Annals of Clinical and Translational Neurology最新文献

Background and objectives: Multiple sclerosis (MS) exhibits racially disparate rates of disease progression. Black people with MS (B-PwMS) experience a more severe disease course than non-Hispanic White people with MS (NHW-PwMS). Here we investigated structural and functional connectivity as well as structure-function decoupling in the sensorimotor and default mode networks (SMN and DMN, respectively), which play a key role in determining physical and cognitive disability in people with MS.

Methods: A total of 176 participants (50 B-PwMS, 50 NHW-PwMS, 41 Black healthy controls (B-HCs), and 35 NHW-HCs) underwent 3T-MRI with T1, resting-state functional, & diffusion imaging, and clinical assessment with Expanded-Disability-Status-Scale (EDSS) & Symbol-Digit-Modalities-Test (SDMT). T1-weighted images were lesion-filled and segmented to obtain cortical, subcortical, and cerebellar structures. Diffusion and functional MRI datasets were preprocessed, and structural and functional connectivity were extracted between regions defined by the AAL3 atlas. Global and local network measures were extracted for both structural and functional connectivity, and structure-function decoupling was quantified by calculating the correlation between the strengths of the two networks, considering only edges with non-zero structural connectivity. Network measures were compared between subgroups, accounting for the impact of demographics and social determinants of health, with correction for multiple comparisons.

Results: Despite similar disease duration, treatment exposure, lesion load and brain volumes, B-PwMS exhibited higher EDSS and lower SDMT scores compared to NHW-PwMS, which were influenced by total income and body mass index. In both B- and NHW-PwMS, structural global efficiency and streamline density were lower in the SMN and DMN compared to their respective HCs. Structural characteristic path length in SMN was significantly higher in B-PwMS versus B-HCs, whereas no significant differences were observed in NHW groups. Extensive local rearrangements of structural and functional hubs were observed in the SMN and DMN of B-PwMS compared to B-HCs and NHW-PwMS. B-PwMS showed greater structure-function decoupling in the SMN as compared to the other groups. There was a trend towards a higher decoupling in the DMN with lower SDMT scores (ρ = -0.20, p = 0.05), and higher decoupling in the SMN with higher EDSS scores (ρ = 0.20, p = 0.06).

Discussion: Despite similar brain volumes and lesion load, B-PwMS showed a greater rearrangement of brain structural and functional connectivity within the SMN and DMN when compared with NHW-PwMS. Moreover, B-PwMS showed a higher degree of structure-function decoupling in the SMN, with a trend towards association with increased physical disability.

Objective: Super-Refractory Status Epilepticus (SRSE) is a rare, life-threatening neurological emergency with unclear etiology in many cases. Mitochondrial dysfunction, often due to disease-causing genetic variants, is increasingly recognized as a cause, with each gene producing distinct pathophysiological mechanisms.

Methods: We describe the detailed clinical, neurophysiological, neuroimaging, and molecular findings of a 19-year-old female with SRSE associated with compound heterozygous variants in OPA1, a key gene for mitochondrial inner membrane fusion and cristae maintenance. In addition, a literature review was performed, identifying 16 previously published cases reporting one or both of the variants observed in the present case.

Results: Despite a longstanding history of generalized hypotonia, celiac disease, optic atrophy, cerebellar ataxia, and progressive motor decline, the proband had no prior history of seizures. She developed super-refractory status epilepticus with occipital-predominant epileptiform activity and MRI showing transient diffusion restriction in the right parieto-occipital cortex and cerebellum. Genetic testing revealed a frameshift variant (p.Val903GlyfsTer3) and a missense variant (p.Ile382Met) in the GTPase domain, known to impair mitochondrial fusion. Unlike POLG or MELAS-associated seizures, typically driven by severe mtDNA depletion and respiratory chain failure, OPA1 dysfunction usually spares mtDNA copy number but disrupts mitochondrial dynamics. In severe biallelic loss-of-function, a "second-hit" stressor may trigger a diffuse energy crisis and catastrophic seizures.

Interpretation: This case of mitochondrial SRSE in a patient with no known infectious, autoimmune, or structural cause emphasizes the possible role of genetic background and mitochondrial disorders in the development of the disease. This case highlights a rare mitochondrial subtype of RSE, emphasizing the need to consider energy metabolism defects in unexplained refractory status epilepticus.

Objective: To examine the value of MRI outcomes as endpoints for preventive and early-stage trials of two polyglutamine spinocerebellar ataxias (SCAs).

Methods: A cohort of 100 participants (23 SCA1, 63 SCA3, median Scale for the Assessment and Rating of Ataxia (SARA) score = 5, 42% preataxic, and 14 gene-negative controls) was scanned at 3T up to 6 times (median follow-up 3 years) in the READISCA study. Structural, microstructural, and neurochemical outcomes were assessed for sensitivity to change. Associations between change in MR and clinical and patient-reported outcomes were evaluated. Sample sizes were estimated for preventive trials (at preataxic stage) and early-stage trials using the most sensitive outcomes.

Results: Infratentorial volumes, middle cerebellar peduncle (MCP) diffusivities and select neurochemical outcomes were more sensitive to change than SARA in both SCAs with moderate-to-high effect sizes (Cohen's d ≥ 0.5). The pons volume was the most sensitive outcome at both preataxic (d = 1.09) and ataxic (d = 1.48) stages. The most sensitive MR measures overlapped between genotypes, except that SCA1 showed faster progression in the cerebellum and SCA3 in the pons. Changes in MCP diffusivities and pontine neurochemical measures were associated with changes in SARA and FARS-ADL (|r| = 0.28-0.47).

Interpretation: The estimated sample sizes to detect a 50% reduction in progression with 80% power using the pons volume as primary outcome measure indicate the feasibility of preventive trials (n = 73 per arm in a 1-year trial) in common SCAs and predict a 6-fold reduction in required sample sizes relative to SARA in early interventional trials. These findings support the use of MRI endpoints in early-stage SCA trials.

Purpose: Air pollution has been linked to several neurological conditions, including stroke and neurodegenerative diseases. Evidence regarding its association with multiple sclerosis (MS) remains conflicting, limited by small sample sizes.

Methods: PubMed, Embase, Scopus, and Cochrane controlled register of trials (CENTRAL) were searched on September 9, 2025 without any language or time restrictions. The inclusion criteria were observational studies that evaluated the association between exposure to air pollutants and MS development or severity. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled as effect estimates using the fixed or random effects model. Exposures included PM2.5, PM10, nitrogen dioxide (NO₂), carbon monoxide (CO), sulfur dioxide (SO₂), and ozone (O₃). Outcomes were MS risk and severity, including relapses, disability progression measured with the Expanded Disability Status Scale (EDSS), and contrast-enhancing lesions (CELs) development.

Results: Twenty-two studies comprising 16,585,206 participants were included. Long-term exposure to PM2.5 (HR = 1.21; 95% CI: 1.07-1.38), PM10 (HR = 1.20; 95% CI: 1.02-1.42), and CO (HR = 3.85; 95% CI: 1.34-11.08) were associated with increased MS risk. Short-term exposure to PM2.5 (HR = 1.20; 95% CI: 1.01-1.43), PM10 (HR = 1.20; 95% CI: 1.01-1.45), NO₂ (HR = 1.13; 95% CI: 1.02-1.25), and O₃ (HR = 1.15; 95% CI: 1.04-1.27) were associated with relapses. Short-term exposure to PM2.5 (HR = 2.20; 95% CI: 1.05-4.60) and PM10 (HR = 1.02; 95% CI: 1.01-1.03) were linked to CELs, while PM10 (HR = 1.31; 95% CI: 1.04-1.65) was associated with disability progression.

Interpretation: Long-term air pollution exposure was associated with higher MS risk, and short-term exposure with greater disease severity. Reducing air pollution may be a key strategy to protect brain health in MS.

Objective: Long-read sequencing and optical genome mapping technologies have the ability to detect large and complex structural variants. This has led to the discovery of novel pathogenic variants in neurodegenerative movement disorders. Thus, we aimed to systematically compare the SV detection capabilities of OGM and ONT in Parkinson's disease.

Methods: Ultra-high molecular weight DNA was derived from blood and fibroblast cultures of 19 patients with mostly early-onset Parkinson's disease, and used for Nanopore sequencing and optical genome mapping. The size distributions of deletions and insertions were compared, and variants were filtered for rare or potentially pathogenic variants in 134 known movement disorder genes.

Results: Both methods identified SVs > 50 kb; however, optical mapping identified fewer structural variants (49,677) compared to Nanopore sequencing (94,400), but detected six times more in the range 50-80 kb. In general, it detected significantly larger deletions and insertions (p < 2.2 × 10^-16). Both methods detected a benign intergenic deletion (195 kb) near ITPR1, and optical mapping validated a previously published 7-Mb PRKN inversion. Small heterozygous deletions in ATXN2, SUCLA2, and PNKD detected by optical mapping were identified to be intronic by Nanopore sequencing. No causal variants were identified in movement disorder genes.

Interpretation: Optical mapping can be a powerful first-line method for detecting large structural variants, but it requires a high-resolution method to refine breakpoint positions. Despite certain limitations, Nanopore sequencing was highly capable of detecting large variants independently and allows for a highly complementary assessment and validation of structural variation in combination with optical mapping.

We report a 58-year-old woman with a novel splice-site variant in the TANK-binding kinase 1 (TBK1:c.993-2A>C p.Ala332TyrfsTer39) who sequentially developed primary lateral sclerosis (PLS) followed by right temporal variant frontotemporal dementia (rtvFTD). Neuroimaging demonstrated right anterior temporal atrophy before cognitive symptoms, and prosopagnosia represented the earliest manifestation of rtvFTD. Molecular analysis revealed reduced levels of correctly spliced TBK1 transcripts, consistent with haploinsufficiency. Given the shared involvement of TDP-43 pathology in both PLS and rtvFTD, this case indicates TBK1 dysfunction as a fundamental genetic factor underlying the coexistence of these phenotypes, underscoring the clinical value of early neuroimaging and genetic evaluation.

Objective: Disrupted neurofluid regulation may contribute to neurodegeneration in Huntington disease (HD). Because neurofluid pathways influence waste clearance, inflammation, and the distribution of central nervous system (CNS)-delivered therapeutics, understanding their dysfunction is increasingly important as targeted treatments emerge. We aimed to evaluate structural and physiological changes in two key neurofluid components, the choroid plexus (ChP), which produces cerebrospinal fluid (CSF), and the parasagittal dural (PSD) space, a major CSF outflow pathway, across the HD spectrum and in relation to CSF flow dynamics.

Methods: PSD and ChP volumes were assessed using a validated deep learning pipeline on 3-Tesla T₂-weighted and FLAIR MRI. CSF flow at the cerebral aqueduct was measured with phase contrast MRI, and ChP perfusion was quantified using pseudo-continuous arterial spin labeling MRI. Linear regression models assessed the relationships between PSD and ChP volume, CSF flow kinetics, ChP hemodynamics, disease severity, disease exposure, and disease presentation, adjusting for age, sex, and intracranial volume.

Results: 80 HD participants and 65 age-matched healthy controls were included. HD showed significantly larger ChP and PSD volumes (p < 0.01) and reduced ChP perfusion (p < 0.01). Greater CAG repeat expansion correlated with larger PSD and ChP volume and lower ChP perfusion (p < 0.01). These alterations were associated with worse motor impairment (p < 0.01).

Interpretation: HD is associated with structural and functional alterations in neurofluid pathways. These findings suggest relevance for disease mechanisms and for optimizing CSF-based therapeutic delivery, highlighting the need for further mechanistic studies.

A 73-year-old man presented with progressive weakness and atrophy predominantly affecting the distal finger flexors and quadriceps muscles. Electrophysiological studies demonstrated mixed myogenic and neurogenic features. Muscle MRI showed inflammatory changes, and muscle biopsy revealed granulomatous myositis with histologic features characteristic of inclusion body myositis (IBM), including rimmed vacuoles, TDP-43 mislocalization, and autophagy activation. Additional extensive laboratory and imaging workup ruled out systemic etiologies. An empiric trial of high-dose corticosteroids yielded no clinical improvement. The diagnostic challenge stemmed from the broad differential diagnosis of granulomatous myositis and the possibility that non-IBM etiologies might be responsive to immunosuppressive treatment. This case underscores the importance of integrating clinical, electrophysiologic, radiologic, and histopathologic findings to accurately diagnose and manage granulomatous myositis.

Introduction: Spinal cord infarction (SCI) is a rare but devastating myelopathy, characterized by a high disability rate and an unfavorable prognosis. It has often been underdiagnosed and misdiagnosed as idiopathic transverse myelitis (ITM). This study aimed to describe the clinical features, radiological biomarkers, treatments, and functional outcome of SCI, distinguishing it from ITM.

Methods: A retrospective observational cohort study included patients who met the diagnostic criteria of SCI and ITM from January 2019 to October 2024. The clinical, radiological data, and diagnosis were recorded, and the functional outcomes were reached via telephone and face-to-face evaluations. Univariate analysis was used to differentiate the two groups.

Results: During the study period, a total of 22 SCI patients with a median age of 53.0 years (interquartile range (IQR): 41.8 to 60.2) were enrolled. Thirteen patients underwent the diffusion-weighted imaging (DWI) and the apparent diffusion coefficient (ADC) sequence, among whom 12 were confirmed as having definite SCI. Compared with ITM, SCI has the following characteristics. The time from onset to nadir in SCI is much shorter, mostly within 6 h (p < 0.001). On sagittal MRI, SCI often manifests as linear lesions, while ITM tends to present as patchy and fusiform lesions (p < 0.001). We have also defined a lesion characteristic of SCI based on T2-weighted sequences, termed the "eccentric sign". Moreover, patients with SCI generally have a poorer prognosis and higher dependence.

Conclusions: SCI can be diagnosed and differentiated from ITM based on clinical features and radiological signs.

This case details a 35-year-old man with no past medical history who presents with acute paraparesis and urinary retention in the setting of progressive paresthesias and weakness of his lower and upper extremities over several months. He was found to have longitudinally extensive transverse myelitis involving the cervical to mid-thoracic cord with concomitant findings of mediastinal and hilar lymphadenopathy. An extensive serum and cerebrospinal fluid (CSF) workup of possible autoimmune, paraneoplastic, infectious, and toxic/metabolic etiologies was overall nonrevealing, but an endobronchial ultrasound-guided biopsy of the enlarged hilar lymph nodes revealed noncaseating granulomas. The patient demonstrated significant improvement after completing two courses of pulse-dose steroids and was ultimately discharged to intensive inpatient rehabilitation for further treatment.