Annals of Neurology最新文献

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: 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.

Objective: Despite treatments which reduce relapses in multiple sclerosis (MS), many patients continue to experience progressive disability accumulation. MS is associated with metabolic disruptions and cerebral metabolic stress predisposes to tissue injury and possibly impaired remyelination. Additionally, myelin homeostasis is metabolically expensive and reliant on glycolysis. We investigated cerebral metabolic changes in MS and when in the disease course they occurred, and assessed their relationship with microstructural changes.

Methods: This study used combined fluorodeoxyglucose (FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI) to measure cerebral metabolic rate of glucose and oxygen, thereby quantifying glycolysis. Twelve healthy controls, 20 patients with relapsing MS, and 13 patients with non-relapsing MS were studied. Relapsing patients with MS were treatment naïve and scanned pre- and post-initiation of high efficacy disease modifying therapy.

Results: In normal appearing white matter, we observed increased glucose utilization and reduced oxygen utilization in newly diagnosed MS, consistent with increased glycolysis. Increased glycolysis was greater in patients with a longer disease duration course and higher disability. Among newly diagnosed patients, different treatments had differential impacts on glucose utilization. Last, whereas hypermetabolism within lesions was clearly associated with inflammation, no such relationship was found within normal appearing white matter.

Interpretation: Increased white matter glycolysis is a prominent feature of cerebral metabolism in MS. It begins early in the disease course, increases with disease duration and is independent of microstructural evidence of inflammation in normal appearing white matter. Optimization of the metabolic environment may be an important component of therapies designed to reduce progressive disability. ANN NEUROL 2024.

Objective: Parkinson's disease (PD) resting tremor is thought to be initiated in the basal ganglia and amplified in the cerebello-thalamo-cortical circuit. Because stress worsens tremor, the noradrenergic system may play a role in amplifying tremor. We tested if and how propranolol, a non-selective beta-adrenergic receptor antagonist, reduces PD tremor and whether or not this effect is specific to stressful conditions.

Methods: In a cross-over, double-blind intervention study, participants with PD resting tremor received propranolol (40 mg, single dose) or placebo (counter-balanced) on 2 different days. During both days, we assessed tremor severity (with accelerometry) and tremor-related brain activity (with functional magnetic resonance imaging), as well as heart rate and pupil diameter, while subjects performed a stressful cognitive load task that has been linked to the noradrenergic system. We tested for effects of drug (propranolol vs placebo) and stress (cognitive load vs rest) on tremor power and tremor-related brain activity.

Results: We included 27 PD patients with prominent resting tremor. Tremor power significantly increased during cognitive load versus rest (F[1,19] = 13.8; p = 0.001; ${\eta }_p^2$  = 0.42) and decreased by propranolol versus placebo (F[1,19] = 6.4; p = 0.02; ${\eta }_p^2$  = 0.25), but there was no interaction. We observed task-related brain activity in a stress-sensitive cognitive control network and tremor power-related activity in the cerebello-thalamo-cortical circuit. Propranolol significantly reduced tremor-related activity in the motor cortex compared to placebo (F[1,21] = 5.3; p = 0.03; ${\eta }_p^2$  = 0.20), irrespective of cognitive load.

Interpretation: Our findings indicate that propranolol has a general, context-independent, tremor-reducing effect that may be implemented at the level of the primary motor cortex. ANN NEUROL 2024.