Annals of Neurology最新文献

Objective: Lactate is increasingly recognized as an energy substrate, but its relevance to amyotrophic lateral sclerosis (ALS) remains unclear. We examined whether blood lactate is associated with survival and weight loss in ALS.

Methods: This retrospective study included an Australian exploratory cohort and a Japanese validation cohort with clinical data matched to measures of blood lactate. The primary outcome was survival from onset to death or tracheostomy. In the exploratory cohort, survival was analyzed using Kaplan-Meier curves stratified by the first quartile (Q1) of lactate and multivariable Cox regression. This cutoff was applied for log-rank analysis in the validation cohort. The secondary outcome was 3-month body mass index (BMI) change (ΔBMI). Associations between baseline lactate and ΔBMI were assessed using multivariable regression in the exploratory cohort, whereas Q1-based stratification was used in the validation cohort.

Results: The exploratory cohort included 110 patients with ALS (57 with ΔBMI data) and 86 healthy controls; the validation cohort included 36 patients (17 with ΔBMI data). In the exploratory cohort, lower lactate levels (below Q1; 1.05 mmol/L) were associated with shorter survival (p = 0.031) and remained independently predictive of higher risk for mortality (adjusted hazard ratio [HR] per 1 SD = 0.57, 95% confidence interval [CI] = 0.35-0.91). This association was confirmed in the validation cohort (p = 0.003). Lactate was independently associated with ΔBMI (β = 0.53, p = 0.032), and patients with lower lactate had a greater BMI decline (p = 0.010).

Interpretation: Lower blood lactate is associated with increased risk for earlier death and greater weight loss in ALS, suggesting that lactate is a prognostic biomarker of nutritional status. ANN NEUROL 2026.

Objective: The relative risks of bleeding with apixaban and aspirin remain unclear. We compared bleeding end points on apixaban versus aspirin in the ARCADIA trial.

Methods: ARCADIA was a multicenter, double-blind, randomized trial of apixaban versus aspirin in patients with cryptogenic stroke and evidence of atrial cardiopathy. International Society on Thrombosis and Hemostasis (ISTH) criteria were used to classify bleeding as intracranial, symptomatic intracranial, major non-intracranial hemorrhages, and any major and minor hemorrhages. We calculated annualized incidence rate differences (IRDs) between apixaban and aspirin. Our primary analysis included the safety sample which censored patients who permanently stopped taking the study drug. Sensitivity analyses included the intention-to-treat sample.

Results: Among 1,015 patients assigned to apixaban or aspirin and followed for a mean 1.8 (±1.2) years, 115 (11.3%) patients experienced 146 hemorrhages: 27 (18.5%) major and 119 (81.5%) minor hemorrhages. Apixaban resulted in significantly fewer intracranial hemorrhages than aspirin in both the safety sample (IRD = -1.4%, 95% confidence interval [CI] = -2.3% to -0.5%) and intention-to-treat sample (IRD = -1.0%, 95% CI = -1.8% to -0.2%). Findings were similar for the risk of symptomatic intracranial hemorrhage in the safety sample (IRD = -1.1%, 95% CI = -1.8% to -0.3%), although this was not statistically significant in the sensitivity analysis of the intention-to-treat sample (IRD = -0.7%, 95% CI = -1.4% to 0.0%, p = 0.11). Risks of major non-intracranial hemorrhage, any major hemorrhage, and minor hemorrhage did not differ significantly between apixaban and aspirin.

Interpretation: We found no increase in any hemorrhage type and a decrease in intracranial hemorrhage with apixaban relative to aspirin in patients with cryptogenic stroke and evidence of atrial cardiopathy. ANN NEUROL 2026.

Objectives: The objective of this study was to elucidate differences in the cumulative incidence of Leucine-rich repeat kinase 2 (LRRK2) p.Gly2019Ser-related Parkinson's disease (PD; LRRK2-PD) between ancestries and countries.

Methods: We included 922 unrelated p.Gly2019Ser variant carriers (affected = 762 and unaffected = 160) from the Global Parkinson's Genetics Program (GP2) in addition to cohorts recruited from the Israeli Ashkenazi Jewish and Tunisian Arab-Berber population. Cox proportional hazard models were applied to examine differences in cumulative incidence across ancestry groups and countries. All analyses were adjusted for biological sex and were exploratory.

Results: The median age at onset (AAO) of LRRK2-PD was 5 years younger in the North African (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.18-1.86, p = 7.0 × 10^-4) compared with the European ancestry group. In contrast, the median AAO was 5 years older in the Ashkenazi Jewish (HR = 0.61, 95% CI = 0.50-0.75, p = 4.0 × 10^-6) compared with the European ancestry group. Additionally, patients from Israel (HR = 1.59, 95% CI = 1.30-1.39, p = 4.0 × 10^-6) and Tunisia (HR = 2.57, 95% CI: 2.16-3.06, P < 2.0 × 10^-16) had a median 5-year and 10-year younger AAO compared with patients from the United States, respectively. Last, when focusing only on individuals with an Ashkenazi Jewish background, patients from Israel still had a younger AAO than those from the United States (HR = 1.82, 95% CI = 1.48-2.24, p = 1.5 × 10^-8). Analogously, assessing only patients from the United States, the Ashkenazi Jewish ancestry group still had an older AAO than the European ancestry group (HR = 0.51, 95% CI = 0.39-0.67, p = 1.3 × 10^-6).

Interpretation: Our results provide evidence that a person's genetic ancestry and country of origin are associated with the AAO of LRRK2-PD. This highlights the potential impact of both genetic and environmental factors on LRRK2-PD AAO. ANN NEUROL 2026.

Objective: Targeted therapies for facioscapulohumeral muscular dystrophy (FSHD) are progressing through clinical trials. Electrical impedance myography (EIM) provides a noninvasive biomarker of muscle composition that may be valuable especially in early phase trials. This study evaluated EIM data from a multicenter FSHD cohort over 24 months.

Methods: Adult patients with FSHD at 8 sites underwent EIM in 6 muscles bilaterally (deltoid, biceps, triceps, vastus lateralis, tibialis anterior, and medial gastrocnemius). EIM outcomes phase and reactance (50 and 100 kHz [kilohertz] frequencies) and 50 of 211 kHz phase ratio were evaluated for reliability, correlations with clinical measures, and sensitivity to change.

Results: One hundred fifty-seven patients (53% male patients) were included. Test-retest reliability was excellent for all EIM outcomes (intraclass correlation coefficient [ICC] ≥0.94). Phase outcomes strongly correlated with the FSHD-composite outcome measure (FSHD-COM; r ≤ -0.69) and Motor Function Measure Domain 1 (MFM1; r ≥ 0.75); reactance outcomes exhibited moderate correlations with the FSHD-COM (r ≥ -0.41) and MFM1 (r ≤ 0.44). Mean declines in phase and phase ratio were apparent at 12 months (eg, -0.25, 95% confidence interval [CI] = -0.45 to -0.05 at 50 kHz), and further progressed through 24 months (-0.66, 95% CI = -0.92 to -0.40] at 50 kHz and -0.65 [95% CI = -0.87 to -0.44] at 100 kHz; both p < 0.0001). Reactance changes were smaller and not significant: -0.21 (95% CI = -0.44 to 0.02) at 50 kHz and -0.13 (95% CI = -0.35 to 0.10) at 100 kHz.

Interpretation: EIM phase outcomes are reliable, valid, and sensitive to change over 12 to 24 months, supporting their potential utility as biomarkers in FSHD clinical trials. ANN NEUROL 2026.

Objective: Biallelic variants in PRKN cause autosomal recessive Parkinson's disease (PD) with a median age at onset of 31 years. When evaluating the 16 previously published carriers of a homozygous deletion of Exon 2 from the International Parkinson's Disease and Movement Disorder Society Gene Database (MDSGene) database, the median age at onset is later (39.5 years) than in carriers of other PRKN pathogenic variants. We investigated whether these carriers show delayed disease onset compared with carriers of other pathogenic PRKN variants and explored the underlying molecular mechanism.

Methods: We compared 26 homozygous PRKN Exon 2 deletion carriers with carriers of other pathogenic variants. Using human-induced pluripotent stem cell (hiPSC)-derived neuronal cell models from an unaffected 86-year-old carrier, genome-edited control lines, neuroblastoma cell lines, and in silico prediction, we investigated the underlying mechanism.

Results: Patients with PRKN Exon 2 deletions showed a later age at onset compared with carriers of other pathogenic variants. We discovered elevated levels of an N-terminally truncated Parkin proteoform lacking amino acids 1-79 due to internal translation initiation. This truncated protein partially retained ubiquitin ligase activity at endogenous levels. Treatment with Parkin modulator BIO-2007817 enhanced this residual function but reduced endogenous full-length Parkin activity.

Interpretation: Residual truncated Parkin function provides a molecular explanation for a delayed disease onset in PRKN Exon 2 deletion carriers. Whereas this retained activity can be pharmacologically enhanced, the modulator's inhibitory effect on endogenous full-length Parkin may mandate strict patient stratification based on genotype. This finding offers mutation-specific counseling opportunities and highlights a potential therapeutic approach for appropriately selected patients with PARK-PRKN. ANN NEUROL 2026.

Objective: To characterize Fc-glycosylation profiles in patients with anti-N-methyl-D-aspartate receptor encephalitis (NMDARe) and assess their association with antibody compartmentalization (cerebrospinal fluid [CSF] vs serum), disease triggers (viral, tumor-related or idiopathic), and 1-year outcomes.

Methods: We analyzed immunoglobulin (Ig) G1 and IgG2/3 Fc-glycosylation by liquid chromatography-mass spectrometry in paired serum/CSF samples from 50 age- and sex-matched patients with NMDARe identified in IDIBAPS/Hospital Clinic of Barcelona database and the Spanish study on herpes encephalitis. Patients were classified by disease trigger as post-herpetic, tumor-related, or idiopathic. One-year outcomes were defined as good (modified Rankin Scale [mRS] ≤2) or poor (≥3). Fc glycoprofiles were quantified for fucosylation, sialylation, galactosylation, and bisecting N-acetylglucosamination.

Results: Across IgG subclasses (IgG1-3), CSF antibodies showed significantly reduced sialylation and galactosylation compared to serum (p < 0.0001), indicating a pro-inflammatory compartmentalized response within the central nervous system. These inflammatory Fc-glycoforms were predominant in post-herpetic cases of NMDARe (p < 0.01) compared to tumor-related and idiopathic forms, suggesting that viral-induced NMDAR may alter antibody Fc-glycosylation via B-cell glycosylation pathway modulation. Furthermore, reduced sialylation, galactosylation and fucosylation in CSF and serum were associated with poor 1-year outcomes (p < 0.05), suggesting that compartmentalized inflammation and enhanced innate immune activation, including natural killer (NK) cell-mediated cytotoxicity driven by afucosylated antibodies, might contribute to neurological dysfunction.

Interpretation: In NMDARe, CSF Fc-glycosylation profiles are both compartment- and trigger-specific. Because glycan signatures shape innate immune interactions (e.g., with NK cells), these findings highlight distinct pathogenic mechanisms and support Fc-glycosylation profiling as a potential prognostic biomarker. ANN NEUROL 2026.

Objective: Pathogenic variants in Kaptin (KPTN) cause KPTN-related disorder (KRD). KPTN modulates mTOR signaling activation within the KICSTOR complex in response to cellular amino acid levels. We define the clinical spectrum and investigate the developmental pathogenesis of KRD.

Methods: We report the genotype and clinical phenotype of 71 KRD individuals (28 female subjects, ages 1 to 55 years) including 48 newly identified KRD individuals. The effects of Kptn knockout on brain development were assayed in vitro and in vivo.

Results: We defined 15 novel KPTN variants. Intellectual disability (ID) was identified in all KRD individuals. Macrocephaly and epilepsy were observed in 46% and 47%, respectively. Neuroimaging revealed megalencephaly but no overt structural abnormalities. Ketotic hypoglycemia and endocrinopathies were identified in KRD. Increased head size was detected in unaffected parents heterozygous for KPTN variants. Two KRD individuals with drug-resistant epilepsy were treated with the mTOR inhibitor sirolimus but did not exhibit improved seizure control. CRISPR/Cas9 Kptn knockout in vitro induced mTOR activation and an mTOR-dependent increase in cell size. Kptn-/- mice exhibited increased cortical mTOR signaling that was reduced by rapamycin. Heterotopic neurons were identified in the subcortical white matter in the Kptn -/- mouse. Focal CRISPR/Cas9 Kptn knockout in cortex via in utero electroporation resulted in white matter heterotopic neurons. Electroencephalogram (EEG) did not detect ictal or inter-ictal abnormalities.

Interpretation: KRD is a multisystem neurodevelopmental disorder associated with ID, macrocephaly, epilepsy, mTOR signaling hyperactivation, and in a mouse model, subtle structural alterations in cerebral cortical cytoarchitecture. ANN NEUROL 2026.

Objectives: Changes in the gut microbiome may be involved in the pathogenesis and progression of Parkinson's disease (PD). This randomized, placebo-controlled, double-blinded study aimed to assess the effects of fecal microbiota transplantation (FMT) on the manifestation of the motor symptoms of PD (The Movement Disorders Society - Unified Parkinson's Disease Rating Scale Part III [MDS-UPDRS III]) over a 12 month long observation and non-motor symptoms as secondary objectives: the Movement Disorders Society-Non-Motor Rating Scale; EuroQol-5 Dimension; PD Quality-of-Life Questionnaire; Montreal Cognitive Assessment (MoCA); UPDRS I, II, and IV; Gastrointestinal Dysfunction Scale for PD; modified Constipation Assessment Scale; and levodopa equivalent dose.

Methods: The patients were randomly assigned to receive either fecal microbiota (Mbiotix, Human Biome Institute) or placebo (auto-fecal microbiota, prepared from the patient's stool) in a 1:1 ratio. The fecal microbiota transplantation was performed via colonoscopy. Assessments were performed before and after 12 months for the MoCA and at 1, 3, 6, and 12 months for the other scales. Intention-to-treat analysis was performed using a multivariable mixed regression model.

Results: Of the 59 patients included, 28 were randomly assigned to the Mbiotix group (median age = 65 years; 15 male patients) and 31 to the placebo group (median age = 63 years; 14 male patients). No significant differences were observed in the MDS-UPDRS III "OFF" state score at 12 months between groups (1.50 points, 95% confidence interval [CI] = -4.28 to 7.28, p = 1.00), however, some non-motor symptoms improved in different study timepoints.

Interpretation: A single FMT does not influence motor symptoms manifestation in patients with PD but could improve non-motor functioning via gut-brain axis. Trial registration information: Clinical Trial ID NCT05204641 was submitted on November 29, 2021. The first patient was enrolled on January 4, 2022. ANN NEUROL 2026.

Objective: Polymicrogyria (PMG) is one of the most common human malformations of cortical development and is often classified by its radiographic pattern of distribution. Unilateral polymicrogyria (uPMG) is a subtype of PMG affecting a portion or all of one cerebral hemisphere. As most PMGs occur bilaterally, there has been no specific investigation as to whether the genetic underpinnings of uPMG comprise a subset of or a distinct entity from bilateral PMG. In this study, our goal was to assess both the genetic etiology of uPMG and the value of diagnostic genetic testing in this setting.

Methods: We conducted a retrospective analysis of clinical data from individuals with uPMG seen in the Brain Development and Genetics Clinic and/or research participants of the Walsh Laboratory at Boston Children's Hospital. The final study cohort included 35 individuals from 30 families who were diagnosed with uPMG on brain magnetic resonance imaging (MRI) and also underwent genetic testing.

Results: A likely genetic cause was identified in 26.7% (8/30) of unrelated individuals with uPMG in this cohort and segregated within one family (10/35 total subjects). Recessive genetic causes included ASPM, WDR62, and TMEM216. Dominant causes included 22q deletion syndrome, DYNC1H1, SCN3A, and hereditary hemorrhagic telangiectasia (HHT) genes, ACVRL1 and ENG. This is the first report of variants in DYNC1H1, TMEM216, and ACVRL1 in association with uPMG.

Interpretation: The genetic causes of bilateral PMG and uPMG can overlap, but some are unique to certain distributions of the malformation. Genetic explanations for uPMG are found at comparable rates to bilateral PMG, suggesting that germline testing for this unique presentation is warranted. ANN NEUROL 2026.