Annals of Clinical and Translational Neurology最新文献

Objective: Several neuromuscular disorders (NMDs) are characterized by progressive muscle damage and are marked by the elevation of circulating muscle proteins from activity-related injury. Despite a diverse array of genetic drivers, many NMDs share similar patterns of exercise intolerance and higher concentrations of muscle injury proteins relative to unaffected individuals. While the interplay between the nature of the muscle injury and the specific genetic driver is poorly understood, the similarities exhibited by various NMDs suggest that a common proteomic signature of muscle injury may exist.

Methods: We used an established exercise challenge and the SOMAscan proteomics platform to study the baseline and post-exercise proteomic profiles in a cross-sectional study of three different muscular dystrophies: Becker muscular dystrophy (BMD) and limb girdle muscular dystrophy types R9 and R12.

Results: Our Results Uncover a Common Signature of Circulating Proteins That Are Elevated in all Three Myopathies, Some of Which Are Further Elevated by Exercise in Becker Muscular Dystrophy and Limb Girdle Muscular Dystrophy Type R9, and Others That Are Not Responsive to Exercise.

Interpretation: Interestingly, these two signatures exhibit opposing trajectories with age in a larger cross-sectional cohort of BMD individuals. This research represents a first step toward defining an annotated protein signature coupled with activity-injury, a defining pathophysiological feature of many myopathies.

Objective: Discriminating between epileptogenic and physiological ripples in the hippocampus is important for identifying epileptogenic (EP) zones; however, distinguishing these ripples on the basis of their waveforms is difficult. We hypothesized that the nocturnal synchronization of hippocampal ripples and cortical delta power could be used to classify epileptogenic and physiological ripples in the hippocampus.

Methods: We enrolled 38 patients with electrodes implanted in the hippocampus or parahippocampal gyrus between April 2014 and March 2023 at our institution. We divided 11 patients (11 hippocampi) who were pathologically diagnosed with hippocampal sclerosis into the EP group and five patients (six hippocampi) with no epileptogenicity in the hippocampus into the nonepileptogenic (NE) group. Hippocampal ripples were detected using intracranial electroencephalography with hippocampal or parahippocampal electrodes. Cortical delta power (0.5-4 Hz) was assessed using cortical electrodes. The Pearson correlation coefficient between the ripple rates and cortical delta power (Corr-RD) was calculated on the basis of the intracranial electroencephalographic signals recorded each night.

Results: Although hippocampal ripples were similar among the EP and NE groups based on their waveforms and frequency properties, the Corr-RDs in the EP group (mean [standard deviation]: 0.20 [0.049]) were significantly lower than those in the NE group (0.67 [0.070]). On the basis of the minimum Corr-RDs, the two groups were classified with 94.1% accuracy.

Interpretation: Our results demonstrate that the Corr-RD is a biomarker of hippocampal epileptogenicity.

Objective: Postoperative delirium, a common neurocognitive complication after surgery and anesthesia, requires early detection for potential intervention. Herein, we constructed a multidimensional postoperative delirium risk-prediction model incorporating multiple demographic parameters and blood biomarkers to enhance prediction accuracy.

Methods: We included 555 patients undergoing radical surgery for colorectal cancer. Demographic characteristics and lipid profiles were collected preoperatively, and perioperative anesthesia and surgical conditions were recorded; blood biomarkers were measured before and after surgery. The 3D-CAM scale was used to assess postoperative delirium occurrence within 3 days after surgery. Patients were divided into the postoperative delirium (N = 100) and non-postoperative delirium (N = 455) groups. Based on machine learning, linear and nine non-linear models were developed and compared to select the optimal model. Shapley value-interpretation methods and mediation analysis were used to assess feature importance and interaction.

Results: The median age of the participants was 65 years (interquartile range: 56-71 years; 57.8% male). Among the 10 machine-learning models, the random forest model performed the best (validation cohort, area under the receiver operating characteristic curve of 0.795 [0.704-0.885]). Lipid profile (total cholesterol, triglycerides, and trimethylamine-N-oxide) levels were identified as key postoperative delirium predictors. Mediation analysis further confirmed mediating effects among total cholesterol, trimethylamine-N-oxide, and postoperative delirium; a nomogram model was developed as a web-based tool for external validation and use by other clinicians.

Interpretation: Blood biomarkers are crucial in predicting postoperative delirium and aid anesthesiologists in identifying its risks in a timely manner. This model facilitates personalized perioperative management and reduces the occurrence of postoperative delirium.

Trial registration: ChiCTR2300075723.

Objectives: Intravenous immunoglobulin (IVIg) is an effective treatment for Guillain-Barré syndrome (GBS), but recovery varies between patients. This study aims to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of a single and a second IVIg dose (SID) in patients with GBS.

Methods: Data were analyzed from the SID-GBS trial, a double-blind, randomized, placebo-controlled study. Patients with poor prognosis (modified Erasmus GBS Outcome Score, mEGOS ≥6) after a standard course of IVIg (0.4 g/kg for 5 days) were randomized to receive either SID or placebo. Serum IgG levels were measured at standard serial time points and clinical outcomes were assessed using the GBS disability score and Medical Research Council sum score. PK modeling was performed to predict IVIg exposure and its association with clinical outcomes.

Results: Serum IgG concentration after a single and double course of IVIg was variable, but accurately described by the current PK model. Lower ΔIgG and IVIg exposure were associated with poorer clinical outcomes. SID increased the IgG concentration, but did not result in an improvement in clinical outcome. Serious adverse events, including thromboembolic events, occurred more frequently in the SID group and were associated with lower IVIg exposure.

Interpretation: SID increases serum IgG levels in GBS patients as predicted by the current PK model, but does not improve clinical outcomes and increases the risk of serious adverse events. Model-informed precision dosing may guide individualization of treatment.

Objective: The claustrum is a small, thin structure of predominantly gray matter with broad connectivity and enigmatic function. Little is known regarding the impact of claustrum pathology in multiple sclerosis (MS).

Methods: This study assessed whether claustrum volume was reduced in MS and whether reductions were associated with specific disability domains. We compared the impact of claustrum volume reductions on neurological disability versus the well-studied thalamus. Data from the 15,793 participants in the MS PATHS study were used for primary analyses. A second cohort of 71 people with MS and healthy controls from our center was used for validation.

Results: Claustrum and thalamic volumes were reduced to a similar degree across MS types. Claustrum volume, like thalamic volume, was associated with disability measures of walking speed, upper extremity dexterity, and cognition. Partial correlation analyses supported that both claustrum and thalamic volumes independently contribute to disability. Interestingly, claustrum volume outperformed thalamic volume as a predictor of future disability progression.

Interpretation: This study suggests that damage and resulting atrophy to the claustrum may be an important component of MS-related disability.

Objective: People with multiple sclerosis (pwMS) may require a high level of daily assistance both for indoor and outdoor activities. Usually, relatives or friends provide daily support to MS patients who have lost personal autonomy. Several factors such as disability level and disease duration may affect the burden of care in caregivers of pwMS; however, the relationship between disease-modifying therapies (DMTs) and caregiver burden has never been explored so far. The aim of this study is to explore the impact of hospital-based therapies on anxiety, depression, and burden of care in caregivers of pwMS.

Methods: Hospital Anxiety and the Depression Scale (HADS) and Caregiver Burden Inventory (CBI) questionnaires were administered to caregivers of pwMS who performed planned visits in the outpatient setting. Multivariable regression models were built to evaluate the association between hospital-based therapies and depression (HADS-D > 7), anxiety (HADS-A > 7) and need to rest (CBI > 24).

Results: Caregivers of pwMS receiving in-hospital therapies achieved higher scores in HADS and CBI questionnaires, resulting in a higher proportion of anxiety, depression, and need to rest among these. The multivariable models also showed that hospital-based therapies were positively associated with caregivers' depression (aOR = 2.38 [1.04-5.5; p = 0.04]), anxiety (aOR = 2.36 [1.03-5.4; p = 0.043]) and need to rest (aOR = 2.06 [0.8-5.29]; p = 0.13).

Interpretation: Hospital-based therapies in pwMS negatively affect the burden of care and mental health of their own caregivers. The availability of home-based highly effective DMTs may contribute to reducing the outdoor caregiver burden without renouncing highly effective treatments.

Objective: Certain frontotemporal lobar degeneration subtypes, including TDP-A and B, can either occur sporadically or in association with specific genetic mutations. It is uncertain whether syndromic or imaging features previously associated with these patient groups are subtype or genotype specific. Our study sought to discern the similarities and differences between sporadic and genetic TDP-A and TDP-B.

Methods: We generated individual atrophy maps and extracted mean atrophy scores for regions of interest-frontotemporal, occipitoparietal, thalamus, and cerebellum-in 54 patients with FTLD-TDP types A or B. We calculated asymmetry as the absolute difference in atrophy between right and left frontotemporal regions, and dorsality as the difference in atrophy between dorsal and ventral frontotemporal regions. We used ANCOVAs adjusted for disease severity to compare atrophy extent or imbalance, neuropsychological tests, and behavioral measures.

Results: For some regions, volumetric differences were found either between TDP subtypes (e.g., worse occipitoparietal and cerebellum atrophy in TDP-A than B), or within subtypes depending on genetic status (e.g., worse thalamic and occipitoparietal atrophy in C9orf72-associated TDP-B than sporadic TDP-B). While progranulin mutation-associated TDP-A and sporadic TDP-A cases can be strongly asymmetric, TDP-A and TDP-B associated with C9orf72 tended to be symmetric. TDP-A was more dorsal in atrophy than TDP-B, regardless of genetic status.

Interpretation: While some neuroimaging features are FTLD-TDP subtype-specific and do not significantly differ based on genotype, other features differ between sporadic and genetic forms within the same subtype and could decrease accuracy of classification algorithms that group genetic and sporadic cases.

Objective: Several genetic loci known to confer risk for Parkinson's disease (PD) function in lysosomal pathways. We systematically screened common variants linked to PD risk by genome-wide association studies (GWAS) for impact on cerebrospinal fluid (CSF) proteins reflecting lysosomal function.

Methods: Starting with 525 candidate gene-single nucleotide polymorphism (SNPs) pairs nominated by Mendelian randomization from published PD GWAS, we filtered SNPs for downstream evaluation, based on strength of association with PD and impact on brain gene expression. We genotyped top SNPs in 173 PD participants, adding three SNPs capturing variation at the TMEM106B, CTSB, and RAB29 loci, encoding genes with known lysosomal function. In the same 173 individuals, we measured 15 CSF proteins (nine lysosomal proteins and six other proteins implicated in neurodegeneration) by parallel reaction monitoring mass spectrometry. We tested SNPs for association with lysosomal proteins. For our top SNP associating with multiple lysosomal proteins, we characterized expression of its target gene CAMLG in human brain tissue.

Results: Sixteen SNPs emerged from our analysis of GWAS-nominated loci. Genotypes at rs12657663 (CAMLG) associated with CSF levels of multiple lysosomal markers (cathepsin F, cathepsin L, hexosaminidase B, and tripeptidyl peptidase I) and genotypes at rs7910668 (ITGA8) with CSF levels of cathepsin B. The protein encoded by CAMLG, calcium modulating ligand (CAML), is highly expressed in neurons of multiple human brain regions, with higher expression in Lewy body disease cases.

Interpretation: Systematic analysis of PD risk loci nominates CAMLG as a neuronally expressed risk gene with effects on lysosomes.

Objective: Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) share clinical, pathological, and genetic risk factors, including GBA1 and APOEε4 mutations. Biomarkers associated with the pathways of these mutations, such as glucocerebrosidase enzyme (GCase) activity and amyloid-beta 42 (Aβ42) levels, may hold potential as predictive indicators, providing valuable insights into the likelihood of cognitive decline within these diagnoses. Our objective was to determine their association with cognitive decline in DLB and PD.

Methods: A total of 121 DLB patients from the European-DLB Consortium and 117 PD patients from the Norwegian ParkWest Study were included in this study. The four most commonly associated variants of GBA1 mutations (E326K, T369M, N370S, L444P), APOEε4 status, and cerebrospinal fluid (CSF) Aβ42 levels and GCase activity were assessed, as well as global cognition using the Mini-Mental State Examination. Linear mixed-effects regression models were used to evaluate the association of CSF biomarkers with cognitive decline in each diagnostic group, adjusted for age, sex, education, and genetic mutation profile.

Results: Low CSF Aβ42 levels were associated with accelerated cognitive decline in DLB, whereas reduced CSF GCase activity predicted faster cognitive decline in PD. These associations were independent of GBA1 gene mutations or APOEε4 status.

Interpretation: Our study provides important evidence on the relationship between brain Aβ deposition and GCase activity in the Lewy body disease spectrum independent of their genetic mutation profile. This information could be relevant for designing future clinical trials targeting these pathways.

Diagnosing frontal variant Alzheimer's disease (fvAD) is difficult and could be even more difficult when amyloid-beta (Aβ) PET retention is low. A 63-year-old woman presenting with a 3-year history of apathy and memory impairment showed executive dysfunction, memory impairment, and severe bilateral frontotemporal atrophy on MRI. Aβ PET showed only equivocal findings in the right frontal lobe and was negative. However, CSF showed a severely decreased Aβ42/40 ratio and increased phospho-tau181. AD-tau-specific (18F)-MK6240 PET revealed increased tracer retention predominantly in the bilateral frontal lobes, confirming the fvAD diagnosis. (18F)-MK6240 PET can be valuable in resolving diagnostic uncertainties in atypical patients with low Aβ retention.