Annals of Clinical and Translational Neurology最新文献

Objective: Progressive brain atrophy has now been widely observed in the chronic stages of moderate-severe traumatic brain injury (msTBI), but there is only coarse information regarding its prevalence and magnitude, and whether rate of atrophy accelerates or attenuates across time. We examined these questions in a Canadian inception cohort from the Toronto Rehab TBI Recovery Study.

Methods: N = 123 patients with post-traumatic amnesia ranging from > 1 h to 10 weeks (70%, > 7 days) were administered up to three MRIs at approximately 5 months, 1 year, and 3 years post-injury. N = 32 healthy controls were scanned up to two times on average 14 months apart. Ventricle-to-brain ratio (VBR) was calculated and manual segmentation of the hippocampi (HPC), corpus callosum (CC), and substructures was employed. For each region, annualized rates of progressive atrophy were modeled from approximately 5 months to 1 year and 1 to 3 years post-TBI; proportions of patients with annualized volume losses of 2.5%-5%, 5%-10%, and > 10% were estimated.

Results: Mixed-effects longitudinal models estimated robust progressive atrophy in both time windows in all regions compared to controls, but with significant attenuation across windows. In the earlier window, > 10% annualized loss was estimated in 76.2% of patients for VBR, 53.2% for CC, and 25.0% for HPC bilaterally. In the later window, at least 5%-10% annualized loss was estimated in 63.3% of patients for VBR, 49.4% for CC, and 17.7% for right HPC; for left HPC, 6.3% of patients showed at least 2.5%-5% annualized decline.

Interpretation: Clinically concerning prevalence and degree of progressive volume losses were observed in the chronic stages of msTBI, with tapering of losses across time, and regional variations. Research is needed to understand and mitigate clinical impact of these declines.

Objective: Plasma p-Tau217 leaves 30%-50% of patients in an indeterminate "gray zone" often requiring Aβ-PET. We developed GRAD (Gatekeeper-Reflex for Alzheimer's Disease), a two-stage Aβ-positivity prediction model to improve classification while reserving Aβ-PET for residual uncertainty.

Methods: GRAD was developed in 145 cognitively impaired ADNI participants and externally validated in 1644 cognitively unimpaired A4/LEARN participants. Stage 1 used p-Tau217 alone; probabilities between 0.25 and 0.75 were considered indeterminate. Stage 2 used L2-regularized logistic regression combining plasma-biomarkers, genetic and demographic features. Aβ-PET served as the reference standard (ADNI florbetapir SUVR > 1.11; A4 Centiloid ≥ 20).

Results: Full model AUC was 0.915 (95% CI, 0.859-0.961) internally and 0.879 (95% CI, 0.861-0.895) externally. In the external gray zone (n = 630), Stage 2 improved discrimination over p-Tau217 alone (AUC 0.793 vs. 0.719; p < 0.001), increased correct classification without PET from 41.4% to 56.2%, and reduced PET referral from 35.9% to 24.3%. In the p-Tau181 subset (n = 256), Stage 2 outperformed p-Tau181 (AUC 0.799 vs. 0.597; p < 0.001). Overall, 89.0% of ADNI and 90.7% of A4/LEARN participants were classified without PET; modeled testing costs were 44%-52% lower than p-Tau217 screening with PET confirmation of the gray zone.

Interpretation: Reflex multimarker testing improves indeterminate p-Tau217 classification while retaining Aβ-PET for residual uncertainty. GRAD may reduce PET use and testing costs in memory-clinic triage, prevention-trial enrichment, and disease-modifying therapy workup.

Objective: Blood biomarkers are increasingly critical for non-invasive Alzheimer's Disease (AD) diagnostics and research but typically require on-site processing. Remote point-of-care collection methods could enhance biomarker testing in clinical and research settings. We evaluated the safety and accuracy of blood collection via venous blood and two capillary blood collection devices (Tasso+ and TAPII) for measurements of amyloid-beta 42/40 ratio (Aβ42/40), phosphorylated-tau-217 (pTau217), neurofilament-light (NfL), and glial fibrillary acidic protein (GFAP) from capillary plasma to simultaneously collected venous plasma and cerebrospinal fluid (CSF).

Methods: Patients seen at the Johns Hopkins Center for CSF Disorders (N = 192) underwent diagnostic lumbar punctures and venipuncture. Warming packs were held to the skin for 5 min before collecting capillary blood (via TAPII or Tasso+ device) and numeric pain scores. CSF, venous, and capillary plasma were analyzed using Quanterix SIMOA immunoassays. Statistical analysis included Pearson/Spearman correlations, Lasso regression, and quantitative comparisons using Bland-Altman plots.

Results: 86 TAPII and 126 Tasso+ plasma samples were collected (77 M, 115 F; mean age 61 ± 18.3 years, range 16-91). Tasso+ devices were 90.3% successful in collecting > 50 μL whole blood, and TAPII devices were 86% successful. Mean pain scores were significantly higher in venous than capillary collections (Venous 2.24/10, TAPII 0.73/10, Tasso+ 0.2/10, p < 0.001). Capillary Aβ42/40, NfL, and GFAP strongly correlated with venous plasma analytes (Tasso+: Aβ42/40 r = 0.75, NfL r = 0.91, GFAP r = 0.80, all p < 0.001; TAPII: Aβ42/40 r = 0.74, NfL r = 0.86, GFAP r = 0.84, all p < 0.001). Tasso+ capillary pTau217 weakly correlated with venous (r = 0.23, p = 0.04). Capillary NfL and GFAP correlated modestly with CSF NfL and GFAP (TAPII NfL r = 0.74, GFAP r = 0.6, all p < 0.0001; Tasso+ NfL r = 0.69, GFAP r = 0.59, all p < 0.0001). Capillary Aβ42/40 and pTau217 did not significantly correlate with CSF measures. Lasso regression identified age and GFAP as significant predictors of AD across capillary and venous samples (Tasso+ AUC = 0.87, TAPII AUC = 0.75, Venous AUC = 0.83).

Interpretation: Neurodegeneration biomarkers Aβ42/40, NfL, and GFAP in capillary plasma (Tasso+, TAPII) strongly correlated with venous plasma measures. Capillary and venous pTau217 correlated weakly, indicating further assay refinement is needed. Tasso+ collection was less painful and caused less hemolysis compared to TAPII.

Background: Dysregulated lipid metabolism, which can affect remyelination and neural repair, has not been extensively investigated in progressive multiple sclerosis (PMS). The goal was to examine whether dysregulated cholesterol metabolism was associated with disability in PMS.

Methods: The study sample comprised 53 Severe PMS patients (Expanded Disability Status Scale, EDSS score: 7.0-9.5) requiring skilled nursing and 53 age, sex- and disease duration-matched community-dwelling Control PMS patients (EDSS score: 3.0-6.5). Patients underwent neurological examinations and provided blood samples. Cholesterol and apolipoprotein (Apo) profiles, nuclear magnetic resonance spectroscopy metabolomic profiles, inflammatory cytokines, neuroaxonal, and glial injury biomarkers were obtained. Disability was measured on the EDSS and the Combinatorial Weight-Adjusted Disability (CombiWISE) scales.

Results: The Severe PMS group had lower high-density lipoprotein cholesterol (HDL-C), ApoA-I, and ApoA-II levels (all p < 0.001) and higher ApoB and ApoE levels. The nutritional status biomarker, albumin, was lower, and the chronic inflammation marker, GlycA, was higher in Severe PMS versus Control PMS (all p < 0.001). Total cholesterol, ApoA-II, and ApoB were associated with disability on the EDSS and CombiWISE scale. Difference-correlogram analyses revealed substantial remodeling of biomarker interdependencies in Severe PMS. ApoE showed stronger associations with lipid and nutritional biomarkers in Severe PMS, but with neuroaxonal markers (serum neurofilament light chain, glial fibrillary acidic protein) in Control PMS. Inflammatory cytokines (tumor necrosis factor, interleukin-6) showed stronger associations with apolipoproteins in Severe PMS, whereas several lipid-inflammation and lipid nutritional correlations were attenuated.

Conclusions: Disrupted cholesterol metabolism and chronic inflammation are strongly linked to greater disability in Severe PMS. Our results also indicate marked alterations in metabolic, inflammatory, nutritional, and neuroglial biomarker networks in Severe PMS.

Objective: Conventional MRI cannot resolve the coexisting pathological processes within multiple sclerosis tissue. Diffusion Basis Spectrum Imaging decomposes the diffusion signal into fiber, cell, and hindered ratios indexing axonal integrity, cellularity, and extracellular space, respectively. We asked how these ratios differ between early relapsing and established non-relapsing disease, change with early treatment, and relate to disability, and secondarily, whether lesions form reproducible microstructural subtypes.

Methods: Thirty-seven participants underwent multi-shell diffusion MRI: 11 healthy controls, 15 treatment-naïve relapsing, and 11 non-relapsing patients. Thirteen were rescanned ~3 months after starting high-efficacy disease-modifying therapy. Metrics were extracted from normal-appearing gray and white matter and lesions (core, rim, and perilesional white matter); Gaussian mixture model clustering of per-lesion fiber, cell, and hindered ratios identified lesion subtypes.

Results: Treatment-naïve relapsing patients showed reduced normal-appearing white matter fiber (p = 0.04) and elevated hindered ratios (p = 0.02) versus controls. Lesions had lower fiber and cell ratios and higher hindered ratio than within-subject normal-appearing white matter (all p < 0.001). After treatment, lesional fiber ratio increased (p = 0.01) while lesional and gray matter cell ratios declined (both p = 0.02). Lesional cell ratio was higher in relapsing than non-relapsing patients at the core (p = 0.03) and rim (p = 0.04) but not perilesionally; treatment-related improvement was similar across compartments. Clustering yielded four reproducible subtypes (edematous-hypocellular, moderately cellular, actively inflamed, structurally preserved); the inflamed subtype predominated in relapsing and the edematous-hypocellular in non-relapsing disease.

Interpretation: Diffusion basis spectrum imaging distinguishes relapsing from non-relapsing disease by lesion-body cellularity and detects treatment-related changes in fiber and cell compartments. Reproducible, hypothesis-generating lesion subtypes support its use for in vivo lesion phenotyping.

Objective: Advancements in disease-modifying therapies for spinocerebellar ataxia Type 3 (SCA3) underscore the need for robust biomarkers to monitor disease progression and evaluate treatment efficacy. Although motor phenotypes have been well characterized, less is known about non-motor and imaging-based features across different disease stages. This study aimed to characterize stage-specific patterns of non-motor and imaging biomarkers in SCA3.

Methods: This cross-observational study included 229 patients with SCA3 and 104 age- and sex-matched healthy controls from the Organization for Southeast China for cerebellar ataxia research. Non-motor symptoms were assessed using a battery of neuropsychological tests. Brain volume loss was assessed by 3.0-Tesla MRI with regions-of-interest (ROI)-based volumetric analysis. Neuroinflammation was quantified in vivo using translocator protein positron emission tomography (TSPO-PET) with the ¹⁸F-DPA-714 radioligand. Additive regression models were fitted to evaluate the cross-sectional associations between biomarkers and disease stages. Receiver operating curve (ROC) analyses were applied to estimate the discriminative ability of the candidate biomarkers.

Results: Non-motor symptoms, including cognitive functions, anxiety, fatigue, depression, and sleep quality, declined after ataxia onset in SCA3. Volume loss in the brainstem and ventral diencephalon diverged from normal controls at 0.7 and 0.2 years before ataxia onset, respectively. Correspondingly, the TSPO signal in the brainstem and ventral diencephalon increased and deviated from normal throughout the disease course.

Interpretation: Our findings propose a staging model of SCA3 that includes a biomarker stage characterized by multidimensional objective indicators of neurodegeneration and neuroinflammation from pre-ataxia to ataxia onset.

Trial registration: ClinicalTrials.gov identifier: NCT04010214.

Juvenile Huntington disease accounts for a small fraction of Huntington disease cases and is driven by the largest trinucleotide repeat expansions. We describe a 6-year-old boy with progressive global regression, generalized dystonia, and epilepsy, in whom serial imaging showed striking cerebellar-predominant atrophy with an initially normal-appearing striatum. Extensive metabolic testing, exome sequencing, and an ataxia repeat expansion panel were nondiagnostic. Research genome sequencing identified a large pathogenic huntingtin CAG repeat expansion that confirmatory testing sized beyond 180 repeats. This case illustrates a cerebellar-predominant imaging signature of extreme repeat expansions and the limitations of exome sequencing for detecting them.

The glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are a relatively new class of drugs that were initially approved by the US Food and Drug Administration to improve glycemic control in patients with type 2 diabetes mellitus and, subsequently, weight reduction in patients with obesity. Multiple sclerosis (MS) is commonly associated with comorbidities for which GLP-1RAs are indicated. An increasing prevalence of comorbid chronic diseases has increased the number of people living with MS (pwMS) who are prescribed a GLP-1RA, for indications of obesity, diabetes, obstructive sleep apnea, metabolic-associated steatohepatitis, and/or chronic kidney disease. This review addresses the following key considerations: (1) the use of GLP-1RAs for weight loss in pwMS and obesity, including considerations related to drug tolerability and safety; (2) the efficacy of the GLP-1RAs for their approved non-MS indications in pwMS; and (3) the potentially pleiotropic effects of the GLP-1RAs on the MS disease course beyond their approved indications.

Diabetes-associated cognitive impairment (DACI) is a common yet underrecognized condition, manifesting along a spectrum from mild cognitive impairment to dementia. DACI encompasses patients who develop vascular dementia (VaD) or Alzheimer's disease (AD) with diabetes as a risk factor; however, in certain patients, particularly those lacking clear VaD or AD features, diabetes may act as a primary driver of neurodegeneration. Mechanistically, DACI can be conceptualized as a neurovascular-metabolic disorder characterized by disruption of the neurovascular unit, impaired cerebral glucose metabolism, brain insulin resistance, and chronic neuroinflammation, contributing to small vessel disease, regional brain atrophy, and accelerated brain aging. In this narrative review, we synthesize current evidence on the clinical and imaging features of DACI, outline key mechanistic pathways linking diabetes to neurodegeneration, and discuss emerging therapeutic strategies, including GLP-1 receptor agonists and SGLT2 inhibitors, with potential neuroprotective effects. Greater recognition of DACI as a neurovascular-metabolic entity may facilitate earlier identification, inform biomarker development, and guide future trials aimed at preserving cognitive function in individuals with diabetes.

Background: Stereoelectroencephalography-guided radiofrequency thermocoagulation (SEEG-RFTC) is a minimally invasive therapy for drug-resistant focal epilepsy. However, the relationship between specific seizure-onset patterns (SOPs), particularly low-voltage fast activity (LVFA), and postoperative scalp EEG normalization remains inadequately characterized. This study investigates whether LVFA predicts RFTC efficacy and whether postoperative EEG serves as an objective complement to clinical outcome measures.

Objective: To evaluate LVFA-dominant SOPs as predictors of seizure freedom and scalp EEG normalization after SEEG-RFTC, and to assess their interaction with MRI findings.

Methods: In a retrospective cohort of 25 patients, seizure-onset patterns (SOPs) were classified as LVFA-present (n = 13) or LVFA-absent (n = 12). Outcomes included Engel classification and 6-month postoperative scalp EEG. Seizure freedom and EEG normalization rates were compared, with MRI-stratified analysis.

Results: The seizure-free rate was 92.3% (12/13) in the LVFA-present group versus 33.3% (4/12) in the LVFA-absent group (p = 0.004). EEG normalization was more frequent in LVFA-present patients (7/8, 87.5%) than in LVFA-absent patients (4/12, 33.3%; p = 0.028); all but one patient with EEG normalization was seizure-free, the sole exception being an LVFA-absent patient who remained Engel III. In MRI-negative patients, LVFA-present had 100% (6/6) seizure freedom versus 20.0% (1/5) without LVFA (p = 0.015). Scalp EEG normalization may serve as a relatively objective marker of complete disintegration of the epileptic network, whereas some patients with persistent EEG abnormalities may still achieve seizure freedom with the aid of antiseizure medications.

Conclusion: In this cohort, LVFA-present SOPs are strongly associated with favorable RFTC outcomes and may represent a prerequisite for postoperative scalp EEG normalization. Postoperative EEG is a sensitive objective endpoint that complements Engel classification. Systematic PET evaluation in larger cohorts may further refine candidate selection in MRI-negative patients.