Annals of Neurology最新文献

Objective: Though it is widely known that tau deposition affects brain structure, the precise localization of these effects is poorly understood, especially in relation to gyral and sulcal anatomy. We investigated whether tau pathology in Alzheimer's disease (AD) preferentially affects sulci, and particularly sulcal depths.

Methods: We analyzed 675 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with magnetic resonance imaging (MRI) and positron emission tomography (PET) data to investigate relationships between neocortical tau PET signal and cortical thickness. We then examined an advanced AD case with postmortem MRI and coregistered whole-brain phospho-tau staining for evidence of sulcal tau distribution in AD. Finally, in a sample of 187 cognitively unimpaired young and older adults with resting-state functional MRI, we examined connectivity strength between tau-vulnerable regions and the hippocampus across adulthood, prior to disease-related cognitive decline.

Results: Our findings revealed that tau-related cortical thinning predominantly occurs in sulcal regions, especially the deepest parts. Postmortem histology confirmed preferential tau accumulation in sulcal depths. Additionally, connectivity analyses revealed that, across adulthood, these primarily sulcal regions most susceptible to tau-related thinning also have stronger connectivity to the hippocampus, suggesting a role for network connectivity in the vulnerability of sulci to the effects of tau pathology later in life.

Interpretation: These findings support the hypothesis that sulci, and particularly their depths, represent structurally and functionally vulnerable regions for tau deposition in AD. Understanding the mechanisms underlying this sulcal vulnerability provides insight into general principles driving regional susceptibility to pathology, and sheds light on the detrimental functional and cognitive effects of tau pathology. ANN NEUROL 2026.

Cladribine tablets are approved for relapsing multiple sclerosis, mediating their clinical effect by moderately depleting lymphocytes. In a prospective, monocentric study including 22 patients completing 2 annual cycles of cladribine, B- and T-cell receptor repertoires and relapse activity were assessed at baseline and after 24 months. T-cell clonality increased, driven by loss of low-frequency, naive clonotypes, and re-expansion of dominant CD8 memory clonotypes, particularly in clinically stable patients. In contrast, B-cell receptor richness increased because of reconstruction by transitional and naive B cells with higher clonotype numbers observed in relapsing patients. Therefore, competing immune reconstitution following cladribine therapy could result in differential clinical responses. ANN NEUROL 2026.

Objective: Peripheral immunity plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We previously showed that elevated neutrophil counts are associated with increased risk of ALS occurrence and faster disease progression, potentially through axonal damage. However, the mechanisms linking neutrophils to ALS occurrence remain unclear. Neutrophil-secreted enzymes, key markers of neutrophil activity, may mediate these effects. We therefore investigated the role of neutrophil-secreted enzymes in ALS occurrence.

Methods: Six neutrophil-secreted enzymes were selected from the UK Biobank-Proteomics Platform. Cox proportional hazards regression was used to examine associations between these enzymes and ALS occurrence. Multiple sensitivity analyses were conducted to ensure robustness. Stratified analyses evaluated potential effect modifications by age, sex, and body mass index (BMI). To investigate whether neutrophil-secreted enzymes contribute to ALS occurrence via a "dying-back" mechanism, mediation analysis was performed to assess the indirect effect of neurofilament light chain (NfL) levels in this relationship.

Results: Individuals who later developed ALS showed significantly higher levels of neutrophil-secreted enzymes prior to disease onset, suggesting that neutrophil activation occurs before ALS occurrence. Elevated enzyme levels were associated with an increased risk ALS occurrence. Furthermore, we observed a linear positive correlation between enzyme levels and NfL concentrations. Mediation analysis indicated that the effects of MPO and S100A12 on ALS onset were partially mediated through axonal injury.

Interpretation: Elevated neutrophil-secreted enzymes are associated with an increased risk of ALS occurrence. This finding provides mechanistic insight into neutrophil involvement in ALS and identifies these enzymes as potential therapeutic targets. ANN NEUROL 2026.

Objectives: Multiple system atrophy (MSA) is classified into parkinsonian (MSA-P) and cerebellar (MSA-C) phenotypes based on predominant motor features, with corresponding pathological classifications of striatonigral (SN) degeneration and olivopontocerebellar (OPC) atrophy; however, disease progression patterns remain poorly understood. We aimed to identify novel MSA subtypes based on neuronal loss patterns using unsupervised machine learning.

Methods: We applied the Subtype and Stage Inference (SuStaIn) algorithm to analyze neuronal loss patterns in 167 autopsy-confirmed MSA. Neuronal loss was semi-quantitatively assessed in 5 brain regions: putamen, substantia nigra, pontine nucleus, inferior olivary nucleus, and cerebellar Purkinje cells. Obtained subtypes were validated by clinicopathological information.

Results: Three distinct subtypes were identified: SN-early subtype (54% [86/160]) with initial SN neuronal loss, OPC-early subtype (28% [44/160]) with early OPC involvement, and SN-OPC-synchronous subtype (19% [30/160]) with concurrent early neuronal loss in both systems. These subtypes corresponded well with clinical phenotypes. The SN-OPC-synchronous subtype exhibited significantly shorter survival (median 6.2 years vs 6.9 and 7.4 years in SN-early and OPC-early subtypes; p = 0.0049), more frequent rapid progression (57% vs 24% and 41% in SN-early and OPC-early subtypes; p = 0.0048), and more frequent early falls (70% vs 36% and 50% in SN-early and OPC-early subtypes; p = 0.0039). Immunohistochemical validation confirmed extensive α-synuclein pathology in both SN and OPC systems in the SN-OPC-synchronous subtype.

Interpretation: The SN-OPC-synchronous subtype provides insights into α-synuclein propagation mechanisms, suggesting multiple initial seeding sites rather than unidirectional spread. This computational approach uncovered disease heterogeneity undetectable by conventional methods, potentially benefiting clinical trials through patient stratification. ANN NEUROL 2026.

Objective: Dopaminergic imaging is a key biomarker for both the investigation of the biology of Parkinson's disease and related synucleinopathies and the evaluation of potential therapies in clinical trials. This work presents a harmonized approach for quantifying dopaminergic molecular imaging tracers, such as [¹²³I]ioflupane (dopamine transporter scan [DaTscan]) single photon emission computed tomography (SPECT) and [¹⁸F]AV133 positron emission tomography (PET), which assess dopaminergic neuronal loss. The proposed method aims to standardize regional outcome measures using a unified scale called Centamines.

Methods: The Centamines framework comprises 3 analysis levels. Level 1 defines the Centamine scale based on healthy subject data from [¹²³I]ioflupane SPECT (n = 224). Level 2 uses head-to-head data between Tracer X and [¹²³I]ioflupane SPECT to map Tracer X onto the Centamine scale. Level 3 maps additional tracers using prior mappings. A level 2 analysis was performed using [¹²³I]ioflupane SPECT and [¹⁸F]AV133 PET data (n = 68) to convert [¹⁸F]AV133 PET into Centamines.

Results: Level 1 successfully established the Centamine scale using healthy [¹²³I]ioflupane SPECT scans. Level 2 revealed moderate-strong linear correlations (R² = 0.51-0.83) between [¹²³I]ioflupane SPECT and [¹⁸F]AV133 PET across 5 brain regions. Mapped Centamine values showed minimal differences between tracers, ranging from 1.5% (post-commissural putamen) to 3% (caudate).

Interpretation: The Centamine scale holds promise for the harmonized quantification of dopaminergic neuronal imaging markers. The Centamine strategy would enable and accelerate clinical trials in Parkinson's disease using dopaminergic imaging outcomes. ANN NEUROL 2026.

Objective: Deep brain stimulation (DBS) is an established surgical therapy for movement disorders, epilepsy, and psychiatric conditions, yet remains underutilized due to perceived risks. We therefore endeavored to compare the safety of DBS to other common elective procedures to provide context for its relative risk.

Methods: This retrospective cohort study utilized the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database, encompassing diverse referral and community hospitals across the United States from 2015 to 2021. Patients with DBS were compared with those receiving one of the 16 most common elective procedures. The primary outcome of interest was the weighted odds of any postoperative complication at 30 days. Secondary outcomes included risk of readmission, reoperation, and discharge disposition. Logistic regression with inverse probability of treatment weighting (IPTW) based on propensity scores adjusted for baseline group heterogeneity.

Results: We identified 2,853,662 patients for analysis, including 4,749 DBS procedures. After IPTW adjustment, patients with DBS experienced lower 30-day complication rates compared with other procedures (1.3% vs 4.1%, OR = 0.32, 95% confidence interval [CI] = 0.25-0.41, p < 0.0001). Readmission rates did not differ significantly (2.2% vs 2.6%, OR = 0.84, 95% CI = 0.69-1.02, p = 0.08). DBS cases had higher odds of discharge home (98.7% vs 96.3%, OR = 2.94, 95% CI = 2.27-3.82, p < 0.0001) and lower reoperation rates (0.7% vs 1.3%, OR = 0.50, 95% CI = 0.35-0.72, p = 0.0002).

Interpretation: DBS demonstrates a favorable safety profile with substantially lower complication rates compared with the most widely performed elective surgeries. These findings support broader consideration of surgical referral for appropriate DBS candidates. ANN NEUROL 2026.

Objectives: Leg dystonia in cerebral palsy (CP) is debilitating but remains underdiagnosed. Routine clinical evaluation has only 12% accuracy for leg dystonia diagnosis compared to gold-standard expert consensus assessment. We determined whether expert-cited leg dystonia features could be quantified to train machine learning (ML) models to detect leg dystonia in videos of children with CP.

Methods: Eight pediatric movement disorders physicians assessed 298 videos of children with CP performing a seated task at 2 CP centers. We extracted leg dystonia features cited by these experts during consensus-building discussions, quantified these features in videos, used these quantifications to train 4,664 ML models on 163 videos from one center, and tested the best performing models on a separate set of 135 videos from both centers.

Results: We identified 69 quantifiable features corresponding to 12 expert-cited leg dystonia features. ML models trained using these quantifications achieved 88% sensitivity, 74% specificity, 82% positive predictive value, 84% negative predictive value, and 82% accuracy for identifying leg dystonia across both centers. Of the 25 features contributing to the best performing ML models, 17 (68%) quantified leg movement variability. We used these ML models to develop DxTonia, open-source software that identifies leg dystonia in videos of children with CP.

Interpretation: DxTonia primarily leverages detection of leg movement variability to achieve 82% accuracy in identifying leg dystonia in children with CP, a significant improvement over routine clinical diagnostic accuracy of 12%. Observing or quantifying leg movement variability during a seated task can facilitate leg dystonia detection in CP. ANN NEUROL 2026.

Paramagnetic-rim lesions are a novel diagnostic marker in multiple sclerosis (MS) and are associated with poor prognosis due to their link with chronic inflammation and disease progression. Analyzing 46 postmortem MS cases, researchers found no iron rims in 67 white matter and 85 grey matter spinal cord lesions, despite most being active. In contrast, iron rims appeared in 20.9% of cortical and 80% of subcortical brain lesions, especially in deeper myelin-rich cortical layers. These findings highlight the regional variability of iron accumulation and have important implications for interpreting iron-rims in MS diagnosis, monitoring, and prognostication. ANN NEUROL 2026.

Objective: Clot composition may offer insights into the mechanism of ischemic stroke. Radiomics, a noninvasive imaging technique, enables tissue characterization through radiomic features (RFs). We aimed to evaluate clot composition using radiomics on non-contrast computed tomography (NCCT).

Methods: In the first phase, we conducted a prospective study comparing RFs with histopathology in thrombi retrieved via mechanical thrombectomy (MT). Thrombi were imaged using micro-computed tomography (micro-CT) and analyzed histologically. Matched micro-CT and histological slices identified red blood cells (RBCs) and fibrin-rich regions. RFs were extracted, and multivariate logistic regression identified features associated with each component. Spearman's correlation was used to assess associations between RFs and percentage composition. The same clots were localized on pre-MT NCCT, and RFs were extracted. Micro-CT and NCCT RFs were correlated to enable histology-informed interpretation. Receiver operating characteristic analysis evaluated the ability of NCCT RFs to discriminate clot composition. In the second phase, radiomics was applied to a retrospective NCCT dataset from patients with ischemic stroke with varying etiologies.

Results: Ten thrombi were analyzed using micro-CT. Total energy (odds ratio [OR] = 1.35, 95% confidence interval [CI] = 1.20-1.54, p < 0.001) and large dependence high gray level emphasis (OR = 1.18, 95% CI = 1.07-1.32, p = 0.01) were associated with RBCs and correlated with >70% RBCs composition on NCCT (Rho = 0.752 and Rho = 0.815). Subsequently, 150 NCCT scans were analyzed, including 50 cardioembolic, 50 large artery atherosclerosis (LAA), and 50 cryptogenic strokes. Radiomic analysis indicated RBCs-predominant composition in 72% of cardioembolic, 30% of LAA, and 50% of cryptogenic clots.

Interpretation: Radiomics is a promising, noninvasive technique for characterizing clot composition. ANN NEUROL 2026.

Objective: Whether cognitive decline in patients with Parkinson's disease (PD) carrying GBA1 variants is accelerated after subthalamic deep brain stimulation (STN-DBS) remains controversial. Clarifying long-term cognitive outcomes is essential for informed decision making.

Methods: We assembled matched cohorts of patients carrying GBA1 variants with STN-DBS (PD_GBA1+DBS+, n = 28) and without (PD_{G BA1+DBS-}, n = 28). Additional cohorts included non-carriers with STN-DBS (PD_GBA1-DBS+, n = 40) and without (PD_GBA1-DBS-, n = 43). Clinical, genetic, and cerebrospinal fluid (CSF) biomarkers (Aβ1-42, h-Tau, p181-Tau, and neurofilament light chain) were analyzed. Cognition was assessed using the Montreal Cognitive Assessment (MoCA). Cognitive slopes were estimated using linear mixed models and the minimally detectable slope difference at 3-year follow-up was 1.33 MoCA points enabling sensitivity to clinically meaningful changes. Secondarily, conversion to dementia was analyzed with Kaplan-Meier-analysis once the MoCA was < 21.

Results: There was no significant difference in cognitive decline between PD_GBA1+DBS+ and PD_GBA1+DBS- (-0.24 MoCA points/year; 95% confidence interval [CI] = -1.11 to 0.70) projecting to -0.72 MoCA points at 3-year-follow-up (p = 0.583). Secondarily, the risk for conversion to dementia did not differ between PD_GBA1+DBS+ and PD_GBA1+DBS- (HR = 0.55, 95% CI = 0.23-1.34, p = 0.119) or between PD_GBA1-DBS+ and PD_GBA1-DBS- (HR = 1.22, 95% CI = 0.53-2.83, p = 0.897). Dementia risk was associated with GBA1 status (HR = 3.04, 95% CI = 1.05-8.79, p = 0.041), baseline MoCA < 26 (HR = 3.05, 95% CI = 1.29-7.21, p = 0.011), and baseline age > 69 years (HR = 4.42, 95% CI = 1.79-10.89, p = 0.001). In GBA1 carriers, a visuospatial/executive domain score < 4/5 predicted dementia (HR = 4.71, 95% CI = 1.25-17.86, p = 0.022).

Interpretation: GBA1 variant carriers meeting general STN-DBS indication criteria did not show accelerated cognitive decline in the presence of STN-DBS. In addition, exploratory predictors of dementia could support counseling of DBS candidates. ANN NEUROL 2026.