Annals of Clinical and Translational Neurology最新文献

Objective: To delineate specific in vivo white matter pathology in neuronal intranuclear inclusion disease (NIID) using diffusion spectrum imaging (DSI) and define its clinical relevance.

Methods: DSI was performed on 42 NIID patients and 38 matched controls. Microstructure was assessed via quantitative anisotropy (QA), generalized fractional anisotropy (GFA), and isotropy (ISO) across 48 white matter tracts. Group comparisons and clinical correlations used stringent multiple comparison corrections.

Results: Our analysis revealed a tripartite signature that constitutes a novel pathophysiological model for NIID: (1) Universal QA reduction (all Bonferroni-p < 0.05), indicating a pervasive loss of axonal integrity as an early event, detectable even before radiological abnormalities (FDR-p < 0.05); (2) GFA reductions in commissural/projection fibers (Bonferroni-p < 0.05) implicated network disconnection, correlating with cognitive/functional deficits (FDR-p < 0.1); (3) ISO decrease in brainstem-cerebellar pathways (Bonferroni-p < 0.05) identified a unique intracellular pathology, uniquely predicting disease duration (FDR-p < 0.05).

Interpretation: Our DSI framework resolves distinct pathological processes in NIID: QA serves as a biomarker for early detection, GFA maps to symptom heterogeneity, and ISO tracks disease progression, collectively advancing the pathophysiological model and clinical assessment of NIID.

Objective: This study aims to identify both fluid and neuroimaging biomarkers for CSF1R-RD that can inform the optimal timing of treatment administration to maximize therapeutic benefit, while also providing sensitive quantitative measurements to monitor disease progression.

Methods: Our study compared neuroimaging and fluid (plasma and cerebrospinal fluid (CSF)) biomarkers across three distinct populations: asymptomatic CSF1R pathogenic variant carriers (N = 14), symptomatic CSF1R pathogenic variant carriers (N = 17), and healthy controls (N = 30). We evaluated biomarker correlations with both an established (Montreal Cognitive Assessment (MoCA)) and a novel (CSF1R Clinical Severity Score (CCSS)) clinical diagnostic scale to investigate potential clinical utility. Additionally, we tested the relationship between select biomarkers and cortical thickness using 3D T1-weighted MPRAGE scans, providing a highly valuable physiological component to our analyses.

Results: Our results demonstrate that while plasma glial fibrillary acidic protein (GFAP) displays a high sensitivity for distinguishing early-stage CSF1R-RD patients from healthy controls, plasma neurofilament light chain (NfL) is more effective for tracking disease progression following the onset of symptoms.

Interpretation: Overall, our study provides evidence for plasma NfL and GFAP as valuable biomarkers of earliest symptom onset and disease progression for CSF1R-RD.

Objective: To determine the concentration of glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) and plasma in Alexander disease (AxD) and whether GFAP levels are predictive of disease phenotypes.

Methods: CSF and plasma were collected (longitudinally when available) from AxD participants and non-AxD controls. The concentration of GFAP was compared between groups using Wilcoxon rank sum test. The Kruskal-Wallis test was used to compare GFAP concentrations across multiple groups (clinical phenotype or common genetic variants occurring at p.Arg79, p.Arg88, p.Arg239).

Results: GFAP concentrations were significantly elevated at baseline in both AxD CSF (N = 44) compared to controls (N = 46, p < 0.0001) and AxD plasma (N = 96) compared to other leukodystrophy plasma controls (N = 67, p < 0.0001). CSF and plasma GFAP concentrations differed between AxD cerebral, intermediate, and bulbospinal phenotypes (Kruskal-Wallis test, CSF: p = 0.0235, plasma: p < 0.0001). The median GFAP change/year among patients sampled < 8 years of age at baseline was an increase of 91,100 [pg/mL]/year (IQR 136,050) in CSF and 2850 [pg/mL]/year (IQR 9500) in plasma compared to patients > 8 years whose medians decreased over time (-41,000 [pg/mL]/year [IQR 90,300], CSF; -843 [pg/mL]/year [IQR 3900], plasma). The fold change in GFAP from first to last sampling were significantly different before and after 8 years at baseline (Wilcoxon rank sum test, CSF: p = 0.0232, plasma: p = 0.0002). A significant association was not detected between GFAP variant and GFAP levels.

Interpretation: GFAP concentrations are higher in the cerebral phenotype and increase over time in young children. These data can be used to formulate biomarker qualification and context-of-use in AxD.

Objectives: T-cell large granular lymphocytic leukemia (T-LGLL), reported in up to 58% of inclusion body myositis (IBM) patients, is a rare leukemia of cytotoxic or less commonly helper T cells. The range of myopathies in T-LGLL and the impact of coexisting T-LGLL in IBM are not well understood. Our objectives are to investigate the spectrum of myopathies in patients with T-LGLL and compare the clinical, serological, pathological, and transcriptomic features of IBM patients with and without T-LGLL.

Methods: We reviewed two Mayo Clinic cohorts: (1) T-LGLL patients evaluated for myopathies (2003-2018), and (2) IBM patients tested for T-LGLL via T-cell receptor gene rearrangement or flow cytometry (2016-2022). We also compared transcriptomic profiles of IBM muscle biopsies with and without T-LGLL.

Results: Of 447 T-LGLL patients, 13 (2.9%) had myopathies, IBM being the most common (n = 7). Of 43 IBM patients, 9 (20.9%) had T-LGLL, with 5 diagnosed prior to the onset of weakness. Clinical and pathological features were largely similar between IBM patients with and without T-LGLL, except for milder finger flexor weakness and more frequent neutropenia (55.6% vs. 0%, p < 0.001) in the T-LGLL group. However, transcriptomic analysis of muscle tissues revealed a more immunologically active profile, with upregulation of T-cell and macrophage markers, elevated levels of IFN-γ gene and IFN-γ-inducible genes, heightened cytokine activity, and enhanced immunoglobulin production in IBM patients with T-LGLL.

Interpretation: IBM is the most common myopathy in T-LGLL patients. While clinico-sero-pathological features were largely similar, transcriptomic differences suggest IBM with T-LGLL may represent a distinct, more immune-driven subtype.

We describe the case of a 41-year-old man diagnosed with adult-onset subacute sclerosing panencephalitis (SSPE). The patient presented with subacute progressive cognitive deficits and a neuropsychological profile indicating predominant frontoparietal dysfunction. MRI showed only mild parietal-predominant cerebral atrophy. The patient later developed periodic myoclonic jerks with time-locked periodic slow wave complexes on electroencephalography. Evidence of intrathecal synthesis of anti-measles IgG was identified in the cerebrospinal fluid. The patient satisfied modified Dyken diagnostic criteria and was diagnosed with SSPE. A frontoparietal pattern of deficits on neuropsychological assessment may be an early clue to the diagnosis of adult-onset SSPE.

Objective: Status epilepticus (SE) is associated with significant mortality. Sleep architecture may reflect normal brain function. Impaired sleep architecture is associated with poorer outcomes in numerous conditions. Here we investigate the association of sleep architecture in continuous EEG (cEEG) with survival in SE.

Methods: Retrospective single-centre study of all adult cEEGs in 2015-2019 with electrographic SE. Patients were dichotomized by the presence of sleep architecture (REM or non-REM) in any epoch per an epileptologist blinded to patient outcome. Categorical variables were assessed using Fisher's exact test. Two-sample t-tests and Wilcoxon rank-sum tests compared normally and non-normally distributed variables, respectively. Survival analysis at 6 months used the Mantel-Cox log-rank test. Multivariate analysis using Firth logistic regression assessed for confounders.

Results: Twenty-five adults (68% male) had electrographic SE (median cEEG duration 2 days, hospitalization 13 days). Mean number of intravenous sedatives was 1.44 and anti-seizure medication 2.96. Thirteen adults had sleep architecture, with shorter cEEG delays (median 1 vs. 2 days, p = 0.0104) and younger age (median 56 vs. 72.5 years, p = 0.0386). Sleep architecture was associated with better outcomes at 6-months (p = 0.0073), higher survival rates at 6-months (76.9% vs. 25%, p = 0.017), and longer survival durations at 6-months (160.9 vs. 73.3 days, p = 0.0034). cEEG delay was not associated with survival (p = 0.107).

Significance: In addition to younger age-a known positive SE prognosticator-sleep architecture during cEEG in adults with electrographic SE was associated with increased survival, possibly due to the resilience of younger brains generating sleep architecture in the face of SE, acting as a marker for improved prognosis.

Objective: Kappa free light chains (KFLCs) in the cerebrospinal fluid (CSF) have a similar performance to CSF-restricted oligoclonal bands (OCB) for multiple sclerosis (MS) diagnosis. To help with implementation, we set out to resolve several remaining uncertainties: (1) performance in a real-world cohort and the 2024 McDonald criteria; (2) equivalence to OCB in the specific clinical scenario when demonstration of intrathecal immunoglobulin synthesis is essential for MS diagnosis; (3) which KFLC metric has the best diagnostic performance.

Methods: A retrospective study of 740 cases was conducted, categorised into three groups: MS (2024 McDonald criteria), other neuroinflammatory disorders and non-inflammatory groups. CSF and serum KFLC and albumin were assayed with immunoturbidimetry. OCB status was assessed using isoelectric focusing. Eight KFLC metrics were tested: CSF KFLC, KFLC index, three population-based models of the upper limit for the CSF/serum kappa quotient corrected for CSF/serum albumin quotient, and their corresponding intrathecal fractions.

Results: The KFLC index and the KFLC intrathecal fraction performed as well as OCB; no cases were missed when KFLC was mandatory to achieve a MS diagnosis. Intrathecal fraction computation improved the performance of the population-based models.

Interpretation: In the setting of the 2024 McDonald criteria, KFLC metrics correcting for the CSF/serum albumin quotient were equivalent to OCBs. The intrathecal fraction provided no advantage over the KFLC index, which is simpler to compute. Importantly, the KFLC index can replace OCB when CSF positivity is essential for diagnosis. We provide an explanation for KFLC's comparable diagnostic performance despite its inability to identify CSF-only clones.

Objective: Glioma recurrence severely impacts patient prognosis, with current treatments showing limited efficacy. Traditional methods struggle to analyze recurrence mechanisms due to challenges in assessing tumor heterogeneity, spatial dynamics, and gene networks. Single-cell combined spatial transcriptomics (ST) offers innovative solutions.

Methods: We analyzed glioma mRNA data from TCGA and single-cell and ST data from GEO. Following quality control, dimensionality reduction, clustering, and cell annotation of single-cell sequencing data, we identified cell types exhibiting significantly aberrant distributions between primary and recurrent samples by analyzing the deviation degree of Ro/e values. Fibroblasts demonstrating the greatest intergroup differences were subsequently selected as the key cellular population for further investigation. Key differentially expressed genes (DEGs) were identified via random survival forest analysis. Drug sensitivity was assessed using GDSC. Deconvolution algorithms mapped cellular spatial distribution, while PROGENy quantified pathway activity. MISTy modeling revealed cell-cell interactions.

Results: Fibroblasts were the primary recurrence-associated subpopulation, with marker genes enriched in extracellular matrix and adhesion pathways. AEBP1, ZNF708, and TSHZ2 were identified as key genes: AEBP1/TSHZ2 correlated with poor prognosis, while ZNF708 showed an inverse trend. These genes were linked to chemosensitivity (Irinotecan, Carmustine, Vincristine, and Cisplatin). Recurrent tumors exhibited increased plasma cell infiltration, with key genes regulating IL-17, Notch, and Toll-like receptor pathways. Spatial analysis highlighted oligodendrocyte-astrocyte interactions in the tumor microenvironment.

Interpretation: Fibroblasts drive glioma recurrence, with AEBP1, ZNF708, and TSHZ2 predicting recurrence and chemoresistance. These genes promote immune suppression (via plasma cells) and activate recurrence pathways. Oligodendrocyte-astrocyte interactions shape the recurrent microenvironment, suggesting new therapeutic targets.

Adaptor protein complex 4-associated hereditary spastic paraplegia (AP-4-HSP), a childhood-onset neurogenetic disorder and frequent mimic of cerebral palsy, is caused by biallelic variants in the adaptor protein complex 4 (AP-4) subunit genes (AP4B1 [for SPG47], AP4M1 [for SPG50], AP4E1 [for SPG51], and AP4S1 [for SPG52]). Diagnosis is often confounded by variants of uncertain significance. We evaluated the ATG9A ratio, a measure of ATG9A mislocalization in patient-derived fibroblasts, as a functional assay of AP-4 deficiency. In six of eight individuals with suspected AP-4-HSP, the assay demonstrated loss of AP-4 function, establishing pathogenicity of novel variants. These findings support the ATG9A ratio as a clinically useful diagnostic tool for confirming AP-4-HSP and aiding the classification of novel variants. Trial Registration: ClinicalTrials.gov identifier: NCT06948019, NCT05518188, NCT06692712, NCT04712812.

Background: Limb girdle muscular dystrophy type R9 (LGMDR9) results from biallelic variants in FKRP. There is limited data to predict loss of ambulation (LOA) among those with LGMDR9.

Methods: Participants in an ongoing dystroglycanopathy natural history study (NCT00313677) with FKRP variants who had achieved ambulation and were more than 3 years old were included (n = 97). LOA was defined as self-reported full-time wheelchair use, weakness preventing completion of the 10-m walk-run test (10MWT) or 10MWT time > 30 s. Interval-censored time-to-event analysis was used to determine median age at LOA. Receiver operating characteristic curves were used to examine the ability of 10MWT and 4-stair climb (4SC) times to predict LOA.

Results: Of 97 participants, 55 (57%) were homozygous for the c.826C>A founder variant. Thirty-one participants lost ambulation; 15 (49%) were homozygous for c.826C>A. Earliest age at LOA was 9 years (non-homozygous for c.826C>A). Median age at LOA for the cohort was 46.0 years. Performances on 10MWT and 4SC were highly predictive of LOA within 3 years, with areas under the ROC curve of 0.89 (10MWT) and 0.87 (4SC) when genotype was included in analysis. Optimal cutoffs for predicting LOA within 3 years differed by genotype and had acceptable sensitivity and specificity.

Discussion: LOA among those with LGMDR9 is strongly predicted by performance on 10MWT and 4SC. These results demonstrate the real-world significance of standardized motor function tests used in LGMDR9 clinical trials and aid in anticipatory guidance.