Annals of Clinical and Translational Neurology最新文献

Objective: Accurate localization of epileptogenic tubers (ETs) in patients with tuberous sclerosis complex (TSC) is essential but challenging, as these tubers lack distinct pathological or genetic markers to differentiate them from other cortical tubers. Approximately 60% of patients fail to have their ETs identified through noninvasive preoperative evaluations, creating an urgent clinical need for effective, noninvasive localization strategies.

Methods: A novel fusion model was developed, integrating lesion network mapping-based risk assessment with a machine learning prediction model that utilizes brain functional connectivity and random forest algorithms. The model was built based on magnetic resonance imaging data. Retrospective analysis was conducted on patients with TSC-related epilepsy who had undergone resective surgery and achieved seizure freedom at the 1-year follow-up; tubers were classified as true epileptogenic tubers (true ETs) or true non-epileptogenic tubers (true non-ETs) according to the resected regions. The model calculated and ranked the probability of each tuber being an ET for every patient.

Results: A total of 47 patients were enrolled in the study. The fusion model successfully ranked the true ETs within the top three in 91% of the cases. Significant differences in the probability rankings of ETs were observed among true ETs, true non-ETs, and random tubers (p < 0.01). Receiver operating characteristic curves were plotted to evaluate the accuracy of true ET localization across different methods, and the fusion model exhibited an area under the curve of 0.86. This performance significantly outperformed that of scalp electroencephalography, semiology, and positron emission tomography based on structural magnetic resonance imaging in the same cohort. Cross-validation in three independent epilepsy centers confirmed the model's high generalizability.

Interpretation: Overall, this fusion model demonstrates high accuracy and robust clinical utility as a noninvasive tool for the localization of ETs. It effectively addresses the current challenges in identifying ETs, providing valuable support for surgical planning in patients with TSC-related epilepsy.

Background: Familial dysautonomia (FD) is a hereditary neurodevelopmental disorder caused by aberrant splicing of the ELP1 gene, leading to a tissue-specific reduction in ELP1 protein expression. Preclinical models indicate that increasing ELP1 levels can mitigate disease manifestations. A blood-based ELP-1 protein assay may provide a reliable way to monitor gene target engagement.

Design and methods: Using a newly developed radioimmunoassay, we quantified ELP1 protein levels in peripheral blood samples collected from 59 homozygous FD patients carrying the IVS20 + 6T>C mutation and 66 heterozygous carriers. To assess the reproducibility of the measurement, replicate samples were collected in 43 participants. Longitudinal variability was evaluated in 22 participants who underwent repeat sampling 1 year later.

Results: ELP1 protein levels were significantly lower in FD patients compared to heterozygous carriers (244 ± 75 vs. 2210 ± 1031 pg/mL, p < 0.001). Replicate analysis of 43 paired samples showed strong consistency in ELP1 levels (p < 0.000). Repeat measurements 1 year after baseline showed longitudinal stability (R² = 0.827, p < 0.001). An ELP1 threshold of 492 pg/mL yielded a sensitivity of 80.2% (CI of 70.6 to 87.2%) and a specificity of 98.2% (95% CI of 90%-99%) with a positive likelihood ratio of 46.5, indicating that individuals with FD were over 46 times more likely to have ELP1 levels below this threshold compared to non-affected carriers.

Conclusion: Blood ELP1 levels are robust and reproducible, with concentrations below 492 pg/mL strongly indicative of disease. Moreover, given their longitudinal stability, ELP1 can serve as a marker of target engagement to evaluate the efficacy of gene-targeted therapies aimed at correcting ELP1 gene splicing and protein production.

Background: Ambulatory ability after intracerebral hemorrhage (ICH) is important to patients. We tested whether asymmetry between ipsi- and contra-lesional corticospinal tracts (CSTs) assessed by diffusion tensor imaging (DTI) is associated with post-ICH ambulation.

Methods: Patients with spontaneous supratentorial ICH were recruited from 8 US sites between 2017 and 2024. For each patient, fractional anisotropy (FA) asymmetry index (AI) was computed for the whole CST and on a subset of fibers restricted to the cerebral peduncle (CP). Clinical and radiographic features were collected. The primary outcome was Barthel Index Mobility Score (BIMS) at 3 months (dichotomized outcome [DO]: BIMS 15 = good [independent ambulation]; BIMS < 15 = poor [non-independent ambulation]; ordinal outcome [OO]: BIMS 0, 5, 10, 15). Two imputation-based multiple logistic regression analyses accounted for whether ICH prevented tracking of CSTs. Odds ratios (ORs) were reported for a change of 0.1 and 95% confidence intervals (CIs).

Results: At 3 months, 124 patients were eligible for inclusion. In addition to known clinical variables, CST and CP FA AI were associated with poor BIMS (OR 2.97, CI 1.12-7.90, p = 0.029; OR 3.80, CI 1.63-8.84, p = 0.002). In Model 1, unresolved FA (FA zero) was not correlated with lower BIMS (DO: OR 3.25, CI 0.62-17.07, p = 0.163; ordinal outcomes: OR 2.02, CI 0.48-8.55, p = 0.341). In Model 2, the combination of CST FA AI and FA zero correlated with lower BIMS (DO: joint p-value =0.041; OO: p = 0.030). CP FA asymmetry was associated with lower BIMS (DO: OR 3.96, CI 1.25-12.55, p = 0.019; OO: OR 3.39, CI 1.24-9.27, p = 0.017).

Conclusion: DTI-assessed CST integrity may be an additional tool physicians can utilize to guide post-ICH ambulatory expectations.

Objective: To characterise the progression of motor symptoms and identify eligibility for device-aided therapies in Parkinson's disease, using both the 5-2-1 criteria and a refined clinical definition, while examining differences across genetic subgroups.

Methods: We analysed 1205 individuals with sporadic and genetic Parkinson's disease from the Parkinson's Progression Markers Initiative (mean follow-up: 5.6 ± 4.3 years). Kaplan-Meier analysis estimated time to meeting the 5-2-1 criteria (five or more daily levodopa doses, two or more hours of OFF time, or one or more hours of troublesome dyskinesia) and a stricter definition of eligibility for device-aided therapy based on disabling, medication-refractory symptoms and/or tremor. In the sporadic Parkinson's disease subgroup (n = 943), we assessed therapy initiation and clinical suitability, including potential contraindications. Genetic subgroup analyses explored differences in progression, eligibility timing and treatment uptake.

Results: Among individuals with sporadic Parkinson's disease, 257 (27.3%) met the 5-2-1 criteria, with 25%, 50% and 75% doing so by 5.3, 8.2 and 10.7 years, respectively. A total of 176 (18.6%) met stricter eligibility criteria, with 50% doing so by 12 years. Only 25% of those meeting the 5-2-1 criteria initiated device-aided therapy within 6.8 years. Most had no contraindications. Deep brain stimulation was the most used therapy. GBA and SNCA carriers met criteria earlier. LRRK2 carriers were more likely to initiate therapy, while PRKN carriers were less likely to meet eligibility thresholds.

Interpretation: Eligibility for device-aided therapy is common but underutilised. These findings highlight missed opportunities and support earlier, genotype-informed treatment planning in Parkinson's disease.

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.