OBJECTIVE:To identify MRI predictors of relapse and quantify relapse and mortality risk in cerebral amyloid angiopathy-related inflammation (CAA-RI). A secondary objective was to assess the association between mycophenolate mofetil use and relapse risk. METHODS:We performed a retrospective cohort study of 36 patients with CAA-RI treated at the Cleveland Clinic from January 2020 to December 2024. Relapse was defined as recurrent vasogenic edema on MRI after corticosteroid treatment. Edema was classified as focal (1 lobar region), multifocal (2-3 regions), or diffuse (≥ 4 regions). Cause-specific Cox models and Gray's test evaluated predictors of relapse and mortality, and the effect of mycophenolate on relapse. RESULTS:Among 36 patients (mean age 71.6 ± 8.2 years; 66.7% female), 11 (30.6%) relapsed, 9 (25.0%) died without having relapse, and 16 (44.4%) had neither event after a median prednisone taper of 4.5 months. 31 patients had follow-up data for time-to-event analyses, with a median follow-up time of 18.7 months. Cumulative relapse rates were 22.4%, 26.3%, and 44.0% at 6, 12, and 24 months, respectively. Diffuse edema strongly predicted relapse (hazard ratio [HR] = 12.26; 95% confidence interval [CI] = 1.95-76.94; p = 0.007). Mycophenolate was used in 11 patients; relapse occurred in 18.2% versus 30.0% without mycophenolate treatment. Initiation of mycophenolate at steroid taper in high-relapse-risk patients was associated with a statistically nonsignificant reduction in relapse risk (HR = 0.36; 95% CI = 0.07-1.09, p = 0.231). INTERPRETATION:Relapse in CAA-RI is common and extends beyond the early post-treatment phase. Diffuse edema on baseline MRI strongly predicts recurrence, enabling effective risk stratification. Mycophenolate shows promise as a steroid-sparing therapy for preventing relapse in high-risk patients and merits prospective evaluation.
OBJECTIVE:Neurofilament light chain (NfL) is a biomarker of neuroaxonal injury in multiple sclerosis (MS), yet associations with functional outcomes remain unclear. Longitudinal associations between serum NfL (sNfL) and daily step count (STEPS) from wearable devices were assessed in a large international progressive MS cohort. METHODS:A post hoc analysis of the Phase III randomized controlled trial SPI2 (high-dose biotin vs. placebo RCT) pooled treatment arms due to no observed therapeutic benefit. Participants with sNfL and step count data were included. STEPS were calculated within ±15-days of baseline, 6, 12, 15, and 27-month visits. Mixed-effects models with 1000 bootstrap iterations assessed contemporaneous associations with each measure alternately specified as the outcome, adjusting for age and sex. Lagged models evaluated whether 0-6-month sNFL changes predicted subsequent 6-12-month STEPS changes. RESULTS:Among 506 participants (53.8% female; mean age 52.7 [SD: 7.7] years; median EDSS 6.0 [4.5-6.0]), mean sNfL z-score was 1.00 (SD: 0.95), and median STEPS were 3029 [1708-5210]. Higher sNfL was associated with lower STEPS (IRR = 0.97, p = 0.014), consistent across sex, treatment, disability, and disease-modifying treatment status. Conversely, higher STEPS were associated with lower sNfL z-scores; a 10% increase in STEPS corresponded to a 0.015 decrease in sNfL z-score (95% CI -0.022 to -0.008; p < 0.001). Greater prior 6-month increases in sNfL were associated with a lower subsequent STEPS (β = -141; 95% CI -302 to 21; p = 0.088; trend), corresponding to 141 fewer steps per 1-SD sNfL increase. INTERPRETATION:Higher sNfL was associated with reduced daily ambulatory activity in progressive MS, and vice versa. Rising sNfL may precede mobility decline, highlighting sNfL as a potential indicator of functional worsening. TRIAL REGISTRATION:ClinicalTrials.gov NCT02936037; EudraCT database 2016-000700-29.
BACKGROUND:The clinical relevance of MGMT promoter methylation in IDH-mutant gliomas remains controversial in the era of molecular classification. We aimed to systematically evaluate its clinical relevance by integrating quantitative assessment, cutoff exploration, and adjustment for clinical confounding. METHODS:A total of 558 patients with WHO grade 2-3 IDH-mutant gliomas were retrospectively analyzed. MGMT promoter methylation was quantified by pyrosequencing. Survival outcomes were assessed using Kaplan-Meier analysis and multivariable Cox regression. Multiple cutoff thresholds were examined, and PSM was applied to balance baseline characteristics. RESULTS:Quantitative methylation stratification demonstrated significantly shorter PFS and OS in unmethylated tumors compared with methylated tumors. However, no clear stepwise association between increasing methylation levels and survival was observed. Across cutoff thresholds (9%-25%), MGMT promoter methylation was consistently associated with improved PFS, whereas its association with OS varied and diminished at higher cutoffs. In the unmatched cohort, MGMT promoter methylation was significantly associated with prolonged PFS (HR = 0.53, 95% CI: 0.33-0.85, p = 0.009) and OS (HR = 0.39, 95% CI: 0.21-0.75, p = 0.005). Following PSM, the direction and magnitude of these associations remained comparable (PFS: HR = 0.47, 95% CI: 0.23-0.98, p = 0.044; OS: HR = 0.35, 95% CI: 0.12-1.05, p = 0.06), although statistical significance was less consistent. CONCLUSION:MGMT promoter methylation is associated with favorable clinical outcomes in IDH-mutant gliomas. Its prognostic significance appears to be influenced by treatment context, methodological factors, and cohort characteristics. These findings support a context-dependent interpretation of MGMT methylation and highlight the need for standardized analytical approaches in future studies.
OBJECTIVE:Idiopathic hypersomnia (IH) presents with excessive daytime sleepiness (EDS) despite apparently preserved nocturnal sleep, challenging traditional models of hypersomnolence based on sleep loss or fragmentation. We aimed to test the hypothesis that EDS in IH reflects excessive stabilization of the sleep state, consistent with dysfunctional thalamocortical control rather than impaired sleep quantity or continuity. METHODS:We analyzed overnight polysomnography from 62 IH and 81 age- and sex-matched healthy controls using sleep bout duration, sleep stage transition dynamics, and automated spindle detection. Principal component analyses derived composite indices of NREM and REM sleep stability. Group differences were assessed using ANCOVAs controlling for age and sex, and associations with EDS severity were examined. RESULTS:Compared with controls, IH patients showed reduced transitions from N3 sleep toward lighter stages and wakefulness. Moreover, REM sleep was characterized by longer durations, fewer transitions to wakefulness, and more frequent transitions to lighter stages. In parallel, spindle amplitude was reduced in IH while spindle density was preserved, and smaller spindle amplitudes were associated with shorter latencies on the Multiple Sleep Latency Test. INTERPRETATION:IH is characterized by excessive N3 stabilization and reduction in transitions toward wakefulness in both NREM and REM sleep. These findings suggest that altered sleep-wake dynamics, rather than impaired sleep continuity, may contribute to persistent daytime sleepiness in IH and support sleep stability as a potential target for future research and therapeutic strategies.
BACKGROUND:Hereditary Spastic Paraplegia (HSP) comprises a group of rare genetic diseases characterized by length-dependent axonal degeneration of the corticospinal tracts and dorsal columns, whose main clinical feature is spastic gait. Pathogenic variants in the SPG4 gene cause Spastic Paraplegia Type 4 (SPG4-HSP), the most common form of HSP. SPG4/SPAST encodes spastin, a protein involved in microtubule regulation and lipid droplet behavior. SPG4-HSP shows extreme heterogeneity in both clinical manifestations and genetics. Although no cure is currently available, several strategies aimed at restoring spastin levels are emerging; however, SPG4-HSP still lacks accessible cellular readouts for clinical studies. This study evaluates a cell-imaging approach that quantifies the distance between nucleus and cell centroid (dcnc) in peripheral blood mononuclear cells (PBMCs) in a genetically and clinically heterogeneous SPG4-HSP cohort. METHODS:PBMCs from 48 molecularly confirmed SPG4-HSP patients and 21 healthy controls (HC) were analyzed by automated cell imaging. Dcnc and additional cytoskeletal and lipid droplet-related parameters were measured. Patient-level discrimination was assessed via cross-validated classification; correlations with molecular and clinical features were explored. RESULTS:At the patient level, dcnc distinguishes SPG4-HSP from HC, independently of mutation type and disease severity, supporting robust cross-validated classification and inverse correlation with spastin protein levels. CONCLUSION:Dcnc is a robust, non-invasive, and mutation-independent cellular candidate biomarker for SPG4-HSP. It also offers preliminary evidence consistent with spastin target engagement supporting evaluation in future clinical trials.
