Annals of Clinical and Translational Neurology最新文献

Patients with neuromyelitis optica spectrum disorder (NMOSD) may experience increased signs and symptoms of their underlying disease when vaccinated against meningococcal disease before receiving complement component 5 inhibitor therapies. This retrospective analysis indicated an overall low relapse incidence (mean [range], 3.3% [0.7%-10.6%]) of physician-reported relapses occurring within 4 weeks of meningococcal vaccination in those screened in CHAMPION-NMOSD (NCT04201262), randomized to eculizumab or placebo in PREVENT (NCT01892345), and from the Japanese postmarketing surveillance of eculizumab in patients with anti-aquaporin-4 antibody-positive NMOSD. Further studies are needed to determine if postvaccination relapses are attributable to vaccination or inherent relapse risk among these patients.

Paramagnetic rim lesions (PRLs) are a subset of chronic active multiple sclerosis (MS) lesions marked by iron-laden microglia and macrophages. Ocrelizumab, a monoclonal antibody targeting CD20+ B cells, suppresses acute MS activity, but its effect on PRLs remains unclear. In a longitudinal study of 29 ocrelizumab-treated patients with at least one PRL on quantitative susceptibility mapping (QSM), 97 PRLs were identified. Before treatment, PRLs showed higher QSM values than non-PRLs (p = 0.001), indicating iron enrichment. After treatment, PRLs demonstrated a greater QSM reduction (p < 0.001), with an accelerated decline in susceptibility. These findings suggest ocrelizumab may attenuate iron-related inflammation in PRLs.

Objective: To provide a comprehensive description of disease progression in synuclein seeding assay (SAA) positive sporadic Parkinson Disease participants, using Neuronal Synuclein Disease integrated biological and functional impairment staging framework.

Methods: We analyzed 5-year longitudinal data from 345 participants recruited in the Parkinson's Progression Markers Initiative with the diagnosis of early (less than 2 years of clinical diagnosis at baseline and untreated) sporadic Parkinson's Disease, who were synuclein seeding assay positive. We assessed 5-year progression in a spectrum of clinical and biomarker measures. We used Cox proportional hazards models to assess the association between baseline stage and time to survival, postural instability, cognitive impairment, and other meaningful milestones. Biomarker analysis included dopamine transporter binding measures, CSF-SAA, amyloid-beta, phosphorylated tau and total tau, as well as serum urate, and neurofilament light chain.

Results: At baseline there was clear separation of participants by Neuronal Synuclein Disease Stages (23% Stage 2b, 67% Stage 3, 10% Stage 4). Participants in stage 4 at baseline had a significantly higher rate of reaching disability, postural instability, cognitive decline, and the autonomic dysfunction milestones. There was a stage-dependent increase in dopamine deficit at baseline. There was no difference in fluid biomarkers between the stages at baseline and longitudinally.

Interpretation: This study highlights the heterogeneity in the early Parkinson's Disease population defined by clinical diagnostic criteria and underscores the importance of shifting from clinical to biologically and functional impairment defined inclusion criteria for clinical trials. Biological drivers of stage heterogeneity must be further explored.

Objective: Plasma p-217tau is a minimally invasive but specific biomarker for diagnosing Alzheimer's disease (AD). However, its disease specificity remains to be clinically evaluated. We validated the reliability of the p-217tau biomarker in 12 other neurological diseases.

Methods: Plasma p-217tau levels were measured in 298 participants, consisting of 81 AD patients, 204 patients with 12 other neurological diseases, and 13 healthy and cognitively unimpaired controls (HCU), using an assay system from Meso Scale Diagnostics. Cerebrospinal fluid (CSF) tau and Aß levels were simultaneously evaluated in AD, amyotrophic lateral sclerosis (ALS), and idiopathic normal pressure hydrocephalus (iNPH).

Results: Plasma p-217tau levels increased in AD with the clinical stage, but also in ALS and iNPH, leading to them having decreased sensitivity and specificity for diagnosing AD. No increases in plasma p-217tau levels were seen in possible tauopathies or synucleinopathies. CSF and plasma p-217tau levels were strongly correlated in AD, but not in ALS. The plasma p-217tau/CSF p-217tau ratio was inversely higher in ALS than in AD. Active and chronic denervation potentials were associated with plasma p-217tau levels. In iNPH, plasma p-217tau was associated with cognitive dysfunction, but not with gait disturbance or urinary incontinence. CSF p-181tau, total tau, and Aß1-40 levels and the Aß1-40/1-42 ratio were reduced in iNPH.

Interpretation: ALS and iNPH are two major pitfalls for the clinical application of plasma p-217tau as a biomarker of AD. Lower motor neuron injury in ALS and cognitive dysfunction in iNPH were both found to be associated with elevated plasma p-217tau levels.

Objective: Stroke remains a major cause of disability and mortality in the US, with significant sex-based disparities, and females remain underrepresented in stroke clinical trials. We aimed to examine sex representation in US-based stroke clinical trials, identify trial characteristics associated with higher female enrollment (≥ 50%), and explore factors influencing recruitment strategies.

Methods: This mixed-methods study analyzed US-based stroke clinical trials registered on ClinicalTrials.gov between January 1, 2010 and December 31, 2020. A thematic analysis of recruitment strategies and eligibility criteria was conducted for trials with ≥ 50% female enrollment. We examined the proportion of female participants enrolled in each trial and trial characteristics, including funding source, principal investigator sex, participant age, and recruitment strategies.

Results: Of 456 eligible trials, only 102 (22%) enrolled ≥ 50% female participants. Compared with trials with < 50% female enrollment, these trials more often included both sexes (99.0% vs. 65.5%) and enrolled a greater median number of female participants (22.5 vs. 10). Female-led studies were more common among trials with higher female representation (40.2% vs. 37.6%). Qualitative analysis revealed that broader inclusion criteria, hybrid recruitment strategies (e.g., combining hospital outreach), and targeted accommodations for stroke-related disability were associated with higher female enrollment. Common barriers included exclusionary eligibility criteria, logistical challenges (e.g., transportation), and language limitations.

Interpretations: Inclusive design, community-engaged recruitment, and structural accommodations including support for sex-based roles like caregiving are potentially influential in promoting equitable participation. Addressing sex disparities in stroke research is essential for improving the relevance, effectiveness, and fairness of stroke interventions in clinical practice.

Von Economo neurons (VENs) have been reported to be vulnerable to neurodegeneration in frontotemporal dementia (FTD), particularly the behavioral variant (bvFTD), but these findings have not been systematically assessed across independent brain banks. We conducted a meta-analysis of neuropathological studies measuring VEN density in the anterior cingulate cortex or frontoinsular cortex in FTD using random-effects models with cluster-robust variance estimation. Seven studies (135 FTD, 68 controls) from four international brain banks showed significantly reduced VEN density in FTD with a large effect size (g = -1.45, 95% CI [-1.69, -1.21], p < 0.001) and remarkable consistency (I² = 0%). VEN loss was greater in FTD than Alzheimer's disease and occurred across TDP-43 and tau pathological subtypes.

The Clinical Assessment Scale in Autoimmune Encephalitis (CASE) tracks disease severity in autoimmune encephalitis (AE), but no threshold for significant change exists. We aimed to determine the minimally clinically important difference (MCID) for CASE. Using our AE cohort, receiver operating characteristic analyses were anchored to ≥ 1-point improvement in mRS over 3-month intervals. Among 222 AE patients (77 NMDAR, 49 LGI1, and 113 seronegative AE), a 30% CASE reduction showed good discriminatory performance for mRS improvement in the first 6 months, particularly in NMDAR and seronegative subgroups. A 30% CASE reduction may standardize AE response definitions.

Objective: PIGM encodes a critical enzyme in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway. While promoter-region mutations in PIGM have been associated with a relatively mild phenotype characterized by portal vein thrombosis and absence seizures, recent evidence suggests that coding-region mutations result in a more severe multisystemic disorder.

Methods: Whole-exome sequencing reanalysis was performed in a patient with early-onset developmental and epileptic encephalopathy, and subsequent matchmaking identified another patient with a similar phenotype. The pathogenicity of the variant was evaluated through multiple functional assays. To further delineate the genotypic and phenotypic spectrum of PIGM, we reviewed all patients reported to date with PIGM variants.

Results: We describe two unrelated patients, both carrying the same homozygous missense variant in PIGM (c.1001A > C, p.Gln334Pro), presenting with early-onset developmental and epileptic encephalopathy, profound neurodevelopmental impairment, multi-organ involvement, and distinctive neuroimaging findings including hypomyelination. Both patients died in infancy due to super-refractory status epilepticus. Treatment with sodium phenylbutyrate was attempted in one patient without clinical benefit. Flow cytometry revealed partial GPI-anchor deficiency. Comparative analysis with previously reported cases highlights a potential genotype-phenotype correlation between coding region variants and disease severity.

Interpretation: Our findings establish PIGM as a causative gene of early-onset developmental and epileptic encephalopathy and expand the clinical and radiological spectrum of PIGM deficiency to include hypomyelination and prenatal onset. This study underscores the importance of including PIGM in the differential diagnosis of developmental and epileptic encephalopathy and leukoencephalopathies and provides further insight into the molecular mechanisms underlying phenotypic variability of GPI-anchor disorders.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated neuropathy featuring progressive weakness, sensory deficits, and areflexia. While corticosteroids, intravenous immunoglobulin, and plasmapheresis are effective first-line immunotherapies, a subset of patients remains treatment-refractory. Daratumumab, an anti-CD38 monoclonal antibody approved for multiple myeloma, demonstrates immunomodulatory effects suggesting utility in refractory neuroimmune disorders. However, evidence for its efficacy in CIDP remains limited. We report a case study of treatment-refractory CIDP successfully managed with daratumumab, including 1 year follow-up data.

Background: Neurodegeneration with brain iron accumulation (NBIA) comprises a genetically and clinically heterogeneous group of rare neurological disorders characterized particularly by iron accumulation in the basal ganglia. To date, 15 genes have been associated with NBIA. Among them, WDR45, linked to beta-propeller protein-associated neurodegeneration (BPAN), represents the only X-linked dominant subtype of NBIA. Herein, clinical, electrophysiological, and neuroimaging evaluations were used to broaden the understanding of BPAN in a newly reported case series.

Methods: This study included 10 individuals with BPAN, categorized into three age groups. WDR45 variant data retrieved from next-generation sequencing or Sanger sequencing were reviewed and reassessed. Comprehensive clinical evaluations including magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET), and video electroencephalographic monitoring were conducted.

Results: The clinical manifestations were highly heterogeneous, with cognitive impairment being a consistent finding among the patients, with variable severity. The associated WDR45 variants are likely to exert loss-of-function effects. Electroencephalogram (EEG) abnormalities included age-dependent background slowing and epileptiform discharges. MRI indicated a characteristic pattern, while two patients lacked these typical findings. FDG-PET imaging demonstrated hypometabolism extending beyond cerebral structures, with predominant cerebellar and pontine involvement in pediatric patients and frontoparietal hypometabolism in adults.

Conclusions: This study contributes further to our understanding of the heterogeneous clinical spectrum of BPAN. Genotype-phenotype correlation in BPAN remains unclear due to the absence of sufficiently large cohorts in the literature, including the present study. Nevertheless, even within this small sample, the phenotypic heterogeneity observed among individuals harboring the same genotype highlights the biological complexity of the disease. Neuroimaging findings may reflect progressive and widespread neurological involvement in an age-dependent pattern, whereas EEG data suggest that epilepsy severity tends to decrease after adolescence.