Annals of Clinical and Translational Neurology最新文献

Objectives: This study aimed to examine the relationship between the McCance Brain Care Score (BCS) and mortality in the general population.

Methods: We conducted a prospective, population-based cohort study using data from the UK Biobank. Participants with complete data enabling calculation of BCS and full mortality information were included. For the longitudinal component, participants without follow-up BCS data were excluded. Mortality information was obtained via the National Health Service (NHS) Information Centre (England and Wales) and the NHS Central Register Scotland, with follow-up through December 31, 2022.

Results: A total of 331,894 participants were included (mean age 56.46 ± 8.07 years; 54.2% women; 91.8% White). Over a median follow-up of 13.83 years (IQR 13.11-14.55), 27,446 deaths (8.27%) occurred. Higher baseline BCS was significantly associated with lower all-cause mortality. As a continuous variable, each 1-point increase in BCS corresponded to a 6% lower risk of death (fully adjusted HR = 0.94; 95% CI 0.94-0.95; p < 0.001). When analyzed in 5-point increments, participants with BCS 5-10, 10-15, and ≥ 15 had 40%, 53%, and 55% lower mortality risks, respectively, compared with the reference group (BCS < 5) (all p < 0.001; p for trend < 0.001). Cause-specific analyses revealed inverse associations between BCS and death from malignant neoplasm (HR = 0.95; 95% CI 0.94-0.95), heart disease (HR = 0.90; 95% CI 0.89-0.92), cerebrovascular disease (HR = 0.96; 95% CI 0.94-0.98), respiratory disease (HR = 0.92; 95% CI 0.90-0.94), and diabetes (HR = 0.90; 95% CI 0.84-0.96) (all p ≤ 0.001). In longitudinal analyses of 7114 participants with repeated BCS measurements over a median 4.52 years, persistently high BCS was associated with a 50% lower mortality risk compared with persistently low BCS (HR = 0.50; 95% CI 0.29-0.87).

Interpretation: These findings suggest that BCS is a practical tool reflecting healthy lifestyle behaviors and clinical measures, aiding early identification of individuals at high risk of mortality and showing promise in health management. Further studies are needed to explore its mechanisms and confirm causality.

Objective: Mild traumatic brain injury (mTBI) may alter glymphatic function; however, its progression and variability remain obscure. This study examined glymphatic function following mTBI within 1 month and after 3 months post-injury to determine whether variations in glymphatic function are associated with post-traumatic symptom severity.

Methods: Glymphatic function was estimated using diffusion tensor image analysis along the perivascular space (DTI-ALPS). This index was measured in 39 individuals with mTBI (47.21 ± 14.88 years) at initial and follow-up assessments, and in 35 age-matched controls (44.62 ± 13.12 years), using manually defined regions of interest at the lateral ventricle level. A linear mixed-effects (LME) model was used to compare ALPS indices among groups. Additional LME analyses evaluated continuous associations between the ALPS index and symptom severity, as assessed by the Rivermead Post-Concussion Symptoms Questionnaire (RPCSQ). Based on ALPS changes, patients were classified into increasing and decreasing subgroups, and comparative analyses of RPCSQ trajectories were conducted.

Results: At baseline, the index did not differ between patients with mTBI and controls; at follow-up, it was significantly lower in the mTBI group. Longitudinal ALPS changes were significantly associated with RPCSQ scores, whereas baseline ALPS showed only a marginal association with initial symptom severity. Individuals in the decreasing ALPS group demonstrated more severe overall symptoms and a slower rate of symptom resolution.

Interpretation: Glymphatic dysfunction, as represented by the ALPS index, may be associated with persistent post-traumatic symptoms. A time-dependent approach incorporating individual recovery trajectories may be essential when assessing glymphatic biomarkers in mTBI.

Objective: Clinical trials for Huntington's disease (HD) enrolling persons before clinical motor diagnosis (CMD) lack validated biomarkers. This study aimed to conduct an unbiased discovery analysis and a targeted examination of proteomic biomarkers scrutinized by clinical validation.

Methods: Cerebrospinal fluid was obtained from PREDICT-HD and ancillary studies. Cohorts included HD family members who were gene-tested and considered prodromal following neuroexam. An initial unbiased mass spectrometry proteomics analysis identified candidate disease biomarkers that were then added to a targeted mass spectrometry assay including 100+ proteins associated with other neurodegenerative diseases. This assay determined relative quantifications of proteins in a single analysis. Significant biomarkers were examined against genetic and clinical measures of disease onset and progression.

Results: Two overlapping targeted analyses using 180 samples from 125 participants (61% female, 89% White, average age of 42 ± 14) were performed; longitudinal duration was 1-4 years. Based on participants' clinical data, 25 proteins correlated significantly with CAG-age-product (CAP) score and Unified HD Rating Scale (UHDRS) motor and cognitive measures. While most proteins increase in abundance with disease progression, proenkephalin and prodynorphin were downregulated before CMD. Power was low for longitudinal analysis. However, the reliability of HD family normal controls indicates that each individual's proteome remains relatively stable over time.

Interpretation: Findings replicate and extend the verification of HD biomarkers. Monitoring proenkephalin and prodynorphin levels in persons with HD may facilitate early detection and disease-tracking. These disease-specific biomarkers may improve the rigor of therapeutic intervention before clinical motor diagnosis. Further studies emphasizing longitudinal changes are needed to assess disease-monitoring.

Trial registration: ClinicalTrials.gov identifier: NCT00051324.

In this study, we analyzed biomarkers of neuronal, glial, and vascular injury in longitudinal paired samples of blood and cerebrospinal fluid after prophylactic cranial irradiation in patients with small cell lung cancer. Neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAP) increased in serum and cerebrospinal fluid after irradiation; serum NfL correlated with cerebrospinal fluid values, apparently independent of blood-brain barrier function, whereas GFAP correlations were weaker. Although several patients developed brain metastases, linear mixed model results were consistent with an independent effect of radiotherapy on serum NfL and GFAP. Serum placental growth factor also rose and correlated with the albumin ratio. Our results support a radiotherapy-associated increase of NfL and GFAP in blood.

Objective: Freezing of gait (FOG) in people with Parkinson's disease (PwPD) is debilitating and has limited treatments. Modafinil modulates beta/gamma band activity in the pedunculopontine nucleus (PPN), like PPN deep brain stimulation. We therefore tested the hypothesis that Modafinil would improve FOG in PwPD.

Methods: PwPD with FOG were randomized to early-start (24 weeks modafinil) or delayed-start (12 weeks each, placebo then modafinil) of oral modafinil 50 mg, followed by a 2-week washout for both arms. Primary outcomes were change in OFF-levodopa stride length and FOG questionnaire scores; secondary outcomes were change in motor Unified Parkinson's Disease Rating Scale (UPDRS), sleep and quality-of-life scores, and post hoc outcome was change in percent freezing time (%FT).

Results: Early- (n = 12) and delayed-start (n = 9) group participants were well matched for age, OFF-levodopa motor UPDRS and FOG-Q scores. Primary and secondary outcomes did not reach statistical significance. Limiting the analysis to study completers with quantifiable visualized freezing at the initial visit and collapsing the two study arms (n = 11), %FT trended to improvement with 50 mg modafinil in 8/11 participants (p = 0.15) and worsening after 2 weeks washout in 9/11 participants (p = 0.09). A future cross-over study with 50 participants would have 0.80 power to detect a 0.5 standard-deviation improvement in %FT.

Interpretation: For future therapeutic trials, selecting PwPD with moderate, quantifiable FOG and utilizing appropriate outcome measures like %FT will improve the ability to identify intervention effects. Even for short trials, analyses must account for gait decline. An FOG outcome measure that requires less analysis time burden than video quantification, and the ability for at-home monitoring is needed.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by biallelic pathogenic variants in the SACS gene. We report the clinical, radiologic and neurophysiologic features of a pair of half-siblings who presented with progressive cerebellar ataxia, peripheral neuropathy and upper motor neuron signs. After significant diagnostic delay, genetic testing revealed both harboured a shared, paternally inherited microdeletion encompassing the SACS gene, and each harboured a different single nucleotide variant in SACS, each likely maternally inherited. Recognition of the clinical and radiologic phenotype of ARSACS may facilitate early diagnosis of this disorder even in the face of uncommon inheritance patterns.

Objective: Patients with minor stroke exhibit slowed processing speed and generalized alterations in functional connectivity involving frontoparietal cortex (FPC). The pattern of connectivity evolves over time. In this study, we examine the relationship of functional connectivity patterns to cognitive performance, to determine neurophysiological underpinnings of improvement, and whether connectivity profiles may be useful in evaluating and predicting longer-term cognitive outcomes.

Methods: Patients hospitalized with a minor ischemic stroke (NIH Stroke Scale < 10) were neurologically evaluated approximately 1 month following discharge. A battery of neuropsychological tests was administered to assess performance across multiple cognitive domains. Functional connectivity was evaluated using resting state magnetoencephalography (MEG). Repeat evaluations were performed 3-6 months later. The Network Localized Granger Causality framework was used to estimate functional connectivity at each visit. Relationships between functional connectivity and cognitive performance at each visit were assessed using cluster-based permutation tests and mixed effects modeling.

Results: Forty-nine patients had available data for both follow-up visits. The average age was 62.4 years; 57% were female; 39% were Black. Mixed effects models indicated significant increases in contralesional frontoparietal beta-band connectivity across visits that corresponded to improved behavioral performance. Early reliance on the contralesional hemisphere was associated with better scores at visit 1, and continued reliance on areas within the ipsilesional hemisphere was associated with poorer performance at visit 2.

Discussion: Specific connectivity profiles are associated with better acute and longer-term cognitive performance and may indicate greater potential for recovery. Further studies are needed to determine if patterns are modifiable.

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a chronic autoimmune neuroinflammatory disease, typically characterized by antibodies against aquaporin 4 (AQP4-IgG) or myelin oligodendrocyte glycoprotein (MOG-IgG). Simultaneous seropositivity for both antibodies in a single patient is exceedingly rare. We present a dual AQP4-IgG/MOG-IgG seropositivity case who was treated with satralizumab throughout the whole preconception-to-postpartum course, to evaluate the effectiveness and safety of satralizumab, especially during the perinatal period. A 34 year-old female, initially presenting with decreased visual acuity in the left eye, was diagnosed with NMOSD as both AQP4-IgG and MOG-IgG seropositive. With traditional treatment of corticosteroids and mycophenolate mofetil, her vision gradually recovered and overall condition stabilized. Due to the desire for conception, her treatment regimen was transitioned to satralizumab monotherapy. Three months later with five doses of satralizumab, she successfully conceived and delivered a healthy female infant at 38 weeks' gestation. Satralizumab treatment was continued throughout the preconception-to-postpartum course. All routine and perinatal assessments were within normal limits, and 4 months postpartum, the condition of both mother and child remained stable, further supporting the favorable effectiveness and safety of satralizumab in this case. The coexistence of AQP4-IgG and MOG-IgG in an NMOSD patient represents an extremely rare and complex clinical scenario. When fertility is desired, the selection of disease-modifying therapy must carefully balance effectiveness and safety. In such cases, satralizumab may serve as a viable option, supported by promising real-world data.

Objective: Spinal Muscular Atrophy (SMA) is a rare genetic disorder marked by progressive muscle weakness and mobility loss. It has a profound physical, emotional and social impact on patients and caregivers, requiring comprehensive medical and supportive care. SMA is classified into Types 1-4, with some individuals identified presymptomatically. This systematic review examined the safety and effectiveness of nusinersen and risdiplam for treating SMA.

Methods: We searched research databases, relevant websites and existing systematic reviews. Screening, data extraction and quality assessment were conducted independently by two authors, with discrepancies resolved by a third. Internal quality appraisal ensured methodological rigour. A total of 131 studies reported in 148 sources were included. The review is registered with PROSPERO (CRD42024512226).

Results: Both treatments showed improvements in motor function and milestones, with high survival rates across most SMA types. Motor function improvements were consistent, but other outcomes-such as bulbar and respiratory function, and ventilation needs-were variable. Adverse events were common across all treatments and SMA types, with some serious cases reported, including deaths in Types 1 and 2.

Interpretation: This comprehensive review highlights the clinical effectiveness and safety of nusinersen and risdiplam across all SMA types. However, variability in outcomes and limited comparative data introduce uncertainty. The findings underscore the need for more high-quality randomised controlled trials to strengthen the evidence base for SMA treatment.

New-onset refractory status epilepticus (NORSE) arises without an identifiable cause or prior epilepsy history, with a 16%-27% mortality rate and significant long-term neurological sequelae. Neuromodulation such as deep brain stimulation (DBS) targeting the anterior and centromedian thalamic nuclei has shown promise when the traditional approach of anti-seizure medications (ASMs), anesthetics, and immunomodulation fails. We present a case of cryptogenic NORSE in a 30-year-old male with autism and developmental delay, with refractory seizures localized to bilateral posterior quadrants. Sensing-enabled DBS targeting the pulvinar thalami led to decreased seizure burden and clinical improvement, highlighting the importance of tailoring neuromodulatory targets to seizure localization.