Annals of Clinical and Translational Neurology最新文献

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.

Objective: To investigate the value of constructing models based on habitat radiomics and pathomics for predicting the risk of progression in high-grade gliomas.

Methods: This study conducted a retrospective analysis of preoperative magnetic resonance (MR) images and pathological sections from 72 patients diagnosed with high-grade gliomas (52 cases as a train cohort and 20 cases as a test cohort). The regions of interest (ROIs) were annotated accordingly. In MRI processing, the ROI was further divided into clusters to extract habitat radiomics features. For whole slide imaging (WSI), the ROI was cropped into equal-sized image patches for weakly supervised learning and deep learning using various network architectures. The optimal model architecture was selected, and pathological features were extracted. After feature selection, four independent models were constructed: habitat radiomics model, pathomics-based model, clinical model, and combined model integrating all information. Model performance was evaluated using the concordance index (C-index) and the area under the receiver operating characteristic curve (AUC).

Results: The combined model demonstrated the best predictive performance, with a C-index of 0.883 and an AUC of 0.965 in the train cohort. In the test cohort, the C-index was 0.840, and the AUC was 0.927. Based on the combined model, patients with high-grade gliomas were divided into high-risk and low-risk groups, with median progression-free survival (mPFS) of 9 months and 77 months, respectively (p < 0.001).

Conclusion: Compared with the habitat radiomics model or the pathomics-based model alone, the combined model can better predict the risk of progression in high-grade gliomas and provides valuable guidance for personalized treatment of high-grade gliomas.

The practice of neurology requires an understanding of clinical ethics for decision-making. In multiple sclerosis (MS) care, there are a wide range of ethical considerations that may arise. These involve shared decision-making around selection of a disease-modifying therapy (DMT), risks and benefits of well-studied medications in comparison to supplements with limited information, allocation of resources and accessibility to MS care, and disparities in healthcare. We share a series of cases that illustrate ethical issues that may arise in the care of patients with MS. This narrative review articulates relevant ethical theories and frameworks that can be applied to common clinical scenarios in the current practice of MS.

Objective: To characterize whole-body intramuscular fat distribution pattern in patients with sarcoglycanopathies and explore correlations with disease severity, duration and age at onset.

Methods: Retrospective, cross-sectional, multicentric study enrolling patients with variants in one of the four sarcoglycan genes who underwent whole-body muscle MRI. Intramuscular fatty replacement was evaluated on T1-weighted images and represented by heatmaps. Dimensionality reduction and linear spline models examined relationships between patterns of intramuscular fat replacement and clinical findings.

Results: MRI scans from 64 patients (age range 4-67 years) covering 4160 muscles were analyzed. Disease severity ranged from asymptomatic (9%) to non-ambulant (39%) patients. Sarcoglycanopathies showed consistent, selective patterns of muscle involvement across genotypes. Latissimus dorsi and subscapularis were the earliest affected muscles in the upper body, whereas head, neck and forearm muscles remained largely preserved. Distinct gradients characterized the topography of degeneration both within individual muscles and along body and limb axes. Disease severity correlated with MRI changes in both upper and lower body muscles, and with one of the dimensions identified by the multi-correspondence analysis. Patients with onset in the first decade showed a steeper cross-sectional association between disease duration and MRI abnormalities, while later-onset patients displayed a more gradual, linear relationship.

Interpretation: Sarcoglycanopathies display selective muscle vulnerability with characteristic gradients of fat replacement. Scapular girdle muscles are affected early in the disease course. Intramuscular fat correlates with functional impairment and disease duration, supporting its use as a surrogate endpoint in clinical trials. Age at onset emerges as a critical prognostic factor.

Tyrosine kinase inhibitors are the cornerstone of chronic myeloid leukemia treatment. Newer agents have more potency and a broader spectrum of action, but also a higher potential for neuropsychiatric side effects. We present a case of a patient on imatinib who developed progressive cognitive, mood, and behavioral alterations. He was investigated for dementia and psychiatric disorders but ultimately improved only after discontinuing imatinib. His decompensation years after therapy start, followed by complete and rapid remission, is atypical. We also review the most recent neurobiological findings on the role of tyrosine kinase alterations in dementia and their importance for mood regulation.

Objective: Abnormalities on peri-ictal diffusion-weighted magnetic resonance imaging (DWI-PMAs) are well-established for patients with status epilepticus (SE), but knowledge on patterns of DWI-PMAs and their prognostic impact is sparse.

Methods: This systematic review and individual participant data meta-analysis included observational studies reporting adult patients with first-time non-anoxic SE with DWI-PMAs. Authors reporting ≥ 10 patients were invited to share standardized individual participant data.

Results: We identified 161 studies reporting on 531 individual patients (average age 52 years) who could be classified into one of six different DWI-PMA patterns. Of all reported DWI-PMAs, 94.3% involved either cortex or hippocampus. Comparing DWI-PMA patterns, pure hippocampal DWI-PMAs (n = 54, 10.2%) were associated with younger age, known epilepsy, and low mortality. Additional thalamic involvement (n = 132, 26.1%) was linked to temporal DWI-PMAs and was an independent predictor of poor functional outcome. Independent of the patterns, bilateral DWI-PMAs and involvement of more than four cortical lobes were associated with worse outcome. Cerebellar involvement (n = 36, 6.8%) was associated with non-temporal lobe DWI-PMAs, coma, and independently associated with poor functional outcome. Lateralization of DWI-PMAs and epileptic discharges showed substantial agreement (Cohen's kappa 0.69, p < 0.001). Lateralized or generalized period discharges were associated with thalamic involvement (54.2%) and were less frequent in patients with pure cortical (33.0%) or hippocampal DWI-PMAs (21.4%, p < 0.001).

Interpretation: DWI-PMA due to SE originates from the cortex and/or hippocampus depending on age and etiology. Additional involvement of the thalamus and cerebellum is associated with worse outcomes, as are more widespread DWI-PMA. Lateralized or generalized periodic discharges are associated with thalamic involvement.

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.