Brain communications最新文献

Astrocytes are key regulators of sleep and neuroinflammatory responses. However, the relationship between objective sleep parameters and astrocytic fluid biomarkers in cognitively unimpaired individuals remains unclear. We examined how sleep architecture relates to astrocytic, neuroaxonal and Alzheimer's disease-related fluid biomarkers in cognitively unimpaired adults and whether age, sex and APOE ε4 moderate these associations. This cross-sectional study included 51 cognitively unimpaired participants from the Sant Pau Initiative on Neurodegeneration cohort. One-night in-lab polysomnography was used to quantify sleep architecture, fragmentation, slow-wave activity and respiratory parameters. CSF biomarkers included glial fibrillary acidic protein (GFAP), chitinase-like-3 protein 1 (YKL-40), Aβ42, Aβ40, pTau181 and tTau; plasma biomarkers included GFAP and neurofilament light chain (NfL). Associations were analysed using Spearman correlations, multiple linear regression, and moderation models, adjusting for age, sex, body mass index, APOE ε4 status and sleep apnoea. Lighter and more fragmented sleep, characterized by longer N1 duration, increased wake after sleep onset, frequent stage transitions and elevated cortical arousal, was associated with higher CSF YKL-40, Aβ40, pTau181 and tTau (ρ = 0.32-0.62, all P < 0.05). In contrast, deeper, more consolidated sleep, indicated by longer total time of sleep, greater N3 duration and higher slow-wave activity, was associated with lower CSF GFAP and YKL-40 (ρ = -0.35 to -0.44, all P < 0.05). These associations remained significant in adjusted regression models. Plasma GFAP and NfL exhibited an inverse profile, with positive associations with deeper sleep (β: 0.16-0.18, P < 0.05) and negative associations with lighter sleep stages (β: -0.23 to -0.29, P < 0.01). Rapid eye movement (REM) sleep was also associated with astrocytic fluid biomarkers, with negative correlations for CSF and plasma GFAP (ρ = -0.49 and ρ = -0.28, respectively, all P < 0.05), while in regression models, REM duration remained a negative predictor of plasma GFAP (β = -0.23, P = 0.003) and a positive predictor of CSF YKL-40 (β = 0.12, P = 0.037). Notably, APOE ε4 consistently moderated associations between sleep and CSF YKL-40 and GFAP, while age and sex influenced plasma GFAP and CSF YKL-40, respectively (all P < 0.05). In cognitively unimpaired adults, sleep architecture is differentially associated with central and peripheral biomarkers of astrocytic activation, neuroaxonal integrity and Alzheimer's disease-related proteins. These findings support the importance of considering sleep as a key factor in the early pathophysiology of neurodegenerative disease.

X-linked female-restricted neurodegenerative disorder with Parkinsonian syndrome and cognitive impairment (NDPACX) is a recently recognized clinical entity caused by heterozygous mutations in SLC9A6 on the X chromosome, which encodes the endosomal Na⁺/H⁺ exchanger NHE6 that contributes to endolysosomal trafficking and acidification. While hemizygous SLC9A6 mutations in males cause Christianson syndrome, a severe neurodevelopmental disorder, emerging evidence indicates that female carriers may develop progressive, adult-onset Parkinsonian syndrome variably accompanied by cognitive decline and psychiatric symptoms. These features often resemble those of corticobasal degeneration, progressive supranuclear palsy, and atypical Parkinson's disease. Although pathological data for NDPACX are currently lacking, mechanistic inferences drawn from Christianson syndrome and animal models implicate endosomal dysfunction, impaired receptor recycling, and tau accumulation, depending on the loss of function. Furthermore, recent findings have linked reduced SLC9A6 expression to the increased vulnerability of the substantia nigra in sporadic Parkinson's disease, suggesting a broader relevance beyond rare monogenic disorders. In particular, NDPACX represents a model of endolysosomal neurodegeneration that may be related to lysosomal storage diseases or autophagy-related mechanisms commonly implicated in Parkinsonian syndromes. In this review, we summarize the clinical, molecular, and emerging pathological insights into NDPACX and propose that targeting endolysosomal homeostasis may open new therapeutic avenues for both hereditary and idiopathic neurodegenerative diseases characterized by proteinopathies.

Multiple sclerosis (MS) is characterized by immune-mediated demyelination and neurodegeneration. While cerebrospinal fluid (CSF) biomarkers can track tissue damage, the relationship between immune cell populations and tissue damage markers remains poorly understood. We performed comprehensive immunophenotyping of CSF samples from 63 participants [29 relapsing-remitting multiple sclerosis (RRMS), 7 primary progressive multiple sclerosis (PPMS), 27 patients with other suspected neurological diseases (OND)]. CSF levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were measured using single-molecule array technology. Relationships between immune cell populations and biomarkers were assessed using partial correlation and multiple regression analyses, adjusting for age and sex. RRMS patients exhibited expanded lymphocyte populations compared with OND, with elevated CD3+ T cells (+5062 cells/mL, P < 0.0001) and CD19+ B cells (+180 cells/mL, P < 0.0001). Patients with multiple sclerosis showed an age-related shift in monocyte subsets, marked by increased CD14+CD16+ cells [r_SP = 0.670, (95% CI: 0.44-0.81), P = 0.0029]. During active relapse, naive CD4+ T cells demonstrated the strongest association with NfL [cumulative geometric mean ratio = 2.892 (95% CI: 1.352-6.188), P < 0.0001], contrasting with non-relapse states [GMR = 0.689 (95% CI: 0.449-1.057), P = 0.101]. This study identifies distinct immunological signatures in multiple sclerosis and demonstrates disease activity-dependent associations between specific immune cell populations and tissue damage markers. The relationship between classical monocytes and GFAP in controls suggests a previously unrecognized role for myeloid cells in physiological CNS homeostasis.

The role of cranial vasodilation in headache pathogenesis sparks ongoing debate. Soluble guanylate cyclase is an enzyme that catalyses the conversion of guanosine triphosphate to cyclic guanosine monophosphate, leading to relaxation of vascular smooth muscle cells. Activation of this pathway might contribute to headache pathogenesis. We evaluated whether oral ingestion of riociguat, a stimulator of soluble guanylate cyclase, could elicit cranial vasodilation and headache in healthy adults. In this randomized, double-blind, placebo-controlled, two-way crossover study, we enrolled 12 healthy adults (nine females, three males; mean age 27.3 (SD 7.8) years). The participants attended two experimental sessions at a single site in Denmark (Danish Headache Center, Rigshospitalet, Denmark), receiving either a single oral dose riociguat 2.5 mg or placebo. The baseline measurements included the diameter of the superficial temporal artery and the blood flow velocity of the middle cerebral artery. These measurements were repeated over a 240-minute period after ingestion. The participants recorded headache occurrence and associated features in a diary for 12 h post-ingestion. For primary outcome (n = 12), results revealed no significant change in the diameter of the superficial temporal artery from baseline to 90 min post-ingestion between riociguat and placebo (P = 0.54). However, significant increases in the diameter were observed at 120 min (P = 0.02) and 240 min (P < 0.01) after riociguat ingestion compared with placebo. The blood flow velocity of the middle cerebral artery decreased significantly from baseline to 240 min post-riociguat ingestion, compared with placebo (P < 0.01). Headache was reported by 10 (83%) of 12 participants after riociguat ingestion, compared with three (25%) participants after placebo (P = 0.02). In conclusion, oral ingestion of riociguat, a stimulator of soluble guanylate cyclase, induces cranial vasodilation and headache. These findings support the hypothesis that cranial vasodilation mediated via direct soluble guanylate cyclase stimulation contributes to headache pathogenesis. Further research is warranted to delineate the relative contributions of nitric oxide-dependent versus nitric oxide-independent soluble guanylate cyclase activation, and to evaluate guanylate cyclase signalling as a potential therapeutic target in headache disorders.

Graphical Abstract.

Repeat expansions are a known cause of progressive myoclonic epilepsy (PME) and familial adult myoclonic epilepsy (FAME). We hypothesized that PME and FAME may have an overlapping phenotypic spectrum and searched for pathogenic repeat expansions in 18 individuals from 15 families with later-onset PME or FAME. We generated whole genome sequencing data by short-read sequencing and searched for known and novel repeat expansions. No known, pathogenic repeat expansions were identified. Instead, we discovered a novel TTGTA expansion in the gene MARCHF6 at the same location as the known, pathogenic FAME3 expansion in a PME family. Targeted long-read sequencing of this locus revealed a large, complex repeat structure harbouring an expansion of the pathogenic TTTCA repeat that causes FAME, surrounded by TTTTA and TTGTA expansions. Motivated by this discovery, we developed a new bioinformatic approach, mixSTR, to search for evidence of such complex expansions and discovered an additional novel configuration of the FAME3 expansion containing hidden pathogenic TTTCA expansions embedded within a TTTTA expansion in a second family clinically diagnosed with FAME. Both families had initially tested negative for the FAME3 expansion with standard RP-PCR and short-read genome sequencing analysis. We searched large epilepsy and population cohorts but did not identify any additional new individuals with complex FAME3 expansions. These findings have two important implications. Firstly, known repeat expansion loci with unusual repeat expansions, even if not known to be pathogenic, warrant further investigation as they may contain hidden pathogenic repeat expansions. Secondly, they provide molecular support for the clinical idea that PME and FAME have an overlapping phenotypic spectrum, and that the known FAME repeat expansions should be part of the diagnostic assessment of unsolved PMEs.

The finding of biallelic pathogenic pentanucleotide RFC1 expansions has extended the spectrum of disease in cerebellar ataxia, neuropathy and vestibular areflexia syndrome. It is clear that for many, a sensory neuropathy is an early feature and raises the question of how to identify which patients with this common neurophysiological presentation should be tested genetically for the condition. We identified patients with idiopathic, sensory predominant neuropathies who had attended the Neurophysiology Department of Auckland Hospital for nerve conduction studies. We undertook a systematic clinical re-evaluation to test whether any of the following hypothesized variables distinguish the presence of pathogenic RFC1 expansions. These were (i) chronic cough, (ii) ataxia, (iii) pure sensory changes on nerve conduction, (iv) a non-length-dependent pattern of sensory loss on nerve conduction studies, (v) small nerves on peripheral nerve ultrasound, (vi) bilateral vestibular dysfunction and (vii) autonomic dysfunction. We recruited 53 patients, of whom 10 had normal repeat nerve conductions. Among the 43 (25 males, 18 females) remaining patients, five were positive for the pathogenic RFC1 expansions. All five reported a chronic cough (versus 4/38 RFC1-negative cases, P = 0.0002). None of the five cases had abnormal motor findings (versus 20/37 RFC1-negative cases, P = 0.07). Four of the five cases had small (<5.2 mm²) mean upper limb nerves by cross-sectional area on ultrasound (versus 2/38 RFC1-negative cases, P = 0.0006). The fifth had concurrent diabetes, which might explain their normal sized nerves. Four of the five cases had a non-length-dependent sensory neuropathy, and one had a length-dependent sensory neuropathy. The RFC1-positive case with a length-dependent neuropathy had small upper limb nerves on ultrasound. There were no differences in ataxia scores between the groups, and only two RFC1-positive cases had vestibular involvement. Two of the five RFC1-positive cases, both Sāmoan, had a novel arrangement in their RFC1 expansion in which the pathogenic AAGGG expansion was preceded by a short AAAAG expansion. Taken together, in this small sample, the presence of a chronic cough with either a non-length-dependent neuropathy on nerve conduction studies or a mean upper limb nerve cross-sectional area <5.2 mm² was strongly associated with the RFC1 expansion (sensitivity 100%, specificity 97%). Patients who fit these criteria should be tested genetically for RFC1. Ultrasound and nerve conduction studies should be seen as complementary in the workup of patients for RFC1 expansions.

Pathological chronic stress is stress exceeding the organism's ability to cope physiologically, which may act as a risk factor in the onset and relapse of alcohol use disorder. Chronic-restraint stress (CRS) and ethanol intake are independently known to induce changes in brain structure and function, however, their combined effects on neurodevelopment over long periods of time remains largely unexplored. We conducted an in vivo longitudinal rat model with three main goals. 1) to determine if chronic stress increases ethanol intake; 2) to determine the effect of chronic- stress and ethanol intake in behavioural measures, brain structure, and function; and 3) to investigate the effect of sex. This observational study included Wistar rats assigned to four groups: 1) ethanol consumption (EtOH+/CRS-), 2) stress exposure (EtOH-/CRS+), 3) both ethanol and stress exposure (EtOH+/CRS+), and 4) control group (EtOH-/CRS-). Our results showed that chronic stress did not affect ethanol intake but led to reduced body weight gain, elevated corticosterone levels, and impaired recognition memory. Structural MRI revealed that both exposures produced additive brain volume changes in olfactory bulb, orbitofrontal cortex, caudate-putamen, hippocampus, and cerebellum. Functional connectivity analysis using network-based statistics identified disrupted cortical-subcortical connections. Results found here were sex-dependent in terms of volumetric changes (higher effects on males) and functional connectivity (higher effects on females). Findings suggest sex-dependent mechanisms where both chronic- ethanol intake and stress affect brain plasticity during neurodevelopment. Understanding region-specific vulnerabilities is crucial for addressing alcohol use disorders and stress-related neuropathology.

Pathological hubs in the brain networks of epilepsy patients are hypothesized to drive seizure generation and propagation. In epilepsy-surgery patients, these hubs have traditionally been associated with the resection area (RA): the region removed during the surgery with the goal of stopping the seizures, and which is typically used as a proxy for the epileptogenic zone. However, recent studies hypothesize that pathological hubs may extend to the vicinity of the RA, potentially complicating post-surgical seizure control. Here we propose a neighbourhood-based analysis of brain organization to investigate this hypothesis. We exploit a large dataset of pre-surgical magnetoencephalography-derived whole-brain networks from 91 epilepsy-surgery patients. Our neighbourhood focus is 2-fold. Firstly, we propose a partition of the brain regions into three sets, namely resected nodes, their neighbours and the remaining network nodes. Secondly, we introduce generalized centrality metrics that describe the neighbourhood of each node, providing a regional measure of hubness. Our analyses reveal that both the RA and its neighbourhood present large hub status, but with significant variability across patients. For some, hubs appear in the RA; for others, in its neighbourhood. Moreover, this variability does not correlate with surgical outcome. These results highlight the potential of neighbourhood-based analyses to uncover novel insights into brain connectivity in brain pathologies, and the need for individualized studies, with large enough cohorts, that account for patient-specific variability.