Annals of Neurology最新文献

Objective: An abundance of select transcripts and proteins has been found to be dysregulated in blood samples of Machado-Joseph disease (MJD) carriers. Here, we aimed to: (1) identify blood transcriptional changes as potential biomarkers of MJD; (2) correlate levels of differentially expressed blood transcripts with MJD carriers features; and (3) evaluate whether the identified differential abundance of blood transcripts in MJD patients is preserved in MJD brains.

Methods: We used unbiased RNA microarray and quantitative polymerase chain reaction to assess transcript levels in blood and brain samples, and western blot analysis to evaluate the abundance of specific proteins in brain samples.

Results: We observed consistent dysregulation of DDIT4, TRIM13, and P2RY13 transcriptional levels in the blood of MJD patients from preclinical to symptomatic stages in Azorean and Brazilian cohorts. Combined blood DDIT4 and TRIM13 transcriptional levels show a very high accuracy to discriminate MJD carriers from matched controls (AUC ≥0.90). Levels of P2RY13 transcripts correlate with age at onset, and an abundance of DDIT4 and TRIM13 transcripts correlate with the expanded CAG repeat size in combined Azorean and Brazilian patients; and levels of TRIM13 transcripts correlate with age at onset of early-stage Azorean patients. Moreover, the abundance of TRIM13 protein is increased in the cerebral cortex of MJD patients.

Interpretation: Overall, blood DDIT4 and TRIM13 transcript levels are potential biomarkers of MJD. Cellular processes involving DDIT4, TRIM13, and P2RY13 appear to be commonly dysregulated in the blood and brain of MJD patients, indicating the involvement of these genes in MJD pathogenesis. ANN NEUROL 2025.

Dystonia research focuses on the identification of converging biological pathways, allowing to define molecular drivers that serve as treatment targets. We summarize evidence supporting the concept that aberrations in purine metabolism intersect with dystonia pathogenesis. The recent discovery of IMPDH2-related dystonia introduced a gain-of-function paradigm in purinergic system defects, offering new perspectives to understand purine-pool imbalances in brain diseases. We discuss commonalities between known dystonia-linked mechanisms and mechanisms emerging from studies of purine metabolism disorders including Lesch-Nyhan disease. Together, we hypothesize that a greater appreciation of the relevance of purine perturbances in dystonia can offer fresh avenues for therapeutic intervention. ANN NEUROL 2025.

GBA1 variants and decreased glucocerebrosidase activity are implicated in Parkinson's disease (PD). We investigated the hypothesis that increased levels of glucosylceramide (GlcCer), a main substrate of glucocerebrosidase, are involved in PD pathogenesis. Using multiple genetic methods, we show that ATPase phospholipid transporting 10D (ATP10D), not GBA1, is the main regulator of plasma GlcCer levels, yet it is not involved in PD pathogenesis. Plasma GlcCer levels were associated with PD, but not in a causative manner, and are not predictive of disease status. These results argue against targeting GlcCer in GBA1-PD, and underscore the need to explore alternative mechanisms and biomarkers for PD. ANN NEUROL 2025.

The physiological basis of cognitive decline remains largely uncharacterized. We identified a protein panel signature, in living humans, that correlates to improvement in neurocognition over a period of 5 years. Our signature is composed of complement proteins, coagulation cascade, and extracellular matrix regulators. In our cohort, SERPINF1 is associated with greater maximal oxygen uptake after an aerobic exercise intervention. Sleep quality is also a key factor in relation to inter-alpha-trypsin inhibitor heavy chain H2, which was associated with greater sleep efficiency. Additionally, we validate that the coagulation profile of decliners' plasma contains procoagulant agonists, leading to greater platelet activation. ANN NEUROL 2025.

Objective: West Nile virus (WNV) is the most common cause of arboviral disease in the United States. Approximately 1% of infections involve the nervous system, most commonly resulting in West Nile encephalitis (WNE), West Nile meningitis (WNM), or acute flaccid paralysis (AFP).

Methods: In this systematic review, we characterized comprehensively the diagnostic and clinical features of WNV neuroinvasive disease (WNND) in the United States, as well as the evidence regarding prognostic factors and long-term outcomes of WNND.

Results: We identified 47 relevant studies reporting data on acute or longitudinal features of WNND. Across studies, the most common presenting symptoms were fever (88%), nausea/vomiting (58%), and fatigue (50%) coupled neurologically with headache (50%), altered mental status (39%), and focal weakness (32%). Pooled mortality was 9.2%, and 42.1% of reported cases required intensive care unit (ICU) admission. In meta-analyses, chronic kidney disease (odds ratio [OR] = 5.99, 95% confidence interval [CI] = 2.71-13.23), diabetes mellitus (OR = 2.43, 95% CI = 1.54-3.84), and hypertension (OR = 4.01, 95% CI = 2.39-6.72) were associated with an increased risk of mortality. Multidomain neurocognitive impairment was reported in several studies at post-hospitalization follow-up, although with marked heterogeneity between study methodology. Subjective neurocognitive impairment, most notably fatigue (37-75%), memory concerns (11-57%), concentration deficits (17-48%), and depression (17-38%), were also common at post-hospitalization follow-up.

Interpretation: These findings underscore the significant mortality and morbidity of WNND in the acute and long-term setting. Our findings may additionally provide utility for risk stratification of hospitalized patients with WNND and suggest the need for further evaluation of novel therapeutics to prevent substantial disease-associated acute and long-term disability. ANN NEUROL 2025.

Objective: Ofatumumab presents a potentially promising alternative to current second-line immunotherapy for refractory anti-N-methyl-D-aspartate receptor autoimmune encephalitis (NMDAR-AE). We aimed to evaluate the efficacy and safety of ofatumumab as a novel second-line immunotherapy for NMDAR-AE.

Methods: This prospective, multicenter, nested cohort study compared patients with NMDAR-AE from the CHina Autoimmune encephalitiS outcomE study registry (CHASE) recruited between October 2011 and February 2024, treated with and without ofatumumab. The primary outcome was the proportion reaching a favorable functional outcome (modified Rankin Scale [mRS] score ≤2) at the last follow-up. Secondary outcomes included mRS scores and Clinical Assessment Scale in Autoimmune Encephalitis (CASE) scores over the first 24-month follow-up and the proportion with further mRS score improvement after ofatumumab initiation. A propensity score matching was performed to balance major confounders.

Results: A total of 715 patients with AE were screened. Fifty-eight propensity score-matched patients with NMDAR-AE each in the ofatumumab group and non-ofatumumab group were analyzed. Fifty-four patients (93.1%) in the ofatumumab group achieved further mRS score improvement with a median time of 14 days from ofatumumab initiation, and 53 (91.4%) reached a favorable functional outcome at the last follow-up. For those who failed first-line immunotherapy, the ofatumumab group demonstrated a faster mRS score and CASE score improvement and more frequently reached a favorable functional outcome at the last follow-up compared with the non-ofatumumab group (87.9% vs. 64.7%, odds ratio [OR] 3.95; 95% confidence interval [CI] 1.12-13.94; p = 0.026). No serious adverse events associated with ofatumumab treatment were reported.

Interpretation: Ofatumumab showed substantial efficacy and safety, particularly in patients who failed first-line immunotherapy, warranting its consideration in NMDAR-AE management. ANN NEUROL 2025.

Objective: Accurate personalized survival prediction in amyotrophic lateral sclerosis is essential for effective patient care planning. This study investigates whether grey and white matter changes measured by magnetic resonance imaging can improve individual survival predictions.

Methods: We analyzed data from 178 patients with amyotrophic lateral sclerosis and 166 healthy controls in the Canadian Amyotrophic Lateral Sclerosis Neuroimaging Consortium study. A voxel-wise linear mixed-effects model assessed disease-related and survival-related atrophy detected through deformation-based morphometry, controlling for age, sex, and scanner variations. Additional linear mixed-effects models explored associations between regional imaging and clinical measurements, and their associations with time to the composite outcome of death, tracheostomy, or permanent assisted ventilation. We evaluated whether incorporating imaging features alongside clinical data could improve the performance of an individual survival distribution model.

Results: Deformation-based morphometry uncovered distinct voxel-wise atrophy patterns linked to disease progression and survival, with many of these regional atrophies significantly associated with clinical manifestations of the disease. By integrating regional imaging features with clinical data, we observed a substantial enhancement in the performance of survival models across key metrics. Our analysis identified specific brain regions, such as the corpus callosum, rostral middle frontal gyrus, and thalamus, where atrophy predicted an increased risk of mortality.

Interpretation: This study suggests that brain atrophy patterns measured by deformation-based morphometry provide valuable insights beyond clinical assessments for prognosis. It offers a more comprehensive approach to prognosis and highlights brain regions involved in disease progression and survival, potentially leading to a better understanding of amyotrophic lateral sclerosis. ANN NEUROL 2025.

Objective: Gain-of-function (GoF) variants in KCNT1 encoding for potassium channels are associated with different epilepsy phenotypes, including epilepsy of infancy with migrating focal seizures (EIMFS), other early infantile developmental and epileptic encephalopathies, and focal epilepsy. Fluoxetine blocks currents from both wild-type (WT) and mutant KCNT1 channels with GoF in vitro features. In this study, we tested the hypothesis that treatment with fluoxetine might improve clinical outcome in patients with EIMFS carrying GoF variants in KCNT1 channels showing in vitro sensitivity to fluoxetine blockade.

Methods: We enrolled three pediatric patients carring de novo KCNT1 genetic variants linked to EIMFS. Functional and pharmacological studies to assess fluoxetine's ability to counteract in vitro variant-induced functional effects were performed with patch-clamp electrophysiology on heterologous channel expression in mammalian Chinese hamster ovary cells. Neuropsychological assessment, electroencephalogram and seizure diary were evaluated at baseline and every 3 months during the study. Electrocardiography and blood levels of medications were monitored for safety.

Results: All 3 KCNT1 variants displayed GoF effects in vitro. Exposure to fluoxetine (10μM) blocked both WT and mutant KCNT1 channels, therefore, counteracting variant-induced functional effects. Treatment with fluoxetine caused a variable reduction of seizure frequency (25-75%). Improvement in visual attention, participation, and muscle tone was also reported. No adverse events were reported except for transient dyskinesia in 1 patient, which was probably related to an increase in fluoxetine plasma level.

Interpretation: Fluoxetine may be a potential targeted medication in EIMFS caused by KCNT1 GoF variants. Further research is needed to assess its long-term efficacy and safety. ANN NEUROL 2025.

Objective: The objective of this study was to investigate the differences in cyclic alternating patterns (CAP) metrics, a non-rapid eye movement (NREM) sleep physiological rhythm, among recently diagnosed patients with Parkinson's disease (PD), and individuals at high and low risk for developing PD based on genetic and prodromal risk.

Methods: In this cross-sectional exploratory study, participants underwent clinical, cognitive, and motor evaluation to compute risk based on the Movement Disorder Society (MDS) prodromal criteria and a standard overnight polysomnography. CAP rate, CAP index, A index subtypes, number of CAP sequences, and CAP sequence duration were computed from the electroencephalogram (EEG) signal.

Results: The study included 30 patients with early PD (mean age = 62.80 ± 7.69, disease duration = 1.10 ± 1.09), 26 participants at risk for PD (age = 64.88 ± 10.09), and 36 participants with low risk for PD (age = 56.83 ± 7.41). Despite comparable macrosleep architecture, most CAP measures were significantly lower in patients with PD compared with the low-risk group, whereas the at-risk group showed transitional values between PD and the low-risk group. The A2 index was significantly lower in both the at-risk and PD groups from the low-risk group (at risk = 7.59 ± 4.59; PD = 7.71 ± 5.83; and low risk = 12.85 ± 8.63; p = 0.010). Lower CAP rate and lower CAP index were associated with greater disease severity (r = -0.23 and - 0.24, respectively).

Interpretation: Patients with early clinical PD exhibit alterations in CAP dynamics despite having comparable macrosleep architecture. Alterations of the NREM microsleep structure may occur early in the neurodegenerative process and the A2 index may be an early event in the evolution of the disease with the potential to serve as an early marker for disease progression. ANN NEUROL 2025.