Annals of Neurology最新文献

As the population ages, certain neurodegenerative diseases (NDs) are becoming a major health issue. For this reason, this review will focus on the most common ND with onset after 65 years old; Alzheimer's disease, Parkinson's disease, Lewy body dementia, and frontotemporal dementia. NDs are the results of multifactorial processes causing pleiotropic changes in molecular and protein networks linking a host of biological processes that lead to protein dysregulation and aggregation that ultimately leads to neurodegeneration. Genetic, transcriptomic, and proteomic studies have been instrumental to identify novel genes and proteins implicated on diseases that point to novel disease mechanism, as well as the identification of disease biomarkers. Here, we provide a review of the genomic, transcriptomic, and proteomic studies on ND so far, as well as future opportunities and challenges. ANN NEUROL 2026.

Objective: Genomic sequencing leaves >50% of dystonia-affected individuals without a diagnosis. Where DNA-oriented approaches remain insufficient, integrating multiomics is essential to advance genome interpretation. Herein, we incorporated RNA sequencing (RNA-seq) data from 167 patients with dystonia across a range of ages and presentations.

Methods: We leveraged an RNA-seq analysis pipeline, focused on the identification of expression and splicing aberrations, on RNA-seq from skin biopsies. The recruited patients had early-onset dystonia in 85.0%, non-focal dystonia in 92.2%, and coexisting features in 76.0%. Thirty-six patient samples with pre-identified variants (36/167, 21.6%) and 131 samples with no previously prioritized diagnostic candidates from genomic sequencing (131/167, 78.4%) were evaluated.

Results: We found that >80% of dystonia-associated genes were detected by fibroblast RNA-seq. Expression and splicing aberration analyses produced a manageable number of significant RNA defects affecting dystonia-associated genes. The approach was especially successful in validating pathogenic effects of loss-of-function variants, with disease-relevant RNA-underexpression detected for 66.7% (10/15). Studying aberrant expression and splicing in the context of other pre-identified variant types yielded relevant results in 28.6% (6/21 samples). We obtained a 6.9% (9/131) diagnostic uplift for patients without prior candidates, all of whom exhibited combined dystonia with autosomal recessive inheritance. The new diagnoses from RNA-seq and genomic reanalysis were based on previously neglected splice-region (3/9) and deep(er) intronic (6/9) variants. For the observed events, integration of new machine-learning scores predicted corresponding aberrant gene expression in the brain.

Interpretation: Fibroblast-based RNA-seq in our selected cohort improved variant interpretation and offered a modest yield in patients without prior candidate variants. ANN NEUROL 2026.

Objective: The optimal treatment for distal medium vessel occlusion (DMVO) stroke remains uncertain, and evidence comparing endovascular therapy (EVT) with medical management (MM) is limited. We aimed to develop and validate a predictive modeling tool to assess individual treatment benefit in DMVO stroke using explainable counterfactual treatment estimation.

Methods: Adults with isolated DMVO stroke (M3-M4, A2-A3, or P1-P2) were retrospectively identified from 7 stroke centers. To estimate individualized probabilities of favorable outcome (modified Rankin Scale [mRS] = 0-2 at 90 days), we developed a Penalized Logistic Regression (Elastic Net) model. This framework was selected a priori over other explored machine learning algorithms (Decision Tree, Support Vector Classifier, and XGBoost) for its superior interpretability and ability to handle multicollinearity among interaction terms. Inverse Probability of Treatment Weighting (IPTW) was implemented to address confounding by indication in the observational data. Internal validation used repeated K-fold cross-validation and bootstrapping; external validation was performed on an independent cohort (n = 86).

Results: Of 321 eligible patients, 179 received EVT (55.8%) and 142 received MM (44.2%). Adjusted models showed no significant overall group differences in favorable outcome (adjusted OR [aOR] = 1.32, 95% confidence interval [CI] = 0.97-1.80), mortality (aOR = 1.20, 95% CI = 0.78-1.85), or symptomatic hemorrhage (aOR = 0.57, 95% CI = 0.21-1.58). However, the model identified significant treatment effect heterogeneity; EVT benefit was amplified in patients with higher National Institutes of Health Stroke Scale (NIHSS) and attenuated with increasing treatment delay. Internal validation demonstrated strong performance (area under the receiver operating characteristic curve [AUC] = 0.77, 95% CI = 0.71-0.82). External validation confirmed generalizability (AUC = 0.74, 95% CI = 0.63-0.84). Individualized treatment estimates showed high concordance with a benchmark causal T-Learner model (Pearson r = 0.97 internal and r = 0.98 external).

Interpretation: Although aggregate outcomes did not differ significantly, the validated Distal and Medium Vessel Occlusion Stroke (DUSK) Tool enables individualized estimation of EVT benefit in DMVO stroke. This explainable counterfactual treatment estimation framework supports precision decision making by identifying specific patient subgroups most likely to benefit from EVT over MM. ANN NEUROL 2026.

Objective: Sudden unexpected death in epilepsy (SUDEP) is a devastating consequence of some generalized convulsive seizures (GCS). Recent work has focused on seizure related apnea as a biomarker of SUDEP risk, frequently without characterizing the adequacy of non-apneic ventilation or identifying other dysfunctional breathing patterns. We hypothesized that GCS frequently induce immediate, severe, non-apneic respiratory dysfunction that can induce critical hypoxia and bradycardia and sought to characterize breathing patterns after GCS.

Methods: Adult patients admitted to an epilepsy monitoring unit were studied. The effects of GCS on breathing and heart rate were analyzed using nasal pressure transducers, chest and abdominal respiratory inductance plethysmography, capillary oxygen saturation, transcutaneous CO₂, electrocardiogram, electroencephalogram, and expert audiovisual analysis. Correlation analyses, the Mann-Whitney test, and an unpaired t test were used to analyze relationships between dysfunctional breathing patterns and both the severity of postictal hypoxemia and the heart rate.

Results: Thirty-two GCS from 22 patients were analyzed and 31 exhibited 1 or more of the following breathing patterns: disordered rhythmicity (n = 28/32, 87.5%), shallow breathing (n = 12/32, 37.5%), thoracoabdominal asynchrony (n = 24/30, 80.0%), and upper airway obstruction (n = 30/32, 93.8%). Oxygen desaturation was more severe when postictal breathing was shallow or irregular in amplitude. The latter was associated with absolute or relative bradycardia.

Interpretation: Nonfatal GCS frequently induce immediate, severe, non-apneic respiratory dysfunction temporally associated with severe hypoxia and bradycardia. Our study suggests that postictal respiratory and cardiac function are tightly coupled and highlights the importance of including all the relevant pathologic variables in studies of SUDEP pathogenesis. ANN NEUROL 2026.

Objective: Quaking-induced conversion (QuIC) tests, which detect prion-seeding activity in cerebrospinal fluid (CSF), have markedly advanced the antemortem diagnosis of prion diseases such as Creutzfeldt-Jakob disease (CJD). These tests provide high diagnostic accuracy and enable timely differentiation from other rapidly progressive neurodegenerative disorders. However, a key limitation of current QuIC tests are the reduced sensitivity in detecting inherited prion diseases and rare sporadic subtypes, including variably protease-sensitive prionopathy (VPSPr). To address this gap, we evaluated a simplified QuIC test, end-point QuIC (EP-QuIC), incorporating a novel recombinant prion protein substrate derived from the North American deer mouse (Peromyscus maniculatus).

Methods: The diagnostic performance of the modified QuIC test was evaluated using CSF samples from 61 sporadic CJD, 50 inherited prion disease, and 5 VPSPr cases.

Results: EP-QuIC with the deer mouse substrate achieved 96.6% sensitivity (111/116) and 100% specificity (35/35), outperforming both standard EP-QuIC (87.1%) and next-generation (IQ-CSF) real-time-QuIC (72.4%) across the same cohort. Notably, this enhanced assay detected inherited mutations, such as D178N, that were previously undetectable with existing diagnostic tests.

Interpretation: These findings demonstrate that adapting EP-QuIC with an optimized substrate, termed enhanced sensitivity QuIC (ES-QuIC), significantly improves diagnostic performance for inherited and atypical prion diseases. By expanding the diagnostic reach of QuIC tests, this study strengthens antemortem surveillance, reduces reliance on postmortem confirmation, and improves opportunities for early intervention and clinical trial enrollment, particularly for genetic cases most likely to benefit from emerging therapeutic strategies. ANN NEUROL 2026.

Among patients with acute ischemic stroke achieving successful large vessel recanalization (defined as expanded Thrombolysis in Cerebral Infarction [eTICI ≥2b]), incomplete tissue-level reperfusion, distinct from visually identifiable distal occlusion on digital-subtraction angiography, remains a significant challenge. Persistent tissue-level hypoperfusion, identified on post-thrombectomy perfusion imaging, involves complex pathophysiology comprising 2 primary mechanisms: territorial hypoperfusion, stemming from distal emboli that often manifest after eTICI 2b to 2c or a posteriori with eTICI 3 recanalization, obstructing small distal arterial branches and forming wedge-shaped patterns; and hypoperfusion within the ischemic core, potentially representing capillary no-reflow, a phenomenon of microvascular perfusion failure despite successful macrovascular recanalization well described in the preclinical literature. Such pathophysiological differences have driven inconsistent designations, causing reported incomplete tissue-level reperfusion rate to vary widely (0-42.5%) even in angiographically complete (eTICI 3) recanalization. Further clouding the scene, territorial hypoperfusion may spontaneously reverse within 24 hours (termed "delayed reperfusion"), yet a distinct delayed hypoperfusion can affect necrotic tissue regardless of no-reflow. Whereas persistent hypoperfusion is significantly associated with functional outcomes, the functional impact of true no-reflow remains unclear. Recent positive randomized controlled trials (RCTs) of intra-arterial thrombolysis after successful recanalization offer a promising therapeutic strategy. However, these trials lacked perfusion imaging, whereas the larger functional benefit in patients achieving eTICI 2b suggests intra-arterial thrombolysis likely acted on distal emboli rather than true microvascular dysfunction. Regarding microvascular dysfunction, preclinical findings highlight potential therapeutic strategies such as targeting pericyte constriction or inflammatory responses, that warrant clinical translation. This review synthesizes current evidence on the mechanisms, assessment methods, and therapeutic strategies for addressing incomplete tissue-level reperfusion following thrombectomy. Further research is warranted to establish standardized definitions, develop targeted therapies for both territorial hypoperfusion and true no-reflow, and translate promising preclinical findings into effective clinical interventions. ANN NEUROL 2026.

Objective: Sporadic late-onset Alzheimer's disease (AD) is characterized by a long pre-clinical phase where amyloid-beta (Aβ) and tau begin to accumulate in the brain. The primary objective was to determine the age at which AD starts by finding the average population age when both positron emission tomography (PET) Aβ (Aβ-PET) and plasma Aβ42/40 become abnormal.

Methods: Two high performance immunoprecipitation-mass spectrometry (IP-MS) assays (WashU/C2N and Shimadzu) were tested on samples from 1,450 participants who were diagnosed as cognitively unimpaired (CU), mild cognitive impairment (MCI), or AD-dementia across 4 international cohorts. Natural history modeling and trajectory analyses of the combined Aβ-PET and plasma Aβ42/40 data were analyzed.

Results: Data from both assays demonstrated Aβ42/40 undergoes a rapid change at approximately 15 Centiloid (CL), at an average population disease age at 66 years. On average, plasma Aβ42/40 becomes abnormal approximately 2 years before Aβ-PET, whereby it falls sharply to a stable level at the onset of preclinical AD. Average disease age where Aβ42/40 becomes abnormal, and the corresponding Centiloid level are lower for APOE allele carriers compared with non-carriers.

Interpretation: Plasma Aβ42/40 ratio presents a step-like function of peripheral change shortly before the detection of plaques by Aβ-PET. Results are consistent with plasma Aβ42/40 falling to a steady-state level in participants with Aβ-PET levels greater than approximately 14CL for both assays. The age at which this occurs is dependent on APOE ε4 carriership, consistent with the approximate 7-year age difference in Centiloid abnormality between carriers and non-carriers. ANN NEUROL 2026.

Objective: Spin refers to reporting strategies that highlight the benefits of an experimental treatment or divert attention from nonsignificant primary outcomes. To assess spin in randomized clinic trials (RCTs) on pharmaceutical efficacy in multiple sclerosis (MS) and explore associated factors.

Methods: A systematic literature search was conducted in MedLine (PubMed), EMBASE, and Cochrane using database-specific thesauri ("Multiple Sclerosis" and "Drug Therapy") to identify relevant studies. We included multiple sclerosis phase 3 and 4 randomized controlled trials with parallel, superiority designs that were published between 2013 and 2024 reporting nonsignificant primary outcomes. Spin was assessed in title, abstract conclusion, results, discussion, and conclusions. A descriptive analysis was followed by exploratory bivariate logistic regression. Independent variables included trial phase, sample size, drug type, comparison, follow-up time, registration, Consolidated Standards of Reporting Trials (CONSORT) mention, risk of bias (RoB2), journal quartile, first author affiliation, and conflict of interest.

Results: Forty articles met inclusion criteria. Spin appeared in at least one section in 25 articles (62.5%) and in 3 or more in 19 articles (47.5%). The most frequent locations were abstract conclusions, discussion, and conclusions. Spin was significantly associated with smaller sample size (odds ratio [OR] = 7.00, 95% confidence interval [CI] = 1.29-37.91, p = 0.024), non-Q1 journals (OR = 4.38, 95% CI = 1.03-18.63, p = 0.046), and first author affiliation outside Europe or the United States (OR = 5.09, 95% CI = 1.15-22.62, p = 0.032).

Interpretation: Spin is common in MS randomized controlled trials with nonsignificant primary outcomes and may mislead clinical decisions. ANN NEUROL 2026.