Annals of Neurology最新文献

Objective: Approximately 20% of familial cases of amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Epidemiological data have identified traumatic brain injury (TBI) as an exogenous risk factor for ALS; however, the mechanisms by which TBI may worsen SOD1 ALS remain largely undefined.

Methods: We sought to determine whether repetitive TBI (rTBI) accelerates disease onset and progression in the transgenic SOD1^G93A mouse ALS model, and whether loss of the primary regulator of axonal degeneration sterile alpha and TIR motif containing 1 (Sarm1) mitigates the histological and behavioral pathophysiology. We subjected wild-type (n = 23), Sarm1 knockout (KO; n = 17), SOD1^G93A (n = 19), and SOD1^G93AxSarm1^KO (n = 26) mice of both sexes to rTBI or sham surgery at age 64 days (62-68 days). Body weight and ALS-deficit score were serially assessed up to 17 weeks after surgery and histopathology assessed in layer V of the primary motor cortex at the study end point.

Results: In sham injured SOD1^G93A mice, genetic ablation of Sarm1 did not attenuate axonal loss, improve neurological deficits, or survival. The rTBI accelerated onset of G93A-SOD1 ALS, as indicated by accentuated body weight loss, earlier onset of hindlimb tremor, and shortened survival. The rTBI also triggered TDP-43 mislocalization, enhanced axonal and neuronal loss, microgliosis, and astrocytosis. Loss of Sarm1 significantly diminished the impact of rTBI on disease progression and rescued rTBI-associated neuropathology.

Interpretation: SARM1-mediated axonal death pathway promotes pathogenesis after TBI in SOD1^G93A mice suggesting that anti-SARM1 therapeutics are a viable approach to preserve neurological function in injury-accelerated G93A-SOD1 ALS. ANN NEUROL 2025.

Objective: Despite the overwhelming evidence for profound and longstanding effects of early-life stress (ELS) on inflammation, brain structure, and molecular aging, its impact on human brain aging and risk for neurodegenerative disease is poorly understood. We examined the impact of ELS severity in interaction with age on blood-based markers of neuroinflammation and neurodegeneration, brain volumes, and cognitive function in middle-aged women.

Methods: We recruited 179 women (aged 30-60 years) with and without ELS exposure before the onset of puberty. Using Simoa technology, we assessed blood-based markers of neuroinflammation and neurodegeneration, including serum concentrations of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL). We further obtained T1-weighted and T2-weighted magnetic resonance images to assess brain volumes and we assessed cognitive performance sensitive to early impairments associated with the development of dementia, using the Cambridge Neuropsychological Automated Test Battery. We used generalized additive models to examine nonlinear interaction effects of ELS severity and age on these outcomes.

Results: Analyses revealed significant nonlinear interaction effects of ELS severity and age on NfL and GFAP serum concentrations, total and subcortical gray matter volume loss, increased third ventricular volume, and cognitive impairment.

Interpretation: These findings suggest that ELS profoundly exacerbates peripheral, neurostructural, and cognitive markers of brain aging. Our results are critical for the development of novel early prevention strategies that target the impact of developmental stress on the brain to mitigate aging-related neurological diseases. ANN NEUROL 2025.

Objective: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is, in most cases, an early stage of Parkinson's disease or related disorders. Diagnosis requires an overnight video-polysomnogram (vPSG), however, even for sleep experts, interpreting vPSG data is challenging. Using a 3D camera, automated analysis of movements has yielded high accuracy. We aimed to replicate and extend prior work using a conventional 2D camera.

Methods: The dataset included 172 vPSG recordings from a clinical sleep center, 81 patients with iRBD and 91 non-RBD healthy controls (63 with a range of other sleep disorders and 28 healthy sleepers). An optical flow computer vision algorithm automatically detected movements during rapid eye movement (REM) sleep, from which features of rate, ratio, magnitude and velocity of movements, and ratio of immobility were extracted.

Results: Patients with iRBD exhibited an increased number of shorter movements and immobility periods. Accuracies for detecting iRBD ranged from 84.9% (with 2 features) to 87.2% (with 5 features). Combining all 5 features but only analyzing short (0.1-2 second duration) movements achieved the highest accuracy at 91.9%. Of the 11 patients with iRBD without noticeable movements during vPSG, 7 were correctly identified.

Interpretation: This work improves prior art by using a 2D camera routinely used in sleep laboratories and improving performance by adding only 3 features. This approach could be implemented in clinical sleep laboratories to facilitate and improve the diagnosis of iRBD. Coupled with automated detection of REM sleep, it should also be tested in the home environment using conventional infrared cameras to detect and/or monitor RBD. ANN NEUROL 2025.

Transient focal neurological episodes (TFNE), often associated with convexity subarachnoid hemorrhage (cSAH), are common in cerebral amyloid angiopathy (CAA), but their pathophysiology remains incompletely understood. In six patients with unremitting TFNE, using high-resolution post-contrast magnetic resonance imaging and vessel wall imaging (VWI), we found various combinations of transient leptomeningeal, parenchymal and vessel wall enhancement; in 5 of 6 the enhancement included regions corresponding anatomically to symptoms. Three patients had resolution of TFNE and enhancement (2 with corticosteroid treatment, 1 without). Our observations suggest that inflammation might contribute to the pathophysiology of CAA-related TFNE and cSAH, with potential wider relevance for the associated high risks of recurrent ICH in CAA more generally. ANN NEUROL 2025.

Objective: Inclusion body myositis (IBM) is an idiopathic inflammatory myopathy with muscle pathology characterized by endomysial inflammation, rimmed vacuoles, and cytoplasmic mislocalization of transactive response DNA-binding protein 43 (TDP-43). We aimed to determine whether loss of TDP-43 splicing repression led to the production of "cryptic peptides" that could be detected in muscle biopsies as a useful biomarker for IBM.

Methods: We used an antisera against a neoepitope encoded by a TDP-43-dependent cryptic exon within hepatoma-derived growth factor-like protein 2 (HDGFL2) for immunohistochemical analysis on muscle biopsy samples of 122 patients with IBM, 181 disease controls, and 16 healthy controls without abnormal muscle pathology. In situ hybridization was also utilized to detect the localization of cryptic HDGFL2 transcripts.

Results: We found cryptic HDGFL2 peptides localized within myonuclei from muscle biopsies in 79 of 122 patients with IBM (65%), and this staining correlated with TDP-43 depletion. In contrast, cryptic HDGFL2 immunoreactivity was absent in 197 muscle biopsies from a variety of disease controls, except for 2 patients with vacuolar myopathies. Notably, we show that cryptic HDGFL2 transcripts are accompanied by the detection of cryptic HDGFL2 in muscle fibers of IBM without rimmed vacuoles and TDP-43 aggregates.

Interpretation: Together, our findings establish that loss of TDP-43 splicing repression occurs in myonuclei of IBM skeletal muscle and suggest that detection of cryptic peptides in muscle biopsies may be a useful biomarker. We suggest that a therapeutic strategy designed to restore TDP-43 function should be considered to attenuate the degeneration of skeletal muscle in this devastating disease. ANN NEUROL 2025.

Objective: Monoallelic variants in the transient receptor potential melastatin-related type 3 gene (TRPM3) have been associated with neurodevelopmental manifestations, but knowledge on the clinical manifestations and treatment options is limited. We characterized the clinical spectrum, highlighting particularly the epilepsy phenotype, and the effect of treatments.

Methods: We analyzed retrospectively the phenotypes and genotypes of 43 individuals with TRPM3 variants, acquired from GeneMatcher and collaborations (n = 21), and through a systematic literature search (n = 22). We included all patients with a pathogenic TRPM3 variant.

Results: The median age at the time of the study was 10 years, with a preponderance of girls (60%) versus boys (40%). Frequent findings were developmental delay and/or intellectual disability (93%), global or axial hypotonia (77%), ocular involvement (70%), musculoskeletal anomalies (65%), and dysmorphic features (58%). Epilepsy was diagnosed in 31 patients (72%), classified in all as developmental and epileptic encephalopathy with or without spike wave activation in sleep (DEE/DEE-SWAS). Patients with the variant p.Val1002Met (n = 24) significantly more often had developmental delay and epilepsy. The most effective anti-seizure medication was primidone. All treated patients showed an improvement in seizure frequency, motor and speech development, and/or learning capability with this drug.

Interpretation: Developmental delay/intellectual disability and epilepsy are dominant phenotypic features in patients with TRPM3 variants. Given that epilepsy can negatively impact development, screening for awake and sleep electroencephalogram abnormalities and other manifestations are essential to offer early intervention. The TRPM3 channel blocker primidone has shown promising effects and should be considered in every child with a TRPM3 gain-of-function variant. ANN NEUROL 2025.

Objective: Among patients with acute stroke, we aimed to identify those who will later develop central post-stroke pain (CPSP) versus those who will not (non-pain sensory stroke [NPSS]) by assessing potential differences in somatosensory profile patterns and evaluating their potential as predictors of CPSP.

Methods: In a prospective longitudinal study on 75 acute stroke patients with somatosensory symptoms, we performed quantitative somatosensory testing (QST) in the acute/subacute phase (within 10 days) and on follow-up visits for 12 months. Based on previous QST studies, we hypothesized that QST values of cold detection threshold (CDT) and dynamic mechanical allodynia (DMA) would differ between CPSP and NPSS patients before the onset of pain. Mann-Whitney U-tests and mixed analysis of variances with Bonferroni corrections were performed to compare z-normalized QST scores between both groups.

Results: In total, 26 patients (34.7%) developed CPSP. In the acute phase, CPSP patients showed contralesional cold hypoesthesia compared to NPSS patients (p = 0.04), but no DMA differences. Additional exploratory analysis showed NPSS patients exhibit cold hyperalgesia on the contralesional side compared to the ipsilesional side, not seen in CPSP patients (p = 0.011). A gradient-boosting approach to predicting CPSP from QST patterns before pain onset had an overall accuracy of 84.6%, with a recall and precision of 75%. Notably, both in the acute and the chronic phase, approximately 80% of CPSP and NPSS patients showed bilateral QST abnormalities.

Interpretation: Cold perception differences between CPSP and NPSS patients appear early post stroke before pain onset. Prediction of CPSP through QST patterns seems feasible. ANN NEUROL 2024.

Objective: Computed tomography perfusion (CTP) imaging is crucial in quantifying cerebral blood flow (CBF) and thereby making an endovascular treatment (EVT) after large vessel occlusion. However, CTP is prone to overestimating the ischemic core. We sought to delineate the optimal regional CBF (rCBF) thresholds of pre-EVT CTP.

Methods: We collected acute ischemic stroke patients due to large vessel occlusion who achieved successful recanalization with baseline CTP, immediate post-EVT diffusion-weighted image (DWI) within 3 hours, and delayed post-EVT DWI between 24 and 196 hours. Core volumes estimated by CTP at various rCBF thresholds were validated against immediate and delayed DWI lesion volumes.

Results: A total of 175 acute large vessel occlusion patients were included. Baseline CTP was taken in a median of 24 minutes (interquartile range [IQR] 21-31 minutes) after arrival; after the CTP, groin puncture in a median of 37 minutes (IQR 28-52 minutes), immediate post-EVT DWI scans in a median of 1.6 hours (IQR 0.8-2.1 hours), and delayed DWI scans in a median of 89 hours (IQR 69-106 hours). The correlations between the rCBF thresholds were the best at rCBF <22% for immediate DWI (0.64; 95% CI 0.55-0.73) and at rCBF <30% for delayed DWI (0.69; 95% CI 0.61-0.76). The interval between CTP and recanalization was inversely correlated with the overestimation of ischemic core volume compared with the subsequent DWI.

Interpretation: Optimal rCBF thresholds for estimating ischemic core using CTP depend significantly on the timing of DWI post-EVT and CTP to recanalization delay. The optimal rCBF thresholds for ischemic core estimation may vary depending on the clinical setting. ANN NEUROL 2024.

Objective: Remote identification of individuals with severe hyposmia may enable scalable recruitment of participants with underlying alpha-synuclein aggregation. We evaluated the performance of a staged screening paradigm using remote smell testing to enrich for abnormal dopamine transporter single-photon emission computed tomography imaging (DAT-SPECT) and alpha-synuclein aggregation.

Methods: The Parkinson's Progression Markers Initiative (PPMI) recruited participants for the prodromal cohort who were 60-years and older without a Parkinson's disease diagnosis. Participants were invited to complete a University of Pennsylvania Smell Identification Test (UPSIT) independently through an online portal. Hyposmic participants were invited to complete DAT-SPECT, which determined eligibility for enrollment in longitudinal assessments and further biomarker evaluation including cerebrospinal fluid alpha-synuclein seed amplification assay (aSynSAA).

Results: As of January 29, 2024, 49,843 participants were sent an UPSIT and 31,293 (63%) completed it. Of UPSIT completers, 8,301 (27%) scored <15th percentile. Of 1,546 who completed DAT-SPECT, 1,060 (69%) had DAT-SPECT binding <100% expected for age and sex. Participants with an UPSIT <10th percentile (n = 1,221) had greater likelihood of low DAT-SPECT binding compared to participants with an UPSIT in the 10th to 15th percentile (odds ratio, 3.01; 95% confidence interval, 1.85-4.91). Overall, 55% (198/363) of cases with UPSIT <15th percentile and DAT-SPECT <100% had positive aSynSAA, which increased to 70% (182/260) when selecting for more severe hyposmia (UPSIT <10th percentile).

Interpretation: Remote screening for hyposmia and reduced DAT-SPECT binding identifies participants with a high proportion positive aSynSAA. Longitudinal data will be essential to define progression patterns in these individuals to ultimately inform recruitment into disease modification clinical trials. ANN NEUROL 2024.