Annals of Clinical and Translational Neurology最新文献

Cavin-4 was identified as a potential autoantigen for immune-mediated rippling muscle disease (iRMD). To validate this, we developed and tested various immunoassays, including a cell-based assay (CBA), cavin-4 recombinant protein ELISA, and multi-peptide ELISA. Among 19 iRMD patients, all exhibited muscle rippling, and 13 had percussion-induced mounding. All immunoassays demonstrated clinical and analytical specificities greater than 95%. The protein ELISA had the highest sensitivity (94.7%) and specificity (99.9%), outperforming CBA (sensitivity 89.5%, specificity 99.6%) and the multi-peptide ELISA (sensitivity 79.0%, specificity 97.2%). Our results suggest that the cavin-4 protein ELISA is a promising tool for high-throughput clinical testing in iRMD.

Objective: Visual disability in Parkinson's disease (PD) is not fully explained by retinal neurodegeneration. We aimed to delineate the brain substrate of visual dysfunction in PD and its association with retinal thickness.

Methods: Forty-two PD patients and 29 controls underwent 3-Tesla MRI, retinal spectral-domain optical coherence tomography, and visual testing across four domains. Voxel-level associations between gray matter volume and visual outcomes were used to define a visual impairment region (visualROI). Functional connectivity of the visualROI with brain networks was analyzed. Covariance analysis of brain regions associated with retinal thinning (retinalROI) was conducted using hierarchical clustering to develop a model of retinal and brain neurodegeneration linked to disease progression.

Results: The amygdala was the primary component of the visualROI, comprising 32.3% and 14.6% of its left and right volumes. Functional connectivity analysis revealed significant disruptions between the visualROI and medial/lateral visual networks in PD. Covariance analysis identified three clusters within retinalROI: (1) the thalamic nucleus, (2) the amygdala and lateral/occipital visual regions, and (3) frontal regions, including the anterior cingulate cortex and frontal attention networks. Hierarchical clustering suggested a two-phase progression: early amygdala damage (Braak 1-3) disrupting visual network connections, followed by retinal and frontal atrophy (Braak 4-5) exacerbating visual dysfunction.

Interpretation: Our findings support a novel, amygdala-centric two-phase model of visual dysfunction in PD. Early amygdala degeneration disrupts visual pathways, while advanced-stage disconnection between the amygdala and frontal regions and retinal neurodegeneration contributes to further visual disability.

Objective: Cerebrospinal fluid (CSF) orexin-A has been suggested to be a biomarker of Alzheimer disease (AD). In both cognitively unimpaired healthy older adults and individuals with symptomatic AD, CSF orexin-A is positively associated with CSF Aβ42, p-tau181, and total tau (t-tau) concentrations. However, a recent systematic review and meta-analysis did not support differences in orexin-A between AD and controls. In this study, we tested the association between CSF orexin-A concentrations, AD biomarkers, and cognitive performance in older adults with and without symptomatic AD.

Methods: Two hundred and seventy community-dwelling older adults underwent standardized cognitive assessments, sleep monitoring with a single-channel electroencephalography test, one night of home sleep apnea testing, biofluid and imaging AD biomarker measurement within 1 year of sleep monitoring, and APOE genotyping. Plasma and CSF AD biomarkers were measured by immunoassay or mass spectrometry. CSF orexin-A was measured by radioimmunoassay.

Results: CSF orexin-A levels did not differ by amyloid positivity, cognitive status, or AD stage. However, CSF AD biomarkers (Aβ40, Aβ42, and t-tau) were positively associated with CSF orexin-A levels even after correction for multiple comparisons. CSF orexin-A was not associated with any measure of cognitive performance.

Interpretation: This study showed that CSF orexin-A is associated with multiple CSF AD biomarkers, but not with AD pathology or cognitive performance. We hypothesize that this is due to similar mechanisms of production/release of these proteins with sleep-wake activity. Future studies measuring other forms of orexin peptides, such as orexin-B, may provide evidence for orexin as a marker for AD.

Objective: We measured clinical and quantitative MRI outcome measures in CMT1A to assess long-term responsiveness, establish longitudinal validity and assess MRI as a bridging biomarker.

Methods: Twenty patients with CMT1A and 20 matched controls underwent MRI, myometry and clinical assessments up to four times over mean 4-year follow-up. Bilateral calf muscle MRI included T1-weighted sequences with Mercuri grading and three-point Dixon quantitative fat fraction assessment. Patients were grouped on baseline calf muscle fat fraction: normal <5%, intermediate 5%-70% and end stage >70%.

Results: Controls showed no significant change on MRI. CMT1A patients' calf muscle fat percentage progressed across all follow-up visits: mean absolute change was +1.3 ± 1.2% (mean ± SD) at 12 months, +2.3 ± 2.2% at 27 months and 2.8 ± 2.9% at 49 months. Mercuri grades increased by 0.07 ± 0.11 per year. Responsiveness of individual muscle fat was less than for both calves combined. Patients with intermediate baseline calf muscle fat showed greater progression of 3.7 ± 2.3% at 27 months. There was strong correlation between rate of progression of calf muscle fat and CMT Examination Score (ρ = 0.71, P = 0.005). Calf muscle fat progression at 12 months correlated significantly with annualised CMT Examination Score progression at final visit (ρ = 0.65, P = 0.01).

Interpretation: We demonstrated a consistent progression of calf muscle MRI fat over 4 years, significant longitudinal correlation between CMT Examination Score and calf muscle fat, and potential as a bridging biomarker by 1 year change in fat correlating with long-term clinical progression. Increasing study duration minimally increased responsiveness; however, selecting patients with intermediate fat fraction significantly increased responsiveness.

Objective: Idiopathic intracranial hypertension (IIH) is a neurological disorder predominantly affecting young women with obesity, characterized by elevated intracranial pressure. While current treatments include weight loss counseling, medical therapies, and surgical interventions, their limitations necessitate exploring novel therapeutic approaches. We investigated the efficacy of liraglutide as an adjunctive therapy in IIH management.

Methods: We conducted a retrospective cohort study, analyzing adult patients with IIH. Through propensity score matching, we compared patients receiving liraglutide alongside standard therapy (n = 204) with those receiving standard therapy alone (n = 204). Primary outcomes included papilledema, headache manifestations, and visual disturbances, assessed at 3, 6, 12, and 24 months posttreatment initiation.

Results: Our matched cohorts were predominantly female (95.1% vs. 97.1%) with comparable mean ages (37.6 vs. 37.3 years). Liraglutide treatment demonstrated significant reduction in papilledema risk at 3 months (RR 0.333, 95% CI 0.167-0.664, p = 0.001), with sustained benefits throughout 24 months (RR 0.524, 95% CI 0.325-0.845, p = 0.006). While improvements were observed in visual disturbances, headache symptoms, and refractory IIH cases, these did not reach statistical significance.

Interpretation: Our findings suggest that liraglutide as an adjunctive therapy significantly improves papilledema outcomes in IIH patients, with the greatest effect observed at 3 months and sustained benefits over 2 years. This study provides promising evidence for liraglutide's role in IIH management, particularly in addressing papilledema.

Objective: To further investigate the association between dynamic cerebral autoregulation (dCA) and the outcomes in patients with acute lacunar infarction.

Methods: Patients were prospectively and consecutively enrolled at The First Hospital of Jilin University between 2016 and 2023. dCA was monitored at 1-3 and 7-10 days after the stroke. The outcomes were evaluated using a 3-month modified Rankin Scale score. Binary and ordered logistic regression were employed to analyze the relationship between dCA parameters and outcomes. dCA-based nomogram models were also developed to assess the predictive value of dCA for these patients.

Results: Overall, 332 patients were included in analysis. dCA showed no significant differences between bilateral cerebral hemispheres, as well as two measurement time points (all P > 0.05). Regression analyses showed that dCA at 1-3 and 7-10 days were independently associated with the outcomes of patients with acute lacunar infarction after adjusting for confounders (all P < 0.05). Incorporating dCA parameters into conventional risk factors enhanced the risk-predictive ability of a 3-month unfavorable outcome, significantly improving the area under the receiver operating characteristic curve from 0.798(95% confidence interval [CI], 0.748-0.848) to 0.829(95% CI, 0.783-0.875) (P = 0.046).

Interpretation: dCA remained consistent in bilateral cerebral hemispheres within acute and subacute periods among patients with lacunar infarction. It was independently associated with 3-month outcomes and could be regarded as a reliable predictor for discriminating outcome.

Febrile infection related epilepsy syndrome (FIRES) is a rare presentation of refractory status epilepticus with immune dysregulation as a potential pathologic mechanism. Despite promising results from second-line immunomodulators, approximately 30% remain refractory to treatment. We describe two children with FIRES who were unable to wean from anesthetic infusions with immunomodulatory treatment and subsequently received concurrent intrathecal dexamethasone and anakinra/tocilizumab as escalation of therapy. Following the initiation of this combined regimen, anesthetic infusions were decreased while maintaining seizure freedom. These cases demonstrate proof of principle that a multi-modal approach may be beneficial and should be considered in the treatment of FIRES.

Cases of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) co-occurring with neoplasms have been reported. In this international, retrospective cohort study in South Korea and the USA, 16 of 445 (3.6%) patients with MOGAD had concurrent neoplasm within 2 years of MOGAD onset, resulting in a standardized incidence ratio for neoplasm of 3.10 (95% confidence interval [CI], 1.77-4.81; P < 0.001) when compared to the age- and country-adjusted incidence of neoplasm in the general population. However, none of the nine tumor tissues obtained demonstrated MOG immunostaining. The slightly increased frequency without immunohistopathological evidence suggest with true paraneoplastic MOGAD is extremely rare.