Annals of Neurology最新文献

Objective: Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant genetic disease characterized by the misfolding and deposition of the transthyretin (TTR) protein. This study aimed to describe the clinical and genetic characteristics of ATTRv in a large multicenter Chinese cohort.

Methods: Patients from 14 centers were included in the study. The clinical and genetic characteristics of all patients were summarized. The peripheral blood white blood cell mitochondrial DNA (mtDNA) was detected in offspring from different genders.

Results: A total of 202 individuals with ATTRv from 148 families were identified. The average age of onset was 50.6 ± 12.4 years. Among these cases, 117 (57.9%) were classified as late-onset (≥50 years) and 85 (42.1%) as early-onset. Overall, the length dependent axonal sensorimotor peripheral neuropathy was the predominant phenotype (89.1%). A total of 42 heterozygous missense variants and 1 deletion variant were identified. The most common variants were Val30Met (19.8%) and Ala97Ser (15.8%) and patients with Val30Met and Ala97Ser were mostly late-onset in our cohort. Thirty-nine of these patients died with a mean age of 56.1 ± 13.5 years. Anticipation according to gender groups of offspring-parent pairs was different, and mother-son pairs showed the largest anticipation. The copies of mtDNA in the mother's offspring outnumbered those of the father's offspring (p < 0.001).

Interpretation: This study highlights that ATTRv patients in China exhibit high heterogeneity in their initial symptoms. The most common variants observed in this cohort is Val30Met. The mtDNA copy number shows gender-linked effects. These results can impact ATTRv diagnosis and patient care strategies. ANN NEUROL 2025.

Objective: We investigated whether the use of antihypertensive medication (AHM) is associated with in vivo Alzheimer's Disease (AD) pathologies in older adults with hypertension and examined if the effect differs by drug-class and blood-brain barrier (BBB) permeability of the drug.

Methods: This cross-sectional study recruited participants from the Korean Brain Aging Study for the Early Diagnosis and Prevention of Alzheimer's Disease. Participants comprised both cognitively normal and impaired older adults diagnosed with hypertension (n = 408). All participants underwent comprehensive clinical assessment and [¹¹C] Pittsburgh Compound B positron emission tomography (PET) for measurement of cerebral β-amyloid (Aβ) deposition. Additionally, a subset of participants (n = 120) was subjected to [¹⁸F] AV-1451 PET to assess tau deposition.

Results: The AHM group (n = 227) exhibited significantly lower Aβ deposition (B [SE] = -0.104 [0.037], p = 0.006) compared to the non-AHM group (n = 181), even after controlling for age, sex, apolipoprotein E ε4-positivity, vascular risk factors, and mean arterial blood pressure. Further analysis by AHM class showed an association between the use of renin-angiotensin system inhibitors (RASi) and less Aβ deposition (B [SE] = -0.143[0.049], p = 0.004). No significant relationships were observed between the use of BBB-permeable AHM and Aβ deposition. Additionally, associations between AHM use and tau deposition did not reach statistical significance.

Interpretation: Our findings suggest that AHM use may be associated with lower Aβ burden in older adults with hypertension. Further studies exploring the underlying mechanism, particularly related to RASi, may provide insights into new therapeutic targets for AD. ANN NEUROL 2025.

Objectives: We analyzed the genotypic and phenotypic features of patients with psychosis of epilepsy (POE).

Methods: Patients with POE recruited to an epilepsy genetics research program underwent phenotyping and genetic analysis. The latter included screening for rare pathogenic variants in epilepsy genes, and polygenic risk score (PRS) calculation for common risk variants associated with schizophrenia.

Results: One hundred twenty-two individuals with POE were identified. Eighty-six of 122 of the individuals (70%) had interictal psychosis, with schizophrenia the most common interictal phenotype (36/86, 42%). Twenty-eight of 122 of the individuals (23%) had postictal psychosis (PIP), 2 of 122 of the individuals (2%) had antiseizure medication-induced psychosis, and 6 of 122 of the individuals (5%) had substance-induced psychosis. Focal epilepsies were more frequently associated with PIP (24/28, 86%) compared to interictal psychosis (39/86, 45%; p < 0.05). Twenty-nine percent of the patients with POE with genetic data had a rare pathogenic variant: 19 in an epilepsy gene (PCDH19, SCN1A, DEPDC5, KCNT1, CHD2, SLC2A1, NPRL3, CLN3, NPRL3, ATP1A3, and CACNA1A) and 4 had a chromosomal anomaly. Fifty-seven percent of the patients with a rare pathogenic variant had interictal schizophrenia/schizophreniform disorder rather than PIP (9%; p < 0.05). PRSs showed that schizophrenia-related common risk variants were enriched in patients with POE compared to population controls (p = 0.0007), however, among the POE phenotypes, a raised PRS was only observed in interictal schizophrenia (p = 0.015) and not in those with PIP or other interictal POEs.

Interpretation: Interictal POE is threefold more common than PIP, and more likely to be associated with both rare pathogenic variants for epilepsy and common risk variants for schizophrenia. Distinguishing between different POE phenotypes enhances clinical practice and our understanding of etiology, paving the way for precision medicine. ANN NEUROL 2025.

Objectives: Rapid advances in transcriptomics have driven efforts to identify deregulated pathways in multiple sclerosis (MS) tissues, though many detected differentially expressed genes are likely false positives, with only a small fraction reflecting actual pathological events. Robust, integrative methods are essential for accurately understanding the molecular mechanisms underlying MS pathology.

Methods: We conducted a gene prioritization analysis of MS white matter pathology transcriptomic studies. Articles were sought in Scopus and PubMed up to July 31, 2024. Potentially eligible publications were those that provided either transcriptomics datasets (deposited in GEO) or lists of differentially expressed genes comparing MS white matter to control white matter.

Results: Applying a vote-count strategy to search for the intersection of genes reported in multiple independent studies with a consistent fold-change direction, followed by a Monte Carlo simulation, we identified 528 highly significant differentially expressed multi-study genes (p < 0.0001; 10,000 simulations). Functional enrichment analysis revealed deregulation of the folate pathway in MS normal-appearing white matter, and tumor necrosis factor (TNF) -related and complement-related pathways in active and chronic active lesions, respectively. Network analysis identified 6 key signaling hubs: PTPRC, HLA-B, MYC, MMP2, COL11A2, MAG. The major nodes identified revealed mechanistic concordance with published in vivo MS models, supporting their value as potential therapeutic targets.

Interpretation: Our strategy provides a robust framework for integrating gene expression data, effectively identifying the intricate pathways altered in human diseased tissues. This method holds potential for translating findings into drug development strategies. ANN NEUROL 2025.

Objective: The objective was to investigate the efficacy and safety of clopidogrel-aspirin versus aspirin alone in patients after ischemic stroke by glycemic status using data from the Intensive Statin and Antiplatelet Therapy for Acute High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial.

Methods: Patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) were randomized to clopidogrel-aspirin or aspirin alone. They were categorized into 3 subgroups according to glycemic status based on medical history and diagnosis by a clinician during hospitalization: without type 2 diabetes mellitus, with newly diagnosed type 2 diabetes, and with a history of type 2 diabetes mellitus. The primary efficacy and safety outcomes were new stroke and moderate-to-severe bleeding risk within 90-day follow-up.

Results: A total of 6,100 patients were enrolled (3,050 in each arm), with a median age of 65 years (interquartile range [IQR], 57-71) and 2,185 female (35.8%). Clopidogrel-aspirin treatment was associated with a reduction in recurrent stroke compared with aspirin alone in patients without type 2 diabetes mellitus (6.3% vs 8.4%; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.59-0.94; p = 0.01) and those with newly diagnosed type 2 diabetes mellitus (5.8% vs 13.0%; HR, 0.30; 95% CI, 0.14-0.66; p = 0.002), but not in those with a history of type 2 diabetes mellitus (10.0% vs 9.9%; HR, 0.98; 95% CI, 0.72-1.33; p = 0.88) (p for interaction = 0.03). Moderate-to-severe bleeding events did not differ significantly by treatment across glycemic subgroups.

Interpretation: In the INSPIRES trial, patients without or with type 2 diabetes mellitus derived greater benefit from clopidogrel-aspirin than those with a history of type 2 diabetes mellitus after mild ischemic stroke or high-risk TIA.

Trial registration: INSPIRES, NCT03635749. Registered 15 August 2018, https://clinicaltrials.gov/search?cond=NCT03635749. ANN NEUROL 2025.