Annals of Neurology最新文献

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 Lower Extremity Motor Score (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.

Objective: The objective of this study was to test the hypothesis that minimally invasive surgery (MIS), an emerging surgical treatment for spontaneous intracerebral hemorrhage (sICH), is associated with better clinical outcomes than open craniotomy with clot evacuation, in a large, nationwide US cohort.

Methods: We performed a retrospective cohort study that included patients with sICH included in the American Heart Association Get With The Guidelines-Stroke registry between January 1, 2011, and December 31, 2021. We excluded patients with a diagnosis of ischemic stroke, subarachnoid hemorrhage, or subdural hemorrhage, and patients transferred to another hospital. The exposure was the type of surgery, classified as either open craniotomy with clot evacuation or MIS (composite of endoscopic evacuation or stereotactic evacuation with fibrinolytic therapy). The primary outcome was in-hospital mortality. Secondary outcomes at discharge included disposition, ambulatory status, and modified Rankin Scale (mRS) score. After overlap-weighted propensity score matching, multiple logistic regression was used to study the association between the type of surgery and outcomes.

Results: Among 564,265 patients with sICH, 7,770 underwent surgical intervention. MIS was performed in 703 patients and open craniotomy was performed in 7,067 patients. In regression analyses, MIS was associated with lower odds of in-hospital mortality (adjusted odds ratio [aOR] = 0.7, 95% confidence interval [CI] = 0.5-0.9), unfavorable discharge (aOR = 0.7, 95% CI = 0.6-0.9), and higher odds of discharge to rehabilitation (aOR = 1.3, 95% CI = 1.1-1.5), but not with functional outcomes.

Interpretation: In this large, representative US cohort of patients with sICH, MIS was associated with reduced in-hospital mortality and better discharge disposition compared to conventional open craniotomy with clot evacuation. ANN NEUROL 2025.

Objective: Traumatic brain injury (TBI) is an established risk factor for dementia, although the underlying mechanisms remain unclear. Our previous research demonstrated that a single severe TBI in wild-type (WT) mice induces a prion-like form of tau (tau^TBI) that spreads throughout the brain, leading to memory deficits. Here, we investigated whether similar self-propagating tau^TBI conformers are generated in humans after severe TBI.

Methods: We biochemically assessed tau and phosphorylated tau (P-tau) levels in human brain contusions surgically removed acutely after severe TBI. Inoculation studies were performed using human TBI brain homogenates in WT and tau knockout (KO) mice to investigate the role of endogenous tau in tau^TBI propagation. Cognitive function was evaluated using the novel object recognition test, the radial arm water maze, and the Y-maze. Pathological changes in the brain of the inoculated mice were analyzed by histological and biochemical analyses, and targeted transcriptomics.

Results: Inoculation of human TBI brain homogenates in WT mice caused widespread tau deposition and cognitive impairment, hippocampal synaptic loss, and disease-associated transcriptomic changes. Effects were similar upon secondary inoculation in WT but not tau KO mice, confirming a tau-dependent mechanism.

Interpretation: Severe TBI induces transmissible tau^TBI conformers in humans acutely after injury, potentially exacerbating post-traumatic pathology, and increasing the risk for dementia later in life. ANN NEUROL 2025.