Annals of Clinical and Translational Neurology最新文献

Objective: Prion disease classically presents with rapidly progressive dementia, leading to death within months of diagnosis. Advances in diagnostic testing have improved recognition of patients with atypical presentations and protracted disease courses, raising key questions surrounding the relationship between patterns of neurodegeneration and survival. We assessed the contribution of fluorodeoxyglucose (FDG-PET) imaging for this purpose.

Methods: FDG-PET were performed in 40 clinic patients with prion disease. FDG-PET images were projected onto latent factors generated in an external dataset to yield patient-specific eigenvalues. Eigenvalues were input into a clustering algorithm to generate data-driven clusters, which were compared by survival time.

Results: Median age at FDG-PET was 65.3 years (range 23-85). Median time from FDG-PET to death was 3.7 months (range 0.3-19.0). Four data-driven clusters were generated, termed "Neocortical" (n = 7), "Transitional" (n = 12), "Temporo-parietal" (n = 13), and "Deep nuclei" (n = 6). Deep nuclei and transitional clusters had a shorter survival time than the neocortical cluster. Subsequent analyses suggested that this difference was driven by greater hypometabolism of deep nuclei relative to neocortical areas. FDG-PET-patterns were not associated with demographic (age and sex) or clinical (CSF total-tau, 14-3-3) variables.

Interpretation: Greater hypometabolism within deep nuclei relative to neocortical areas associated with more rapid decline in patients with prion disease and vice versa. FDG-PET informs large-scale network physiology and may inform the relationship between spreading pathology and survival in patients with prion disease. Future studies should consider whether FDG-PET may enrich multimodal prion disease prognostication models.

Objective: Patients with ovarian cancer (OC) may develop anti-Yo-associated paraneoplastic cerebellar degeneration (PCD)-a cerebellar ataxia associated with tumor-induced autoimmunity against CDR2 and CDR2L proteins. Dysregulation of circulating exosomal microRNAs (miRNAs) occur in OC. Here, we investigated whether PCD is associated with changes in the exosomal miRNA profiles of OC patients.

Methods: Serum exosomes were isolated from patients with OC (n = 15), patients with OC and anti-Yo-associated PCD (n = 14) and healthy controls (HC, n = 15). Small RNA sequencing was used to identify differentially expressed miRNAs. Receiver operating characteristic curves were used to evaluate biomarker sensitivity and specificity, and miRNA target prediction analysis was employed to elucidate gene targets.

Results: OC patients with PCD exhibited a distinct exosomal miRNA expression profile. We detected 103 differentially expressed exosomal miRNAs in PCD patients compared to OC patients without PCD and 139 differentially expressed exosomal miRNAs compared to controls. Particularly miR-486-5p, miR-4732-5p, miR-98-5p and miR-21-5p exhibited notable sensitivity and specificity for discriminating PCD patients from both OC patients without PCD and healthy controls. miRNA target prediction showed that several of the differentially expressed miRNAs in PCD patients targeted the CDR2 and CDR2L genes.

Interpretation: Our results demonstrate that OC patients with anti-Yo-associated PCD exhibit a distinct exosomal miRNA profile compared to OC patients without PCD. Several of the differentially expressed exosomal miRNAs in PCD patients showed diagnostic potential and may hold relevance for understanding the pathogenesis of PCD.

Background: While advances in endovascular thrombectomy (EVT) have led to high reperfusion rates, most patients treated with EVT do not avoid disability. Post-reperfusion hemorrhagic transformation (HT) is a potential target for improving outcomes. This study examined pretreatment blood-brain barrier (BBB) disruption in tissue that would subsequently become part of the final infarct to evaluate its role in post-EVT HT.

Methods: This post hoc analysis of the FRAME study, which enrolled patients with anterior large vessel occlusion who received EVT within 6 hours of onset, included patients if they had successful pretreatment MRI perfusion weighted imaging (PWI) and underwent successful EVT. BBB disruption was measured as the percent signal change due to gadolinium leakage on the PWI source images prior to thrombectomy. Mean permeability derangement (MPD) was defined as the average of all voxels in the stroke core that are two standard deviations above normal. The primary outcome was hemorrhagic transformation with parenchymal hematoma (PH).

Results: In total, 164 patients were included; mean age was 71 and 48% were female. PH occurred in 57 patients. Median MPD was 13.5% for patients with PH versus 3.6% for patients without (p < 0.0001). Elevated MPD was independently associated with PH with a 20% increased risk of PH for each 5% increase in MPD (OR 1.206; 95% CI 1.037:1.405; p = 0.0147, adjusted for NIHSS and procedure duration).

Conclusions: Even in patients who are successfully recanalized in an early time window, pretreatment BBB disruption in regions that go on to infarct is associated with an increased risk of post-EVT HT.

Objective: Subcutaneous ocrelizumab is being developed to provide treatment flexibility and additional choice to patients with multiple sclerosis. OCARINA I (NCT03972306) is an open-label, multicenter, Phase 1b, dose-finding study to investigate the pharmacokinetics, safety, tolerability, and immunogenicity of subcutaneous ocrelizumab and to select a dose for the Phase 3 OCARINA II study (NCT05232825).

Methods: Patients with relapsing or primary progressive multiple sclerosis (aged 18-65 years; Expanded Disability Status Scale score 0.0-6.5) were enrolled into two groups: previously treated with intravenous ocrelizumab (Group A) or naïve to ocrelizumab (Group B). Patients received single ascending doses of subcutaneous ocrelizumab up to 1200 mg. Following dose escalation, new patients in Group A were randomized (1:1) to receive a single 600 mg intravenous ocrelizumab dose or the candidate subcutaneous dose, which was predicted to result in similar exposure as the 600 mg intravenous dose while being safe and well tolerated. The area under the concentration-time curve for both formulations was used to select the subcutaneous ocrelizumab dose. Patients in all cohorts could enter a dose-continuation phase.

Results: Eighty-eight and 47 patients were enrolled into Group A and B, respectively; most patients were female (72.7%/63.0%), and mean age at baseline was 45.7 and 39.7 years, respectively. Subcutaneous ocrelizumab was well tolerated across all doses tested. The 920 mg subcutaneous ocrelizumab dose was selected for the OCARINA II study based on pharmacokinetic and safety data.

Interpretation: Subcutaneous ocrelizumab may provide patients with multiple sclerosis with an additional treatment option.

Objectives: Dysregulated RNA alternative splicing is the hallmark of myotonic dystrophy type 1 (DM1). However, the association between RNA mis-splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown.

Methods: Eighty-two participants (42 adults with DM1 and 40 children with CDM) with muscle biopsies and measures of myotonia, motor function, and strength were combined from five observational studies. Data were normalized and correlated with an aggregate measure of alternative splicing dysregulation, [MBNL]_inferred, in skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL]_inferred using clinical outcome measures alone. Similar analyses were performed to predict 12-month physical function using baseline metrics.

Results: Myotonia (measured via vHOT) was significantly correlated with RNA mis-splicing in our cross-sectional population of all DM1 individuals; CDM participants alone displayed no myotonia despite a similar range of RNA mis-splicing. Measures of motor performance and muscle strength were significantly associated with [MBNL]_inferred in our cohort of all DM1 individuals and when assessing children with CDM independently. Multiple linear regression analyses yielded two models capable of predicting [MBNL]_inferred from select clinical outcome assessments alone in all subjects (adjusted R² = 0.6723) or exclusively in children with CDM (adjusted R² = 0.5875).

Interpretation: Our findings establish significant correlations between skeletal muscle performance and a composite measure of alternative splicing dysregulation, [MBNL]_inferred, in DM1. The strength of these correlations and the development of predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM.

Objective: Paramagnetic rim lesions (PRLs) are a biomarker of chronic active lesions (CALs), and an important driver of neurological disability in multiple sclerosis (MS). The reason subtending some acute lesions evolvement into CALs is not known. Here we ask whether a relatively lower oxygen content is linked to CALs.

Methods: In this prospective cross-sectional study, 64 people with multiple sclerosis (PwMS), clinically isolated syndrome and radiologically isolated syndrome underwent a 7.0 Tesla (7 T) brain magnetic resonance imaging (MRI). The scanning protocol included a T₂-w fluid-attenuated inversion recovery (FLAIR), and a single echo gradient echo from which susceptibility-weighted imaging (SWI) was derived. WM lesions were identified on the T₂-w-FLAIR whilst PRLs were identified on the SWI sequence. T₂-lesions were classified as PRLs and rimless lesions (PRLs-). We registered a universal vascular atlas to each subject's T₂-w-FLAIR and classified each T₂-lesions according to its location into watershed- (ws), non-watershed- (nws), and mixed-lesion (m). Ws-lesions were defined as lesions that were fully located in a region between the territories of two major arteries.

Results: Out of 1,975 T₂-lesions, 88 (4.5%) were PRLs. Ws-regions had a higher number (p = 0.005) and proportion (p < 0.001) of PRLs- compared to nws-regions. Ws-PRL- were larger compared to nws-ones (p = 0.009). The number (p = 0.043) and proportion (p < 0.001) of PRLs was higher in ws-regions compared to nws-ones. Ws-PRLs were not significantly larger than nws-ones (p = 0.195).

Interpretation: We propose the novel concept of a link between arterial vascularization and chronic activity in MS by demonstrating a preferential localization of CALs in ws-territories.

Objective: Lennox-Gastaut syndrome (LGS) is a severe, childhood-onset epilepsy that is typically refractory to treatment. We surveyed the current landscape of LGS treatment, aiming to identify challenges to the development of efficacious therapies, and to articulate corresponding priorities toward clinical trials that improve outcomes.

Methods: The LGS Special Interest Group of the Pediatric Epilepsy Research Consortium integrated evidence from the literature and expert opinion, into a narrative review.

Results: We provide an overview of approved and emerging medical, dietary, surgical and neuromodulation approaches for LGS. We note that quality of care could be improved by standardizing LGS treatment based on expert consensus and empirical data. Whereas LGS natural history is incompletely understood, prospective studies and use of large retrospective datasets to understand LGS across the lifespan would enable clinical trials that address these dynamics. Recent discoveries related to LGS pathophysiology should enable development of disease-modifying therapies, which are currently lacking. Finally, clinical trials have focused chiefly on seizures involving "drops," but should incorporate additional patient-centered outcomes, using emerging measures adapted to people with LGS.

Interpretation: Clinicians and researchers should enact these priorities, with the goal of patient-centered clinical trials that are tailored to LGS pathophysiology and natural history.

Objective: This study examined the effect of cognitive status, education, and sex on the association between subjective cognitive decline (SCD) and Alzheimer's disease (AD) biomarkers in non-demented older adults.

Methods: Vanderbilt Memory and Aging Project participants (n = 129), dementia or stroke free, completed fasting lumbar puncture, SCD assessment, and cognitive assessment. Cerebrospinal fluid (CSF) biomarkers for AD were analyzed. Linear regression models related SCD to CSF AD biomarkers and follow-up models assessed interactions of SCD × cognitive status, sex, reading level, and education on AD biomarkers.

Results: In main effect models, higher SCD was associated with more amyloidosis (p-values <0.004). SCD was not associated with tau, p-tau, or neurofilament light (NFL) levels (p-values >0.38). SCD score interacted with cognitive status (p < 0.02), sex (p = 0.03), and education (p-values <0.005) on amyloidosis. In stratified models, higher SCD was associated with more amyloid in cognitively unimpaired (p-values <0.003), men (p = 0.0003), and higher education. No SCD score × reading-level interaction was found (p-values >0.51) though SCD related to amyloid markers in the higher reading-level group (p-values <0.004).

Interpretation: Higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD appears most useful in detecting early AD-related brain changes prior to objective cognitive impairment, in men, and those with higher quantity and quality of education and highlight the importance of considering these factors.

Diffuse midline gliomas present a particularly intricate and challenging clinical scenario. This rare case involves a patient with comutant H3F3A and FGFR diffuse midline glioma with a clinical presentation of fulminant leptomeningitis. A 22-year-old male presented with fatal and fulminant diffuse leptomeningitis. Next-generation sequencing of plasma and cerebrospinal circulating tumour DNA revealed diffuse midline gliomas with H3F3A and FGFR mutations. Methylome analysis of meningeal tissue collected during autopsy confirmed the diagnosis. Liquid biopsy plays a crucial role in the diagnosis of diffuse midline gliomas, mainly those with exclusively leptomeningeal presentations.

Objectives: Many cases of cervical artery dissection are considered "spontaneous." Recent data suggest that while cervical artery dissection may proportionally explain more strokes in young patients, hospitalization for dissection increases with age, suggesting a potential role of acquired vascular disease. In this study, we hypothesized that traditional vascular risk factors and comorbidities are associated with cervical artery dissection.

Methods: We performed a retrospective cohort study using administrative claims data from a 5% sample of Medicare beneficiaries. Exposures of interest included traditional vascular risk factors and comorbidities: coronary artery disease, hyperlipidemia, hypertension, diabetes mellitus, heart failure, chronic kidney disease, chronic obstructive pulmonary disease, valvular heart disease, atrial fibrillation, tobacco use, and alcohol abuse. The primary outcome was a new diagnosis of cervical artery dissection. Marginal structural Cox models were used to characterize the association between the exposures and outcomes, adjusted for time-dependent confounding.

Results: Among 2,256,710 eligible Medicare beneficiaries, 730 (0.03%) developed cervical artery dissection. The following exposures were found to be significantly associated with the development of cervical artery dissection: hypertension (HR 1.84 [95% CI: 1.40-2.41]), alcohol use (HR 1.83 [1.52-2.21]), atrial fibrillation (HR 1.80 [1.53-2.11]), tobacco use (HR 1.80 [1.52-2.13]), coronary artery disease (HR 1.56 [1.33-1.82]), and valvular heart disease (HR 1.23 [1.05-1.45]).

Interpretation: In a large cohort of older people, several traditional vascular risk factors and comorbidities were associated with subsequent cervical artery dissection. Further studies exploring the role of such factors in the development of cervical artery dissection are warranted.