and long-term mortality were assessed by correlation analyses and progressively adjusted multivariable models, with cross-compartment correlations corrected by the Benjamini-Hochberg false discovery rate (FDR). Results: Intrathrombus markers defined prognostically distinct phenotypes: CD61 tracked functional recovery, NE preserved collateral circulation and CitH3 long-term survival, each remaining significant after multivariable adjustment. Circulating NE, myeloperoxidase and leukocyte count instead tracked the macroscopic red-blood-cell-fibrin composition of retrieved thrombi. Cross-compartment concordance was limited: after FDR correction the only significant plasma-thrombus association was an inverse correlation between plasma cell-free DNA and intrathrombus NE, and no intrathrombus marker correlated positively with its circulating counterpart. Conclusions: Local immunothrombotic signatures therefore provide clinically relevant information not captured by plasma markers, and median-defined intrathrombus thresholds represent hypothesis-generating cutoffs for external validation and NET-targeted treatment stratification.

Phantom limb pain (PLP) is common after amputation, yet why poor sleep becomes pain in only some individuals is unknown. We hypothesized that a regulatory response is interpretable only against the reserve sustaining it, and thus we tested whether autonomic capacity relative to demand moderates the sleep-pain relationship in 121 amputee adults. Sleep was assessed with the Pittsburgh Sleep Quality Index; PLP, residual limb pain (RLP), and phantom limb sensation (PLS) on 0-10 scales. Heart rate variability was summarized as autonomic reserve (log-transformed SDNN, RMSSD, total and high-frequency power) and autonomic drive (normalized low-frequency power). Poorer sleep was associated with greater PLP and RLP, but not PLS. No single HRV index moderated these associations, but the sleep x reserve x drive interaction did for PLP (b =-0.51, p = 0.026). Poor sleep predicted pain most strongly under high drive with reduced reserve. PLP vulnerability reflects autonomic capacity relative to demand, instead of any single HRV marker alone.