Annals of Clinical and Translational Neurology最新文献

We describe two patients with variably protease-sensitive prionopathy (VPSPr) who developed progressive upper motor neuron symptoms, insomnia, behavioral and cognitive decline, compatible with primary lateral sclerosis associated with frontotemporal dementia (FTD). Neuropathology revealed a spongiform encephalopathy with frontotemporal and pronounced thalamic involvement, associated with fine synaptic abnormal prion protein conformer (PrP^Sc) deposits, microplaques, and intraneuronal aggregates. Western blot analysis revealed a characteristic VPSPr proteolytic profile, lacking the diglycosylated band. Both patients were methionine homozygous at PRNP codon 129 and carried no pathogenic mutations. These cases illustrate that VPSPr can present with a prominent motor neuron syndrome and FTD features.

Objective: To determine the test performance of cutaneous phosphorylated alpha-synuclein (P-SYN) in dementia with Lewy bodies (DLB), individuals with reduced Montreal Cognitive Assessment (MoCA) and healthy controls.

Methods: This is the first subgroup analysis of the Synuclein-One study, a prospective, blinded study evaluating P-SYN detection from skin biopsies in 218 subjects with a referral diagnosis of control (N = 151) and DLB (N = 67). All subjects completed detailed examinations, questionnaires, and had skin biopsies for detection of P-SYN. DLB patients were included if meeting the 4th DLB consensus probable criteria. Control subjects, aged 40-99, had no history, examination findings, or symptoms suggestive of a synucleinopathy or neurodegenerative disease. An expert review panel, blinded to pathological data, determined the final diagnosis. Controls with reduced MoCA (MoCA < 26, N = 26) at screening were analyzed separately.

Results: After expert panel review, only 50/67 patients met consensus criteria for DLB, 26/151 controls had a reduced MoCA, and 120/151 controls had a normal MoCA. The proportions of subjects with cutaneous P-SYN detected by skin biopsy were 96.0% (48 of 50) of the DLB group, 31% (8 of 26) of the controls with reduced MoCA, and 3.3% (4 of 120) of the controls with normal MoCA.

Interpretation: In this prospective, blinded, cross-sectional study, a high proportion of subjects meeting clinical consensus criteria for DLB had P-SYN detected in skin biopsies. Almost 1/3 of subjects with reduced MoCA testing also had P-SYN detected. These results support a role for skin biopsy detection of P-SYN in patients with DLB.

Trial registration: NCT04700722.

Background: Myasthenia gravis (MG) is a rare, autoimmune disorder characterized by fluctuating muscle weakness and potential life-threatening crises. While continuous specialized care is essential, access barriers often delay timely interventions. To address this, we developed MyaLink, a telemedical platform for MG patients. This study evaluated whether frequently assessed clinical outcomes via MyaLink can capture symptom variability between clinical visits.

Methods: In this randomized, controlled, 12-week study, 45 MG patients received either standard care (control, N = 15) or standard care with additional telemedical treatment (intervention, N = 30) including assessment of patient-reported outcome measures, sensor-based data, and patient-physician messaging via a mobile application. Physicians performed telemedical check-ups (TCUs) via a web-based platform, adjusting treatment as needed.

Results: In the intervention group, variability in clinical scores and sensor-derived data was observed, particularly among those who experienced MG-related hospitalizations or exacerbations (H&E subgroup). This subgroup showed larger MG-ADL score fluctuations (mean range: 5.8 vs. 2.6 points), sent more messages, had more steroid dose adjustments (40% vs. 0%), and more frequent TCU interventions (93.3% vs. 60%) than the Non-H&E subgroup.

Interpretation: Telemedical platforms in MG might detect early signs of worsening. High-risk patients (H&E subgroup) require increased medical support, which can be effectively addressed through MyaLink.

Trial registration: The study was registered under the German clinical trial registry (DRKS00029907).

Amyotrophic lateral sclerosis (ALS) risk differs by sex and age, implicating sex hormones as potential modifiers. This study examined plasma levels of biologically active sex hormones and their association with ALS odds and survival in cases (females n = 131, males n = 189) and controls (females n = 138, males n = 150) from the University of Michigan Pranger ALS Clinic. Higher 11-ketotestosterone levels were associated with increased ALS odds. In females, higher estrone, androstenedione, and 11-hydroxyandrostenedione were associated with increased ALS odds, while elevated estrone and estradiol predicted shorter survival. These findings highlight the potential significance of sex hormones in ALS.

Background: Pediatric anti-NMDA receptor encephalitis (pNMDARE) is an autoantibody-mediated disorder that can cause severe autonomic dysfunction, including symptomatic bradycardia and asystole. Dysautonomia can last for years, making it very challenging to manage.

Objective: To describe outcomes of 5 pNMDARE patients with life-threatening bradycardic and/or asystolic events who were managed with permanent or semi-permanent pacemaker implantation.

Methods: We performed a retrospective chart review of 5 patients from multiple institutions. We included patients with a diagnosis of pNMDARE (confirmed by positive cerebrospinal fluid and/or serum anti-NMDAR antibodies) who had a permanent or semi-permanent pacemaker placed due to symptomatic bradycardia, sinus pauses, and/or asystole. Assessed outcomes included mortality, the presence of additional bradycardic/asystolic events after pacemaker implantation, pacemaker complications (lead/device infection, device malfunction), and the ongoing need for ventricular pacing.

Results: Four patients had permanent pacing systems placed, and one patient had a semi-permanent pacemaker placed. Three patients required continued intermittent ventricular pacing months to years after disease onset. None of the patients had further episodes of symptomatic bradycardia or asystole after pacemaker implantation. One patient, who had a severe, intractable form of pNMDARE, died after discontinuing immunotherapies; she had multiple pacemaker interrogations that demonstrated no sign of pacemaker dysfunction.

Conclusion: Permanent and semi-permanent pacemakers are a safe, effective management strategy for cases of pNMDARE with prolonged courses of severe bradycardia and/or asystole.

We estimated the statistical power of studies predicting seizure freedom after epilepsy surgery. We extracted data from a Cochrane meta-analysis. The median power across all studies was 14%. Studies with a median sample size or less (n ≤ 56) and a statistically significant result exaggerated the true effect size by a factor of 5.4, while the Bayesian estimate of the odds ratio only exaggerated the true effect size by a factor of 1.6. We conclude that Bayesian estimation of odds ratios attenuates the exaggeration of significant effect sizes in underpowered studies. This result could improve interpretation of studies with small sample sizes.

Background: Myasthenia gravis (MG) is an autoimmune disorder characterized by antibody-mediated complement activation. Efgartigimod, a neonatal Fc receptor (FcRn) antagonist, is approved for treating generalized MG (gMG). However, its modulatory effects on upstream innate and adaptive immune cells remain largely unexplored.

Methods: We first quantified FcRn expression in peripheral immune subsets from acetylcholine receptor antibodies (AChR-Ab) positive gMG. Then we assessed efgartigimod's impact on immune cells via in-depth profiling in vitro and later validated these findings in a prospective real-world cohort treated with efgartigimod.

Results: High FcRn expression was abundantly expressed on monocytes and lymphocytes in an exploratory MG cohort (n = 29), with notable intracellular presence. In vitro studies showed efgartigimod significantly decreased intracellular FcRn in monocytes (p < 0.001) and lymphocytes (p = 0.019). After efgartigimod treatment, non-classical monocytes (CD14^lowCD16⁺, 17.89 ± 9.60 vs. 14.58 ± 9.89 cells/μl, p < 0.001; 3.20 ± 2.06 vs. 2.61% ± 2.12%, p < 0.001) and Th17.1 cells (CXCR3⁺CCR6⁺, 95.83 ± 66.56 vs. 84.06 ± 61.70 cells/μl, p = 0.010; 10.42 ± 4.82 vs. 9.06% ± 4.46%, p = 0.000) were significantly downregulated. In contrast, antibody-producing B cells and effector-memory CD4⁺ and CD8⁺ T cells were expanded. Longitudinal assessments in the gMG cohort displayed similar findings, which likely reflect the direct inhibitory effect of efgartigimod on monocytes, coupled with negative feedback due to decreased IgG levels.

Conclusions: By integrating in vitro and clinical findings, we demonstrate that efgartigimod modulates peripheral immune cell populations, highlighting its significant immunomodulatory effects and clinical potential.

Acute intermittent porphyria (AIP) is a rare metabolic disorder that may present with subacute neuropathy and systemic symptoms, often leading to diagnostic delay. We report a 37-year-old woman with eight weeks of progressive bilateral upper extremity weakness and paresthesias, followed by lower extremity involvement and falls, in the setting of chronic abdominal pain, presyncope, weight loss, and neuropsychiatric symptoms. Examination revealed profound proximal arm weakness, sensory deficits, bulbar involvement, and autonomic features. MRI of the brain and spine and cerebrospinal fluid analysis were normal. Electrodiagnostic studies demonstrated a severe diffuse motor neurogenic process. Markedly elevated urinary porphobilinogen and aminolevulinic acid levels confirmed the diagnosis of acute intermittent porphyric neuropathy, supported by identification of a variant of uncertain significance in the HMBS gene. This case underscores the importance of considering AIP in patients with subacute motor-predominant neuropathy accompanied by abdominal pain and autonomic dysfunction, as early diagnosis enables timely treatment and improved outcomes.

Objective: Dystonia is one of the most common movement disorders, with variants in multiple genes identified as causative. However, an understanding of which developmental stages, brain regions, and cell types are most relevant is crucial for developing relevant disease models and therapeutics. One approach is to examine the timing and anatomical expression of genes in which variants are dystonia-causing, on the assumption that deleterious variants have a greater impact where higher levels of expression are observed.

Methods: We investigated the expression patterns of 44 genes linked with a dystonia phenotype across two bulk and two single-nuclei RNA-sequencing datasets, derived from prenatal and postnatal human brain tissue.

Results: Dystonia genes were most strongly enriched in the striatum, cerebral cortex, hippocampus, amygdala and substantia nigra, and demonstrated higher postnatal expression. Individual genes exhibiting differences in expression across adult brain regions include SQSTM1, SGCE, KMT2B, PRKRA, YY1, DNAJC12, KCNA1, CACNA1A (highest expression in cerebellum), ADCY5, GNAL, ANO3 (highest expression in striatum), RHOBTB2, FOXG1 (highest expression in cerebral cortex). Single-nuclei RNA-sequencing analyses from human frontal cortex, striatum, cerebellum and substantia nigra indicated that dystonia genes are predominantly expressed in neurons (glutamatergic, GABAergic and dopaminergic). Gene Ontology analysis showed prominent enrichment in biological processes such as dopamine biosynthetic and metabolic processes, and in the cellular components axons and neuron projection.

Interpretation: These analyses provide important insights into the anatomical, developmental, and cellular expression patterns of genes associated with dystonia, potentially guiding the development of disease-relevant models and improving the targeting of future therapeutic interventions.

Objective: People with epilepsy (PWE) may experience cognitive deficits but fail to undergo formal evaluation. This study compares cognitive status between PWE and healthy controls in the West African Republic of Guinea.

Methods: A cross-sectional, case-control study was conducted in sequential recruitment phases (July 2024-July 2025) at Ignace Deen Hospital, Conakry. Adult (≥ 18 years) PWE enrolled consecutively, excluding those with a seizure within the past 24 h. Controls were healthy adults accompanying PWE at the hospital. Cognitive status was assessed with the Montreal Cognitive Assessment (MoCA) in French or translated into the patient's preferred language (Pular, Susu, Maninka, Kissi) as needed.

Results: We enrolled 100 PWE (mean age 30.4 years, range 18-71, SD = 12.0) and 100 controls (mean age 39.4 years, range 19-70, SD = 12.3). Although 93% of PWE had previously used anti-seizure medications (ASMs), only 85% were currently receiving treatment and 50% reported interrupted access to ASMs, primarily due to cost barriers. The mean MoCA score of controls (21.8, SD = 4.9) was higher than that of PWE (17.9, SD = 6.1; mean difference -4.2, 95% CI [-5.6, -2.8], SE = 0.69, p < 0.001), adjusted for education level, sex, age, and language. Participants who attended lower secondary, upper secondary, or university education scored 4.9, 5.3, and 8.3 points higher, respectively, than those with no school or primary education (all p < 0.001). Speaking an indigenous language was on average associated with a 2.5-point decline in MoCA scores (95% CI [-3.8, -1.2], SE = 0.65, p < 0.001).

Interpretation: PWE in Guinea demonstrated significantly lower cognitive performance on the MoCA compared to healthy controls, even after adjusting for covariates.