搜索结果：Annals of neurology

Traumatic brain injury (TBI) significantly reduces the quality of life for millions of survivors worldwide, causing persistent brain tissue damage and cognitive impairments, with no established therapeutic interventions currently available. Slow-wave activity, a hallmark of deep sleep, has been implicated in recovery after TBI, but pharmacological approaches to enhance it lack specificity and scalability, complicating efforts to identify slow-wave activity as a direct mechanistic contributor and severely limiting clinical translation. To overcome these limitations, we developed a preclinical closed-loop auditory stimulation (CLAS) paradigm that targets sleep's slow waves, enabling highly specific and temporally precise enhancement of slow-wave activity. Therefore, we delivered 30-ms sound triggers targeting the up-phase of real-time detected slow-waves (upCLAS: TBI n = 8), or no sound stimulation (mockCLAS: non-TBI n = 8, TBI n = 7) during sleep to healthy controls (non-TBI) or brain injured (TBI) rats. Concomitantly, we assessed the ability of upCLAS-enhanced sleep to counteract brain tissue damage (primary outcome) and symptomatic sequelae (secondary outcome) of TBI. Bayesian analysis revealed that sound-mediated slow-wave activity enhancement: (1) reduces diffuse axonal injury, with TBI mockCLAS posterior estimates falling outside the 95% confidence intervals of both other groups, whereas the posterior distributions of TBI upCLAS and non-TBI groups largely overlapped (~13% posterior differences >0), consistent with a negligible effect size between groups; (2) decreases demyelination, with approximately 97% posterior differences >0 between TBI mockCLAS and TBI upCLAS groups, compared to approximately 60% between non-TBI and TBI upCLAS groups; and (3) preserves cognitive ability, with recognition indexes in the novel object recognition test significantly above chance level in non-TBI (*p = 0.031) and TBI upCLAS (*p = 0.026) groups, in contrast to mockCLAS-treated TBI rats (p = 0.156), presenting pronounced cognitive deficit. Furthermore, microglial response to brain injury was increased by deep sleep enhancement, with reduced ionized calcium-binding adaptor molecule 1+ area coverage in TBI upCLAS rats (*p = 0.0445) compared to non-TBI ones. These results unambiguously demonstrate slow-wave activity enhancement confers robust disease modification following TBI while overcoming major limitations of other preclinical approaches. Our findings constitute proof-of-concept that boosted sleep intensity mitigates histopathological and cognitive sequelae of brain trauma, suggesting that a clinically relevant, nonobtrusive, sleep-based therapy may represent a novel therapeutic intervention for TBI survivors. ANN NEUROL 2026.

Cerebral ischemia remains a major cause of disability, and the contribution of the hyperacute immune response is increasingly recognized. The aim of this study was to investigate the local inflammatory response in the affected brain of stroke patients with large vessel occlusion during the hyperacute phase of stroke. To decipher the role of myeloid immune cells in stroke-induced inflammation, we performed an unsupervised multiomics analysis of innate immune pathways in ischemic blood obtained directly from the occluded middle cerebral artery in 54 patients undergoing mechanical recanalization. Paired nonischemic arterial blood served as an internal control. Stroke triggered a local hyperacute activation of classical monocytes and neutrophils in the ischemic cerebral vasculature, with interleukin (IL)-1β emerging as a key mediator of inflammation. Elevated plasma adenosine triphosphate levels and inflammasome priming in intravascular monocytes were associated with IL-1β production within the occluded middle cerebral artery within 4.5 hours of stroke onset. IL-1β release coincided with increased neutrophil-attracting chemokines (C-X-C motif chemokine ligand 1 [CXCL1], IL-8). Locally activated neutrophils formed neutrophil extracellular traps (NETs) within the ischemic vasculature, a hallmark of thromboinflammation. Postmortem analyses revealed NET deposition within ischemic brain parenchyma. These findings indicate increased IL-1β expression and enhanced NET formation within the cerebral circulation in stroke caused by large vessel occlusion, suggesting that these mechanisms might contribute to early stroke pathophysiology and represent potential targets for immunomodulatory strategies. ANN NEUROL 2026.

The objective of this study was to determine whether baseline computed tomography (CT) markers of cerebral small vessel disease (cSVD), as a surrogate of brain frailty, explain the association between age and functional outcome, potentially accounting for the reduced apparent benefit of mechanical thrombectomy (MT) in elderly patients in the RESILIENT trial. RESILIENT was a multicenter, prospective, randomized, open-label trial with blinded outcome assessment conducted in Brazil. Patients with anterior circulation large-vessel occlusion stroke were randomized to MT plus guideline-based care or guideline-based care alone, including intravenous alteplase when eligible. A vascular neurologist blinded to clinical data evaluated baseline CT scans for cSVD markers (leukoaraiosis, lacunes, and atrophy) to derive a composite cSVD score. Multivariable logistic regression identified independent predictors of good functional outcome (modified Rankin Scale [mRS] =&#x2009;0-2 at 90&#x2009;days). Treatment effects were assessed across subgroups defined by age (<70 or &#x2265;70&#x2009;years) and cSVD score (0-1 vs 2-3). Mediation analysis quantified the indirect effect of age on outcome through cSVD. Patients with good outcomes were younger, had lower National Institutes of Health Stroke Scale (NIHSS) scores, better collaterals, lower glucose levels, lower cSVD burden, and were more frequently treated with MT. Independent predictors of good outcome included lower NIHSS, MT, lower cSVD score, and lower glucose levels. MT benefit was restricted to patients <70&#x2009;years with low cSVD burden (odds ratio [OR] =&#x2009;4.16, 95% confidence interval [CI] =&#x2009;1.6-10.4, p&#x2009;<&#x2009;0.01). No benefit was observed in older patients or in those with cSVD >&#x2009;1. Mediation analysis showed that cSVD significantly mediated the association between age and outcome (average causal mediation effect [ACME] = -0.003, 95% CI = -0.005 to 0.00, p&#x2009;=&#x2009;0.010). Baseline CT markers of cSVD were independently associated with poorer outcomes and mediated the association between age and functional outcome in the RESILIENT trial, potentially explaining the lack of MT efficacy in older patients. ANN NEUROL 2026.

Drug-resistant epilepsy (DRE) remains a clinical challenge, as therapies modifying disease trajectory are lacking. Increasing evidence implicates gut microbiota dysbiosis in epilepsy pathophysiology, with short-chain fatty acids (SCFAs) emerging as key microbial metabolites with neuroprotective and anti-inflammatory properties. Clinical studies show that people with DRE exhibit gut microbiota alterations that may impair fecal SCFAs production. Here, we investigated whether supplementation of SCFAs confers disease-modifying effects in a preclinical model of DRE. Adult male mice were subjected to status epilepticus (SE) and subsequently treated with a balanced mixture of acetate, propionate, and butyrate, or vehicle. Seizure frequency and temporal progression were monitored for 70 days by electroencephalography (EEG). At the study end point, cognitive performance, brain and gut histopathology, and neuroinflammation were assessed, together with metabolomic profiling of feces and blood. Brain SCFA levels and receptor expression were also analyzed in mice and in brain tissue from individuals with DRE. SCFA supplementation reduced the proportion of mice exhibiting a progressive phenotype and decreased the overall progression index (PI) 3-fold, without significantly altering overall daily seizure frequency. Treatment reduced seizure clustering, improved cognitive deficits, restored hippocampal and intestinal alterations, and partially normalized cerebral SCFAs levels. Metabolomic profiling in epileptic mice and analysis of human epilepsy brain tissue support a mechanistic contribution of gut-brain axis dysfunction to disease progression. These findings identify SCFAs supplementation as a therapeutic strategy capable of modifying disease trajectory in experimental DRE, with clear translational relevance. ANN NEUROL 2026.

The objective of this study was to examine whether machine learning has the capacity to prospectively identify and predict the emergence of Fragile X-associated tremor/ataxia syndrome (FXTAS) among male fragile X premutation carriers (PCs). We explored neuropsychological and motor evaluation metrics, brain magnetic resonance imaging (MRI), and health metrics in 103 male participants (72 PCs, mean&#x2009;=&#x2009;60.4&#x2009;years at enrollment) and 31 healthy controls (HCs; mean&#x2009;=&#x2009;57.8&#x2009;years at enrollment) across a total of 299 visits to identify optimal FXTAS risk markers. We compared different machine learning model and feature selection method combinations to identify the best features and models for (a) identifying patients with FXTAS and (b) for predicting which individuals were likely to later develop FXTAS in the study to date. Using an optimal set of features (including age, psychological symptoms, executive function and motor measures, IQ, body mass index (BMI), and structural brain measurements), we developed random forest binary classifiers for the 2 tasks. We split the dataset randomly into multiple different train and test splits and observed the average classification performance metrics across all the splits. The models showed promising ability to identify and pre-emptively predict the emergence of FXTAS and achieved a reasonable balance between precision and recall. Accumulation of body fat (BMI), executive function weaknesses, slower reaction time and dexterity, and mental health changes, are clinical factors that may significantly increase a carrier's risk. Structural brain MRI measurements significantly added to the predictive power of the models. These results suggest that machine learning has the potential to inform prediction of risk for FXTAS early, enabling better planning, timely interventions, and provision of necessary care. ANN NEUROL 2026.

The objective of this study was to provide clinical and pathological characterization, and evaluation of the diagnostic and prognostic implications of levodopa response in Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Long-duration levodopa response in patients with pathology-confirmed PD, MSA, and PSP was collated from medical records. Associations between definite levodopa response (>50% motor improvement sustained >2&#x2009;years) with clinical and pathological features were reported. Risk of disease milestones using multivariate Cox regression and diagnostic accuracy parameters were estimated for several measures of levodopa response. Fourteen percent of 132 patients with PD (57.1% men, age at onset 60.0&#x2009;&#xb1;&#x2009;11.8&#x2009;years) did not have a definite levodopa response associated with older age and postural-instability and gait-difficulty subtype without global or nigral pathological differences. Definite levodopa responders had 55% lower falls, 69% lower dementia risk, and 69% increased survival. Eight percent of 115 patients with MSA (55.7% men, age at onset 57.9&#x2009;&#xb1;&#x2009;10.4&#x2009;years) showed a definite levodopa response without distinctive clinical or pathological features, and no impact on disease milestones. Two percent of 191 patients with PSP (64.4% men, age of onset 67.6&#x2009;&#xb1;&#x2009;7.6&#x2009;years) showed a definite levodopa response associated with a PSP-parkinsonism subtype, and more frequent and severe Lewy copathology. Definite levodopa response showed excellent diagnostic accuracy (sensitivity 86.4% and specificity 95.8%) to distinguish PD from MSA and PSP. Short-duration (acute dopaminergic drug challenge) response had suboptimal diagnostic value and modest correlation with long-duration response. Levodopa response in PD, MSA, and PSP has important clinical, pathological, diagnostic, and prognostic implications. ANN NEUROL 2026.

To characterize the magnetic resonance imaging (MRI) lesion dynamics, comorbidities, predictors of relapse, and outcomes in anti-&#x3b3;-aminobutyric acid type A receptor (GABAAR) encephalitis, and assess the utility of LIM-domain-only-protein 5 (LMO5) antibodies as tumor markers. GABAAR antibodies were confirmed by 2 techniques in serum or cerebrospinal fluid. Long-term outcomes were defined as good (modified Rankin scale, mRS&#x2009;=&#x2009;0-1) or poor (mRS 2-5) at &#x2265;12&#x2009;months. LMO5 antibodies were assessed by cell-based assays and Western blot. Thirty-three patients were identified (4 children, 29 adults; median age, 5.5 and 60&#x2009;years; 61% male). Ten patients (10/32, 31%) had concurrent systemic autoimmunity. Adults presented with seizures and cognitive/behavioral symptoms, often with thymoma, gastrointestinal, or other tumors (18/33, 55%), whereas children frequently had seizures and ataxia with cerebellar MRI lesions. Multifocal T2/fluid-attenuated inversion recovery hyperintensities were present at onset in 23 of 31 (74%) or developed later in those with absent or single lesions. Lesions showed dynamic changes, suggesting ongoing inflammation even without clinical correlate. Relapses occurred in 17 of 31 (55%, all adults) and were associated with older age (p&#x2009;=&#x2009;0.02) and lack of second-line immunotherapy (p&#x2009;=&#x2009;0.02). Four patients (4/33, 12%) died. After a 32.5-month median follow-up, 9 of 20 (45%) had persistent cognitive deficits, and 6 of 20 (30%) had a poor outcome, which was associated with relapses (p&#x2009;=&#x2009;0.04). LMO5 antibodies were absent in patients and controls. Anti-GABAAR encephalitis shows age-dependent presentations, most commonly seizures. MRI reveals dynamic changes consistent with an ongoing "clinically silent" inflammation. Relapses and cognitive sequelae are common and associate with not receiving second-line immunotherapy. LMO5 antibodies lack tumor-predictive value. ANN NEUROL 2026.

Pathogenic variants in GNAO1 cause a spectrum of epilepsy, movement disorders, and developmental impairment. Clinical heterogeneity complicates prognosis and therapeutic development. We present the first longitudinal natural history study of GNAO1-related disorders (GNAO1-RD) to delineate phenotypic trajectories. Sixty-six individuals with GNAO1-RD were included in a cross-sectional analysis. Of these, 21 were enrolled in a prospective natural history arm (March 2021-December 2024), undergoing annual standardized evaluations with validated clinical scales to monitor phenotypic progression. Our cohort exhibited broad phenotypic and severity variability. GNAO1-RD severity scores ranged from 0.5 to 13. Neurodevelopmental impairment varied: 45.5% lacked head control, whereas 22.7% achieved independent walking; and 65% had no expressive language. Movement disorders were nearly universal (95.5%), with dyskinetic crises in 54.5%. Epilepsy affected 51.5%, with different seizure types. Individuals carrying recurrent variants showed consistent phenotypes and severity, supporting a genotype-phenotype correlation reinforced by molecular functional data. Molecular functional analysis for 20 of 31 missense variants correlated with severity scores. Longitudinal data from 21 patients in the natural history cohort showed overall stability or mild improvement across most functional domains. No significant deterioration was observed in global severity, motor function, cognition, or quality of life. However, severe patients experienced progressive worsening of movement disorder. This largest GNAO1-RD cohort and first longitudinal natural history study provide insights into disease progression. GNAO1-RD generally follows a non-degenerative course, showing stability or mild improvements over time in cognition, language, adaptive skills, and motor function. Importantly, although global severity scores remained stable overall, severe cases showed cumulative functional burden driven by progressive movement disorder, rather than global neurodegeneration. Mortality occurred in a subset of patients because of complications from dyskinetic crises, infections, and epilepsy-related events. Genotype-phenotype data and the GNAO1-RD severity score support early risk stratification and personalized treatment development. ANN NEUROL 2026.

Restless legs syndrome (RLS) is a sensorimotor disorder marked by an uncontrollable urge to move the legs. A pathophysiological hallmark of RLS is brain iron deficiency. The endothelial cells (ECs) of the blood-brain barrier (BBB) are responsible for regulating brain iron uptake. Our objective is to determine if brain iron uptake is altered in ECs in RLS. Human ECs were generated from induced pluripotent stem cells (iPSCs). ECs were exposed to RLS (n&#x2009;=&#x2009;14) or control cerebrospinal fluid (CSF) (n&#x2009;=&#x2009;15), and 57Fe-Transferrin transport was determined. Immunoblotting and quantitative polymerase chain reaction were used to analyze protein, microRNA (miRNA), and messenger RNA (mRNA) expressions. We performed miRNA and transferrin receptor 1 (TfR1) 3' iron-responsive elements (IRE) interaction in HEK-293 cells by using a pMIR-REPORTER luciferase vector. Free and protein-bound iron in CSF from RLS subjects were decreased compared to controls. Exposure of ECs to RLS CSF significantly decreased the uptake and transport of 57Fe compared to the control. TfR1 expression decreased while iron regulatory proteins (IRP) increased in RLS-CSF exposed ECs. TfR1 expression was also regulated by miRNAs. The miR-124-3p levels were higher in RLS CSF-derived extracellular vesicles than in the control. It binds the TfR1 3' IRE sequence in the pMIR-REPORTER vector, reducing luciferase expression. When ECs are treated with CSF from RLS patients, they show a profile of iron deficiency, except that the TfR1 expression does not increase as would be predicted. The decrease in TfR1 protein expression is because of a reduction in TfR1 mRNA stability by the binding of increased miR-124-3p. ANN NEUROL 2026.

Dysarthria is one of the most common and disabling side effects of subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). Stimulation often exacerbates speech dysfunction beyond the effects of PD progression, likely because of current spread to structures surrounding the STN. This study aimed to develop speech biomarkers sensitive to DBS-induced dysarthria by isolating stimulation side effects and mapping their emergence across incrementally increased amplitudes. Twenty-four PD patients with bilateral STN-DBS completed a standardized speech assessment in each hemisphere separately, including sustained phonations, rapid syllable repetitions, and reading passages across 7 increasing stimulation amplitudes defined relative to a clinically determined stimulation-induced dysarthria threshold. A composite dysarthria index based on 7 key acoustic features, patient perceptual self-ratings, and intelligibility scores were extracted. More than 2,500 speech task recordings were analyzed. Both the composite dysarthria index and subjective self-ratings worsened rapidly with increasing stimulation amplitude above a threshold (p&#x2009;<&#x2009;0.001), whereas intelligibility scores varied markedly and did not reach significance. Among individual acoustic features, phonation duration, voice quality, and monopitch exhibited significant sensitivity to increasing stimulation amplitudes. Left-sided stimulation induced greater speech deterioration than right-sided stimulation. We systematically identified speech biomarkers that capture DBS-induced dysarthria, characterized the progressive deterioration of speech with increasing amplitude, and highlighted the pivotal role of left basal ganglia circuitry in speech production. Our objective metric holds promise as safety outcome measure for surgical therapies, guidepost for initial and troubleshooting DBS programming, and input for adaptive, closed-loop stimulation control. ANN NEUROL 2026.

The pathophysiology of idiopathic intracranial hypertension (IIH) is poorly understood and disease-specific biomarkers are lacking. We aimed to shed light on IIH pathophysiology and identify disease-specific biomarkers. This prospective cross-sectional cohort study included patients with new-onset IIH and age-, body mass index-, and sex-matched healthy controls from 2 tertiary Danish Headache Centers (discovery cohort). Liquid chromatography coupled to tandem mass spectrometry analysis was used to measure reproducible proteomic profiles for paired serum and cerebrospinal fluid (CSF) samples. Results were validated using 3 validation cohorts comprising patients with IIH (pwIIH), cerebral sinus venous thrombosis (pwCSVT), and normal pressure hydrocephalus (pwNPH). We included 53 pwIIH and 35 controls. PwIIH presented with papilledema and increased median lumbar puncture opening pressure (interquartile range [IQR]) (38.0 [33-46] vs 19.0 [17.0-23.0] cmH2O; p&#x2009;<&#x2009;0.001) compared to controls. Machine learning analysis identified 20 IIH-predicting proteins for serum and CSF segregating pwIIH, but neither pwCSVT nor pwNPH, from controls with areas under the curve (AUC) of 0.84 and 0.92 (pwIIH, discovery cohort), 0.99 and 0.90 (pwIIH, validation cohort 1), 0.63 (plasma; pwCSVT), and 0.67 (CSF; pwNPH), respectively. Serum carbonic anhydrases (CA) 1 and 2 were upregulated and among the most IIH-predicting proteins as were amyloid precursor protein (APP), S100P, and S100A12. We identified a panel of independently validated IIH-specific candidate biomarkers. The serum candidate biomarkers pointed toward CA2 driven CSF hypersecretion in IIH providing a possible explanation for the therapeutic efficacy of CA inhibitors. The regulation of markers associated with neuronal impairment (APP, S100P/S100A12) confirmed the non-benign character of IIH. ANN NEUROL 2026.

Spinocerebellar ataxia 1 (SCA1) is a fatal hereditary neurodegenerative disorder with no approved therapies, and gene-targeting strategies have thus far failed in clinical trials. Exercise remains the only intervention shown to provide clinical benefit in patients with spinocerebellar ataxias (SCAs), yet the underlying mechanisms remain poorly understood. Using the Atxn1154Q/2Q knock-in mouse model, we implemented a prolonged voluntary wheel-running paradigm from 4 to 16&#x2009;weeks of age. Mice were then phenotyped using motor and cognitive behavioral assays. Following euthanasia, cerebellar tissue was harvested for histological analysis and unbiased transcriptomics. Unrestricted exercise rescued motor ataxia but not degeneration in this SCA1 mouse model at the ages in this study. Transcriptional profiling of cerebellar tissue separated wild-type (WT) sedentary and exercise mice by differential gene expression, but in SCA1 mice the most pronounced changes occurred at the level of RNA splicing, particularly in ion channel modules. Exercise led to a significant rescue of splicing events in SCA1 mice, with minimal impact on gene expression changes. Further, both exercised SCA1 and WT mice exhibited splicing patterns more similar to each other than their sedentary counterparts. Together with emerging evidence in other SCAs, our findings confirm aberrant splicing as a central driver of SCA pathophysiology and identify splicing-regulated networks as actionable therapeutic targets. The observed benefits in SCA1 mice suggest that correcting mis-spliced ion channels may be a viable strategy for disease modification across SCAs and related neurodegenerative disorders. ANN NEUROL 2026.

A research biologic definition and staging of neuronal alpha-synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, is critical toward improving clinical trial design and drug development. Neuronal synuclein disease, and the companion Integrated Staging System, are a biologic definition and staging system conceptualized by multiple stakeholders including academia, industry, advocacy organizations, and importantly, people with lived experiences. In large part, this was informed and enabled by the knowledge garnered from the Parkinson's Progression Markers Initiative. This review provides a historical perspective and details contributions from the Parkinson's Progression Markers Initiative, among others, that made this advancement possible. These include the key role it played in validation of an in vivo biomarker of neuronal alpha-synuclein, longitudinal characterization of dopaminergic dysfunction imaging, biospecimen collection and assays, comprehensive genetic characterization, and clinical phenotyping. In addition, the Parkinson's Progression Markers Initiative is generating and sharing data that will be used to address key gaps in knowledge, revisions, and future refinements of a biologic definition and staging of synucleinopathies. ANN NEUROL 2026.

The objective of this study was to evaluate the effectiveness and adverse effect profile of prophylactic levetiracetam in preventing epilepsy after traumatic brain injury (TBI). This retrospective cohort study used the TriNetX Research Network, encompassing >150 million patients. Adults (&#x2265;18&#x2009;years) with a first TBI and Glasgow Coma Scale (GCS) score recorded were included. Patients with pre-existing epilepsy, seizures on the day of injury, or prior levetiracetam exposure were excluded. The cohort (n&#x2009;=&#x2009;51,263) was stratified into mild (GCS 13-15; n&#x2009;=&#x2009;33,625) and severe (GCS 3-8; n&#x2009;=&#x2009;10,805) TBI. The risk of early (<7&#x2009;days) and late (<1&#x2009;year) epilepsy was assessed using Cox proportional hazards models adjusted for known predictors. Adverse events were evaluated for up to 5&#x2009;years. Levetiracetam was administered to 14,630 patients (30%). After adjustment, levetiracetam reduced early epilepsy in severe TBI (hazard ratio [HR]&#x2009;=&#x2009;0.55, 95% confidence interval [CI] =&#x2009;0.31-0.97, p&#x2009;=&#x2009;0.04) but not in mild TBI (HR&#x2009;=&#x2009;0.85, 95% CI&#x2009;=&#x2009;0.45-1.61, p&#x2009;=&#x2009;0.61). Levetiracetam did not reduce late epilepsy in either mild (HR&#x2009;=&#x2009;1.00, 95% CI&#x2009;=&#x2009;0.79-1.15, p&#x2009;=&#x2009;0.997) or severe (HR&#x2009;=&#x2009;0.90, 95% CI&#x2009;=&#x2009;0.68-1.19, p&#x2009;=&#x2009;0.45) TBI. Older age, cerebral edema, and subdural hemorrhage were consistent risk factors. Adverse outcomes included impaired memory and awareness, metabolic disorders, and psychiatric symptoms. Levetiracetam prophylaxis reduced early epilepsy only in severe TBI and conferred no long-term protection. Given its adverse effect burden, routine prophylaxis should be limited to severe TBI or high-risk patients. These findings support re-evaluation of current seizure prophylaxis guidelines, which are based on older antiseizure medications and predate large-scale real-world data. ANN NEUROL 2026.

The focus of epilepsy research has largely been on seizure onset; however, physicians typically examine the patterns of seizure spread past seizure onset as well. This study aims to align automated seizure analysis with clinical practice, leverage deep learning to standardize seizure annotations that varies among physicians, and understand common seizure spread patterns across patients. We developed deep learning algorithms on a small subset of patients to detect seizure activity and deployed these algorithms across 275 seizures in 71 patients to analyze the patterns of seizure spread (extent, timing, surgical outcomes, and common patterns) along with incorporating diffusion-weighted imaging to understand how these patterns relate to the structural connections of the brain. Deep learning algorithms outperform single features (line length, absolute slope, and power) in ranking seizure onset contacts using physician annotations as a benchmark. We also find that poor outcome patients have more extensive brain regions involved in their seizures while also having more rapid spread between temporal lobes. Incorporating diffusion-weighted imaging, we find that an increase in structural connectivity between temporal lobes is associated with quicker seizure spread. Finally, we identify clusters of spread patterns common across patients based on spread timing, location, and extent. Analyzing seizure spread can reveal new insights into seizure evolution and its relationship with surgical outcomes in patients with epilepsy. The findings also suggest that focusing beyond seizure onset is crucial for understanding and treating epilepsy. ANN NEUROL 2026.

The role of microglia has emerged as a critical driver of disease progression in multiple sclerosis (MS), but we lack broadly applicable monitoring tools. Here, we investigated whether hyperreflective foci (HRF), as detected by optical coherence tomography (OCT) within the inner nuclear layer (INL) of the retina, can be used as a marker for microglial pathology. We demonstrate that HRF counts are increased in persons with relapsing and progressive MS and correlate with global white and gray matter, as well as deep gray matter [18F]GE-180 uptake. [Color figure can be viewed at www.annalsofneurology.org] ANN NEUROL 2026;99:1480-1485.

To better understand the earliest stages of alpha-synucleinopathy, the Parkinson's Progression Markers Initiative (PPMI) has enrolled participants prior to the diagnosis of Parkinson's disease (PD) or dementia with Lewy Bodies (DLB). In this review, we describe lessons learned from prior enrollment and current strategies for PPMI eligibility. Severe hyposmia remains the strongest clinical predictor of aggregated synuclein as measured by a positive cerebrospinal fluid alpha-synuclein seed amplification assay (CSF aSyn SAA). CSF aSyn SAA is positive before dopamine transporter binding decreases, as measured by dopamine imaging. PPMI's adaptive eligibility criteria have enabled efficient identification of people in the early stage of neuronal synuclein disease defined by biomarkers alone and can inform future therapeutic studies. ANN NEUROL 2026.

Our goal was to examine whether pre-diagnostic plasma carotenoids and tocopherols are associated with amyotrophic lateral sclerosis (ALS). A nested case-control study within 4 United States cohorts, where 154 participants with pre-diagnostic blood-draw, were diagnosed during follow-up with amyotrophic lateral sclerosis&#xa0;(ALS). Controls were randomly selected from participants alive on the date a case was diagnosed, matched 2:1 by cohort, sex, age, race/ethnicity, fasting-status, time of blood-draw. Carotenoid and tocopherol levels were quantified by high-performance liquid-chromatography with diode array-detector. ALS incidence or death rate ratios (RR) were estimated using conditional logistic regression adjusting for body mass index, smoking status, physical activity, cholesterol, and urate levels. The association between beta-carotene and ALS varied by sex (p-for-interaction&#x2009;=&#x2009;0.007). After matched- and multivariable-adjustment, women with higher cis-, trans- and total beta-carotene had lower incidence of ALS (RR for 1-standard deviation [SD] increase in total beta-carotene: 0.68; 95% CI: 0.48-0.98; p&#x2009;=&#x2009;0.038), whereas a positive association was seen in men (1-SD increase: RR&#x2009;=&#x2009;1.44; 95% CI: 1.03-2.01; p&#x2009;=&#x2009;0.033). However, after further adjustment for other correlated carotenoids, the association in men was attenuated, whereas it remained significant in women. Women with higher beta-cryptoxanthin, but not men, had a lower risk of ALS (1-SD increase: RR&#x2009;=&#x2009;0.67; 95% CI: 0.48-0.94; p&#x2009;=&#x2009;0.02; p-for-interaction&#x2009;=&#x2009;0.12). Alpha-carotene, lutein-zeaxanthin, lycopene, retinol, and tocopherols were not associated with ALS, except for a borderline inverse association of gamma-tocopherol in men (RR&#x2009;=&#x2009;0.74; 95% CI: 0.54-1.01; p&#x2009;=&#x2009;0.059). Higher pre-diagnostic plasma levels of beta-carotene and beta-cryptoxanthin in women and gamma-tocopherol in men were suggestively associated with lower ALS risk. Other carotenoids or tocopherols were not clearly associated with ALS. ANN NEUROL 2026.

The benefit of intravenous thrombolysis (IVT) before endovascular treatment (EVT) in patients with acute ischemic stroke due to large vessel occlusion (LVO) who present directly to EVT-capable centers remains uncertain, and the effect may differ according to underlying stroke etiology. We assessed whether the benefit of IVT plus EVT versus EVT alone varied by stroke etiologies (large-artery atherosclerosis, cardioembolism, or other/undetermined). We performed an individual participant data meta-analysis of 6 randomized controlled trials (RCTs) that compared IVT plus EVT to EVT alone in patients with LVO within 4.5&#x2009;hours of stroke onset or time last known well. The heterogeneity of treatment effect was assessed using ordinal logistic regression models with interaction terms for stroke etiology and treatment in the intention-to-treat population, followed by subsequent mixed-effects meta-analysis. An additional analysis was performed to assess whether the treatment effect of IVT plus EVT differed by atrial fibrillation status. Among 2,313 eligible patients from 6 RCTs, 1,160 were randomized to the IVT plus EVT group and 1,153 to the EVT alone group. Median age was 71&#x2009;years (interquartile range [IQR] =&#x2009;62-78&#x2009;years), and 44.3% of patients were women. Stroke etiology was classified as cardioembolism in 977 of 2,313 patients (42%), large artery atherosclerosis in 430 (19%), and other or unknown/undetermined in 906 (39%). No evidence of treatment effect modification by stroke etiologies on the association between IVT and 90-day functional outcome was observed (P for interaction&#x2009;=&#x2009;0.60). For patients with other/undetermined stroke etiology, IVT plus EVT was associated with better 90-day functional prognosis (adjusted common odds ratio for a lower level of disability&#x2009;=&#x2009;1.34, 95% confidence interval [CI] =&#x2009;1.05-1.69). No treatment effect modification by stroke etiology was found for safety outcomes. No treatment effect heterogeneity by atrial fibrillation was found for all outcomes. Among patients with LVO presenting directly to EVT-capable centers, stroke etiologies do not modify the overall efficacy or safety of IVT before EVT. The isolated benefit observed in the other/undetermined subgroup requires confirmation. ANN NEUROL 2026 ANN NEUROL 2026.