Annals of Neurology

Objective There are limited population‐based data regarding the prevalence of cerebral amyloid angiopathy (CAA) and associated risks of mortality and incident cerebrovascular events. Methods We performed a retrospective cohort study using inpatient and outpatient claims from 2008 to 2022 from a 5% national sample of Medicare beneficiaries. CAA and ischemic and hemorrhagic stroke were identified using validated International Classification of Diseases 10th Revision (ICD‐10) codes. We ascertained CAA from October 1, 2015 through 2022, and used data from 2008 through September 30, 2015 to ascertain comorbidities including prevalent stroke. We used Cox regression to examine the association of CAA with subsequent death and incident stroke subtypes after adjustment for demographics, vascular risk factors, and Charlson comorbidities. Results Among 1,920,312 Medicare beneficiaries in our sample, 2,161 (11.3 per 10,000) had a diagnosis of CAA. In adjusted Cox regression analysis, there was an association between CAA and subsequent mortality (HR 4.9; 95% CI 4.6–5.2). Among 1,872,474 patients without prevalent stroke, including 900 of the CAA patients, there was a significant association between CAA and an increased risk of any stroke (HR 8.0; 95% CI 6.7–9.6), ischemic stroke (HR 4.6; 95% CI 3.6–6.0), intracerebral hemorrhage (HR 26.9; 95% CI 20.3–35.6), and subarachnoid hemorrhage (HR 21.6; 95% CI 12.2–38.1). After a diagnosis of CAA, absolute risks of ischemic stroke and intracerebral hemorrhage were broadly similar. Interpretation In a large, nationwide cohort of Medicare beneficiaries, the prevalence of clinically diagnosed CAA was approximately 11 per 10,000. CAA was associated with an increased risk of mortality and incident stroke, both hemorrhagic and ischemic. ANN NEUROL 2025

Parkinson's disease (PD) is a neurodegenerative disorder characterized by α‐synuclein aggregation in neurons. Recent advances suggest α‐synuclein aggregates could serve as a biomarker for PD and related synucleinopathies. This study used surface‐based fluorescence intensity distribution analysis (sFIDA) to measure α‐synuclein aggregates in urine. Patients with PD and isolated rapid eye movement sleep behavior disorder, a precursor to PD, had elevated concentrations compared with healthy controls. Sensitivity and specificity were 83% and 65% for PD versus controls and 89% and 62% for isolated rapid eye movement sleep behavior disorder versus controls. The findings highlight sFIDA's potential for diagnosing synucleinopathies. ANN NEUROL 2025

Objective The objective of this study was to evaluate the prognostic value of several muscle damage biomarkers. Methods Data from Piemonte and Valle d'Aosta Amyotrophic Lateral Sclerosis (PARALS) were considered for this study. Survival was defined as the time from diagnosis to death, tracheostomy, or the censoring date. Blood levels of potassium, creatinine, creatine kinase, phosphorus, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) diagnosis were evaluated as potential prognostic biomarkers. A Cox model was developed for each biomarker and adjusted for sex, onset age, onset site, and diagnostic delay. Significant findings from PARALS were evaluated in the Pooled Resource Open‐Access Amyotrophic Lateral Sclerosis Clinical Trials (PRO‐ACT) database. Additionally, a joint model was constructed to evaluate the prognostic role of phosphatemia slope over time using longitudinal data from PRO‐ACT. Results A total of 1,444 and 1,023 patients were included in the PARALS and PRO‐ACT cohorts, respectively. Only creatinine (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.50–0.85) and phosphorus (HR = 1.14, 95% CI = 1.04–1.24) showed a significant association with survival in the PARALS cohort. These findings were further validated in the PRO‐ACT cohort (creatinine HR = 0.21, 95% CI = 0.13–0.35, p < 0.0001; phosphorus HR = 2.35, 95% CI = 1.13–4.88, p = 0.02). Longitudinal data from the PRO‐ACT database showed that an increase of 0.1 mmol/l per month in phosphate levels was also associated with a HR of 8.26 (95% CI = 1.07–96.6, p = 0.044). Interpretation Creatininemia was confirmed as a prognostic marker in amyotrophic lateral sclerosis (ALS). Additionally, both phosphatemia levels at diagnosis and its rate of change over time were identified as a potential prognostic marker for ALS. As with other blood biomarkers, phosphate levels are cost‐effective and minimally invasive to measure, supporting their potential use in clinical trials. ANN NEUROL 2025

Objective Neuroimaging is routinely utilized to identify new inflammatory activity in multiple sclerosis (MS). A large language model to classify narrative magnetic resonance imaging reports in the electronic health record (EHR) as discrete data could provide significant benefits for MS research. The objectives of the current study were to develop such a prompt and to illustrate its research applications through a common clinical scenario: monitoring response to B‐cell depleting therapy (BCDT). Methods An institutional ecosystem that securely connects healthcare data with ChatGPT4 was applied to clinical MS magnetic resonance imaging reports in a single institutional EHR (2000–2022). A prompt (msLesionprompt) was developed and iteratively refined to classify the presence or absence of new T2‐weighted lesions (newT2w) and contrast‐enhancing lesions (CEL). The multistep validation included evaluating efficiency (time and cost), comparison with manually annotated reports using standard confusion matrix, and application to identifying predictors of newT2w/CEL after BCDT start. Results Accuracy of msLesionprompt was high for detection of newT2w (97%) and CEL (96.8%). All 14,888 available reports were categorized in 4.13 hours ($28); 79% showed no newT2w or CEL. Data extracted showed expected suppression of new activity by BCDT (>97% monitoring magnetic resonance images after an initial “rebaseline” scan). Neighborhood poverty (Area Deprivation Index) was identified as a predictor of inflammatory activity (newT2w: OR 1.69, 95% CI 1.10–2.59, p = 0.017; CEL: OR 1.54, 95% CI 1.01–2.34, p = 0.046). Interpretation Extracting discrete information from narrative imaging reports using an large language model is feasible and efficient. This approach could augment many real‐world analyses of MS disease evolution and treatment response. ANN NEUROL 2025

Objective Vascular NOTCH3 protein ectodomain aggregation is a pathological hallmark of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small vessel disease typically caused by cysteine‐altering variants in NOTCH3 . Given their high population frequency, these NOTCH3 variants are an important genetic contributor to stroke and vascular dementia worldwide. Disease severity in CADASIL is highly variable and is mainly determined by the position of the pathogenic NOTCH3 variant in the NOTCH3 ectodomain. Here, we aimed to investigate the association between NOTCH3 aggregation load in skin vessels, cysteine‐altering NOTCH3 variants, and disease severity in a prospective cohort study of 212 patients with CADASIL with 39 distinct cysteine‐altering NOTCH3 variants. Methods NOTCH3 aggregation load in skin vessels was determined by calculating the NOTCH3 score; the fraction of skin vessel wall area positive for NOTCH3 staining. Variant‐specific NOTCH3 scores were calculated for variants present in 10 or more participants, by averaging the NOTCH3 scores of individuals with that distinct variant. The associations between the NOTCH3 score, NOTCH3 variants, and neuroimaging and clinical outcomes were investigated using multivariable linear mixed models, Cox regression, and mediation analyses. Results The NOTCH3 score was significantly associated with lifetime stroke probability and small vessel disease neuroimaging outcomes, but not with age. Variant‐specific NOTCH3 scores reflected differences in disease severity associated with distinct NOTCH3 variants. Interpretation These findings suggest that differences in NOTCH3 aggregation propensity underlie the differences in disease severity associated with NOTCH3 cysteine‐altering variants, and show that NOTCH3 ‐variant specific NOTCH3 scores can contribute to improved individualized disease prediction in CADASIL. ANN NEUROL 2025

The need for pragmatic clinical trials evaluating therapeutic interventions in patients with neurological disease is continually increasing due to availability of multiple therapeutic interventions (comparative effectiveness), multifaceted approaches (multiple concurrent synergistic therapeutic interventions), and gaps in trial‐specific and real‐world population outcomes. Several designs for pragmatic trials are available, including individual randomized trials with pragmatic characteristics, cluster‐randomized and non‐randomized trials, and observational prospective cohort studies. Cluster trials may have parallel cluster and crossover (unidirectional, bidirectional, and alternating crossover) designs. There are unique aspects of consenting and data collection leveraging existing registries, electronic health records (EHRs), and claims data that make pragmatic trials most suited to study the effectiveness of therapeutic interventions in patients with neurological diseases in real‐world settings. ANN NEUROL 2025

Objective To compare clinical and radiological outcomes among relapsing multiple sclerosis patients treated with autologous hematopoietic stem cell transplantation (AHSCT), alemtuzumab (ATZ), and ocrelizumab (OCR). Methods From a London (UK) hospital‐based observational cohort, modeled data were obtained from 621 relapsing–remitting multiple sclerosis patients, who were treated with AHSCT (n = 103), ATZ (n = 204), and OCR (n = 314), and were followed up for 43, 43, and 32 median months, respectively. The annualized relapse rate, new magnetic resonance imaging (MRI) lesions, and disability progression on Expanded Disability Status Scale were assessed. Results AHSCT showed superior efficacy compared with ATZ and OCR. After 5‐year follow up, the mean annualized relapse rate (0.026 vs 0.087; p < 0.001), the risk of relapses (HR 0.29, 95% CI 0.13–0.63; p = 0.002), and of MRI activity (HR 0.33, 95% CI 0.15–0.72; p = 0.006) were significantly lower in AHSCT versus ATZ group. Compared with OCR, after 3‐year follow‐up AHSCT showed a significantly lower annualized relapse rate (0.028 vs 0.073; p = 0.02) and a trend to reduced risk of relapse (HR 0.45, 95% CI 0.18–1.14; p = 0.09), but similar low rates (6%) of new MRI activity (HR 0.86, 95% CI 0.28–2.67; p = 0.80). In addition, there was a similar risk of Expanded Disability Status Scale progression in AHSCT, and both ATZ (HR 1.19, 95% CI 0.71–2.00; p = 0.50) and OCR (HR 1.08, 95% CI 0.57–2.04; p = 0.82) groups. Interpretation AHSCT was followed by greater prevention of relapses compared with ATZ and OCR, and suppressed more profoundly MRI activity than ATZ, but similarly to OCR, albeit with shorter follow up. The risk of accumulating disability was similar among the treated groups. Studies with larger sample sizes and longer follow up may enable confirmation of these findings or detection of any additional differential effects. ANN NEUROL 2025

Objective The phenotype of patients with Parkinson's disease carrying GBA 1 variants (GBA‐PD) suggest similarities to symptomatology associated with early cholinergic system degeneration. Therefore, this study aims to investigate the clinical features and the cholinergic innervation pattern in patients with early GBA‐PD versus those without the GBA1 mutation (non‐GBA‐PD). Methods A total of 46 GBA‐PD and 104 non‐GBA‐PD subjects were included. Clinical assessments included motor and non‐motor evaluation, as well as a comprehensive neuropsychological examination. Cholinergic system integrity was assessed using ¹ ⁸ F‐Fluoroethoxybenzovesamicol ( ¹⁸ F‐FEOBV) positron emission tomography (PET) to investigate the differences between GBA‐PD and non‐GBA‐PD. Given the higher prevalence of females in GBA‐PD, analyses were repeated when stratified by sex. Additionally, we examined the association between cognitive domains and whole‐brain cholinergic binding in both groups. Exploratory analyses examined clinical and ¹⁸ F‐FEOBV binding differences among GBA1 variants. Results GBA‐PD patients exhibited a higher burden of non‐motor symptoms and lower cognitive performance on executive functions and attention. We observed a more pronounced cholinergic denervation in GBA‐PD, compared to non‐GBA‐PD, primarily in the anterior, central, and limbic regions. However, the distribution of cholinergic loss and its association with attention and executive dysfunction was comparable between GBA‐PD and non‐GBA‐PD. In addition, the clinical presentation and cholinergic binding differed significantly between sexes. Interpretation These results suggest an important role of early cholinergic denervation in GBA‐PD patients, which is related to more severe cognitive dysfunction. ANN NEUROL 2025

UNC13A (rs12608932‐CC) is associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and shortens survival in ALS. We aim to describe the association for UNC13A and survival in FTD. We included 626 patients with FTD from Dutch memory clinics, including a subcohort of 150 patients with TDP‐43 pathology. Survival analyses were performed using Cox proportional hazard models in a recessive manner. Homozygosity for rs12608932‐C in UNC13A was associated with a shorter survival compared with other genotypes (hazard ratio [HR] = 1.28, 95% confidence interval [CI] = 1.02–1.60, p = 0.033), which has implications for patient counselling and trial design. ANN NEUROL 2025

Multiple sclerosis (MS) and Alzheimer's disease are neurodegenerative diseases with age‐related disability accumulation. In MS, inflammation spans decades, whereas AD is characterized by Aβ plaques and neurofibrillary tangles (NFT). Few studies explore accumulation of amyloids in MS. We examined Aβ deposition and NFT density in temporal and frontal cortices from postmortem MS ( n = 75) and control ( n = 66) cases. Compared with controls, MS cases showed reduced Aβ, especially in those aged <65 years, and reduced NFT, notably in cases aged >65 years. Aβ deposition predicted greater NFT density both in MS cases and controls. MS‐related factors may affect Aβ/NFT deposition and/or clearance, offering new therapeutic insights for both diseases. ANN NEUROL 2025

Objective Despite substantial advancements in uncovering the genetic basis of Parkinson's disease (PD), a significant portion of cases characterized by familial PD remain genetically elusive. Here, we reported that biallelic variants in EPG5 , a key autophagy gene responsible for Vici syndrome, are associated with PD. Methods Whole‐exome sequencing (WES) was performed in the first cohort including 171 pedigrees with autosomal recessive PD (ARPD), 1,746 cases of sporadic early‐onset PD (sEOPD, age at onset ≤ 50 years) and 1,652 healthy controls. Whole‐genome sequencing (WGS) was performed in the second cohort consisting of 1,947 sporadic late‐onset PD (sLOPD, age at onset >50 years) and 2,478 healthy controls. Results We identified 7 participants harboring compound heterozygous variants within the EPG5 gene across 1 family with ARPD (ARPD‐F1), 4 sporadic EOPD cases, and 1 sporadic LOPD individual. A total of 10 novel variants in EPG5 were discovered in the 7 individuals, comprising 3 nonsense variants and 7 missense variants. The compound heterozygous variants in the EPG5 gene led to decreased expression of EPG5 protein, and impaired autophagy‐lysosome function in cells derived from EPG5 ‐PD individuals. We also revealed several key pathological features, including abnormal accumulation of autophagic vacuoles, aggregation of α‐synuclein in skin tissue from EPG5 ‐PD individuals. In mice, EPG5 deficiency led to progressive dopaminergic neurodegeneration in the substantia nigra of the midbrain. Interpretation Our results unveil a novel association between biallelic variants in EPG5 gene and PD, providing compelling initial evidence for the involvement of EPG5 and autophagy dysregulation in the development of PD. ANN NEUROL 2025

Objective This study aimed to evaluate the association between computed tomography perfusion (CTP) parameters and outcomes in basilar artery occlusion (BAO), and to select patients with BAO who may benefit from thrombectomy. Methods We performed a post‐hoc analysis of patients from the ATTENTION trial with available admission CTP data. CTP parameters evaluated included time to maximum ( T max ) >6 s/8 s/10 s, relative cerebral blood flow (rCBF) <20%/30%/34%/38%/50%, Critical Area Perfusion Score (CAPS), and CTP‐posterior circulation acute stroke prognosis early computed tomography score (CTP‐pc‐ASPECTS), pons‐midbrain‐thalamus (PMT) hypoperfusion. Multivariable Firth logistic regression was used to analyze associations between CTP parameters and outcomes and to explore treatment interactions. The primary outcome was favorable outcome, defined as modified Rankin Scale score of 0–3, at 90 days. Results The study included 109 patients (70 thrombectomy, 39 control). Multivariable analysis showed that lower CAPS, smaller rCBF <34% volume, and higher CTP‐pc‐ASPECTS were associated with favorable outcome. Patients who underwent thrombectomy had a higher likelihood of favorable outcome with increasing CAPS ( T max > 6 s) compared to control ( P interaction = 0.048 for continuous variable). When CAPS ( T max > 6 s) was treated as a categorical variable, the interaction remained significant ( P interaction = 0.03). Similarly, the treatment effect was also modified by PMT hypoperfusion ( T max >6 s) ( P interaction = 0.03). In patients with CAPS ( T max >6 s) >3 or with PMT hypoperfusion ( T max >6 s), thrombectomy was associated with favorable outcome. Interpretation Higher CAPS correlated with a decrease in the rate of favorable outcomes. However, patients with higher CAPS were more likely to benefit from thrombectomy compared to medical management alone, suggesting that severe hypoperfusion should not preclude endovascular treatment. ANN NEUROL 2025

Objective Although dopamine transporter (DaT) imaging is a valuable diagnostic biomarker, few studies have investigated its utility in objectively monitoring disease progression in patients with Parkinson's disease (PD). To date, no study has established a longitudinal relationship between the DaT signal decline and the motor symptom increase, potentially due to neglected factors such as brain regions, disease laterality, and symptom subtypes, which this study addresses. Methods This cohort study included participants who met the Movement Disorder Society (MDS) criteria for PD, with longitudinal imaging and clinical data from the Parkinson's Progression Markers Initiative Database. Linear mixed model analyses were used to investigate the relationship between the DaT signal decline and the motor symptom severity increase over time. We hypothesized that a decline in putaminal DaT availability in the less affected hemisphere would be associated with increasing contralateral motor symptoms, measured by the Unified Parkinson's Disease Rating Scale (UPDRS). Additional models explored the effects of different brain regions (caudate and putamen), symptom categories (MDS UPDRSIII score with and without tremor items), and disease onset laterality (left or right hemisphere). Results We included 719 participants (443 male patients and 276 female patients; mean age = 62.2 ± 9.5 years) with 1,981 available data points. As hypothesized, we observed a significant association between the decrease in the less affected putaminal DaT signal and motor symptom increase in the contralateral body side, independent of including or excluding tremor scores. Interpretation Our findings support the use of repetitive DaT imaging for objectively monitoring PD progression. This could facilitate personalized disease tracking, subtyping, and intervention testing in the future. ANN NEUROL 2025

This final part 3 review builds on the practical applications discussed in part 2 and explores how artificial intelligence (AI) is transforming data management, neurological education, and neurological care across large healthcare networks and datasets. The review also highlights AI's role in real‐world and synthetic data, digital twins, and innovative clinical trial designs, such as in silico and adaptive trials. The review emphasizes AI's ability to drive continuous improvements in care and discovery through comparative effectiveness research and learning health systems. The global healthcare implications discussed here tie back to earlier discussions on human‐AI collaboration and precision care, underscoring the neurological sciences' responsibility to adopt AI advances judiciously, while managing their ethical, economic, and environmental impacts. ANN NEUROL 2025

Objective We aimed to quantify differences in the brain and spinal cord between Friedreich ataxia and controls, stratified by age and disease stage, including for the first time in young children. Methods TRACK‐FA is the largest prospective, longitudinal, multi‐modal neuroimaging study in Friedreich ataxia to date. We assessed individuals with Friedreich ataxia and controls, 5 to 42 years, at 7 sites across 4 continents. The 17 imaging primary outcome measures (POMs) were selected from metrics that showed a significant longitudinal change in previous small‐scale studies. These included brain and spinal cord morphometry (structural magnetic resonance imaging [MRI]) and microstructure (diffusion MRI); brain iron levels (quantitative susceptibility mapping); and spinal cord biochemistry (magnetic resonance spectroscopy). This study is registered with ClinicalTrials.gov (NCT04349514). Results Between February 2021 and August 2023, we assessed 169 individuals with Friedreich ataxia and 95 controls. Compared to controls, individuals with Friedreich ataxia had lower volume of dentate nucleus and superior cerebellar peduncles; smaller cross‐sectional area of spinal cord; lower fractional anisotropy and higher diffusivity in spinal cord and superior cerebellar peduncles; and lower total N‐acetyl‐aspartate/myo‐inositol ratio in spinal cord. Morphometric differences in spinal cord and superior cerebellar peduncles increased dramatically with age during childhood, with rapid development in controls, but not in Friedreich ataxia. Many imaging POMs showed significant associations with clinical severity. Interpretation Our findings provide strong imaging evidence of impaired development of spinal cord and superior cerebellar peduncles during childhood in Friedreich ataxia and open the way for the use of neuroimaging biomarkers in clinical trials. ANN NEUROL 2025

A host of acquired abnormalities in visual function are known to occur in persons who suffer stroke, traumatic brain injury, and neurodegenerative disorders. Cerebral visual impairment occurs in children with early neurological injury or disorders, especially neonatal hypoxic‐ischemic injury. With the improved survival of pre‐term infants through meticulous neonatal intensive care unit care, cerebral visual impairment in children has become much more common in developed countries. In recent months a number of National Institutes of Health institutes and the American Academy of Pediatrics have brought new attention to this major public health problem, which is highly relevant to child neurologists, neuro‐ophthalmologists, as well as the general neurologists who will care for affected individuals as they enter adulthood. ANN NEUROL 2025