Neurology

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.

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.

Objective: Spinocerebellar 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. Methods: Structural 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. Results: Atrophy 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. Interpretation: Cross-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.

Background: Type 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). Methods: Using 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. Results: We 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. Conclusions: Our 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.

BackgroundAlthough neurogenic orthostatic hypotension (nOH) is a common and debilitating feature of multiple system atrophy (MSA), little is known about the burden of symptoms in the real world. ObjectivesTo design and conduct a cross-sectional community-based research survey targeting patients with MSA, with and without nOH. MethodsWe recruited patients with MSA to complete an anonymous online survey covering three core themes: 1) timely diagnosis, 2) nOH pharmacotherapy and refractory symptoms, and 3) confidence in physician knowledge. Responses were grouped by pre-specified diagnostic certainty levels. Relationships between symptoms, function, and pharmacotherapy were assessed using univariate and multivariate methods. ResultsWe analyzed 259 respondents with a self-reported diagnosis of MSA (age: M=64.38, SD=8.09 years; 44% female). In total, 42% also had a diagnosis nOH; 40% had symptoms highly suspicious of nOH, but no diagnosis; and 21% reported having never had their blood pressure measured in the standing position at a clinical visit. Treatment with a pressor agent was independently associated with the presence of other symptoms of autonomic failure. Each additional nOH symptom reported increased the odds of requiring pharmacotherapy by 18%. Yet, despite anti-hypotensive medication use, 97% of patients reported limitations in their ability to bathe, cook, or arise from a chair/bed with 76% needing caregiver support for refractory nOH symptoms. ConclusionsThis cross-sectional representative sample shows nOH is underrecognized and undertreated in MSA patients, leading to substantial functional limitations. It is our hope that these findings are leveraged for planning future trials and advocating for better treatments.

Background: Sleep wake and circadian disturbances are increasingly recognised in people living with amyotrophic lateral sclerosis (plwALS), but endogenous circadian phase timing and its prognostic significance in early disease remain unclear. We assessed whether salivary dim-light melatonin onset (DLMO), an objective marker of central circadian phase, is altered in early plwALS and whether it provides prognostic information. Methods: In this prospective longitudinal observational study, plwALS within 18 months of symptom onset underwent home-based salivary melatonin sampling under dim light conditions at six predefined time points around habitual sleep onset (HSO). Melatonin profiles were modeled using cubic smoothing splines, and DLMO was defined as the first time the fitted curve reached 3 pg/mL. Clinical, respiratory, and sleep assessments were collected at baseline (T0) and after 6 months (T6); a subgroup repeated saliva sampling at T6. Age and sex matched controls underwent melatonin profiling. Associations with disease progression, incident respiratory symptoms, and survival/tracheostomy were examined using regressions and survival analyses. Results: Fifty plwALS were enrolled. Compared with controls, plwALS showed an earlier DLMO (20:24 vs 20:58; p=0.028) despite similar HSO and chronotype. Within ALS cohort, a later baseline DLMO correlated with worse functional/motor status, faster progression of disease, incident dyspnea/orthopnea by T6 (adjusted OR 3.02; p=0.017), and poorer survival/tracheostomy-free outcome. In re-sampled subgroup (n=28), DLMO and other melatonin-derived metrics did not change over 6 months. Conclusions: Circadian phase alterations are detectable in early ALS. Baseline DLMO may represent a non-invasive prognostic biomarker for progression, respiratory symptom emergence and survival, warranting validation in larger multicentre cohorts.

Background Friedreich ataxia (FRDA) is a rare neurodegenerative disorder with substantial heterogeneity in clinical presentation and progression, complicating prognosis and trial design. Neuroimaging offers objective biomarkers to track disease evolution, yet variability in progression patterns remains poorly understood. Objective To identify biologically meaningful FRDA progression subtypes using longitudinal multimodal MRI and assess their associations with demographic, genetic, and clinical factors. Methods Longitudinal structural and diffusion MRI data from 54 FRDA and 57 controls were analysed. Annualised progression rates of macrostructural (volumetric) and microstructural (diffusion) features across cerebellum, brainstem, and spinal cord regions were clustered using Gaussian Mixture Models. Cluster robustness was assessed using per-cluster Jaccard similarity and other validation metrics. Random Forest classification examined predictors of cluster membership. Results Three reproducible clusters/subtypes emerged: micro-dominant/dual progression, characterised by widespread microstructural deterioration with modest volumetric decline; macro-dominant, marked by pronounced volumetric decline with minimal microstructural change; and minimal/no progression, showing negligible change in all measures. FRDA participants predominated in the first two clusters. Random Forest prediction of cluster membership using clinical and demographic variables identified length of the trinucleotide repeat expansion in the FXN gene as key predictor. Conclusions Data-driven clustering of longitudinal MRI identified distinct FRDA subtypes with unique co-progression patterns, underscoring genetic burden as a key driver. Recognising such heterogeneity can improve patient stratification, enable personalised monitoring, and guide targeted therapeutic strategies. Future studies should validate these subtypes in larger, more diverse cohorts and integrate additional biomarkers for enhanced precision.

Biological aging is accelerated in people with multiple sclerosis, but whether such acceleration occurs during the pre-symptomatic phase or varies by organ system is understudied. We analyzed two independent proteomics datasets profiled using distinct platforms: the Johns Hopkins cohort profiled using the SomaScan platform (348 multiple sclerosis/49 age-matched controls) and the Department of Defense cohort profiled using the Olink platform (134 multiple sclerosis/79 age-matched controls), including 117 pre-symptomatic samples from people with multiple sclerosis (median lead time: 4.0 years), to estimate systemic and organ-specific proteomic age gaps using established clocks in pre-symptomatic and symptomatic phases, and assess their associations with severity. In the Johns Hopkins cohort, people with multiple sclerosis demonstrated acceleration of systemic ({beta}=2.2, 95% CI 1.2-3.2, P<0.001, FDR<0.001), brain ({beta}=1.7, 95% CI 0.6-2.7, P=0.003, FDR=0.01), muscle ({beta}=2.5, 95% CI 1.3-3.7, P<0.001, FDR<0.001), and immune age ({beta}=1.8, 95% CI 0.6-2.9, P=0.003, FDR=0.01), with findings reproduced in the Department of Defense cohort for systemic ({beta}=0.7, 95% CI 0.0-1.4, P=0.04, FDR=0.34) and brain age (3.2 years, 95% CI 2.1-4.3, P<0.001, FDR<0.001). Proteomic age acceleration was evident prior to symptom onset [systemic: ({beta}=1.0, 95% CI 0.4-1.7, P=0.002, FDR=0.02); brain: ({beta}=2.4, 95% CI 1.2-3.7, P<0.001, FDR=0.002)], whereas no immune age acceleration was detected before or after onset. Higher systemic age gap was associated with greater global Age-Related Multiple Sclerosis Severity Score ({beta}=0.14, 95% CI 0.05-0.24, P=0.005, FDR=0.03) and slower walking speed ({beta}=0.02, 95% CI 0.01-0.03, P=0.006, FDR=0.04), while higher muscle age gap was associated with greater global Age-Related Multiple Sclerosis Severity Score ({beta}=0.17, 95% CI 0.10-0.24, P<0.001, FDR<0.001), poorer manual dexterity ({beta}=0.28, 95% CI 0.04-0.52, P=0.03, FDR=0.30), slower walking speed ({beta}=0.02, 95% CI 0.01-0.03, P=0.002, FDR=0.02), lower peripapillary retinal nerve fiber layer ({beta}= -0.26, 95% CI -0.41 to -0.10, P=0.001, FDR=0.02) and ganglion cell-inner plexiform layer thicknesses ({beta}= -0.35; 95% CI -0.65 to -0.05; P=0.02, FDR=0.30). Higher brain age gap was associated with several imaging measures, including lower whole-brain ({beta}= -0.002, 95% CI -0.003 to -0.001, P=0.002, FDR=0.02), and lower peripapillary retinal nerve fiber layer thickness ({beta}= -0.21, 95% CI -0.39 to -0.03, P=0.02, FDR=0.10). Proteomic age acceleration in multiple sclerosis is detectable years before symptom onset and distinct organ-specific aging signatures are associated with disease severity. Proteomic aging may provide a biologically informative marker of early disease processes and a clinically relevant readout of disease heterogeneity.

ObjectiveTo describe the design, feasibility, and baseline characteristics of the Migraine Impact on Neurocognitive Dynamics (MIND) study, a 30-day smartphone-based cohort for high-frequency assessment of cognition and symptoms in adults with migraine. BackgroundCognitive symptoms are an important component of migraine burden, but they are difficult to measure using single-visit testing or retrospective questionnaires. Repeated smartphone-based assessment may better capture real-world variability in cognition and symptoms. MethodsAdults meeting International Classification of Headache Disorders, 3rd edition, criteria for migraine were enrolled remotely and completed 30 days of once-daily ecological momentary assessments and mobile cognitive tasks delivered through the Mobile Monitoring of Cognitive Change platform. Baseline measures assessed demographics, migraine characteristics, disability, mood, stress, and treatment patterns. Feasibility was evaluated using enrollment, completion, and retention metrics. ResultsA total of 177 participants enrolled (mean age 38.8 {+/-} 11.9 years; 79.7% female), including 80/177 (45.2%) with chronic migraine. Across the 30-day protocol, 3688 daily assessments were completed, representing 70.8% of all possible study days, and 70.6% of participants completed at least 20 days of monitoring. Completion remained above 60% across study days. At baseline, chronic migraine was associated with greater burden than low-frequency and high-frequency episodic migraine, including higher MIDAS scores (98.6 vs. 38.7 and 70.3), more days with concentration difficulty (16.0 vs. 7.9 and 11.5), and more days with functional interference (18.5 vs. 7.6 and 13.0). ConclusionsThe MIND study demonstrates the feasibility of high-frequency smartphone-based assessment of cognition and symptoms in migraine and provides a methodological foundation for future analyses of within-person cognitive and symptom dynamics across the migraine cycle.

ObjectiveLevetiracetam is commonly prescribed for seizure prophylaxis after acute ischemic stroke (AIS) and often continued beyond discharge. While its short-term effectiveness for preventing post-stroke seizures is established, it is unclear whether prolonged use improves survival, particularly in older adults. We estimated the effect of continued levetiracetam use on 90-day mortality among Medicare beneficiaries after AIS. MethodsUsing Traditional Medicare claims data (2008-2021), we identified beneficiaries aged [&ge;]66 years hospitalized for AIS who initiated outpatient levetiracetam within 90 days of discharge. After one month of continued post-stroke use of levetiracetam (start of follow-up), we compared 90-day mortality between patients with a new levetiracetam dispensation within a 14-day grace period post-follow up and those without one. We performed cloning, censoring and weighting to address immortal time bias and estimated standardized mortality risks, risk differences, and 95% confidence intervals (CI). ResultsAmong 3,212 eligible beneficiaries, 1,779 (55.4%) received a new levetiracetam dispensation within the 14-day grace period. Median age was 76 years (IQR 70-83); 57.8% were female. After adjustment for demographics, hospitalization characteristics, timing of initiation, and comorbidities, continued use was associated with lower 90-day mortality than discontinuation (53 vs 62 deaths per 1,000; risk difference -9 per 1,000; 95% CI: (-12,-5)). The reduction was observed primarily among patients aged [&ge;]75 years. SignificanceAmong older Medicare beneficiaries who initiated levetiracetam after AIS, continued outpatient use was associated with modestly lower 90-day mortality, particularly in those aged [&ge;]75 years. These findings suggest potential benefits of levetiracetam continuation beyond the immediate post-stroke period.

BackgroundAccelerated long-term forgetting (ALF), defined as an increased rate of memory loss over extended intervals, has so far been detected in a pilot study of patients with mild multiple sclerosis (MS). This study aimed to (I) confirm the presence of ALF in a larger, heterogeneous MS sample, (II) explore associations with patient-reported outcomes, and (III) assess the diagnostic performance of ALF tests for subjective memory impairment. MethodsThis study compared 62 MS patients and 65 age-, sex-, and education-matched healthy controls using standardized memory tests (RAVLT, WMS-IV Logical Memory subtest). Recall was assessed immediately, after 30 minutes, and after 7 days. Seven-day/30-minute recall ratios (QRAVLT, QWMS) served as primary outcomes. Self-report measures included memory complaints, fatigue, depression, and sleep disturbances. Linear regression and Receiver operating characteristic (ROC) analyses assessed predictors and diagnostic accuracy. ResultsALF was observed in multiple sclerosis since QRAVLT was lower in patients than in controls (0.64 [95% CI 0.59-0.69] vs. 0.78 [0.73-0.82], p < 0.001), as was QWMS (0.79 [95% CI 0.74-0.84] vs. 0.95 [0.90-1.00], p < 0.001), despite comparable initial learning. Greater fatigue, higher memory complaints, longer disease duration, older age, and greater disability were associated with lower ALF scores. The combined ALF score moderately discriminated subjective memory impairment (AUC 0.74; sensitivity 0.73; specificity 0.73). ConclusionMS patients showed ALF despite normal initial learning, indicating a specific memory deficit undetected by standard tests. Long-delay recall using RAVLT and WMS-IV Logical Memory subtest may improve cognitive impairment detection in MS.

BackgroundPhenoconversion to Parkinsons disease (PD) or dementia with Lewy bodies (DLB) currently relies on established clinical diagnostic criteria. Availability of in vivo biomarkers--CSF -synuclein seed amplification assay (CSFaSynSAA) and dopamine transporter (DAT) imaging--offer the opportunity to investigate congruency between clinical phenoconversion and biologically defined disease. MethodsWe analyzed Parkinso[n]s Progression Markers Initiative participants who phenoconverted to PD, DLB, multiple system atrophy (MSA), Alzheimers disease (AD) or other dementias from prodromal and non-manifesting genetic carrier (NMC) groups and controls. Site investigators determined phenoconversion based on established diagnostic criteria. All phenoconverters with [&ge;]1 annual follow-up visit, with available biomarkers and persistent clinically defined diagnosis at last observation were included. Neuronal alpha-Synuclein Disease Integrated Staging System (NSD-ISS) staging was applied. ResultsAmong 121 phenoconverters, 103 had evaluable CSFaSynSAA and DAT data and were included in analysis: 92 PD, 7 DLB, 2 MSA, 2 AD/other dementias. Phenoconversion annual rates varied widely across groups: iRBD 7.9%, hyposmia 4.2%, GBA1 0.3%, LRRK2 1.3%, LRRK2+GBA1 0.9%, and controls 0.5%. Median time from baseline to phenoconversion ranged from 13-14 months in iRBD and hyposmia to 36-85 months in NMCs. The expected biomarker profile (CSFaSynSAA+/DAT+) for clinically-diagnosed synucleinopathy occurred in 74 (71.8%) participants. Biological alignment (CSFaSynSAA+/DAT+) was present in 87% hyposmics and 72% iRBD phenoconverters. CSFaSynSAA negativity was high among LRRK2 phenoconverters (67%), who also were more likely to have a preserved sense of smell (83%). Phenoconversion occurred later than onset of functional impairment: 15/47 (31.9%) iRBDs and 7/38 (18.4%) hyposmics were already NSD-ISS stage [&ge;]4 at time of phenoconversion. ConclusionsClinical phenoconversion did not necessarily align with biological evidence of synucleinopathy or dopaminergic loss and can be delayed compared to onset of meaningful functional impairment. Longitudinal follow up on converters without biological evidence of PD is required to confirm conversion diagnosis and evaluate for a later occurrence of biomarker positivity.

BackgroundTraumatic brain injury with loss of consciousness (TBI-LOC) is an established risk factor for dementia, yet the pathways linking remote TBI to Alzheimers disease (AD) biology remain incompletely defined. APOE {varepsilon}4 is the strongest genetic predictor of amyloid accumulation in late-onset AD, it may moderate the long-term consequences of head injury. This study investigates whether history TBI-LOC independently contributes or synergistically interacts with APOE {varepsilon}4 to amplify late-life amyloid and tau burden. Methods429 participants completed the Ohio State University TBI screening tool and an amyloid PET scan (centiloids). A subcohort (n=352) also underwent tau PET. TBI history was classified by recency (<10 vs >10 years) and severity (no TBI, dazing/confusion [TBI-DZ], TBI-LOC). Analyses were stratified by degree of clinical impairment as assessed by Clinical Dementia Rating (CDR=0 vs CDR>0). Logistic and linear regression models examined associations between TBI and amyloid, adjusting for age, sex, education, and APOE {varepsilon}4, including an APOE*TBI-LOC status interaction term, while Fishers exact tests evaluated TBI recency and biomarker positivity. ResultsIn CDR=0 participants (n=365), 119 reported a history of TBI, comprising 56 TBI-DZ and 63 TBI-LOC. TBI-LOC but not TBI-DZ, correlated with elevated amyloid PET levels (p<0.001; [4.6-17]). Furthermore, an interaction between APOE {varepsilon}4 and TBI-LOC indicated that TBI-LOC augmented the amyloid-related risk associated with the APOE {varepsilon}4 allele (p=0.003; [4.3-21]). The interaction persisted when stratified by TBI recency with only remote TBI-LOC (occurring more than 10 years prior) associated with increased amyloid PET (p=0.003 [5.2-25]). No association between TBI and tau was identified in a subset with tau PET, and no TBI-amyloid correlations were observed among symptomatic participants (CDR>0; n=64) suggesting a ceiling effect of pathology once clinical dementia is present. ConclusionsHistory of remote TBI-LOC is linked to elevated amyloid PET levels in later life, particularly among APOE {varepsilon}4 carriers with a CDR=0. The robust findings for amyloid, contrasted with null tau results and the reduced association in symptomatic cases underscore the importance of considering TBI history when screening for preclinical AD and assessing early-stage risk.

1.PurposeSYNGAP1-related developmental and epileptic encephalopathy (SYNGAP1-DEE) is characterized by high rates of both epilepsy and autism spectrum disorder (ASD). While the clinical spectrum is well-documented, the link between specific seizure semiologies and caregiver-reported autistic behaviors is not well understood. This study analyzed the correlation between ten distinct seizure types, their frequencies, and a caregiver-reported autistic behavior score. MethodClinical data were extracted from the PATRE (PATient-based phenotyping and evaluation of therapy for Rare Epilepsies) Registry for SYNGAP1, in the framework of the EURAS project (Grant No. 101080580, Horizon Europe). This study employed a retrospective cross-sectional analysis of caregiver-reported registry data. Analysis was restricted to an analytic cohort of N=337 participants with complete data for both the epilepsy questionnaire (including epilepsy status, seizure semiology, and peak seizure frequency items) and the behavior questionnaire (from a total N=522 registry participants). Caregiver-reported autistic behaviors were quantified using a standardized caregiver-reported scale (Likert 1-5). Statistical associations were evaluated using the Wilcoxon rank-sum test to compare caregiver-reported autistic behavior scores across different seizure semiologies and Spearmans rank correlation to assess the impact of seizure frequency (9-point scale). ResultsWithin the analytic cohort (N=337), epilepsy was reported in 259 patients. Eyelid myoclonia was the most prevalent semiology, affecting 64.9% (n=168) of the epilepsy-positive group. Atypical absences (n=77) demonstrated the most profound and statistically robust association with higher caregiver-reported autistic behavior scores (FDR-adjusted p = 0.001). Significant associations were also observed for typical absences (n=70, FDR-adjusted p = 0.018), eyelid myoclonia (FDR-adjusted p = 0.018), myoclonic-atonic seizures (n=40, FDR-adjusted p = 0.019), and atonic seizures (n=72, FDR-adjusted p = 0.025). Focal and tonic-clonic seizures showed weaker associations (FDR-adjusted p = 0.026 and p = 0.047, respectively). Crucially, quantitative analysis revealed no significant correlation between ordinal caregiver-reported peak seizure frequency ratings and caregiver-reported autistic behavior scores across all semiologies (e.g., Eyelid Myoclonia: p=0.096; Atypical Absences: p=0.744), indicating no detectable association between peak-frequency ratings and caregiver-reported autistic behavior scores. ConclusionHigher caregiver-reported autistic behavior scores in SYNGAP1-DEE were most strongly associated with the presence of atypical absences, representing a generalized, thalamocortical seizure network dysfunction. In contrast, no detectable association was observed between caregiver-reported autistic behavior scores and the ordinal caregiver-reported peak seizure frequency metric. Atypical absences and related semiologies may serve as clinical "red flags" for increased neurodevelopmental comorbidity severity, regardless of reported peak seizure frequency. Abstract SummaryThis study investigates the relationship between ten seizure semiologies, seizure frequency, and severity of caregiver-reported autistic behaviors in a large-scale international cohort of N=337 patients with SYNGAP1-DEE. We identify a robust association between elevated caregiverreported autistic behavior scores and specific thalamocortical seizure patterns, most prominently atypical absences. Notably, our analysis reveals that this association is independent of seizure frequency, demonstrating no detectable association between this ordinal, caregiver-reported seizure frequency metric and caregiver-reported autistic behaviors.

Post-stroke cognitive recovery is difficult to predict using focal lesion characteristics alone. The brain's capacity to maintain cognitive function depends also on structural integrity of the whole brain. One way to measure brain health is through the severity of cerebral small vessel disease (CSVD) markers, which reflect aging-related pathologies that erode structural integrity. Here, we propose a composite measure of CSVD (cCSVD) integrating three independently validated biomarkers automatically quantified using T1-weighted MRIs: white matter hyperintensity volume (WMH; representing vascular injury), perivascular space count (PVS; putative glymphatic clearance), and brain-predicted age difference (brain-PAD; structural atrophy). We hypothesize that cCSVD, which captures the shared variance across these CSVD biomarkers, will be a robust indicator of whole-brain structural integrity and predict cognitive changes 3 months after stroke. We analyzed 65 early subacute stroke survivors with assessments within 21 days (baseline) and at 90 days (follow-up) post-stroke. WMH volume, PVS count, and brain-PAD were quantified from baseline T1-weighted MRIs, and then residualized for age, sex, days since stroke, and intracranial volume. Principal component analysis (PCA) of the residualized biomarkers was used to derive cCSVD. Beta regression with stability selection using LASSO was used to model three outcomes: baseline Montreal Cognitive Assessment (MoCA) scores, follow-up MoCA scores, and longitudinal change (follow-up score adjusted for baseline score). Logistic regression was used to test if baseline cCSVD predicted improvement in those with baseline cognitive impairment (MoCA < 26). The PCA revealed that the first principal component (PC1) explained 43.1% of the total variance among WMH volume, PVS count, and brain-PAD. The three biomarkers contributed nearly equally to PC1, which was subsequently used as the baseline cCSVD score. Lower baseline cCSVD was significantly associated with better MoCA scores at follow-up ({beta} = -0.19, p = 0.009), even after adjusting for baseline MoCA ({beta} = -0.12, p = 0.042), and, importantly, outperformed all individual biomarkers. Furthermore, lower cCSVD at baseline significantly increased the likelihood of improving to cognitively unimpaired status at three months (OR = 0.34, p = 0.036), independent of age and education. The composite CSVD captures the additive impact of vascular injury, glymphatic dysfunction, and structural atrophy on recovery in a way that individual measures do not. cCSVD accounts for shared variance across these domains, reflecting a patient's latent capacity for cognitive recovery, where relative integrity in one CSVD domain may mitigate effects of another. This automated, T1-based framework offers a scalable tool for predicting post-stroke recovery.

Background: Rett Syndrome (RTT) is a severe neurodevelopmental disorder affecting approximately 1 in 10,000 live female births worldwide. The Rett Syndrome Behaviour Questionnaire (RSBQ), remains one of the most widely used standardized behavioral assessment tools for RTT. However, the RSBQ was originally validated only in British English, limiting its applicability for Spanish-speaking caregivers and clinical centers across Latin America and Spain. Objective: The primary aim of this study was to develop and validate the comprehension of the Spanish translation of the RSBQ to ensure cultural and linguistic equivalence, enhance data reliability, and facilitate earlier, more accurate clinical assessments among Spanish-speaking RTT populations. Methods: Surveys were administered in two phases to Spanish-speaking caregivers between November 2023 and September 2025. Phase I consisted of 12 guided survey administrations with participants being able to ask clarifying questions and offer linguistic modifications of RSBQ questions. Phase II consisted of independent online administration of the refined Spanish RSBQ and a retest at least 7 days later. Participants were recruited through direct outreach and supported virtually during questionnaire completion. Results: Following data cleaning and quality control, a total of 51 caregivers successfully completed both surveys. The Spanish RSBQ demonstrated high caregiver comprehension and strong engagement across multiple Latin American countries, including Argentina, Mexico, and Peru. Responses were highly correlated between test and retest timepoints, and no question showed biased response distributions. A slight effect of response interval on test-retest correlation was observed, potentially indicating the impact of natural disease progression confounding retest evaluation for long (>80 day) intervals; however this effect did not impact the overall linguistic validation results as analysis of only <21 day test-retest responders confirmed the findings. Conclusions: This linguistic validation study represents the first formal step toward the clinical validation of the Spanish RSBQ, enabling broader inclusion of Spanish-speaking populations in RTT research. The collaborative, bilingual data collection strategy proved both feasible and effective, paving the way for multinational trials and expanding therapeutic accessibility through localized, patient-centered innovation.

Background: Acute necrotizing encephalopathy (ANE) is a rare and severe neurologic complication of viral infection in children, thought to result from a hyperacute cytokine storm causing blood-brain barrier disruption and central nervous system injury. Despite characteristic clinical and radiologic features, ANE remains poorly understood at the molecular level, with no validated biomarkers or targeted therapies. We aimed to determine whether genetic predisposition to ANE due to RANBP2 variants is associated with a distinct immunologic signature. Methods: We conducted a prospective biological study of familial ANE (ANE1, NCT06731790). We included 23 heterozygous carriers of the RANBP2 c.1754C>T (p.Thr585Met) variant from 10 families, and 28 noncarriers (median age, 40 years [range, 4-72]). Soluble immune mediators, transcriptomic analyses, multiparameter flow cytometry, and cellular imaging were analysed in peripheral blood mononuclear cells (PBMCs) and monocytes. Baseline and resiquimod stimulated immune responses were analysed within the same statistical model, with genetic status as the primary predictor. Findings: The RANBP2 Thr585Met mutation was associated with a dysregulated inflammatory phenotype characterized by reduced basal mediator production and exaggerated TNF- responses following stimulation (estimated difference, +2,098 pg/mL; 95% CI, 1,121 to 3,076; P=0.0001). Transcriptomic and flow cytometry analyses showed broad reprogramming of myeloid cells with enrichment of CXCR3-high CD14-high subsets. Expansion of these populations was associated with increased long-term disease burden. The RANBP2 variant was the only independent factor associated this inflammatory phenotype. Interpretation: RANBP2-associated ANE is characterised by a distinct immunological signature that can inform disease stratification and support the development of targeted immunotherapeutic approaches.

Background Outcome after stroke varies according to stroke subtype by location, but healthcare systems data studies do not include subtyping information. We linked natural language processing (NLP) of brain imaging reports to routinely collected data to estimate risk of death and other outcomes after stroke subtypes in a nationwide dataset. Methods We applied a previously validated NLP algorithm to all CT and MRI head scan reports in Scotland between 2010 and 2018. We linked the reports to hospital readmissions, prescriptions and death data to identify and characterize people with stroke, and to categorize into deep and cortical ischemic stroke, deep and lobar intracerebral hemorrhage (ICH), subarachnoid hemorrhage, and subdural hemorrhage. We used a matched cohort design, and age- and sex-matched four controls per case who never had a stroke. By subtype, we estimated rehospitalization with stroke, myocardial infarction (MI), cancer, dementia, epilepsy and death, accounting for confounders and competing risk of death. Results From 785,331 people with a head scan, we identified 64,219 with clinical stroke phenotypes (mean age 73.4yrs, 49.5% male), and subtyped 12,616 with deep ischaemic stroke; 14,103 with cortical ischaemic stroke; 1,814 with deep ICH; and 1,456 with lobar ICH. There was higher absolute rate of 1-year hospital readmission for lobar compared with deep ICH (4.9% [95%CI 3.9% - 6.1%] vs 3.4% [2.6% - 4.3%]), higher risk of dementia beyond 6 months after lobar ICH compared to controls than for other stroke subtypes (aHR 3.5 [2.3-5.3]); and higher risk of MI within 6 months of cortical ischemic stroke than for other stroke subtypes (aHR 4.6 [3.4-6.3]). Conclusions NLP of free-text reports linked to coded data successfully subtyped stroke at scale, and we estimated risk of clinically relevant outcomes. Future work should use free text to enable large-scale audit and epidemiology of people with stroke.

BackgroundAcute basilar artery occlusion (BAO) causes devastating strokes. Despite the benefit of endovascular treatment, the optimal management remains sometimes controversial, such as for patients with mild deficits, and would benefit from robust prognostic tools. Given the dense white matter networks within the posterior fossa, we tested whether quantifying disconnections from acute diffusion-weighted imaging (DWI) could improve outcome prediction and responders to recanalization compared with conventional metrics. MethodsWe conducted a secondary analysis from a prospective multicenter stroke registry, including consecutive patients (2017-2024) with BAO and admission MRI. Ultra-high-resolution diffusion MRI was acquired in healthy participants to build normative tractograms with optimized posterior fossa quality. Patient infarcts delineated on DWI were projected onto these tractograms to estimate disconnected fiber volume. The primary outcome was 90-day modified Rankin Scale (mRS) 0-3 vs 4-6. Predictive performance of disconnected fiber volume was compared with baseline NIHSS, infarct volume, and posterior circulation ASPECTS (pc-ASPECTS) using logistic regressions and areas under receiver operating characteristic curves (AUC). Ordinal regressions tested associations across the full mRS spectrum, stratified by recanalization status. Analyses were repeated in patients with NIHSS [&le;]10. ResultsAmong 201 patients (median age 70; NIHSS 10), 97 (48.3%) had poor outcome. Despite small median infarct volume (4.75 mL), disconnected fiber volume was substantial (median 25.15 mL). Disconnected fiber volume achieved an AUC of 0.84, outperforming NIHSS (0.67; p<0.0001), infarct volume (0.75; p=0.00059), and pc-ASPECTS (0.76; p=0.0127). Low disconnected fiber volume predicted better outcomes across the full mRS (OR=0.12 [95% CI, 0.065-0.204]) and greater benefit from successful recanalization (OR=0.33 [95% CI, 0.15-0.70]). In patients with NIHSS [&le;]10 (n=102), disconnected fiber volume remained the strongest predictor (AUC=0.83). ConclusionsDisconnected fiber volume derived indirectly is a robust prognostic marker of BAO outcomes that outperforms conventional predictors and may support future treatment decisions. Registrationhttps://clinicaltrials.gov - NCT03776877.