Annals of Neurology最新文献

Objective: Carpal tunnel syndrome (CTS) can drastically impair one's ability to work and interferes with activities of daily living. We recently demonstrated that, in rodents, conditioning electrical stimulation (CES) delivered to the nerve 7 days prior to surgery imparts a conditioning lesion-like effect by accelerating the rate of regeneration along the entire length of the nerve. The goal of this study is to test the hypothesis that CES could accelerate nerve regeneration and improve function in patients with moderate or severe CTS.

Methods: Using a double-blind randomized controlled study design, patients received surgery + CES or surgery + sham stimulation. They were evaluated at regular intervals for 12 months following intervention. Primary outcome was motor unit number estimation (MUNE), supplemented with secondary outcomes including motor and sensory nerve conduction studies, Semmes Weinstein Monofilaments, and Moberg Pick-Up Test.

Results: Sixty-four participants were randomized to either the treatment or control groups. There was no significant demographic or physiological difference at baseline between the groups. No major adverse event was found with treatment. Following intervention, there was significantly greater increase in MUNE of 62 ± 71 in the treatment group compared to 25 ± 66 in the controls after 12 months. In the treatment group, there was correspondingly better physiological and functional recovery and hand dexterity compared with the controls.

Interpretation: CES is a safe, feasible, and efficacious treatment to improve nerve reinnervation and functional outcomes in patients with moderate or severe CTS. This may open future possibilities for more effective treatment for other peripheral nerve injuries. ANN NEUROL 2026.

Objective: Cervical artery dissection (CeAD) may be limited to the extracranial extradural space or extend to the intradural space. Intradural extension can potentially increase the risk of stroke and subarachnoid hemorrhage. However, the factors associated with intradural extension and its impact on clinical outcome remain unclear.

Methods: This was a secondary analysis of the STOP-CAD observational, multi-center study. Patients with CeAD and intradural extension (CeADid) were compared with those with pure CeAD extradural dissections (CeADed) using multiple regression analyses.

Results: Of 4,023 patients with CeAD, 534 (13.3%) had CeADid. In comparison to patients with CeADed, those with CeADid more often had clinical overt stroke or transient ischemic attack (TIA) at presentation, acute infarcts on imaging, a vertebral artery affected, and severe stenosis of the involved vessel (p < 0.001 for all). In contrast, carotid involvement and complete occlusions were more frequent in patients with CeADed (p < 0.001 for both). CeADid was associated with a shift in the distribution of scores on the modified Rankin Scale (mRS) toward worse functional outcome (odds ratio [OR] = 0.76, 95% confidence interval [CI] = 0.62-0.92) but the odds for favorable outcomes (mRS = 0-2) did not differ between the groups after appropriate adjustments on multivariate analysis. CeADid was independently associated with higher mortality at 180 days on multivariate analysis (adjusted OR = 2.84, 95% CI = 1.50-5.38).

Interpretation: CeADid is associated with more severe clinical presentation, a shift toward less favorable outcomes, and higher mortality rates. These findings suggest that CeADid may represent a high-risk type of CeAD. 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.

Objective: The objective of this study was to compare the long-term safety profiles of ocrelizumab and rituximab in persons with multiple sclerosis (MS).

Methods: Using retrospective data from the University of California (UC) Health System, we simulated a target clinical trial. The primary cohort from UC San Francisco (UCSF) and a validation cohort from 5 other UC Medical Centers were analyzed. After applying exclusion criteria and propensity score matching based on disease characteristics, demographics, and socioeconomic factors, we compared UCSF patients receiving ocrelizumab (n = 542) and rituximab (n = 271)and validated in the UC-wide MS population (n = 486 and n = 162 patients, respectively). The primary outcome was an all-cause hospitalization rate; secondary outcomes included hypogammaglobulinemia development and infection incidence.

Results: Rituximab showed higher all-cause hospitalization rates compared to ocrelizumab in both UCSF (incidence rate ratio [IRR] = 2.29, 95% confidence interval [CI] = 1.37-3.82, p = 0.001) and UC-wide cohorts (IRR = 4.54, 95% CI = 4.30-7.61, p < 0.001). Cumulative hazard ratios (HRs) were similarly elevated with rituximab at UCSF (HR = 2.27, 95% CI = 1.37-3.75, p = 0.001) and UC-wide (HR = 4.01, 95% CI = 2.25-6.32, p < 0.001). The risk of developing hypogammaglobulinemia was higher with rituximab at both UCSF (HR = 2.72, 95% CI = 1.18-6.29, p = 0.003) and UC-wide (HR = 4.79, 95% CI = 2.04-11.25, p < 0.001).

Interpretation: A more favorable safety profile was observed for ocrelizumab, with lower rates of hospitalization and hypogammaglobulinemia across 2 independent cohorts. These findings may help guide treatment strategies in persons with MS. ANN NEUROL 2026;99:248-260.

Objective: Myotonic dystrophy type 1 (DM1) is a highly variable, multisystemic genetic disorder caused by a CTG repeat expansion in the 3' untranslated region of DMPK. Toxicity is exerted by repeat-containing DMPK transcripts that sequester muscleblind-like (MBNL) proteins and lead to deleterious yet predictable changes in alternative splicing. To contend with high phenotypic and molecular variability that complicate application of viral-based therapies, we develop and test a DM1-responsive genetic element to control viral-based therapeutic output.

Methods: We used MBNL-dependent cassette exons to generate adeno-associated virus (AAV)-compatible control elements (DMX^on). Minigenes were tested in vitro using a Dox-inducible MBNL1 cell model and induced pluripotent stem cell (iPSC)-derived DM1 myotubes and in vivo using DM1 model mice following intramuscular and systemic AAV injection. DMX^on splicing, correction of endogenous splicing or skeletal muscle myotonia, and prevention of cardiac toxicity associated with therapeutic MBNL1 overexpression were assessed.

Results: DMX^on cassettes respond to MBNL1 dose or expression of CUG repeat RNA. DMX^on controlled expression of therapeutic MBNL1 protein can improve skeletal muscle myotonia or prevent cardiac toxicity due to MBNL1 overexpression in mice.

Interpretation: DMX^on control elements can increase the therapeutic window of viral-based therapeutics in DM1, and activity is dependent upon delivered cargo and model severity. ANN NEUROL 2026;99:211-222.

Objective: To identify clinical and radiological features of cerebral amyloid angiopathy-related inflammation (CAA-ri), and compare these features with those of sporadic CAA, to improve the understanding, diagnosis, and clinical care of CAA-ri.

Methods: We retrospectively reviewed routine clinical data from 37 patients with CAA-ri and 158 patients with sporadic CAA, including conventional vascular risk factors and comorbidities. We assessed brain magnetic resonance imaging for: radiological markers of CAA; features of amyloid-related imaging abnormalities with edema/effusion (ARIA-E) including parenchymal white matter hyperintensities, sulcal hyperintensities, and gyral swelling; and evidence of neurodegeneration (medial temporal atrophy and global cortical atrophy).

Results: Compared with patients with sporadic CAA, patients with CAA-ri had more numerous lobar cerebral microbleeds (median 207[IQR 33-811] vs 19[IQR 7-58], p < 0.001), and higher rates of medial temporal and global cortical atrophy. In comparison with sporadic CAA, all ARIA-E features were much more common in patients with CAA-ri (parenchymal hyperintensities 89% vs 3%, sulcal hyperintensities 78% vs 9%, and gyral swelling 86% vs 0.6%), as were conventional vascular risk factors (hypertension, dyslipidemia) and long-term comorbidities (inflammatory and infectious disorders, autoimmune or connective tissue disorders, or malignancies).

Interpretation: Features of ARIA-E (parenchymal white matter hyperintensities, sulcal hyperintensities, and gyral swelling) are more common in CAA-ri in comparison with "non-inflammatory" sporadic CAA, suggesting shared mechanisms with Alzheimer's disease immunotherapy and a potential role in improving diagnostic accuracy for CAA-ri. The high prevalence of atrophy and lobar cerebral microbleeds suggests a potential mechanistic role for capillary CAA, Alzheimer's disease, or both, in CAA-ri. Cardiovascular risk factors and other long-term comorbidities may also be relevant to the underlying mechanisms of CAA-ri. ANN NEUROL 2026;99:148-158.

Objective: Our goal was to investigate the impact of polygenic susceptibility to hypertension on systolic blood pressure (BP), uncontrolled hypertension, and stroke among hypertensive patients with BP treatment prescription.

Methods: This genetic association study used data from the All of Us Research Program (2017-2023) and replicated findings using the United Kingdom Biobank (2006-2010). Participants prescribed BP medication ≥4 years, with diagnosed hypertension or ≥2 systolic BP measurements >130mmHg, and without a previous stroke were categorized as having low, intermediate, or high polygenic susceptibility to hypertension using percentiles (<20, 20-80, >80) of a polygenic risk score for systolic BP. Primary outcomes were systolic BP, and uncontrolled hypertension (systolic BP > 140mmHg). The secondary outcome was incident stroke during 4-years follow-up. Multivariable linear, logistic, and Cox proportional hazards regressions assessed the influence of polygenic susceptibility to hypertension on each outcome.

Results: A total of 51,006 participants (mean age = 56, 55% female) were included. Intermediate and high genetic risk were associated with higher systolic BP (intermediate: beta = 2.55, standard error [SE] = 0.16, high: beta = 4.81, SE= 0.20, all p < 0.001), and with 36% (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.28-1.44) and 80% (OR = 1.80, 95% CI = 1.69-1.93) higher odds of uncontrolled hypertension, respectively. Furthermore, high genetic risk was associated with 23% (hazard ratio [HR] = 1.23, 95% CI = 1.03-1.46) increased stroke hazard. These results were replicated in 84,259 participants (mean age = 61, female sex = 46%).

Interpretation: Among hypertensive adults who were prescribed BP medication, polygenic susceptibility to hypertension correlates with higher systolic BP and higher rates of uncontrolled hypertension and stroke. Our findings support further research on personalized interventions targeting high-risk individuals. ANN NEUROL 2026;99:124-133.