Annals of Neurology最新文献

Objective: The evidence regarding adherence to dietary patterns and Parkinson's disease (PD) risk is inconsistent. Because of the long prodromal PD phase, reverse causation represents a major threat to investigations of diet in relation to PD. We examined whether adherence to the Mediterranean (MED) and Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diets is associated with PD incidence, while considering reverse causation, in a large cohort of women with a 25-year follow-up.

Methods: Participants from the E3N (Etude Epidémiologique auprès des femmes de la Mutuelle Générale de l'Education Nationale) study were prospectively followed-up from 1993 to 2018. PD diagnoses were validated using medical records and drug claim databases. Baseline MED and MIND scores were computed using a validated food questionnaire. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariable Cox regression models. Exposures were lagged by 5 years in main analyses and longer lags in sensitivity analyses. We performed age-stratified analyses and adjusted for prodromal symptoms.

Results: Analyses (5-year-lag) are based on 71,542 women (845 PD patients). Higher adherence to MED and MIND diets was not associated with PD overall, but was associated with lower PD incidence in women <71 years old (MED, HR_{high vs. low+medium} = 0.76 [0.58-1.00], p-Age × MED interaction = 0.038; MIND, HR_{high vs. low+medium} = 0.75 [0.58-0.97], p-Age × MIND interaction = 0.035). Legumes and high unsaturated to saturated fat ratio had the strongest contribution for the MED diet, while beans and olive oil had the strongest contribution for the MIND diet. Results were consistent after adjustment for constipation/depression and in analyses with lags up to 20 years.

Interpretation: Adherence to the MED and MIND diets was associated with lower PD incidence <71 years in women. These findings are important for planning preventative interventions. ANN NEUROL 2026.

Objective: The objective of this study was to determine whether missing individual doses of anti-seizure medications (ASMs) elevate short-term seizure risk in people with drug-resistant epilepsy.

Methods: In a prospective, community-based cohort, adults with drug-resistant epilepsy (≥ 3 seizures/month) or their caregivers recorded seizures and ASM intake with smartphone applications for 10 months each. Individual level analysis modeled the relationships between ASM adherence with seizure occurrence, as well as with a simplified seizure forecast via a 90-day moving average ("Napkin method"). Group-level analysis with a mixed-effects model was performed to examine the relationship between ASM adherence and simplified forecasts, while controlling for differences in individual seizure frequency via random effects.

Results: Twenty-seven participants (median age = 29 years) contributed 7,853 person-days. Individual analysis showed that only a small (n = 2) number of participants had a weak relationship between ASM adherence with seizure occurrence. Group-level analysis showed that seizure occurrence was highly linked to the Napkin method, but not ASM adherence.

Interpretation: Among individuals with frequent, drug-resistant epilepsy, occasional missed ASM doses did not measurably raise immediate seizure risk. Whereas sustained nonadherence remains a clinical concern, clinicians may reassure patients that infrequent brief lapses are unlikely to trigger seizures acutely, yet they should continue emphasizing overall adherence for long-term seizure control. ANN NEUROL 2026.

The risk allele rs10191329*A is associated with disease severity and brain atrophy in people with multiple sclerosis (MS). We investigated the association of rs10191329 with age-related brain atrophy in a population-based cohort using 10,308 magnetic resonance imaging (MRI) scans of 4,815 participants aged ≥ 45 years without MS in cross-sectional and longitudinal analyses. We observed associations between the rs10191329*A allele and lower total brain volume and gray matter volume in middle-aged (< 55 years of age), but not in older participants. These data suggest that rs10191329*A contributes to earlier onset of atrophy in the general population, and that mediating mechanisms of accelerated neurodegeneration extend beyond MS. ANN NEUROL 2026.

Objective: The objective of this study was to characterize the neurodevelopment and risk factors for impairment at age 5 to 6 years after acute provoked neonatal seizures.

Methods: Multicenter study of neonates with acute provoked seizures. Wechsler Preschool and Primary Scale of Intelligence IV (WPPSI-IV), Vineland-3 Adaptive Behavior Scales, Behavior Assessment System for Children, Behavior Rating Inventory of Executive Function, Social Responsiveness Scale, cerebral palsy (CP), and epilepsy were assessed at age 5 to 6 years. Latent class analysis defined outcome profiles. Least absolute shrinkage and selection operator (LASSO) was used to determine outcome predictors.

Results: We characterized 3 latent classes among 164 children: (1) Typical Development (63%); (2) Behavioral Dysregulation (13%; low likelihood of physical impairment or severely impaired cognition, high likelihood of attention deficit hyperactivity disorder [ADHD]); and (3) Multi-Domain Impairment (24%; high likelihood of epilepsy and impairment across all domains). Among 144 children with standardized testing, mean WPPSI-IV was 91 ± 25 and Vineland-3 Adaptive Behavior Composite 90 ± 20. Twenty-nine percent had ADHD or elevated attention/hyperactivity scores; 19% had autism or elevated Social Responsiveness scores; 20% had epilepsy, and 19% had CP. Risk factors for Multi-Domain Impairment were abnormal neonatal neurologic examination (odds ratio [OR] = 3.94, 95% confidence interval [CI] = 1.74-8.95), impaired functional development at age 24 months (OR = 3.82, 95% CI = 1.25-11.66), and CP (OR = 3.71, 95% CI = 1.74-7.90). No neonatal or infant characteristics were significantly associated with Behavioral Dysregulation.

Interpretation: Nearly two-thirds of 5 to 6-year-old children with provoked neonatal seizures had typical development. Yet, executive and behavioral dysregulation were prevalent, even with preserved cognitive and physical function. These findings can inform outcome discussions and interventions to promote neurodevelopment. ANN NEUROL 2026.

Objective: This study aimed to evaluate the efficacy of brain-computer interface (BCI)-controlled exoskeleton training on lower-limb functional recovery, psychological outcomes, and neural plasticity in patients with spinal cord injury (SCI).

Methods: We conducted a single-center, prospective, randomized, single-blind pilot trial (ChiCTR2300074503) including 21 patients with SCI. Participants were randomized to a BCI-exoskeleton group (B + E, n = 10) or an exoskeleton-only group (E, n = 11) for lower-limb training. Both groups received conventional rehabilitation plus 30 minutes of training, 6 days per week, for 4 weeks. The primary outcomes were Walking Index for Spinal Cord Injury II (WISCI II) scoring. Secondary outcomes included Lambert-Eaton myasthenic syndrome (LEMS), Spinal Cord Independence Measure version III (SCIM III), International Association of Neurorestoratology Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS), 10-Meter Walk Test (10MWT), 6-Minute Walk Test (6MWT), and Hospital Anxiety and Depression Scale (HADS). Cortical plasticity was assessed by electroencephalography (EEG) and magnetic resonance imaging (MRI).

Results: The B + E group showed a significant improvement in LEMS (p = 0.003), whereas both groups improved in IANR-SCIFRS (p < 0.05). The B + E group demonstrated significant within-group gains in walking speed (10MWT, p < 0.001) and endurance (6MWT, p = 0.031), although between-group differences were not significant. Compared with the E group, the B + E group had larger reductions in HADS scores (p = 0.003). EEG analyses revealed stronger μ/β desynchronization and increased network efficiency, whereas MRI showed no structural changes.

Interpretation: BCI-controlled exoskeleton training enhanced motor function, walking performance, and depressive symptoms more than exoskeleton training alone, likely through cortical reorganization. Extended training may further consolidate these benefits, supporting BCI-exoskeleton integration as a promising rehabilitation strategy for SCI. ANN NEUROL 2026.

Drug trial design is at an inflection point in epilepsy and neurological disorders. We are moving from conventional parallel-group randomized controlled trials (RCTs) to other designs, such as n-of-1 trials. Historically, inclusion criteria for antiseizure medicine (ASM) RCTs have stipulated a minimum number of seizures in the baseline period to judge ASM efficacy. For Dravet syndrome, RCTs have demanded 4 or more seizures/month in the baseline period. However, only 25% of children have sufficiently frequent seizures to qualify for RCTs. Trial outcomes should be tailored to the disease and long-term issues for patients, a much broader remit than seizure frequency alone. ANN NEUROL 2025.

Objective: Dysautonomia affects many patients with Parkinson's disease and correlates with increased cardiovascular mortality. We describe the frequency and onset time of autonomic dysfunction relative to disease onset in early-onset Parkinson's disease (EOPD) and explore its association with mortality.

Methods: We identified all incident Parkinson cases with motor-symptom onset before age 50 years evaluated at the Mayo Clinic Health System (1990-2022) including sex- and age-matched controls for each patient. Medical record review confirmed clinical diagnosis and assessed the presence and onset of autonomic symptoms, relative to Parkinson onset.

Results: We included 829 patients with EOPD and 829 healthy controls. The median age at disease onset was 42 years (interquartile range [IQR] = 37-46 years). Autonomic symptoms were present in 63.4% of patients, compared with 27.0% of unaffected controls, and proceeded motor symptoms in 91.4%. Forty-seven percent of patients with early-onset Parkinson's disease had constipation, 27.4% had bladder urgency, 19.3% had orthostatic intolerance, and 15.4% had sweat dysfunction. Among male patients, 36.8% had erectile dysfunction. In our EOPD population only, the presence of any autonomic-impairment symptoms correlated with a 2.71-fold increased mortality risk; each additional reported symptom increased the relative mortality risk by 50% (p < 0.001). Patients with constipation or orthostatic intolerance had a 3.22- and 2.78-fold higher mortality than patients without these symptoms.

Interpretation: Autonomic impairment affects 63.4% of patients with EOPD and carries a 3-fold higher mortality risk, which increases with every additional autonomic symptom reported. In our cohort, autonomic symptoms appeared most commonly after motor onset, contrasting with prodromal autonomic impairment seen in late-onset Parkinson's disease (LOPD). ANN NEUROL 2025.

Objective: This 24-month longitudinal study involving isolated rapid eye movement sleep behavior disorder (iRBD), early-stage Parkinson's disease (PD), and matched healthy control subjects aimed to assess whether acoustic speech features from real-world smartphone calls provide passive progressive biomarkers in synucleinopathies.

Methods: Participants underwent clinical assessments at baseline, 1, and 2 years. Speech was continuously captured during phone calls via a standardized smartphone application, segmented, and analyzed for speech impairment severity end points and key acoustic features of monopitch, vowel articulation, voice quality, and articulation rate. We used linear mixed-effect modeling to estimate speech progression and calculated sample size requirements to demonstrate slowing of progression under anticipated treatment effects.

Results: Over 31,000 phone calls (>1,000 hours) were collected from 71 participants including those with iRBD, PD, and healthy controls. Compared with controls, both individuals with iRBD and PD showed significant declines in speech impairment severity end points based on spectral changes and artificial intelligence-based neural embeddings. The subjects with iRBD also exhibited declines in vowel articulation and articulation rate. For a 2-year neuroprotective trial aiming for 50% drug efficacy, the most efficient sample size estimate based on time-to-event analysis was 74 iRBD and 84 PD participants per arm using the neural embedding end point.

Interpretation: The phone call analysis requiring no patient effort or clinical supervision can detect speech decline in prodromal and early synucleinopathies, providing a potential paradigm shift for clinical trial design and neuroprotective intervention end points. ANN NEUROL 2025.