Neurology

INTRODUCTION: Amyloid-related imaging abnormalities with microhaemorrhage (ARIA-H) are an important safety consideration with anti-amyloid therapies, yet evidence exploring short-term risk prediction remains limited. METHODS: We analysed longitudinal MRI data from the A4 study, constructing a discrete person-interval dataset for modelling the short-term risk of ARIA-H. Models incorporated baseline covariates, alongside dynamic variables of recent microhaemorrhage accumulation and current microhaemorrhage burden. Incident ARIA-H was defined as 2 or more new microhaemorrhages or 1 or more new superficial siderosis between consecutive MRI scans. RESULTS: Among 1,069 participants (3,647 intervals), 171 ARIA-H events occurred. Both current burden (time-to-event: OR 1.37, 95% CI 1.09-1.73; all-event: OR 1.24, 95% CI: 1.04-1.49) and recent microhaemorrhage accumulation (time-to-event: OR 1.83, 95% CI 1.01-3.30; all-event: OR 1.43, 95% CI: 1.00-2.04) were independently associated with an increased risk of ARIA-H. DISCUSSION: Temporal imaging variables may provide independent prognostic information beyond baseline risk, supporting a dynamic model of haemorrhagic risk in Alzheimer's disease.

BackroundNearly all individuals with type 1 diabetes develop diabetic retinopathy over time, known to relate to cerebral small vessel disease. We investigated associations between early vascular changes in the eye and brain by optical coherence tomography angiography (OCTA) and brain magnetic resonance imaging (MRI) in middle-aged, neurologically asymptomatic individuals with type 1 diabetes. Research Design and MethodsIndividuals with type 1 diabetes (n=159, median age 48.0 years, diabetes duration 29.3 years, 53% female) and 49 healthy controls underwent clinical and biochemical assessments, brain MRI to evaluate cerebral microbleeds (CMBs) and white matter hyperintensities (WMHs), and macular 3x3 mm OCTA imaging to assess vessel densities of superficial (SCP) and deep (DCP) retinal capillary plexuses, and the area of the foveal avascular zone (FAZ). ResultsNo differences in OCTA parameters were observed between individuals with type 1 diabetes and healthy controls. However, SCP and DCP vessel densities (45.1% vs 46.5%, p=0.034, and 49.9% vs 52.9%, p<0.001, respectively), were smaller in individuals with type 1 diabetes with CMBs compared with those without. No such evidence was found for FAZ. In univariate linear regression models, SCP and DCP vessel densities were negatively associated with age, diabetes duration, blood pressure, kidney function (eGFR), number of CMBs, and WMHs. FAZ was related to diabetes duration, age of diabetes onset, and LDL cholesterol concentration. Of these, in multivariate models, diabetes duration remained associated negatively with vessel densities and positively with FAZ (SCP: standardized {beta} =-0.210 [p=0.014]; DCP: standardized {beta} =-0.275 [p<0.001]; FAZ: standardized {beta}=0.295 [p<0.001]). None of the retinal markers differed in individuals with or without WMHs and type 1 diabetes. ConclusionIn middle-aged, neurologically asymptomatic adults with long-standing type 1 diabetes, lower SCP and DCP vessel densities were associated with cerebral microbleeds, suggesting OCTA may aid cerebrovascular risk stratification but not WMH assessment. Research insightsO_ST_ABSWhat is currently known about this topic?C_ST_ABSNearly all individuals with type 1 diabetes develop diabetic eye disease within 30 years following the diagnosis. We observed previously that one third of neurologically asymptomatic individuals with type 1 diabetes have cerebral microbleeds in routine brain magnetic resonance imaging. Cerebral microbleeds were more common among those with advanced forms of diabetic eye disease. What is the key research question?To investigate associations between markers of cerebral small vessel disease and metrics of optical coherence tomography angiography among individuals with type 1 diabetes. What is new?Vessel densities of the macula were smaller among those individuals with type 1 diabetes and cerebral microbleeds. Vessel densities were negatively and area of the foveal avascular zone positively associated with duration of diabetes. How might this study influence clinical practice?OCTA may aid cerebrovascular risk stratification among individuals with long-standing type 1 diabetes

Chronic traumatic encephalopathy-neuropathologic change (CTE-NC) has been primarily studied in contact sport athletes with repetitive head impacts (RHI). An association with isolated traumatic brain injury (TBI) is less clear. We systematically reviewed the autopsied cohort of Late Effects of TBI (LETBI), characterized primarily by isolated TBI but also including RHI, for features of CTE-NC. A consecutive series of 44 brains underwent comprehensive neuropathologic evaluation, exceeding recommended CTE consensus protocols. Of the 44, 6 (13.6%) (age range, 3rd-7th decades; median, 6th decade) had CTE-NC, forming the basis for this exploratory analysis. Ex vivo neuroimaging (in 4 of 6) highlighted traumatic and white matter microvascular lesions, facilitating histological sampling of subtle neuropathologies that might otherwise have been missed by conventional sectioning. Macroscopically, 5 had cortical (contusional) and white matter (torsional) volume loss, with septal lesions and hydrocephalus ex vacuo (i.e., structural lesions of moderate-severe TBI). Microscopically, tau-immunopositive neuronal and astrocytic pathology in a perivascular arrangement within sulcal depths met current pathognomonic criteria for CTE-NC in 5 (3 "low" and 2 "high" burden); 1 had more limited findings considered "suspicious" for CTE-NC. Five of 6 cases with any CTE-NC reported substantial exposure to RHI, through contact sport ranging over at least 16 years. One case had no known exposure to RHI: this case (death: 6th decade) had 2 isolated severe TBIs (sustained 30y and 3y prior to death). Of note, one case with "high" CTE also had Alzheimer Disease Neuropathologic Change (high stage), Lewy Body Disease (limbic), and TDP43 accumulation ("polyproteinopathy"). Aging-related tau astrogliopathy, mostly subpial, was seen in 4 cases. Glial tau was also noted around old cavitary contusions in 2. These findings converge with prior studies demonstrating that CTE is largely associated with RHI and is infrequent among individuals with isolated TBI.

BackgroundCardiovascular health optimization during middle age benefits brain health. The American Heart Associations Lifes Simple 7 recently added sleep duration as a key determinant of cardiovascular health becoming the Lifes Essential 8. We tested the hypothesis that suboptimal sleep duration is associated with poorer neuroimaging brain health profiles in asymptomatic middle-aged adults. MethodsWe conducted a prospective MRI neuroimaging study in middle-aged persons without stroke, dementia, or multiple sclerosis enrolled in the UK Biobank. Self-reported sleep duration was categorized as short (<7 hours), optimal (7-<9 hours), or long ([&ge;]9 hours). Evaluated neuroimaging markers of brain health included white matter hyperintensities (presence and volume) and diffusion tensor imaging metrics (fractional anisotropy and mean diffusivity) evaluated in 48 distinct neuroanatomical regions. We used multivariable logistic and linear regression models, as appropriate, to test for association between sleep duration and neuroimaging markers of brain health. ResultsWe evaluated 39,502 middle-aged persons (mean age 55, 53% female). Of these, 28,712 (72.7%) had optimal, 8,422 (21.3%) short, and 2,368 (6%) long sleep. Compared to optimal sleep, short sleep was associated with higher risk (OR 1.11; 95% CI 1.05-1.17; P<0.001) and larger volume (beta=0.06, SE=0.01; P<0.001) of white matter hyperintensities, while long sleep was associated with higher volume (beta=0.04, SE=0.02; P=0.01) but not higher risk (P>0.05) of white matter hyperintensities. Short (beta=0.03, SE=0.01; P=0.004) and long sleep (beta=0.07, SE=0.02; P<0.001) were associated with worse fractional anisotropy, while only long sleep associated with worse mean diffusivity (beta=0.05, SE=0.02; P=0.005). ConclusionsAmong middle-aged adults without clinically observed neurological disease, suboptimal sleep duration is associated with poorer neuroimaging brain health profiles. Because the evaluated neuroimaging markers precede stroke and dementia by several years, our findings support early interventions aimed at correcting this modifiable risk factor.

BackgroundPromising evidence indicates that treating hearing loss with hearing aids (HAs) could reduce dementia risk. We extend this evidence by investigating the effect of HAs on plasma biomarkers of Alzheimers disease and related dementias (ADRD). MethodsWe emulated two target trials using observational data from Australian participants of the ASPREE study. Eligible participants had self-reported hearing problems, no past HA use, and were dementia-free. HA prescriptions and frequency of HA use were measured by questionnaire. Phosphorylated-tau181 (pTau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid-{beta} (A{beta}) 42/40 were measured after approximately 6-8 years. We estimated the effect of new HA prescription (first target trial) and the frequency of HA use (second target trial) using targeted maximum likelihood estimation, with multiple imputation for missing data. ResultsAcross imputed datasets, a median of 2842 eligible individuals were included (mean age 75 years, 48% female), with a median of 735 receiving a new HA prescription. Among survivors, the estimated mean differences comparing HA prescription and no HA prescription were 1.8 pg/mL (95% CI: -0.6, 4.1), 0.1 pg/mL (-7.8, 8.0), -2.2 pg/mL (-14.5, 10.1), and -0.7 (-2.6, 1.2) for the concentrations of pTau181, NfL, GFAP, and (A{beta}42 x 1000)/A{beta}40, respectively. Mean differences did not differ substantially across levels of potential baseline effect modifiers, including APOE-{varepsilon}4 genotype and cognition. ConclusionIn community-dwelling older people with hearing loss and no dementia, we found minimal effects of HA prescription and frequency of HA use on plasma ADRD biomarkers after a 7-year follow-up.

BackgroundWord-finding difficulty is prevalent but poorly understood in persons with relapsing-remitting multiple sclerosis (RRMS). ObjectiveInvestigate our hypothesis that phonological processing ability is below expectations and related to word-finding difficulty in patients with RRMS. MethodData were analyzed from patients with RRMS (n=50) on patient-reported word-finding difficulty (PW-WFD) and objective performance on WIAT-4 Phonemic Proficiency (PP; analysis of phonemes within words), Word-Reading (WR, proxy of premorbid literacy and verbal ability), and Sentence Repetition (SR; auditory processing of word-level information). ResultsPerformance (mean [95% CI]) was reliably lower than normative expectations for PP (- 0.41[-0.69, -0.13]) but not for WR (0.02[-0.21, 0.25]) or SR (0.08[-0.15, 0.31]. Within-subjects performance was worse on PP than both WR (t[49]=4.00, p<0.001, d=0.47) and SR (t[49]=3.76, p<0.001, d=0.54). Worse PR-WFD was specifically related to lower PP (F2,47=6.24, p=0.004, {eta}2=0.21); worse PP performance at PR-WFD Often (n=13; -1.16[-1.49, -0.83]) than Sometimes (n=17; -0.14[-0.68, 0.41]) or Rarely (n=20; -0.16[-0.58, 0.27]. PR-WFD was unrelated to WR or SR (Ps>0.25). ConclusionPhonological processing was below expectations and specifically linked to word-finding difficulty in RRMS. Findings are consistent with early disease-related cortical changes within the posterior superior temporal / supramarginal region. Results inform our developing model of MS-related word-finding difficulty.

BackgroundIt is unclear how post-stroke cognitive trajectories differ by stroke type and ischemic stroke subtype. We studied associations between stroke types (ischemic, hemorrhagic), ischemic stroke subtypes (cardioembolic, large artery atherosclerotic, lacunar/small vessel, cryptogenic/other determined etiology), and post-stroke cognitive decline. MethodsThis pooled cohort analysis from four US cohort studies (1971-2019) identified 1,143 dementia-free individuals with acute stroke during follow-up: 1,061 (92.8%) ischemic, 82 (7.2%) hemorrhagic, 49.9% female, 30.8% Black. Median age at stroke was 74.1 (IQR, 68.6, 79.3) years. Outcomes were change in global cognition (primary) and changes in executive function and memory (secondary). Outcomes were standardized as T-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Median follow-up for the primary outcome was 6.0 (IQR, 3.2, 9.2) years. Linear mixed-effects models estimated changes in cognition after stroke. ResultsOn average, the initial post-stroke global cognition score was 50.78 points (95% CI, 49.52, 52.03) in ischemic stroke survivors and did not differ in hemorrhagic stroke survivors (difference, -0.17 points [95% CI, -1.64, 1.30]; P=0.82) after adjusting for demographics and pre-stroke cognition. On average, ischemic stroke survivors showed declines in global cognition, executive function, and memory. Post-stroke declines in global cognition, executive function, and memory did not differ between hemorrhagic and ischemic stroke survivors. 955 ischemic strokes had subtypes: 200 (20.9%) cardioembolic, 77 (8.1%) large artery atherosclerotic, 207 (21.7%) lacunar/small vessel, 471 (49.3%) cryptogenic/other determined etiology. On average, small vessel stroke survivors showed declines in global cognition and memory, but not executive function. Initial post-stroke cognitive scores and cognitive declines did not differ between small vessel survivors and survivors of other ischemic stroke subtypes. Post-stroke vascular risk factor levels did not attenuate associations. ConclusionStroke survivors had cognitive decline in multiple domains. Declines did not differ by stroke type or ischemic stroke subtype.

IntroductionAnti-amyloid immunotherapies are approved by the United States Food and Drug Administration (FDA) for the treatment of Alzheimers disease. The adoption and safety profile of these medications in routine clinical practice have not been described. MethodsWe performed a retrospective observational cohort study using nationwide electronic health record data from Epic Cosmos. The principal objective was to describe the baseline characteristics of patients prescribed anti-amyloid immunotherapy in routine clinical practice. Secondarily, we wished to determine whether prescription of anti-amyloid immunotherapy (with or without an acetylcholinesterase inhibitor [AChEI] or memantine) was associated with an increased risk of key safety end points when compared to an AChEI or memantine alone. We used a target trial emulation framework to identify and mitigate sources of bias. The primary end point was time to first nontraumatic intracranial hemorrhage (ICH). Secondary end points included other cardiovascular conditions (ischemic stroke (IS), myocardial infarction (MI), and a composite of ICH, IS, or MI), headache, diarrhea and overall healthcare utilization. Exploratory end points included adverse events linked to other immunotherapies. We used propensity score overlap weighting to balance baseline demographic and clinical characteristics across treatment groups. ResultsBetween July 1, 2023 and January 1, 2025, 2,616 patients (median age 74.8 years [IQR 69.8-78.8]; 53.9 % female) were prescribed anti-amyloid immunotherapy (with or without AChEI/memantine), and 1,065,192 patients (median age 79.98 [IQR 73.6-85.6], 57.9% female) were prescribed AChEI/memantine alone. In total, 401 patients prescribed anti-amyloid immunotherapy and 274,470 patients prescribed AChEI/memantine were assessed for safety end points. Compared with AChEI/memantine, prescription of anti-amyloid immunotherapy was not associated with increased hazard of ICH after adjustment (owHR 0.73 [95% CI 0.11-5.46]). Anti-amyloid immunotherapy prescription was associated with a higher risk of headache (owHR 2.16 [95% CI 1.12-4.16]) and respiratory infection (owHR 1.57 [95% CI 1.04-2.37]) but was not associated with other immune-related safety endpoints. ConclusionAnti-amyloid immunotherapy has been principally adopted by patients who are younger and medically healthier than patients receiving AChEI/memantine alone. Prescription of anti-amyloid immunotherapy was not associated with an increased risk of ICH.

Monogenic forms of stroke have been thought to be rare with high penetrance. However, recent studies have reported typical monogenic stroke pathogenic variants are much commoner than expected in the general population. Whether such variants are associated with disease, and why the phenotype of these variants varies so widely remain unclear. In 454,787 individuals in UK Biobank, we identified typical pathogenic variants in NOTCH3, HTRA1 and COL4A1/2 genes in 1 in 467, 1 in 832 and 1 in 1353 subjects, respectively. Variants in all three genes were associated with stroke risk, and NOTCH3 and HTRA1 with dementia risk. Cardiovascular risk (assessed by Framingham cardiovascular risk score), polygenic risk (assessed by a polygenic stroke risk score), and variant location within each gene, were all associated with penetrance of NOTCH3 and HTRA1 variants. Our results suggest intensive cardiovascular risk factor modification may reduce stroke and dementia risk in individuals with such variants.

BackgroundCovert cerebrovascular disease (CCD), comprising covert brain infarction (CBI) and white matter disease (WMD), is common in older adults and linked to increased risk of stroke and dementia. While most CCD research relies on MRI, CT remains the predominant imaging modality in clinical care. The influence of imaging modality on detection and prognosis of incidentally discovered CCD remains unclear. MethodsWe identified 18,626 patients aged [&ge;]50 years from Kaiser Permanente Southern California who underwent both CT and MRI brain scans within 30 days between 2009- 2022. Patients with known prior stroke or dementia were excluded. Natural language processing algorithms were applied to radiology reports to identify CBI and WMD status and WMD severity (none, mild, moderate, severe). We assessed prevalence, cross-modality agreement (Cohens kappa), and reclassification patterns. Prognostic associations with incident stroke or dementia were estimated using Cox Proportional Hazards regression adjusted for vascular and cognitive risk factors. FindingsCBI prevalence was similar for CT (6.3%) and MRI (6.1%), but agreement was modest ({kappa}=0.27). WMD was reported far more often on MRI (60.5%) than CT (24.4%). Among 15,551 patients with classifiable severity on both modalities, 47.9% (n=7,441) had discordant grades, with 92.3% upgraded on MRI. The incidence rates of stroke or dementia per 1,000 person-years were 12.7 (95% CI 11.5 - 14.0) for patients without WMD on either modality (36.3% of the cohort), 22.6 (21.0 - 24.2) for WMD detected on MRI only (39.2% of the cohort), and 52.2 (48.69 to 55.95) for WMD detected on both CT and MRI (21.2% of the cohort). In adjusted Cox models, WMD detected on MRI only was associated with a 23% higher hazard of stroke or dementia (HR=1.23, 95% CI 1.07-1.41) compared with no WMD on either modality, while WMD detected on both CT and MRI was associated with an 82% higher hazard (1.82, 1.58-2.11). InterpretationMRI detects substantially more WMD than CT; however, WMD visible on CT has stronger prognostic significance, despite CTs low sensitivity. These findings emphasize modality-based diagnostic and prognostic differences and support the need for modality-specific approaches when translating CCD research into clinical risk assessment and patient counselling. FundingThis work is funded by an Alzheimers Drug Discovery Foundation (ADDF) award (RC-202209-2024187) and National Institutes of Health (NIH) grants (2 RF1 NS102233-05, R01 NS134859-01). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSMost knowledge about covert cerebrovascular disease (CCD), including covert brain infarction (CBI) and white matter disease (WMD), comes from MRI-based research cohorts. However, CT is the dominant imaging modality in routine care, where incidental CCD is identified. Previous studies identified from our literature search suggest that CT and MRI may differ in sensitivity, but no studies have directly compared diagnostic and prognostic differences across both modalities within the same patients in routinely-obtained neuroimaging. Added value of this studyThis is the first large-scale, within-subject analysis of CT and MRI CCD findings obtained in routine care. We found that MRI detects substantially more WMD, while CT-detected WMD is more strongly associated with future stroke and dementia. CBI prevalence was similar across modalities, but agreement was modest. Implications of all the available evidenceOur findings suggest that clinically meaningful CCD is usually captured by CT scan; pragmatic research studies need to incorporate this modality.

Importance: Accurate prediction of chronic traumatic encephalopathy (CTE) remains challenging in life. Objective: To assess the reliability and validity of the NINDS traumatic encephalopathy syndrome (TES) criteria to predict CTE pathology in life. Design: Clinicopathological Diagnostic/Prognostic Study Setting: Six brain banks with varied recruitment criteria Participants: Brain donors were selected across 6 brain banks (15+ donors each), 5 age groups spanning ages 20 to 80+ (25+ donors each) and 9 repetitive head impact (RHI)/traumatic brain injury (TBI) groups (15+ donors each): (1) college or professional American football; (2) less than college football; (3) college or professional contact sports, non-football; (4) less than college contact sports, non-football; (5) military combat, no contact sports; (6) military combat and contact sports; (7) concussion with loss of consciousness, no RHI; (8) moderate to severe TBI, no RHI; (9) no RHI/TBI. Exposures: Blinded to neuropathological information, clinicians reviewed prospective study and medical records and conducted informant interviews, and an expert panel adjudicated TES diagnoses, including provisional levels of certainty for CTE pathology (suggestive/possible/probable). TES diagnoses were a priori dichotomized: TES with possible/probable CTE (CTEpos/prob) vs. no TES/TES with suggestive CTE (CTEsug). Main Outcomes and Measures: Blinded to clinical information, neuropathologists applied NINDS/NIBIB CTE neuropathological criteria and staging (I-IV). CTE diagnoses were a priori dichotomized: stages II-IV vs. no CTE/stage I. Results: Among 193 brain donors [men:153 (79.3%), mean age:66.4 (SD:22.0)], 57 (29.5%) donors met clinical criteria for CTEpos/prob and 42 (21.8%) donors met neuropathological criteria for CTE stages II-IV. There was high agreement between panelists for CTEpos/prob vs. no TES/CTEsug (ICC:0.95, 95%CI:0.88-0.97). CTEpos/prob sensitivity, specificity, positive likelihood ratio (LR) and negative LR for CTE stages II-IV were: 0.77 (95%CI:0.64-0.89), 0.84 (95%CI:0.78-0.90), 4.8 (95%CI:3.02-7.61), 0.28 (95%CI:0.15-0.50); age[&ge;]50:0.90 (95%CI:0.80-1), 0.90 (95%CI:0.85-0.96), 9.2 (95%CI:4.9-17.27), 0.11 (95%CI:0.04-0.33). All younger false positives (age<50; n=13) had a mental health, substance use and/or pain disorder. All older false positives (age[&ge;]50; n=11) had non-CTE neurodegenerative and vascular pathologies. Among 10 false negatives, 8 had stage II CTE. Conclusions and Relevance: The NINDS TES criteria demonstrated good reliability, sensitivity and specificity, and provided moderate to large evidence to both rule out and rule in CTE pathology, particularly above age 50.

INTRODUCTIONSelf-reported sleep duration is associated with dementia-risk and vascular brain injury markers, including white matter hyperintensities (WMHs), yet how additional cerebrovascular pathology alters these relationships remains unclear. METHODIn a deeply-phenotyped cohort (735) including healthy and Alzheimers continuum individuals (subjective and mild cognitive impairment (MCI), dementia (AD), MCI and AD with high vascular burden (+V)), sleep was assessed using the Pittsburgh Sleep Quality Index. Individuals were classified as WMH-only or WMH+ (WMHs with microbleeds, infarcts, or cerebral amyloid angiopathy). Linear models tested interactions between sleep duration, WMH+ status, and diagnostic group on WMH burden and cognition. RESULTSIn MCI+V and AD, WMH+ significantly amplified the association between shorter sleep and greater WMH burden. In AD, longer sleep related to better cognition in WMH+, but worse cognition in WMH-only (exploratory). DISCUSSIONAdditional vascular brain injury modifies how sleep relates to WMH burden and cognition across the AD continuum, highlighting the importance of moving beyond WMHs alone.

ObjectiveThrough the utilization of the data specifically related to early-onset ischemic stroke, we aimed to investigate the causal effects of migraine and its subtypes on the risk of early-onset ischemic stroke using the two-sample Mendelian randomization method. MethodsGenetic instrumental variables were acquired from two sources with the largest sample sizes available. Summary data for early-onset ischemic stroke was acquired from a study encompassing individuals aged 18 to 59 years, comprising 16,730 cases and 599,237 non-stroke controls. The random-effects inverse variance weighted method was used as the primary analysis approach. ResultsThe Mendelian randomization analysis revealed no association between overall migraine and migraine without aura with the risk of early-onset ischemic stroke. However, migraine with aura showed a suggestive association with an elevated risk of early-onset ischemic stroke, with odds ratios of 1.114 (95% confidence interval = 1.005 to 1.236, p-value = 0.040) and 1.062 (95% confidence interval = 1.002 to 1.126, p-value = 0.042) based on instruments from two independent sources. The odds ratio was 1.074 (95% confidence interval = 1.022 to 1.130, p-value = 0.005) based on instruments from both two sources. No evidence of heterogeneity or horizontal pleiotropy was found. Furthermore, a positive genetic correlation was found between migraine with aura and early-onset ischemic stroke (genetic correlation = 0.208, 95% confidence interval = 0.038 to 0.377, p-value = 0.016). By contrast, migraine with aura was not related to ischemic stroke of all adults. ConclusionThis study provides evidence of a causal relationship between migraine with aura and the risk of early-onset ischemic stroke.

Cortical superficial siderosis (cSS) is the strongest marker of future intracranial hemorrhage (ICH) in cerebral amyloid angiopathy (CAA), a condition without disease-modifying therapy. Emerging evidence suggests that cSS may reflect meningovascular inflammation potentially amenable to immunosuppression. We conducted a single-center matched cohort study comparing high-dose corticosteroid therapy versus no immunosuppression in patients with probable CAA and cSS. Treated patients were matched 1:2 to untreated patients by demographics, cSS multifocality, and baseline intracerebral hemorrhage. The primary outcome was incident ICH; secondary outcomes were any cerebrovascular event and mortality. Kaplan-Meier analysis assessed event-free survival. cSS progression was evaluated in patients with [&ge;]6 months MRI follow-up, and inflammation in a subgroup with post-contrast vessel-wall-imaging (VWI). Thirty-six patients were included (12 treated, 24 untreated; mean age 77.4 years; 91% disseminated cSS). Over a median follow-up of 2.23 years, 11 patients had cerebrovascular events (15 ICHs, 3 ischemic strokes), all in the untreated group (p=0.041 for ICH; p=0.037 for any event). Mortality did not differ (p=0.634). cSS progressed in 2/6 (33%) treated versus 4/7 (57%) untreated patients. Baseline VWI detected inflammation in 7/9 patients (78%), which regressed after corticosteroids. Corticosteroid therapy was associated with fewer cerebrovascular events in high-risk CAA, supporting prospective controlled validation.

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by NOTCH3 mutations. While CADASIL affects both sexes, differences in clinical presentation and brain magnetic resonance imaging (MRI) findings remain unclear. This study aims to investigate sex-specific variations in vascular risk factors, clinical manifestations, and brain MRI features among Korean CADASIL patients. MethodsA nationwide retrospective study analyzed 368 CADASIL patients (179 men, 189 women). Clinical characteristics, vascular risk factors, and NOTCH3 variants were compared between sexes. Brain MRI findings, including white matter hyperintensity, lacunes, cerebral microbleeds, atrophy, and enlarged perivascular spaces, were evaluated. Kaplan-Meier analysis assessed sex differences in the onset of ischemic stroke, intracerebral hemorrhage (ICH), and dementia, and recurrent headaches. ResultsMen exhibited a higher prevalence of ischemic stroke (70.9% vs. 44.4%, p<0.001), whereas women were more likely to report recurrent headaches (35.4% vs. 16.9%, p<0.001). Survival analysis showed that men had a significantly earlier onset of ischemic stroke (Hazard Ratio[HR]: 2.78, 95% CI: 1.92-4.03, p<0.001) while being male was associated with significantly later onset of recurrent headache (HR: 0.59, 95% CI: 0.38-0.90, p=0.016). No significant sex differences were observed for ICH (HR: 2.04, 95% CI: 0.80-5.18, p=0.136) or dementia (HR: 1.26, 95% CI: 0.56-2.84, p=0.579). On brain MRI, male sex was associated with significantly higher risk for lacune burden (Odds Ratio[OR] 3.03, 95% CI 1.70-5.38, p<0.001) along with age (OR 1.03, 95% CI 1.01-1.05, p=0.002) and hypertension (OR 1.86, 95% CI 1.15-3.03, p=0.002). ConclusionThis study highlights significant sex-based differences in CADASIL, with men experiencing earlier and higher risk of ischemic stroke, along with a greater burden of lacunes, while women showed an increased likelihood of recurrent headaches at an earlier age. These findings underscore the importance of integrating sex-specific considerations into CADASIL prognosis and treatment planning.

BackgroundChronic relapsing inflammatory optic neuropathy (CRION) is a steroid-dependent form of optic neuritis with incompletely understood pathophysiology. The identification of myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) in a substantial patient subset has challenged the diagnostic and therapeutic management. The aim of this study was to investigate clinical profiles and treatment outcomes of patients with CRION, comparing MOG-IgG-positive (MOG+) and seronegative (MOG-) subgroups. MethodsPatients from six European tertiary centers fulfilling diagnostic criteria for CRION were included. All underwent cell-based autoantibody testing. Clinical outcomes (visual acuity, annualized relapse rate), laboratory and imaging findings (MRI, OCT), and treatment responses were retrospectively analyzed. ResultsSixty patients were included (median age 33 years; 70% female); 27 (45%) were MOG+. MOG+ CRION was associated with later onset, higher ARR before treatment (median [IQR] 2 [1-3] vs. 1 [1-2], p = 0.023), and a trend toward shorter inter-relapse intervals. Additional distinguishing features included higher frequencies of antinuclear antibody positivity, elevated CSF interleukin-6, and extensive optic neuritis on MRI. Relapse burden correlated with visual acuity decline and retinal thinning. In MOG+ patients, monoclonal antibody therapy reduced the ARR (n = 21; 2 [1-3] vs. 0 [0-2], p = 0.024), primarily driven by tocilizumab (n = 11; 2 [1-3] vs. 0 [0-1], p = 0.023). In MOG-patients, rituximab and azathioprine showed a trend toward ARR reduction. ConclusionCRION represents a heterogeneous syndrome encompassing distinct subgroups. MOG+ patients demonstrate higher disease activity but respond favorably to tocilizumab. Serological testing is critical for treatment stratification and preventing relapses.

IntroductionLong-term systolic blood pressure variability (BPV) has been proposed as a novel risk factor for dementia, but the underlying mechanisms are largely unknown. We aimed to investigate the association between long-term blood pressure variability (BPV), brain injury, and cognitive decline in patients with mild cognitive symptoms and cerebral amyloid angiopathy (CAA), a well-characterized small-vessel disease that causes cognitive decline in older adults. MethodsUsing a prospective memory clinic cohort, we enrolled 102 participants, of whom 52 with probable CAA. All underwent a 3-tesla research MRI at baseline and annual neuropsychological evaluation over 2 years, for which standardized z-scores for four cognitive domains were calculated. BPV was assessed using a coefficient of variation derived from serial outpatient BP measurements (median 12) over five years. We measured the peak width of skeletonized mean diffusivity (PSMD) as a marker of white matter integrity, and other neuroimaging markers of CAA, including lacunes and cortical cerebral microinfarcts. Using regression models, we evaluated the association of BPV with microstructural brain injury and whether CAA modified this association. We also examined the association of BPV with subsequent cognitive decline. ResultsSystolic BPV was dose-dependently associated with PSMD (estimate=0.22, 95% CI: 0.06, 0.39, p=0.010), independent of age, sex, mean BP, common vascular risk factors, brain atrophy, and CAA severity. The presence of probable CAA strengthened the association between BPV and PSMD (estimate=9.33, 95% CI: 1.32, 17.34, p for interaction = 0.023). Higher BPV correlated with greater ischemic injury (lobar lacunes and cortical cerebral microinfarcts) and a decline in global cognition and processing speed (estimate=-0.30, 95% CI: -0.55, -0.04, p=0.022). DiscussionLong-term BPV has a dose-dependent association with alterations in white matter integrity, lobar lacunes, and cortical cerebral microinfarcts, and predicts cognitive decline. Controlling BPV is a potential strategic approach to prevent cognitive decline, especially in early-stage CAA. "TAKE-HOME POINTS" FOR SOCIAL MEDIAO_LITwitter handle: @LSveikata C_LIO_LIWhat is the current knowledge on the topic? Long-term blood pressure variability (BPV) has been proposed as a novel risk factor for dementia, but the underlying mechanisms are largely unknown. Brains affected by cerebral amyloid angiopathy (CAA), a well-characterized small-vessel disease, may be at risk of developing BPV-related brain injury. C_LIO_LIWhat question did this study address? Is long-term blood pressure variability (BPV) associated with brain injury and cognitive decline in patients with cerebral amyloid angiopathy (CAA)? C_LIO_LIWhat does this study add to our knowledge? This prospective memory clinic cohort study demonstrated a dose-dependent relationship between systolic BPV and altered white matter integrity, independent of demographic and vascular risk factors and more pronounced in individuals with evidence of CAA. Higher BPV was also associated with greater ischemic brain injury and cognitive decline. C_LIO_LIHow might this potentially impact on the practice of neurology? These findings suggest that BPV may be a modifiable risk factor for brain injury and cognitive decline, particularly in individuals with CAA, and could be targeted in preventative strategies. C_LI

Background and ObjectivesSleep has been associated with cognition and risk of dementia. However, sleep is a highly complex and multi-dimensional state, and there is uncertainty about which aspects of sleep are most relevant to cognitive performance and dementia risk. We applied a data-driven approach to identify clusters of sleep variables that reflect meaningful sleep composites and examined their association with cognitive performance and dementia risk. MethodsData from the Sleep and Dementia Consortium, consisting of 5 US population-based cohorts were utilized. Participants had methodologically consistent, home-based polysomnography, self-report habitual sleep, neuropsychological assessments, and dementia risk surveillance. The pooled cognitive analysis included 5,958 participants aged [&ge;]45 years, and the incident dementia analysis included 5,471 participants aged [&ge;]60 years. A cluster around latent variables analysis was used to derive 9 latent sleep composites from 44 sleep metrics. Global cognitive composite z-scores were derived from principal component analysis. Linear regression models were used to assess associations between sleep composites and cognitive performance. Cox proportional hazard models assessed associations between sleep composites and incident dementia. ResultsMean (SD) age was 70 {+/-} 11 and 74 {+/-} 12 years for the cognitive and dementia analysis, respectively. There were 1,134 incident dementia cases (median follow-up time of 5-19 years). 9 sleep composites were identified, together explaining 49% of the total variance in the original 44 sleep metrics: Sleep quantity and efficiency, sleep fragmentation, light NREM predominance, N3 predominance, spindle number and duration, REM sleep bouts, respiratory disturbances, slow oscillation-spindle coupling and spindle amplitude. Of these, composites reflecting greater sleep quantity and efficiency (i.e., longer and more consolidated sleep; pooled {beta} per one-unit change in composite, 0.03; 95% CI: 0.004 - 0.06; p=0.033) and stronger slow oscillation-spindle coupling (pooled {beta}, 0.04; 95% CI: 0.003 - 0.07; p=0.039) were associated with better global cognition. However, no significant associations were identified between the 9 sleep composites and dementia risk. DiscussionOur data-driven approach identified longer, more consolidated sleep and stronger slow oscillation-spindle coupling as the composites of sleep most strongly related to cognitive performance. These composites may be useful in guiding further investigations of sleep-brain health relationships.

Numerous large-scale epidemiological studies investigating the trajectory of cognitive recovery after ischemic stroke have presented data suggesting an immediate drop in cognition acutely post-stroke followed by persistent, accelerated decline over time when averaged as a group. We sought to further examine this trend, speculating that the average persistent decline may be a reflection of two subgroups with vastly different prognoses: 1) a minority experiencing decline secondary to neurodegenerative processes like vascular dementia and Alzheimers disease, and 2) a majority without marked progressive brain atrophy who typically see improvement. Our team thus investigated atrophys association with language recovery, hypothesizing that declining naming performance in the year after left hemisphere ischemic stroke would be correlated to atrophy of the contralesional hemisphere. We postulated that volume loss within the lesioned hemisphere would be less informative due to separate confounding processes related to the stroke itself like Wallerian degeneration and encephalomalacia. Participants (n=72; M[SD] age=60[11]) in a longitudinal cohort study of language following left hemisphere ischemic stroke were included if they completed an MRI both acutely and chronically (either 6- or 12-months post-stroke). Naming performance was assessed using the Boston Naming Test, stroke volumes were extracted from acute imaging, and atrophy was measured as the monthly percent change in hemispheric volume from baseline to chronic scan for each individual. Pearsons correlations were calculated to determine the relationship between lesion volume and atrophy along with atrophy and change in Boston Naming Test score. Lesion volume was negatively correlated to the monthly percent change of volume in the left (ipsilesional) hemisphere (r=-0.48; p<0.0001) but was not correlated to rate of right (contralesional) hemisphere volume loss. While there was no clear relationship between atrophy of the left hemisphere and language recovery, we found that volume changes of greater negative magnitude within the right hemisphere (increased atrophy) were associated with worse functional recovery of language (r=0.38; p=0.0025). By showing that atrophy of the right hemisphere was not significantly impacted by left hemisphere lesion size, we suggest that accelerated volume loss in the non-lesioned hemisphere after stroke may be indicative of a separate pathology. We then go on to support this claim with behavioral data showing that greater rates of volume loss within the non-lesioned hemisphere were associated with poorer naming recovery. Together, these findings imply that contralesional atrophy after stroke may have negative implications for recovery and could serve as a useful imaging signature for separate neurodegenerative processes.

ObjectiveTo replicate and extend recent findings suggesting that higher serum alpha-linolenic acid (ALA) levels are associated with reduced disease activity and progression in multiple sclerosis (MS). MethodsWe reanalysed clinical trial data from 85 people with MS, who had serum ALA, magnetic resonance imaging (MRI), and clinical (EDSS, PASAT) assessments collected for two years, with additional follow-up at 12-years. Linear and mixed models were used to assess the relationship between ALA and clinical and MRI outcomes. Mediation analyses tested whether ALA mediated associations between brain volume or T2 lesion load, and disability. ResultsALA measures were consistent over time ({kappa}= 0.83). Higher ALA predicted lower EDSS ({beta} = -0.41, 95% CI [-0.73, -0.08]) and larger brain volume ({beta} = 0.22, 95% CI [0.09, 0.36]). ALA was a non-significant mediator of brain volume or lesion effects on EDSS and did not predict long-term clinical or cognitive change. DiscussionWe replicate prior associations between higher serum-ALA levels and reduced disability in MS and extend these by showing a beneficial association of serum-ALA with brain volume. However, ALA did not predict long-term progression, limiting its prognostic value.