Annals of Neurology最新文献

Cryptogenic new-onset refractory status epilepticus (cNORSE) is a devastating condition with unclear pathogenesis. Here, we analyzed the genetic underprints of 31 cNORSE patients from an autoimmune encephalitis observational cohort through whole-genome sequencing. Compared to their controls, cNORSE patients exhibited elevated polygenic risk scores (PRS) for traits associated with autoimmune diseases. The individual PRS against these diseases were correlated with specific clinical phenotypes of cNORSE. The variants were enriched in genes expressed in the central nervous system and lymphocytes. These results suggest a shared genetic framework between cNORSE and other autoimmune/autoinflammatory diseases, and its involvement in the disease pathogenesis. ANN NEUROL 2024;96:1201–1208

Biallelic variants in phosphatidylinositol glycan anchor biosynthesis, class G (PIGG) cause hypotonia, intellectual disability, seizures, and cerebellar features. We present 8 patients from 6 families with a childhood-onset motor neuropathy and neurophysiology demonstrating variable motor conduction block and temporal dispersion. All individuals had a childhood onset tremor, 5 of 8 had cerebellar involvement, and 6 of 8 had childhood febrile seizures. All individuals have biallelic PIGG variants, including the previously reported pathogenic variant Trp505*, plus 6 novel variants. Null enzyme activity is demonstrated via PIGO/PIGG double knockout system for Val339Gly and Gly19Glu, and residual activity for Trp505* due to read-through. Emm negative blood group status was confirmed in 1 family. PIGG should be considered in unsolved motor neuropathy. ANN NEUROL 2024.

Obesity is implicated in the development of multiple sclerosis (MS), but its effect on disability is less well-established. This study examined the effects of various obesity measures on MS severity in 12,584 MS cases, using Mendelian randomization to mitigate confounding. Results showed a significant association between higher genetically-determined body mass index (N = 806,834) and increased MS severity (P = 0.02). This finding was supported by additional measures of general obesity but not adiposity distribution. The convergence of this genetic evidence with prior observational studies strengthens the association between obesity and adverse long-term disability in MS, suggesting weight management as a potential therapeutic strategy. ANN NEUROL 2024.

Background: Previous studies have observed liver abnormalities in amyotrophic lateral sclerosis (ALS) patients. This study aimed to investigate whether early signs of liver disease, measured by magnetic resonance imaging-derived iron-corrected T1-mapping (cT1), are risk factors for developing ALS.

Methods: cT1 and proton density fat fraction were measured and automatically analyzed using LiverMultiScan® software. The Fibrosis-4 index was calculated using an established formula based on age and blood markers. Cox proportional hazard models were used to examine the relationship between liver disease, liver biomarkers, and incident ALS.

Results: In a cohort of 533,707 individuals from UK Biobank, 24 ALS cases were identified among 28,328 participants with liver disease during the follow-up period. Among a total of 33,959 individuals with complete liver imaging data, 15 incident ALS cases were observed during a median follow-up period of 5.6 years. Individuals with liver disease had a higher risk of developing ALS, with an adjusted hazard ratio of 7.35 (95% CI 4.47-12.09; p < 0.001). An increase in cT1 was also associated with a higher risk of ALS. After adjusting for age, sex, Townsend deprivation index, smoking status, alcohol intake frequency, body mass index, proton density fat fraction, Fibrosis-4, and metabolic syndrome, an increase in cT1 remained significantly associated with a higher risk of ALS, with an adjusted hazard ratio of 3.15 (95% CI 1.79-5.55) per 1-SD increase. Sensitivity analyses confirmed these robust results.

Interpretation: Liver disease activity, indicated by cT1, increases the risk of developing ALS, independent of metabolic syndrome, liver fat, or fibrosis. ANN NEUROL 2024.

Objective: Despite the advances in treatments for multiple sclerosis (MS), unremitting neurodegeneration continues to drive disability and disease progression. Smoldering/slowly expanding lesions (SELs) and dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) are pathologic hallmarks of MS cortex and intricately tied to disability and neurodegeneration, respectively. We hypothesized that neuronal hnRNP A1 dysfunction contributes to neurodegeneration and is exacerbated by smoldering/SELs in progressive MS.

Methods: Neuronal hnRNP A1 pathology (nucleocytoplasmic mislocalization of hnRNP A1) was examined in healthy control and MS brains using immunohistochemistry. MS cases were stratified by severity of hnRNP A1 pathology to examine the link between RBP dysfunction, demyelination, and neurodegeneration.

Results: We found that smoldering/SELs were only present within a subset of MS tissues characterized by elevated neuronal hnRNP A1 pathology (MS-A1^high) in adjacent cortical gray matter. In contrast to healthy controls and MS with low hnRNP A1 pathology (MS-A1^low), MS-A1^high showed elevated markers of neurodegeneration, including neuronal loss and injury, brain atrophy, axonal loss, and axon degeneration. Additionally, we discovered a subpopulation of morphologically intact neurons lacking expression of NeuN, a neuron-specific RBP, in cortical projection neurons in MS-A1^high cases.

Interpretation: hnRNP A1 dysfunction contributes to neurodegeneration and may be exacerbated by smoldering/SELs in progressive MS. The discovery of NeuN-negative neurons suggests that some cortical neurons may only be injured and not lost. By characterizing RBP pathology in MS cortex, this study has important implications for understanding the pathogenic mechanisms driving neurodegeneration, the substrate of disability and disease progression. ANN NEUROL 2024.

Objectives: Clemastine has emerged as a promising therapy for the restoration of neurologic function in patients with multiple sclerosis (MS). However, clemastine and other agents with prodifferentiative effects on oligodendrocyte progenitor cells (OPCs) in rodent models have underperformed in clinical trials. We hypothesized that the preclinical studies showed more robust effects because of the abundance of OPCs in rodent models. To better examine the therapeutic potential of clemastine, we examined its effect on demyelinated white matter lesions in rabbits, which exhibit progenitor densities and limited remyelination more closely matching those found in tissues from patients with MS.

Methods: We used lysolecithin to induce demyelination in white matter of New Zealand rabbits and then administered oral clemastine (10mg/kg/day) for various periods before assessing the OPC and oligodendrocyte (OL) populations in these lesions.

Results: Daily administration of clemastine for the full study period (56 days) increased oligodendrogenesis in white matter lesions. However, shorter durations of treatment failed to increase overall OL density despite enhancing OPC-to-OL differentiation. This effect was due to exhaustion of the OPC pool, as the differentiating progenitors were not replaced because of reduced OPC proliferation. Notably, delayed administration of clemastine led to an accumulation of activated OPCs expressing markers of senescence.

Interpretation: Although capable of driving OL differentiation, clemastine treatment in rabbits hampered progenitor pool replenishment, induced senescence, and promoted conversion of microglia/macrophages to a proinflammatory phenotype. Whether these effects would also occur in humans or with other prodifferentiative therapies should be studied further, but our data suggest the need to carefully consider progenitor dynamics in the treatment of MS. ANN NEUROL 2024.

Objective: To investigate the longitudinal dynamics of serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) levels in people with multiple sclerosis (pwMS) under B-cell depleting therapy (BCDT) and their capacity to prognosticate future progression independent of relapse activity (PIRA) events.

Methods: A total of 362 pwMS (1,480 samples) starting BCDT in the Swiss Multiple Sclerosis (MS) Cohort were included. sGFAP levels in 2,861 control persons (4,943 samples) provided normative data to calculate adjusted Z scores.

Results: Elevated sGFAP levels (Z score >1) at 1 year were associated with a higher hazard for PIRA (hazard ratio [HR]: 1.80 [95% CI: 1.17-2.78]; p = 0.0079) than elevated sNfL levels (HR, 1.45 [0.95-2.24], p = 0.0886) in a combined model. Independent of PIRA events, sGFAP levels longitudinally increased by 0.49 Z score units per 10 years follow-up (estimate, 0.49 [0.29, 0.69], p < 0.0001). In patients experiencing PIRA, sGFAP Z scores were 0.52 Z score units higher versus stable patients (0.52 [0.22, 0.83], p = 0.0009). Different sNfL Z score trajectories were found in pwMS with versus without PIRA (interaction p = 0.0028), with an average decrease of 0.92 Z score units per 10 years observed without PIRA (-0.92 [-1.23, -0.60], p < 0.0001), whereas levels in patients with PIRA remained high.

Interpretation: Elevated sGFAP and lack of drop in sNfL after BCDT start are associated with increased risk of future PIRA. These findings provide a rationale for combined monitoring of sNfL and sGFAP in pwMS starting BCDT to predict the risk of PIRA, and to use sGFAP as an outcome in clinical trials aiming to impact on MS progressive disease biology. ANN NEUROL 2024.