Neurology

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.

Objective: Cranial artery stenosis and dilatation are distinct large artery phenotypes that often coexist with cerebral small vessel disease (cSVD), yet their downstream microvascular functional correlates remain unclear. Methods: In the prospective Mild Stroke Study 3, we recruited patients with lacunar or mild non-lacunar stroke. At baseline, large artery stenosis (LAS), basilar artery dolichoectasia (BADE), and intracranial arterial diameters were assessed. Multimodal MRI quantified cerebrovascular reactivity (CVR), blood-brain barrier (BBB) permeability, plasma volume fraction, and intracranial pulsatility. cSVD markers were evaluated at baseline and 1 year. Associations between large artery phenotypes and vascular function were examined with multivariable regression. Mediation analyses tested whether vascular dysfunction linked large artery pathology to cSVD progression. Results: Among 224 participants (mean age 66.0, SD 11.2 years; 66.5% men), BADE (n=36, 16.1%) was independently associated with lower CVR in normal-appearing white matter (NAWM; {beta} -0.01, 95% CI -0.016 to -0.004, P=0.003). Larger mean intracranial arterial diameter was associated with lower CVR in NAWM and white matter hyperintensities (WMH), while showing a U-shaped association with BBB permeability. LAS (n=46, 20.5%) was unrelated to CVR, BBB permeability, or pulsatility, but was associated with higher plasma volume in WMH. CVR in NAWM partially mediated the association between BADE and both baseline cSVD burden and 1-year progression. Interpretation: Large artery dilatation may serve as a macroscopic signal of small-vessel dysfunction, being associated with lower CVR and altered BBB permeability. Reduced CVR in NAWM partially mediated the impact of dolichoectasia on cSVD progression and may represent a potential therapeutic target.

BackgroundPeripheral microvascular abnormalities may reflect systemic microvascular dysfunction relevant to cerebral small vessel disease (cSVD), yet their relationship to individual neuroimaging markers and overall cSVD burden remains unclear. We evaluated whether abnormalities in nailfold capillaroscopy (NFC) are associated with specific cSVD markers and with the total cSVD score in a population-based cohort. MethodsAtahualpa residents aged [≥]60 years underwent NFC and brain MRI. Capillary tortuosities, dilatations, density, and megacapillaries were quantified using automated software with expert validation. Neuroimaging markers included white matter hyperintensities (WMH), lacunes, deep cerebral microbleeds (CMB), and enlarged basal ganglia perivascular spaces (BG-PVS). Logistic regression models assessed associations between NFC abnormalities and cSVD markers. Poisson regression was used to model the total cSVD score. All models were adjusted for demographics, educational attainment, and cardiovascular risk factors. ResultsAmong 289 participants (mean age 71.3 {+/-} 7.5 years; 51% women), lower capillary density was independently associated with CMB (OR: 0.70; 95% C.I.: 0.51-0.96) and lacunes (OR: 0.67; 95% C.I.: 0.50-0.91), with a borderline association for WMH (p=0.062). Megacapillaries were independently associated with moderate-to-severe WMH (OR: 5.01; 95% C.I.: 1.42-17.68). Tortuosities and dilatations showed no significant associations. Higher capillary density was inversely associated with the total cSVD score ({beta}: -0.179; 95% C.I.: -0.283 to -0.075). ConclusionsReduced capillary density and megacapillaries track with the burden of cSVD. NFC may provide a noninvasive window into cerebral microvascular health and could inform risk stratification for cSVD progression and related outcomes.

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.

A prominent radiological manifestation of cerebral amyloid angiopathy (CAA) is enlargement of perivascular spaces (EPVS), which is suggested to result from fluid stagnation due to impaired perivascular clearance. Here, we report a novel observation of hypointense rims in cerebral white matter surrounding EPVS near haemorrhages on in vivo 7T Gradient Echo MRI. We hypothesised that the observed black rim pattern denotes iron accumulation that may be caused by incomplete clearance following bleeding. We investigated the occurrence and localisation of this marker on in vivo and ex vivo MRI and examined its histopathological correlates. From MRI data of the prospective longitudinal natural history study of hereditary Dutch-type CAA (D-CAA) at Leiden University Medical Centre, we selected the first 20 consecutive patients who underwent 7T imaging and assessed the presence of black rims on MRI. Post-mortem material was available from one donor with black rims on in vivo scans. Formalin-fixed coronal brain slabs were scanned at 7T MRI, including a high-resolution T2*-weighted sequence. Guided by ex vivo MRI, tissue blocks from representative areas with black rims were sampled for histopathological analysis. Serial sections were stained for iron, calcium, myelin, and general tissue morphology. On in vivo 7T MRI, 9 out of 20 participants exhibited one or several black rims, all located close to a haemorrhage. In the D-CAA donor, ex vivo MRI signal loss matched the in vivo contrast changes. Thirty-six vessels with ex vivo-observed black rims were retrieved and histopathologically examined, showing iron accumulation surrounding perivascular spaces, but the pattern and severity of iron deposition varied. Across groups, vessels displayed microvascular degeneration, including hyaline vessel wall thickening, adventitial fibrosis, and perivascular inflammation. We identified black rims on in vivo 7T MRI and confirmed their correspondence on ex vivo imaging. Iron deposition was determined as the underlying correlate of black rims, but the histopathology appears heterogeneous. The preferential deposition of iron around EPVS may indicate incomplete clearance of iron-positive blood-breakdown products after bleeding. The varied pattern of iron accumulation and microvascular alterations may reflect different pathophysiological mechanisms related to the formation and maintenance of black rims in D-CAA.

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.

Background. Poor sleep quality is common in people with multiple sclerosis (pwMS) and reduces quality of life. Objectives. To examine associations between modifiable factors and sleep quality in pwMS. Methods. In a prospective clinic cohort (2017-2023), we evaluated whether baseline measures of disability, depression, fatigue, and pain were associated with poor sleep quality (Pittsburgh Sleep Quality Index, PSQI) cross-sectionally using covariate-adjusted linear regression, structural equation modeling (SEM), and LASSO logistic regression, and longitudinally using mixed-effects models. Results. In this cohort (n=750; mean age 48.9 years; 80.3% women, 88.7% relapsing type), higher body mass index ({beta} [95% CI]: 0.06 [0.01, 0.12], p=.001) and area deprivation index (6.78 [2.17, 11.39], p<.001) were associated with worse baseline PSQI scores. In adjusted analyses (n=730), disability, depression, fatigue, and pain were each associated with worse sleep. In SEM, pain had a moderate direct effect on sleep ({beta} [95% CI]: 0.56 [0.48, 0.64], p<.001). LASSO models that included pain outperformed the benchmark (AUROC 0.741 vs 0.517). Longitudinally (n=382), time and higher baseline pain predicted worse sleep ({beta} [95% CI]: time in months 0.04 [0.02, 0.06], p<.001; pain 0.36 [0.31, 0.41], p<.001). Conclusion. Pain is a key, potentially modifiable driver of poor sleep quality in pwMS.

BackgroundTheory of Mind (ToM) deficits are well-documented in right-hemisphere stroke but remain understudied in post-stroke aphasia. Prior work suggests that performance on tasks assessing ToM may be relatively preserved in aphasia and dissociable from language impairment, but these findings are based largely on small studies. This study examined performance on nonverbal false-belief tasks in post-stroke aphasia, its relationship with aphasia severity, and whether vascular brain health, operationalized using cerebral small vessel disease (CSVD) markers, contributed to variability in performance. MethodsForty-four individuals with aphasia completed two nonverbal belief-reasoning tasks assessing spontaneous perspective-taking and self-perspective inhibition. Task accuracy served as the primary outcome. Linear regression models examined associations between task performance, aphasia severity (Western Aphasia Battery-Revised Aphasia Quotient), and CSVD markers, including white matter hyperintensities, cerebral microbleeds, lacunes and enlarged perivascular spaces in the basal ganglia and centrum semiovale. ResultsPerformance was heterogeneous across tasks, with reduced performance observed in 23% of participants on the Reality-Unknown task and 36% on the Reality-Known task. Aphasia severity was not associated with task accuracy. Greater cerebral microbleed count was associated with lower accuracy on both tasks, while greater basal ganglia enlarged perivascular spaces burden showed a more selective association with lower performance. ConclusionsPerformance on nonverbal false-belief tasks in aphasia is variable and not explained by aphasia severity alone. These findings suggest that apparent ToM-related difficulties in aphasia may be shaped by broader vascular brain health, supporting a more multidimensional framework for interpreting social-cognitive task performance after stroke.

Importance: NGLY1 (N-Glycanase 1) Deficiency is an ultra-rare autosomal recessive disorder affecting ~165 patients worldwide, characterized by developmental delay, hyperkinetic movement disorders, and shortened life expectancy. Despite its severe neurological manifestations, comprehensive neuroimaging characterization has been limited to case reports and small descriptive studies. Objective: To investigate alterations in brain morphology in patients with NGLY1 Deficiency and determine whether these metrics associate with clinical phenotypes. Design, Setting, and Participants: This case series analyzed real-world MRI scans performed on 11 patients with NGLY1 Deficiency between 1999-2023 at sites across the globe. Ages ranged from 2 to 19 years at scan time (5 female, 6 male). Exposure: Molecular diagnosis of NGLY1 Deficiency. Main Outcomes and Measures: Cortical and subcortical morphology, including subcortical volume, and cortical thickness, surface area, volume, and curvature, were measured with 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. Z-scores were calculated using normative models from CentileBrain for patients >3 years old or custom models for patients <3 years old. Clinical phenotypes were matched to Human Phenotype Ontology codes. Results: 16 scans from 11 patients met quality criteria for analysis. Both age groups (under and over 3 years old) showed significantly reduced subcortical volumes, particularly in bilateral thalamus and putamen. Younger patients demonstrated widespread reductions in cortical surface area, volume, and curvature, indicating altered gyrification patterns. Older patients showed thinner dorsal and thicker ventral cortical regions with limited surface area reductions. Thalamic volume reduction in older patients correlated with gait disturbance, dysphagia, and EEG abnormalities, with additional cortical associations with sleep and hearing abnormalities. Seizure presence in younger patients correlated with altered cortical thickness, surface area, and curvature patterns. Conclusions and Relevance: NGLY1 Deficiency is associated with pervasive alterations in brain development affecting both subcortical and cortical morphology. Age-dependent patterns of cortical alterations indicate disrupted neurodevelopmental trajectories that may reflect impaired neuronal migration and/or altered synaptic pruning. Correlations with clinical variables suggest that these measures may serve as useful biomarkers for tracking disease progression and/or treatment efficacy. These findings provide a comprehensive neuroimaging characterization of NGLY1 Deficiency and establish a foundation for understanding brain structure-function relationships in this ultra-rare disorder.

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.

Migraine is a common and disabling neurological disorder linked to alterations in neuronal activity and waste clearance in the brain. MRI-visible perivascular spaces (PVS) are key components of the glymphatic system which may serve as imaging biomarker of such disorder. We hypothesised that higher frequency of migraine episodes would be associated with increased PVS burden, reflecting greater levels of impaired glymphatic clearance. In this retrospective case-control study of 90 participants (20 episodic migraineurs, 18 chronic migraineurs, and 52 age- and sex-matched healthy controls; 58 females, median [Q1, Q3] age=28.6 [25.1, 39.4] years) we investigated PVS alterations in episodic migraineurs (n=20) and 18 chronic migraineurs (n=18). PVS volumes and cluster counts were quantified in the white matter (WM), basal ganglia (BG), midbrain, and hippocampus. We stratified PVS metrics by white matter lobes and arterial vascular territories. After adjusting for age, sex, and total brain volume, episodic migraineurs exhibited significantly lower BG-PVS volumes (exp({beta})=0.76, 95%CI [0.61, 0.94], p=0.01) compared to controls. Chronic migraineurs exhibited significantly lower PVS cluster counts in the parietal (exp({beta})=0.8, 95%CI [0.68, 0.94], p=0.01) and temporal lobes (exp({beta})=0.72, 95%CI [0.53, 0.96], p=0.03) and middle cerebral artery territory (exp({beta})=0.82, 95%CI [0.68, 0.97], p=0.03) compared to healthy controls. Within migraineurs, those with aura (n=20) exhibited significantly lower PVS burden in all brain regions, vascular territories, and across the frontal, parietal, and temporal lobes (all pFDR<0.05). Our findings suggest that the aura symptom, rather than the migraine disorder itself, may primarily drive changes in perivascular spaces, with effects varying across brain regions.

Background: Anomia is common in frontotemporal dementia (FTD), although its clinical prominence varies by subtype, with the most marked impairment typically observed in primary progressive aphasia (PPA). It remains unclear whether naming impairment reflects language-specific impairment or broader cognitive severity, and how it relates to other cognitive domains across FTD syndromes. Methods: Fifteen healthy controls and twenty-two individuals across the FTD spectrum, including variant-specified and unclassifiable (NOS) presentations, completed two confrontation naming tasks (Boston Naming Test and Multilingual Naming Test) and a global cognitive screening measure (Montreal Cognitive Assessment, MoCA). Patient participants additionally completed a standardized language battery (Western Aphasia Battery Revised) and a comprehensive neuropsychological assessment (Uniform Data Set). Naming performance was compared between groups and associations with language severity, global cognition, and domain-specific cognitive functions were examined using regression analyses. Results: Naming was impaired in patients relative to healthy controls but did not differ between patient groups. Naming was strongly associated with language severity, but not global cognition. A significant group-by-MoCA interaction indicated that MoCA was positively associated with naming only in the unclassifiable group. In addition, naming was associated with episodic memory across both verbal and non-verbal domains. Conclusions: Naming in FTD primarily reflects language severity rather than global cognitive impairment. A robust association between naming and episodic memory suggests potential contributions from semantic cognition, shared frontally mediated retrieval processes, or parallel cognitive decline. These findings support the use of naming as a marker of language dysfunction while highlighting its relevance to broader cognitive systems in FTD.

Background: In atrial fibrillation (AF), cerebral microbleed (CMB) burden guides anticoagulation decisions, yet AF is itself inconsistently associated with CMBs, a paradox unexplained by frameworks that treat CMBs as a unitary marker of small vessel disease. We hypothesized that the white matter hyperintensity (WMH) context in which CMBs arise modifies their vascular meaning, and that this context-dependence underlies the inconsistent AF-CMB association. Methods: From a multicenter Korean stroke registry, we analyzed 5,735 first-ever ischemic stroke patients imaged at nine centers using susceptibility-weighted MRI. WMH volume and CMB count were extracted by validated deep learning pipelines. Patients were cross-classified by age-adjusted WMH residual (median split) and CMB count (2) into four groups. The AF-CMB association was estimated by multivariable logistic regression within each WMH stratum with formal interaction testing. Spatial CMB distribution was analyzed against the Automated Anatomical Labeling atlas. Results: In the full cohort (mean age 69.5 years; 57.7% male), AF was not associated with CMBs (OR 1.04; 95% CI 0.87-1.25). Stratification yielded divergent estimates: the adjusted AF OR was 1.46 (1.11-1.93; P = 0.007) in the WMH-low stratum and 0.95 (0.73-1.22; P = 0.665) in the WMH-high stratum, with significant interaction (OR 0.56; P < 0.001). The discordant phenotype (low WMH, high CMB; 8.9%) was enriched for AF (28.0%) and showed fronto-temporal cortical predominance with deep structure sparing. AF independently reduced the proportion of deep CMBs (IRR 0.80; P = 0.040). The interaction was preserved across prespecified sensitivity analyses. Conclusions: The AF-CMB association is confined to patients with low WMH burden relative to age and is accompanied by a topographically distinct CMB distribution. Clinical assessment of small vessel disease based on WMH alone may overlook a CMB phenotype linked to AF.

Background: Huntington ' s disease (HD) causes progressive postural control deficits, but how sensory reweighting mechanisms degrade across disease stages remains poorly understood. Objective: To determine whether objective markers of postural sway track disease severity and altered sensory reweighting across the HD spectrum. Methods: Ninety-seven adults (46 {+/-} 14 yrs) were categorized into four groups: 29 with HD, 27 pre-manifest (PM), 28 not at risk (AR-), and 13 age-matched healthy controls (HC). Participants performed three trials of quiet standing with eyes open and eyes closed on a force plate. Results: Manifest HD individuals exhibited greater AP, ML, and total COP sway displacement compared with the PM, AR-, and HC groups. HD and PM groups demonstrated greater instability with eyes closed. COP wavelet power was concentrated below 1 Hz across all groups. The eyes-open to eyes-closed change in 0-1 Hz power predicted total COP sway in HC (68%), AR- (45%), and PM (46%), but this relation was substantially weaker in HD. Conclusions: Progressive weakening of oscillatory-sway coupling distinguishes manifest HD from premanifest stages. PM individuals demonstrate early sensory reweighting deficits that manifest only when vision is removed, while HD individuals show decoupled oscillatory activity that fails to support stable postural regulation. This progressive decoupling may serve as a candidate marker of disease conversion prior to overt motor diagnosis.

ObjectiveMigraine attacks are frequently accompanied by patient-reported "subjective" cognitive symptoms, but objective findings have been inconsistent. We used high-frequency, smartphone-based cognitive testing to assess within-person changes in subjective and objective cognition across migraine phases using daily diaries. MethodsAdults with migraine were recruited through social media. Eligible participants met ICHD-3 migraine criteria and had 3 to 22 monthly headache days. For 30 days, they completed daily smartphone-based reports on headache features, cognitive symptoms, and three smartphone-based objective cognitive tasks. Objective tests included Symbol Search (processing speed/visual search), Color Dots (visual working memory/attention), and Grid Memory (visuospatial working memory). Primary analyses contrasted assessments on current headache days (ictal) versus days with no headache (nonictal). When possible, non-ictal days were subclassified using information from adjacent days as pre-ictal, post-ictal, and interictal days. Outcomes included subjective cognition, reaction time (mean across correctly scored trials), accuracy, and a speed-accuracy composite (Reaction Time/Accuracy). Mixed-effects models adjusted for age, sex, and practice effects. ResultsThe 139 eligible participants (84.9% female; mean age 38.2 years) contributed 3,014 person-days for ictal versus nonictal comparisons (2,097 nonictal; 917 ictal); for 1,828 person-days precise phase classification was possible. Subjective cognitive symptoms were worse on ictal days, with higher odds of more severe brain fog (OR=3.39, 95% CI 2.70-4.27) and task forgetting (OR=2.82, 95% CI 2.29-3.49). In adjusted models, reaction times were slower on ictal days for Symbol Search (reaction time ratio =1.043, 95% CI 1.028-1.059) and Color Dots (ratio=1.015, 95% CI 1.003-1.026) but not Grid Memory (reaction time ratio =1.006, 95% CI 0.985-1.028). Grid Memory accuracy was lower on ictal days (OR=0.867, 95% CI 0.823-0.914). In analyses based on phase, most nonictal phases showed faster reaction time and lower subjective symptom burden relative to ictal days, with limited differentiation among preictal, postictal, and interictal periods. ConclusionsIn persons with migraine, daily smartphone assessments revealed subjective cognitive impairment on ictal vs nonictal days in brain fog and forgetfulness. Objective testing revealed slowing in processing speed and attention and modest differences in the accuracy of working-memory. High-frequency digital cognition appears feasible and may provide scalable functional endpoints for real-world monitoring and treatment evaluation.

ObjectiveSpinocerebellar ataxia type 1 (SCA1) is a rare, inherited neurodegenerative disease characterised by progressive deterioration of motor and cognitive function. Here, we illustrate the pattern and evolution of brain atrophy in people with SCA1 using a large multisite dataset. MethodsStructural magnetic resonance imaging data from SCA1 (n=152) and healthy control (n=131) participants from seven sites and two consortia were analyzed using voxel-based morphometry. Cross-sectional stratification and correlations were undertaken with ataxia severity and duration to profile disease evolution. Cerebrocerebellar structural covariance analysis was used to understand the relationship between cerebral and cerebellar tissue atrophy. ResultsAtrophy in SCA1 first manifests in the lower brainstem and cerebellar white matter (WM), before progressing to the pons, anterior cerebellum, and cerebellar lobule IX. The midbrain and peri-thalamic WM and the remainder of the cerebellar cortex are then affected, with preferential involvement of specific motor and cognitive areas. Finally, degeneration in the striatum and cerebral WM corresponding to the corticospinal tract become apparent. Atrophy and correlations with ataxia severity are most pronounced in the cerebellar WM and pons. Structural covariance analysis showed reduced correlations between cerebellar and cerebral WM volume in SCA1 participants. InterpretationCross-sectional stratification of a large SCA1 cohort by ataxia severity indicates a pattern of atrophy spread across the brainstem, cerebellum, and subcortical grey and white matter. Ongoing volume loss throughout the disease course is most evident in a core set of infra-tentorial brain regions. Atrophy of cerebellum spans both motor and cognitive functional zones. Cerebellar degeneration is not directly mirrored by downstream effects in the cerebrum.

BackgroundType 2 diabetes mellitus (T2DM) has long been considered a risk factor for cerebral small vessel disease (cSVD), yet the exact relationship between glycemic markers and cSVD remains unclear. This study explores the genetic overlap and causal associations between T2DM, glycemic indices, and cSVD phenotypes using genome-wide association studies (GWAS). MethodsUsing large consortium-based GWAS data, we examined relationships between T2DM, glycemic indicators (glycated hemoglobin, fasting glucose, 2-hour glucose after oral challenge, and fasting insulin), and cSVD phenotypes (white matter hyperintensity volume, lacunar stroke, cerebral microbleeds, and enlarged perivascular spaces). Our multi-level genomic strategy included: 1) identifying pleiotropic single nucleotide polymorphisms (SNPs) through PLEIO and eQTL analysis, 2) assessing genome-wide genetic correlations using LDSC and GNOVA, and 3) determining causal relationships with two-sample and multivariable Mendelian randomization analyses. ResultsWe identified 14 pleiotropic SNPs with significant shared associations among T2DM, glycemic indicators, and cSVD phenotypes. Notably, MICB gene expression was elevated in brain, vascular, and pancreatic tissues, while three HLA genes (HLA-DQA1, HLA-DRB1 and HLA-DRB5) showed reduced expression. Genetic correlation analysis revealed positive correlations between T2DM, fasting glucose, and postprandial glucose with multiple cSVD phenotypes including WMH, lacunar stroke, and perivascular spaces. Mendelian randomization demonstrated that T2DM, 2-hour glucose, and HbA1c level causally increased lacunar stroke risk (OR 1.16 [1.09-1.23], OR 1.46 [1.20-1.77], OR 1.52 [1.04-2.23], respectively). Multivariable Mendelian randomization analysis confirmed that T2DM and postprandial glucose maintained a robust direct effect on lacunar stroke independent of other cSVD phenotypes, while HbA1c did not retain significance after conditioning on cSVD imaging markers. ConclusionsOur multi-level genomic analysis reveals links between T2DM, glycemic traits, and cSVD through specific genetic variants, genome-wide correlations, and causal relationships. The involvement of immune-related genes suggests potential biological mechanisms. The causal effect of postprandial glucose on lacunar stroke suggests that impaired glucose tolerance may be a relevant therapeutic target for lacunar stroke prevention.

Wolfram syndrome (WFS) is characterized by youth-onset insulin-dependent diabetes and neurological deficits. Brain white matter deficiency has been reported, but its trajectory remains unclear. Applying diffusion basis spectrum imaging models longitudinally in 29 individuals with WFS (baseline ages, 5.2 to 25.8 years; maximum 7 visits) and 52 matched controls, we found that WFS is associated with microstructural alterations suggesting diminished axonal integrity, myelin content, and cellularity. These changes were present and stable early in the disease progression in visual and auditory-related regions, whereas abnormalities in the corpus callosum appeared later in adolescence and adulthood. Our results support developmental hypomyelination as a neurophenotype of WFS.

BackgroundFunctional neurological disorder (FND) is one of the most common, but least researched, conditions in neurology. Debate exists as to whether the clinical entity referred to as FND is truly a single disorder or is in fact multiple entities which have been erroneously amalgamated into the same condition. We sought to provide empirical evidence on this question by treating it as a problem of model comparison. MethodsWe formulated statistical models equivalent to: (1) FND being a single entity with variation in phenotype, represented by latent trait (binary factor/item response theory) models, and (2) FND being multiple discrete entities, represented by latent class analysis (LCA) models. We fitted these models to data on the symptoms experienced by 697 people with FND from the FND Research Connect database (fnd-research.org) and used Bayesian model comparison methods to compare them. ResultsAll but one of the latent trait models, representing FND as a single entity with heterogeneous phenotype, fit the data better than all the LCA models. Secondary analysis of the LCA models showed results compatible with the models capturing discretisation of continuous variation rather than true discrete categories. DiscussionOur results suggest that the symptom structure of FND is the result of a single pathophysiological process, either as a single entity, or a common pathway preceded by multiple causative processes where the common pathway is solely responsible for the phenotype of the condition.

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular benefits in type 2 diabetes mellitus (T2DM); however, their association with post-stroke outcomes following acute ischemic stroke (AIS) remains uncertain. MethodsWe conducted a retrospective propensity score-matched (PSM) cohort study using the TriNetX Global Collaborative Network. Adults with T2DM and AIS between January 2020 and January 2025 were included. Pre-stroke GLP-1 RA users were compared with non-users. Primary outcomes were all-cause mortality, intracerebral hemorrhage (ICH), ICD-10-coded stroke severity (NIHSS categories), and transient ischemic attack (TIA). ResultsAfter PSM, GLP-1 RA use was associated with significantly lower all-cause mortality at all time points (RR 0.44-0.52; HR 0.43-0.45; all p<0.001). ICH risk was reduced within 1-3 days (RR 0.683; 95% CI 0.496-0.940; p=0.019) and within 7 days (RR 0.575; 95% CI 0.516-0.641; p<0.001). A severity-dependent gradient was observed across NIHSS categories, with risk reductions ranging from 37% for minor strokes (NIHSS 0-5; RR 0.626) to 67% for very severe strokes (NIHSS >20; RR 0.327; all p<0.001). TIA risk was 29% lower (RR 0.712; 95% CI 0.668-0.759; p<0.001). E-value analysis demonstrated that an unmeasured confounder would need to be associated with both GLP-1 RA use and 30-day mortality by a risk ratio of at least 3.95 to fully explain the observed association, and by a risk ratio of at least 3.53 to shift the confidence interval to include the null. ConclusionsIn this large real-world cohort, pre-stroke GLP-1 RA use was associated with lower post-stroke mortality, reduced ICH, and a severity-dependent reduction in ICD-10-coded stroke severity among patients with T2DM. Residual confounding cannot be excluded, and these findings warrant confirmation in prospective randomized trials.