Brain communications最新文献

Repeated low-intensity blast overpressure exposures, frequently sustained by Special Operations Forces during breaching, combat training, and weapons use, are thought to initiate tau-related neurodegenerative changes that may remain clinically silent for years. The long-term impact of cumulative blast overpressure on brain health is poorly understood, and sensitive biomarkers are needed for early detection and monitoring of subclinical injury in high-risk populations. In this cross-sectional study, 25 actively serving male Canadian Special Operations Forces personnel (mean [SD] age, 43.6 [6.1] years) with ≥16 years of breaching and explosives experience were compared with 10 age-matched Canadian Armed Forces controls (mean [SD] age, 39.8 [6.8] years) with minimal blast exposure. All participants underwent [¹⁸F]flortaucipir PET imaging to quantify cortical tau deposition, MRI, ultrasensitive digital immunoassay for plasma biomarkers, and comprehensive clinical and neurocognitive testing. Group differences in regional [¹⁸F]flortaucipir standardized uptake value ratios were assessed using analysis of covariance, and voxelwise Z-score mapping identified clusters of elevated tracer uptake (>2 SD above control mean). Linear regression analyses were conducted to examine associations between PET tau signal, plasma biomarkers, cumulative blast exposure and clinical outcomes. Special Operations Forces personnel exhibited significantly higher [¹⁸F]flortaucipir uptake in the frontal (P & 0.022) and temporal cortices (P & 0.037) compared with controls. Voxelwise mapping revealed tau clusters in 88% of exposed individuals, with nearly half localized to the frontal cortex. Elevated PET signal correlated with cumulative years of breaching, post-concussive symptoms, sleep disturbance and functional impairment. Plasma biomarkers showed converging evidence of neurodegeneration: brain-derived tau, glial fibrillary acidic protein and amyloid-β42 levels were significantly associated with regional tau PET uptake. A reduced amyloid-β42/40 ratio and elevated phosphorylated tau isoforms further supported early molecular changes consistent with neurodegeneration. Cumulative occupational blast overpressure exposure in Special Operations Forces is associated with frontal-predominant tau deposition and plasma biomarker signatures of astroglial activation, axonal injury and CNS-specific tau release. These convergent imaging and molecular findings support a link between repetitive blast exposure and early-stage tauopathy, and highlight the value of combined tau PET imaging and fluid biomarkers as non-invasive tools for early detection, monitoring, and targeted risk mitigation in blast-exposed populations.

Fatigue is one of the most disabling symptoms of multiple sclerosis (MS), yet its neurobiology remains unclear, and there are no objective biomarkers. Previous studies using electroencephalography alone have revealed altered movement-related beta Event-Related Desynchronization (ERD) and Synchronization (ERS) dynamics in fatigued patients, but without providing mechanistic insight. In this cross-sectional study, we combined electroencephalography with transcranial magnetic stimulation, structural magnetic resonance imaging with diffusion tensor imaging (DTI), and clinical measures to probe the mechanistic basis of movement-related beta modulation depth (ERS-ERD) and its link with fatigue. Based on the Fatigue Severity Scale score (FSS), we enrolled 41 relapsing-remitting MS patients, 19 with clinically significant fatigue, 22 without (aged 25-55 years, 25 females), alongside 18 age- and sex-matched healthy volunteers. Participants underwent neuropsychological assessment, blood sampling for inflammatory and neurodegeneration-related biomarkers, structural magnetic resonance imaging with DTI to assess grey and white matter integrity, transcranial magnetic stimulation to quantify cortical excitatory and inhibitory balance, and continuous electroencephalography during 300 cued pinch movements to characterize movement-related beta dynamics. Compared with non-fatigued patients and healthy volunteers, fatigued patients exhibited reduced beta peak ERD to ERS modulation (P < 0.001), especially in frontal regions. The modulation depth correlated with fatigue severity (ρ = -0.54, P = 0.0006), intracortical facilitation (ρ = 0.49, P = 0.0009), and caudate nucleus volume (ρ = 0.35, P = 0.010). A nested elastic-net logistic regression integrating demographic, clinical, structural, and functional markers showed robust held-out performance (mean Receiver Operating Characteristic-Area Under the Curve = 0.92, Precision Recall-Area Under the Curve = 0.83, accuracy = 0.89, Brier score = 0.10). Variables with the strongest protective association with fatigue were higher intracortical facilitation, better mental health, larger caudate volume, greater beta modulation over the frontal regions, and higher corticospinal tract and superior longitudinal fasciculus integrity. These findings support frontal beta modulation as a mechanistically grounded, non-invasive biomarker of central fatigue in multiple sclerosis and highlight its potential utility for clinical diagnosis and targeted therapeutic intervention.

We examined the impact of COVID-19 hospitalization on neuroimaging biomarkers and the association of these neuroimaging biomarkers with cognitive measures and plasma biomarkers. A total of 179 dementia-free people, including 52 hospitalized COVID-19 patients, across four medical centres in the USA and UK underwent 7T brain MRI scans, cognitive tests and blood collection. We found that hospitalized patients exhibited a comparable white matter hyperintensity burden, lower total hippocampal volume and lower plasma glial fibrillary acidic protein concentration, along with poorer memory performance, compared to age-matched non-hospitalized participants. Higher white matter hyperintensity burden was associated with older age, worse cognitive scores and higher plasma biomarker levels; higher total hippocampal volume was associated with younger age, better cognitive scores and lower plasma phosphorylated tau levels. However, these correlation coefficients did not differ between the hospitalized and non-hospitalized groups. Longitudinal studies are needed to clarify the long-term impact of COVID-19-related hospitalization.

Paraneoplastic motor neuron disease is an uncommon paraneoplastic neurologic syndrome whose existence has fallen into ambiguity. Epidemiologic studies that have addressed the association between cancer and motor neuron disease have provided conflicting results. Case studies that report motor neuron disease presentation at the time of active malignant disease, in the presence of another paraneoplastic neurologic syndrome or onconeural antibody or with neurologic response to antineoplastic treatment provide strong evidence for paraneoplastic motor neuron disease. However, conclusive evidence about the existence and the clinical and laboratory profiles of this neurologic syndrome is lacking. In this study, we report four new cases of paraneoplastic motor neuron disease, two of whom with expression of Sry-like high mobility group box 1 (SOX1) antibody. We also present a systematic review of all cases of paraneoplastic motor neuron disease reported to date that fulfill prespecified inclusion criteria with individual participant data meta-analysis of the demographic, clinical and laboratory features of the disease. Our data demonstrate that motor neuron disease can present as a paraneoplastic neurologic syndrome. Paraneoplastic motor neuron disease spans the whole motor neuron disease phenotypic spectrum, and it is associated with a wide variety of neoplastic diseases, onconeural antibodies and it may present concurrently with other well-recognized paraneoplastic neurologic syndromes. Paraneoplastic motor neuron disease may be clinically indistinguishable from idiopathic motor neuron disease. Its only distinctive clinical feature is the rapidly progressive course. A subset of cases display immune derangements in cerebrospinal fluid, including increased white cell count, elevated protein, albumin index, IgG index and/or oligoclonal band expression. Cancer-induced inflammatory pathways may trigger the disease in genetically predisposed individuals harboring amyotrophic lateral sclerosis-causing genetic deficits. A thorough evaluation for neoplastic diseases should be carried out upon strong suspicion of this rare paraneoplastic neurologic syndrome to increase the diagnostic yield for this entity. Paraneoplastic motor neuron disease apparently results from complex interactions between degenerative and immune pathways and its pathophysiology may elucidate previously unresolved aspects of idiopathic motor neuron disease pathogenesis.

Alzheimer's disease (AD) is characterized by progressive brain changes, including protein aggregation and structural changes. Cerebrospinal fluid (CSF) system abnormalities, such as ventricular dilation, increased choroid plexus volume or positron emission tomography (PET) ligand uptake in the CSF, have also been consistently described. We aimed to examine whether changes in CSF production and clearance might be associated with brain protein aggregation across biological stages of Alzheimer's disease. We hypothesized an association between brain protein aggregation and changes on the CSF system. We examined 378 individuals from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort with T1-weighted magnetic resonance imaging (MRI), amyloid-PET and tau-PET assessments. We assessed the lateral ventricle and choroid plexus volumes, both corrected for intracranial volume, in the MRI native space. Non-specific ventricular tracer standardized uptake value ratio (SUVR), derived from amyloid- and tau-PET images, was used as an indirect marker of choroid plexus-related clearance activity and served as a metric of CSF dynamics. Linear models tested associations amongst lateral ventricular volume (reflecting CSF space enlargement), choroid plexus volume (reflecting secretory tissue morphology) and ventricular SUVR (reflecting tracer activity within the CSF compartment and serving as an indirect marker of choroid plexus-related clearance function and CSF dynamics) with Aβ and tau aggregations. Analyses were restricted to within-modality associations, relating ventricular radioactivity to cortical pathology for each PET tracer. We found that when considered independently, larger ventricular and choroid plexus volumes were associated with higher neocortical Aβ-PET SUVR, particularly in the precuneus and cingulate cortices. Additionally, lower ventricular radioactivity (derived from amyloid-PET) showed strong negative associations in the dorsal apex of the neocortex. However, when all three ventricular parameters were included in the same model, these effects were mediated by ventricular volume. By contrast, the effect of the ventricular parameters on tau load was mediated by Aβ in the neocortex. Therefore, ventricular enlargement appears to be associated with Aβ load. Distinct from neurodegeneration, changes in ventricular parameters, particularly ventricular volume, are associated with upstream Alzheimer's disease pathophysiology. While ventricular volume significantly mediated ventricular amyloid clearance, no such effect was observed for tau, suggesting distinct clearance mechanisms for these pathologies in Alzheimer's disease.

Lissencephaly (LIS) is a spectrum of cortical malformations including agyria, pachygyria and subcortical band heterotopia, which arises from aberrant neuronal migration and is associated with severe neurodevelopmental impairments. Despite advancements in prenatal imaging, diagnosing LIS remains challenging. Genetic factors play a crucial role in LIS, involving multiple genes and signalling pathways, yet research on prenatal diagnosis and the genetic basis is still limited. This study aimed to assess the diagnostic yield of whole exome sequencing (WES) in LIS and to examine genotype-phenotype correlations, addressing the challenge of 'phenotype lag' in prenatal LIS diagnosis. This study included 20 fetuses with LIS suggested by prenatal imaging and 20 children with LIS diagnosed after birth; all cases were diagnosed by magnetic resonance imaging and underwent genetic testing. In addition, a literature review was conducted and 80 studies were included, of which 1 was used to compare detection efficacy and 79 studies totalling 210 cases were used to assess genotype-phenotype correlation. In the prenatal cohort, 85.0% (17/20) of cases exhibited concurrent anomalies, predominantly ventriculomegaly (50.0%) and microcephaly (25.0%). In the postnatal cohort, the most common phenotypes were epilepsy (80.0%, 16/20) and global developmental delay (65.0%, 13/20), with half of the cases (10/20) showing no abnormalities in the prenatal period. The diagnostic yields were 55.0% (11/20) and 65.0% (13/20), respectively, with PAFAH1B1 point mutations or 17p13.3 microdeletions being the predominant genetic variant in both cohorts, accounting for 31.3% (prenatal) and 25.5% (postnatal) of cases, respectively. DARS2 and NPRL3 were reported to be associated with LIS for the first time in this study. Literature synthesis revealed an overall diagnostic yield of 79.04%, dominated by PAFAH1B1 (26.3%), DYNC1H1 (11.9%), and DCX (10.2%). By reviewing the prenatal images, up to 48.05% (74/154) of the cases had no specific findings in the prenatal period, and the most common presentations were ventriculomegaly/hydrocephalus (52.63%) and head circumference anomalies (29.82%). This study highlights the significant genetic heterogeneity, phenotypic complexity and diagnostic challenges of LIS by integrating data from our cohort and the published literature. We developed a comprehensive genetic aetiology classification framework for LIS and identified novel associations with non-canonical genes such as NPRL3 and DARS2. With a high molecular diagnostic yield of 79.04%, we recommend WES as the first-line genetic test. Furthermore, the establishment of an integrated prenatal imaging-molecular diagnostic system, along with a postnatal multidisciplinary model, is crucial for improving prognosis assessment, clinical decision-making and genetic counselling.

Targeted electrical approaches to the treatment for Parkinson's disease include deep brain stimulation, which is effective for core motor symptoms, such as essential tremor. Interestingly, treating comorbid depressive symptoms in Parkinson's disease, using electroconvulsive therapy, also appears to help motor disability. But it is unclear whether such electrical strategies have any impact on the underlying disease processes of Parkinson's disease. Since aggregation of misfolded alpha-synuclein fibrils is a pathological hallmark of Parkinson's disease, this may be an important therapeutic target. To this end, we presently assessed whether direct current stimulation (DCS) of cortical neurons that were seeded with wild-type or A53T alpha-synuclein mutant pre-formed fibrils (PFFs) would reduce their aggregation. We found that both wild-type and A53T alpha-synuclein PFFs readily induced alpha-synuclein aggregation in primary cortical neurons and this effect was more pronounced at embryonic Day 17 (E17), compared to less mature E14-derived neurons. We did find that DCS time dependently reduced alpha-synuclein accumulation (phosphorylated and aggregate forms) within neurons and increased neuronal viability. Increased extracellular alpha-synuclein levels suggest that the DCS induced an increase in neuronal activity causing the clearance of the intracellular alpha-synuclein. These data have implications for non-invasive neuromodulation strategies to lower alpha-synuclein burden and possibly correct aberrant neuronal firing in Parkinson's disease and other alpha-synucleinopathies.

The final editorial from our founding editor-in-chief introduces the new editor-in-chief, Professor David Belin from University of Cambridge, UK.

Following acute infective illness, patients frequently exhibit neurological symptoms, with persistent neurological symptoms commonly observed following severe infection. However, the association between systemic infection and the concentration of blood-based biomarkers of brain injury and the relationship between these and markers of the host response to infection are poorly characterized in the literature. Further, the association between acute illness and the Alzheimer's disease-associated biomarker phosphorylated-tau-217 (p-tau-217) is unknown. In acute samples from 26 patients attending the emergency department with suspected sepsis (clinically suspected or proven infection, a National Early Warning Score or National Early Warning Score 2 score ≥ 5), the levels of serum biomarkers of brain injury (neurofilament light [NfL], glial fibrillary acidic protein (GFAP), total tau and ubiquitin C-terminal hydrolase L1) and p-tau-217 were compared to age- and sex-matched non-infected controls, with further assessment of the correlation between the biomarker levels and cytokine profiles. p-tau-217 levels were additionally compared to a positive control group of patients with diagnosed Alzheimer's disease. Both total tau (P = 0.006, Wilcoxon rank-sum test) and NfL (P = 0.044, Wilcoxon rank-sum test) levels were significantly higher in patients with suspected sepsis as compared to controls, with no significant differences in levels of GFAP or ubiquitin C-terminal hydrolase L1. Within suspected sepsis patients, serum total tau levels were associated with multiple cytokines and a summary cytokine score (Spearman's rank correlation coefficient ρ = 0.65, P < 0.001). There were significantly higher p-tau-217 levels in suspected sepsis patients as compared to non-infected controls (P < 0.001, Dunn-Kruskal-Wallis test), with no significant difference compared to Alzheimer's disease controls (P = 0.118, Dunn-Kruskal-Wallis test). Of patients with suspected sepsis, 29% had a p-tau-217 level classified as high (>0.63 pg/ml) with a further 17% classified as intermediate (0.4-0.63 pg/ml). In conclusion, we have identified elevated levels of total tau and NfL compared to age- and sex-matched controls, along with significant correlations between these tau levels and cytokine levels. Additionally, we observed elevated levels of p-tau-217 in the patient cohort, with levels comparable to those seen in Alzheimer's disease patients. Further analysis is required to replicate the findings of this study in larger cohorts. However, the results suggest a potentially extracranial source of tau expression in the context of infection or physiological stress. Given the potential for acute illness to influence p-tau-217 levels, our results raise important considerations regarding the interpretation of p-tau-217 as a diagnostic marker for Alzheimer's disease in patients with active infection.

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder marked by abdominal pain and changes in stool consistency or frequency. Recent studies have explored the link between IBS and alterations in brain networks using functional MRI. Despite these efforts, an effective diagnostic or predictive model for IBS remains elusive. This shortfall is twofold: firstly, the sample sizes in these studies are typically small, and secondly, the machine learning or deep learning models currently in use fail to adequately detect the subtle and dynamic pathological changes present in functional MRI data for IBS. In this study, we extracted rs-functional MRI of 79 subjects with IBS and 79 healthy controls, then put them into spatio-temporal graph convolution network (ST-GCN) for classification. We also incorporated a novel interpretability module into this model to identify potential regions of interest (ROI) associated with IBS. Our model outperformed other state-of-the-art machine learning and deep learning methods with the highest average accuracy of 83.51% on our dataset. Furthermore, based on the results of our interpretability module, the Inferior Parietal Lobule (IPL.R), Inferior Frontal Orbital part (ORBinf.R), Postcentral Gyrus (PCG.R), Middle Frontal Orbital part (ORBmid.R), and Superior Medial Frontal Orbital part (ORBsupmed.L) were identified as top 5 important brain regions for distinguishing IBS patients from the control group, which are consistent with the brain regions identified in previous literature reviews. We also conducted three external data-driven experiments to further validate the effectiveness of the interpretability module: (1) Experiment only on important brain regions; (2) Comparison with the Perturbation-Based Methods; (3) Correlation analysis. The results indicate that the selected regions significantly impact IBS.