Brain communications最新文献

Blood-based biomarkers are crucial for individualized management of multiple sclerosis (MS). Blood neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have shown promising clinical utility in MS, but they are insufficient to guide clinical management. Plasma tau proteins remain underexplored despite the growing evidence of shared pathology in Alzheimer's disease and MS. We aimed to: (i) assess the utility of plasma tau biomarkers [phosphorylated tau 181 (p-tau181), p-tau217 and total tau (t-tau)] in MS diagnosis, subtyping and prognosis; and (ii) compare their performance with NfL and GFAP. From a clinic-based prospective cohort, we evaluated 160 people with MS [pwMS; 117 with relapsing-remitting MS, 43 with progressive MS (PMS)] and 20 non-MS controls, all with baseline plasma samples. We measured baseline plasma concentrations of p-tau181, p-tau217, t-tau, NfL and GFAP using ultrasensitive immunoassays. We collected demographics, clinical information, and longitudinal multi-modal outcomes (Patient Determined Disease Steps, normalized age-related MS severity score, walking speed, manual dexterity, cognitive performance, retinal nerve fibre layer thickness, total brain volume and grey matter volume) over a median follow-up of 3.0 years (interquartile range, 3.5). Adjusting for demographic and clinical covariates, we evaluated associations between biomarkers and MS diagnosis, subtypes, and prognosis. We examined the enhanced value of tau markers, in addition to NfL and GFAP, for subtype distinction and outcome prediction. Participants were enrolled between 2017 and 2023. Assays were performed in August 2023. Analyses were conducted in December 2024. Participants (n = 180) had a median age of 51 years and were predominantly women (68%) and non-Hispanic white (91%). Compared with controls, pwMS had higher levels of p-tau217 (1.0 versus 0.7 pg/ml; P = 0.04) and NfL (14.1 versus 9.0 pg/ml; P < 0.01). Among pwMS, higher p-tau181 (adjusted odds ratio (aOR) [95% confidence interval (CI)] = 2.3 [1.4, 4.1]) and p-tau217 (aOR [95% CI] = 3.0 [1.8, 5.7]) were associated with PMS. These markers improved MS subtype classification accuracy beyond clinical features, NfL and GFAP. Higher baseline p-tau181 and p-tau217 predicted worse disability, functional outcomes and imaging outcomes independent of other biomarkers. Plasma p-tau181 and p-tau217 are promising biomarkers for MS subtype classification and disability prediction, providing complementary information to NfL and GFAP. Further studies to validate their potential clinical utility in guiding MS management are warranted.

Previous genome-wide association studies (GWAS) have identified several risk genes for stroke; however, it remains unclear how they confer risk for the disease. We conducted an integrative analysis to identify candidate genes for stroke and stroke subtypes by integrating blood-derived multi-omics data with genetic data. We systematically integrated the latest stroke GWAS database with human plasma proteomes and performed proteome-wide association studies, Mendelian randomization (MR), Bayesian colocalization analysis and transcriptome-wide association study to prioritize genes that associate the risk of stroke and its subtypes with their expression and protein abundance in plasma. The target genes were verified by performing tissue and cell type specificity, and functional analysis using the Genotype-Tissue Expression database, single-cell RNA sequencing and Gene Ontology databases. A two-step MR analysis was followed to explore the potential mechanisms. We found that the protein abundance of seven genes (MMP12, F11, SH3BGRL3, ENGASE, SCARA5, SWAP70 and SPATA20) in the plasma was associated with stroke and its subtypes, and six genes (MMP12, F11, SH3BGRL3, SCARA5, SWAP70 and SPATA20) causally related with stroke and its subtypes. The effect of F11, SH3BGRL3, SPATA20 and SWAP70 on each subtype was mediated by Factor XI inhibitors, atrial fibrillation, type 2 diabetes and systolic blood pressure, respectively (P < 0.05). We also found that SCARA5 and SWAP70 were related to stroke and ischemic stroke at the transcriptome level. Our present proteomic findings may offer potential future therapeutic targets for stroke prevention.

Epilepsy with myoclonic-atonic seizures, formerly myoclonic-astatic epilepsy or Doose syndrome, accounts for 1-2.2% of childhood-onset epilepsies. We investigated genetic determinants, long-term clinical outcomes and prognostic indicators in a large cohort using homogeneous inclusion criteria. We studied 60 patients (26.7% female), mean age 14.5 years (±9.1, range 3.2-41), followed between 1986 and 2024 at two paediatric neurology centres. Average follow-up was 11.7 years. Inclusion criteria were seizure onset between 6 months and 8 years, generalized 2-6 Hz spike-wave discharges and video-EEG documented myoclonic-atonic, myoclonic seizures or both. We analysed clinical, EEG, neuroimaging, neuropsychological and genetic data obtained with next-generation sequencing. We used χ² test, t-test, Log-rank test, Cox regression, population-averaged logistic models and Benjamini-Yekutieli procedure to identify predictors of seizure outcome, intellectual disability and other neurodevelopmental comorbidities. We observed myoclonic-atonic seizures in 55/60 (91.7%), tonic-vibratory seizures in 44/60 (73.4%), absence seizures in 30/60 (50%), myoclonic seizures without post-myoclonic atonia in 25/60 (42%) and non-convulsive status epilepticus in 13/60 (21.7%). A 'stormy' onset occurred in 26/60 patients (43.3%). The most effective drugs were valproate, ethosuximide, benzodiazepines and phenobarbital, used in different combinations, whereas the newer drugs offered no benefit. Long-term outcomes were variable. Thirty-seven patients (61.7%) achieved seizure freedom after 5.1 years on average. We observed drug resistance in 23/60 patients (38.3%) and intellectual disability in 35/60 (58.3%). One adult patient died (mortality rate 1.80/1000-person-years). Attention deficit hyperactivity disorder was the most common comorbidity (24/60, 40%). 'Stormy' onset did not predict a worse prognosis. Global developmental delay at epilepsy onset was associated with drug resistance (P = 0.004, Q = 0.064) and with intellectual disability (P = 0.003, Q = 0.048). We found pathogenic variants in 15/39 (38.5%) patients undergoing next-generation sequencing, including four genes novel for this syndrome (KMT2E; POGZ; SHANK3; YWHAG), with exome sequencing yielding higher diagnostic rates than gene panels. Epilepsy with myoclonic-atonic seizures is a complex syndrome with diverse genetic causes and variable seizure severity and outcomes. Our findings expand its genetic landscape and highlight the prognostic value of prompt overall neurodevelopmental assessment at clinical onset. Whole exome sequencing should be prioritized for early diagnosis and counselling.

Visual snow syndrome is a neurological disorder characterized by persistent visual disturbances and associated symptoms. Although the neural basis of the visual snow syndrome remains poorly understood, it may involve increased neuronal excitability and/or altered neuroplasticity in the visual cortex, which could, in turn, affect visual gamma oscillations. An altered excitation-inhibition balance is hypothesized to alter the modulation of gamma power and frequency by stimulation intensity, while maladaptive neuroplasticity may impact time-dependent changes in gamma power during repeated stimulation. To investigate potential alterations in the excitation-inhibition balance and neuroplasticity in visual snow syndrome, we used magnetoencephalography to record visual gamma oscillations in 26 patients with this disorder and 27 healthy controls. Participants were exposed to repeatedly presented high-contrast annular gratings, which were either static or drifting at varying speeds to systematically manipulate stimulation intensity. We also assessed heart rate variability during rest and repetitive visual stimulation to explore the relationship between time-dependent gamma changes and parasympathetic activation, which is known to promote activity-dependent plasticity. Our results showed no significant group differences in gamma power or frequency, nor in their modulation by drift rate, suggesting that the excitation-inhibition balance in the V1 area remains largely intact in visual snow syndrome. Both groups exhibited an initial brief decrease in gamma power followed by a sustained linear increase with stimulus repetition, likely reflecting activity-dependent plasticity. Heart rate variability parameters were comparable across groups, with the parasympathetic-sympathetic balance index correlating with repetition-related increase in gamma power, further supporting the link between time-dependent gamma changes and neuroplasticity. Notably, patients with visual snow syndrome exhibited a steeper repetition-related increase in gamma power, indicating atypically heightened activity-dependent plasticity in this group. These findings provide the first experimental evidence suggesting that altered activity-dependent neuroplasticity plays a role in the pathophysiology of the visual snow syndrome. Furthermore, they identify repetition-related increases in gamma power as a potential biomarker of aberrant neuroplasticity, offering novel insights into the pathophysiology of the visual snow syndrome and potential avenues for targeted therapeutic interventions.

Restless limbs syndrome (RLS) is a neurological disorder characterized by an uncontrollable urge to move the limbs. Although it affects up to 10% of the general population, its underlying mechanisms remain poorly understood. Neurophysiological excitability testing may help elucidate mechanisms related to sensorimotor integration, axonal ion channel dysfunction and impaired neural inhibition. This study aimed to assess both CNS and PNS function by examining cortical, spinal and peripheral nerve excitability within the same individuals for the first time. To investigate potential widespread excitability changes in RLS, we specifically analysed hand muscles, offering new insights into the extent of neural involvement beyond the lower limbs. The study included 56 RLS patients, divided into treated and untreated groups, along with 32 healthy controls. Notably, none of the patients experienced symptoms in their hands. Cortical excitability was assessed via threshold-tracking transcranial magnetic stimulation (TMS) to evaluate intracortical inhibition and facilitation. Sensory-motor integration was measured via long-latency reflexes (LLRs), while spinal cord excitability was assessed using F-waves, H-reflexes and RIII-reflexes. Axonal excitability was examined using the extended TRONDNF protocol. TMS revealed a significant reduction in short-interval intracortical inhibition (SICI) in patients, particularly at inter-stimulus intervals (ISIs) of 2.5 and 3 ms. When averaging across ISIs from 1 to 7 ms, patients on medication exhibited significantly less inhibition compared to healthy controls. Long-interval intracortical inhibition (LICI) was also reduced at ISIs of 150 and 200 ms, while facilitation parameters remained within normal ranges. Patients exhibited increased amplitude of the second component of the LLR recorded from the abductor pollicis brevis, whereas RIII reflex measurements showed no significant differences. Axonal excitability testing revealed a graded increase in hyperpolarization-activated currents in patients with more severe symptoms. The observed reductions in SICI and LICI suggest impaired intracortical inhibition in the M1 hand area, offering indirect evidence of cortical dysfunction in regions clinically unaffected by the disease. The increased LLR amplitudes further indicate altered sensorimotor integration at the cortical level, whereas the absence of significant changes in RIII reflexes suggests that segmental spinal dysfunction within the pain pathway of the upper limbs is unlikely. Finally, axonal excitability findings point to a potential role of hyperpolarization-activated currents in either contributing to or predisposing individuals to RLS symptoms.

In Disorders of Consciousness, ¹⁸F-fluorodeoxyglucose PET (FDG-PET) is known to be effective in distinguishing vegetative state/unresponsive wakefulness syndrome from minimally conscious state, and when combined with MRI techniques, the risk of misdiagnosis decreases. However, FDG-PET studies on chronic patients with different etiologies (traumatic, vascular, and anoxic brain injury) are limited, and the association between metabolic activity and resting-state functional MRI (fMRI) networks remains unclear. This study combined FDG-PET with resting-state functional MRI and MRI to assess: i) the diagnostic accuracy of FDG-PET metabolism in different etiological groups of patients; ii) whether resting-state fMRI networks presence or absence was associated with higher versus lower FDG-PET metabolism. A group of 84 chronic patients underwent FDG-PET (47 vegetative state/unresponsive wakefulness syndrome, 31 minimally conscious state, and six emerged from a minimally conscious state), equally distributed in traumatic, vascular, and anoxic etiologies. Eight cases of covert cortical processing were identified. A subgroup of 68 patients also underwent resting-state fMRI. Standardized uptake values were calculated for these areas of interest: 10 resting-state fMRI networks, the precuneus, and a whole-brain mask. Patients in a vegetative state/unresponsive wakefulness syndrome exhibited a significant decrease in metabolism compared to patients in a minimally conscious state across all areas of interest. Patients with covert cortical processing showed intermediate metabolic levels between the two diagnostic categories. The anoxic group displayed a severe decrease in metabolism compared to patients with traumatic and vascular etiologies. The highest diagnostic accuracy among the areas of interest was reached in the precuneus and medial visual network (Area Under the Curve, AUC = 0.82-0.83). However, when anoxic patients were excluded, the diagnostic accuracy did not reach statistical significance, although the medial visual network and precuneus retained a trend of gradually increasing metabolism as clinical conditions improved. Identification of resting-state functional MRI networks was associated with increased metabolism in all networks at the group level, even excluding patients with severe structural damage. FDG-PET proves to be a technique capable of distinguishing vegetative state/unresponsive wakefulness syndrome from minimally conscious state even in chronic patients, although its diagnostic accuracy can be significantly affected by the etiology. There is a concordance between the metabolism level and the presence of resting-state fMRI networks.

Although traditionally viewed as relatively spared in Alzheimer's disease (Ad), the cerebellum is increasingly recognized for its contribution to cognitive and behavioural dysfunction. However, longitudinal data delineating subregional cerebellar involvement across the Ad continuum remain limited. In this study, we investigated longitudinal cerebellar atrophy and its clinical correlates in 259 older adults classified via amyloid PET into four biomarker-defined groups: cognitively normal controls, preclinical Ad, Ad-related mild cognitive impairment and Ad dementia. Structural MRI data were analysed using the Spatially Unbiased Infratentorial Template (SUIT), and longitudinal changes in 28 cerebellar subregions were assessed via generalized estimating equations, controlling for demographic and biological covariates. Across longitudinal analyses, cerebellar structural alterations in preclinical Ad were closely associated with both cognitive and behavioural measure changes. Reductions in lobule VI and Crus I/II were correlated with episodic memory decline, emphasizing the cerebellum's contributions to early cognitive deterioration. The same regions were involved in associations with apathy and behavioural dysregulation, suggesting the cerebellar contribution to emerging neuropsychiatric symptoms through disruption of motivational and executive circuits. In addition, stage-dependent cortico-cerebellar coupling was noted, with coordinated volume loss between cerebellar lobule VI and temporo-orbitofrontal cortices in the preclinical stage, but selective posterior cerebellar-posterior cingulate synchrony in dementia, indicating progressive network reorganization and eventual decoupling along the disease continuum. This study provides the first biomarker-defined longitudinal mapping of cerebellar subregional atrophy in Ad. The findings demonstrate that cerebellar degeneration is not confined to advanced stages but emerges early and dynamically interacts with cortical networks, influencing both cognitive decline and neuropsychiatric symptoms. The distinct atrophy patterns and cortico-cerebellar decoupling underscore the cerebellum's potential as a disease-stage-specific biomarker and therapeutic target in Ad.

Huntington's disease has traditionally been considered a motor disorder, but it is currently classified as a multisystem neurodegenerative disease that involves brain regions, such as the amygdala, and causes depression. The aim of the present study was to analyse the distribution of huntingtin in the human amygdaloid basolateral complex, considering its nuclei, sex, triplet repeats and Vonsattel score, as well as to characterize the cellular relationships between huntingtin and associated copathologies. The present study included 23 human brain samples from patients (males and females) with and without Huntington's disease, Parkinson's disease and Alzheimer's disease. An unbiased stereology approach was used to quantify huntingtin deposits. Multiple immunofluorescence experiments were conducted to analyse the relationship between huntingtin and glial populations. Immunohistochemistry against pathological markers of other neurodegenerative diseases was also carried out. Quantification data did not reveal differences among different nuclei (basomedial, basolateral or lateral) in the basolateral complex or according to sex. Huntingtin deposits did not correlate with cytosine-adenine-guanine (CAG) repeats. However, these deposits were positively correlated with pathological Vonsattel grades. Additional aggregates of other pathological proteinopathies were also observed. This correlation between the human basolateral amygdaloid complex and the Vonsattel stage provides a new perspective for neuropathological diagnosis and helps in understanding nonmotor symptoms such as depression.