Brain最新文献

Dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) cause diverse and largely distinct channelopathies, including inherited forms of neuromuscular disease, skeletal dysplasias and arthropathy. Pathogenic TRPV4 mutations cause gain of ion channel function and toxicity that can be rescued by small molecule TRPV4 antagonists in cellular and animal models, suggesting that TRPV4 antagonism could be therapeutic for patients. Numerous variants in TRPV4 have been detected with targeted and whole exome/genome sequencing, but for the vast majority, their pathogenicity remains unclear. Here, we used a combination of clinical information and experimental structure-function analyses to evaluate 30 TRPV4 variants across various functional protein domains. We report clinical features of seven patients with TRPV4 variants of unknown significance and provide extensive functional characterization of these and an additional 17 variants, including structural position, ion channel function, subcellular localization, expression level, cytotoxicity and protein-protein interactions. We find that gain-of-function mutations within the TRPV4 intracellular ankyrin repeat domain target charged amino acid residues important for RhoA interaction, whereas ankyrin repeat domain residues outside of the RhoA interface have normal or reduced ion channel activity. We further identify a cluster of gain-of-function variants within the intracellular intrinsically disordered region that may cause toxicity via altered interactions with membrane lipids. In contrast, assessed variants in the transmembrane domain and other regions of the intrinsically disordered region do not cause gain of function and are likely benign. Clinical features associated with gain of function and cytotoxicity include congenital onset of disease, vocal cord weakness and motor-predominant disease, whereas patients with likely benign variants often demonstrated late-onset and sensory-predominant disease. These results provide a framework for assessing additional TRPV4 variants with respect to likely pathogenicity, which will yield critical information to inform patient selection for future clinical trials for TRPV4 channelopathies.

With rising life expectancy and advancements in disease management, we expect the multiple sclerosis population is getting older. However, evidence supporting this hypothesis remains sparse. Our study aimed to determine whether the mean age of the Danish multiple sclerosis population has increased and to analyse the developments in sex distribution, incidence and prevalence, all of which affect age composition. We conducted a cohort study by linking nationwide data from the Danish Multiple Sclerosis Registry to the Population Statistics Registry, the Danish Cause of Death Registry, and the Historical Migration Registry. We included all living patients with a confirmed multiple sclerosis diagnosis who lived in Denmark on the 1st of January each year from 1950 to 2023. We calculated the mean and median age, age distribution, sex distribution, incidence and prevalence of the Danish multiple sclerosis population annually from 1950 to 2023. We included 28 145 individuals with multiple sclerosis. The mean age of the Danish multiple sclerosis population increased until the late 1970s to ∼52.5 years, where it stabilized until 1990. The mean age experienced a slight decline to 51.2 years in 2005, followed by a subsequent rise to its peak of 54.2 years in 2023. In 1975, females comprised 58.7% of the multiple sclerosis population, increasing to 65.7% by 2000 and 68.5% in 2023. The incidence of multiple sclerosis remained stable at ∼3.5 per 100 000 until 1975 and steadily increased by more than three times in 2000 to 11.4 per 100 000. Despite fluctuations, it remained relatively stable from 2000 until 2022, showing a slight decrease in 2022 compared to the previous two decades. Both overall and sex-specific prevalence exhibited an upward trend, particularly among females. Our study demonstrates that the mean age of the Danish multiple sclerosis population has increased, although not as decisively as expected. The female proportion has grown in tandem with prevalence, while incidence appears to have stabilized in recent decades after years of increase. Denmark's robust registry data and universal healthcare system offer a unique opportunity for reliable epidemiological analysis. Our results establish a benchmark for future demographic studies in the field of multiple sclerosis.

Facioscapulohumeral muscular dystrophy type 1 (FSHD1) patients exhibit marked variability in both age at onset (AAO) and disease severity. Early onset FSHD1 patients are at an increased risk of severe weakness, and early onset has been tentatively linked to the length of D4Z4 repeat units (RUs) and methylation levels. The present study explored potential relationships among genetic characteristics, AAO and disease severity in FSHD1. This retrospective and observational cohort study was conducted at the Fujian Neuromedical Centre (FNMC) in China. Genetically confirmed participants with FSHD1 recruited from 2001 to 2023 underwent distal D4Z4 methylation assessment. Disease severity was assessed by FSHD clinical score, age-corrected clinical severity score (ACSS) and onset age of lower extremity involvement. Mediation analyses were used to explore relationships among genetic characteristics, AAO and disease severity. Finally, machine learning was employed to explore AAO prediction in FSHD1. A total of 874 participants (including 804 symptomatic patients and 70 asymptomatic carriers) were included. Multivariate Cox regression analyses indicated that male gender, low DUZ4 RUs, low CpG6 methylation levels, non-mosaic mutation and de novo mutation were independently associated with early onset in FSHD1. Early onset patients (AAO < 10 years) had both a significantly higher proportion and an earlier median onset age of lower extremity involvement compared to the typical adolescent onset (10 ≤ AAO < 20 years), typical adult onset (20 ≤ AAO < 30 years) and late onset (AAO ≥ 30 years) subgroups. AAO was negatively correlated with both clinical score and ACSS. We found that AAO exerted mediation effects, accounting for 12.2% of the total effect of D4Z4 RUs and CpG6 methylation levels on ACSS and 38.6% of the total effect of D4Z4 RUs and CpG6 methylation levels on onset age of lower extremity involvement. A random forest model that incorporated variables including gender, age at examination, inheritance pattern, mosaic mutation, D4Z4 RUs and D4Z4 methylation levels (at CpG3, CpG6 and CpG10 loci) performed well for AAO prediction. The predicted AAO (pAAO) was negatively correlated with ACSS (Spearman's ρ = -0.692). Our study revealed independent contributions from D4Z4 RUs, D4Z4 methylation levels, mosaic mutation and inheritance pattern on AAO variation in FSHD1. AAO mediates effects of D4Z4 RUs and methylation levels on disease severity. The pAAO values from our random forest model informatively reflect disease severity, offering insights that can support efficacious patient management.

Although both central and peripheral inflammation have been observed consistently in depression, the relationship between the two remains obscure. Extra-axial immune cells may play a role in mediating the connection between central and peripheral immunity. This study investigates the potential roles of calvarial bone marrow and parameningeal spaces in mediating interactions between central and peripheral immunity in depression. PET was used to measure regional TSPO expression in the skull and parameninges as a marker of inflammatory activity. This measure was correlated with brain TSPO expression and peripheral cytokine concentrations in a cohort enriched for heightened peripheral and central immunity comprising 51 individuals with depression and 25 healthy controls. The findings reveal a complex relationship between regional skull TSPO expression and both peripheral and central immunity. Facial and parietal skull bone TSPO expression showed significant associations with both peripheral and central immunity. TSPO expression in the confluence of sinuses was also linked to both central and peripheral immune markers. Group-dependent elevations in TSPO expression within the occipital skull bone marrow were also found to be significantly associated with central inflammation. Significant associations between immune activity within the skull, parameninges, parenchyma and periphery highlight the role of the skull bone marrow and venous sinuses as pivotal sites for peripheral and central immune interactions.

Intracellular trafficking involves an intricate machinery of motor complexes, including the dynein complex, to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains, as well as cytoplasmic light and intermediate chains, have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of neurodevelopmental disorder manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.

Both sleep alterations and epileptiform activity are associated with the accumulation of amyloid-β and tau pathology and are currently investigated for potential therapeutic interventions in Alzheimer's disease. However, a bidirectional intertwining relationship between sleep and neuronal hyperexcitability might modulate the effects of Alzheimer's disease pathology on the corresponding associations. To investigate this, we performed multiple day simultaneous foramen ovale (FO) plus scalp EEG and polysomnography recordings and acquired 18F-MK6240 tau PET-MR in three patients in the prodromal stage of Alzheimer's disease and in two patients with mild and moderate dementia due to Alzheimer's disease, respectively. As an eligibility criterion for the present study, subjects either had a history of a recent seizure (n = 2) or subclinical epileptiform activity (SEA) on a previous scalp EEG taken in a research context (n = 3). The 18F-MK6240 standard uptake value ratio (SUVR) and asymmetry index (AI) were calculated in a priori-defined volumes of interest. Linear mixed-effects models were used to study associations between interictal epileptiform discharges (IEDs), polysomnography parameters and 18F-MK6240 SUVR. Epileptiform activity was bilateral but asymmetrically present on FO electrodes in all patients and ≥95% of IEDs were not visible on scalp EEG. In one patient, two focal seizures were detected on FO electrodes, both without visual scalp EEG correlate. We observed lateralized periodic discharges, brief potentially ictal rhythmic discharges and lateralized rhythmic delta activity on FO electrodes in four patients. Unlike scalp EEG, intracranial electrodes showed a lateralization of epileptiform activity. Although the amount of IEDs on intracranial electrodes was not associated to the 18F-MK6240 SUVR binding in different volumes of interest, there was a congruent asymmetry of the 18F-MK6240 binding towards the most epileptic hemisphere for the mesial (P = 0.007) and lateral temporal cortex (P = 0.006). IEDs on intracranial electrodes were most abundant during slow wave sleep (SWS) (92/h) and non-REM sleep 2 (N2, 81/h), followed by non-REM sleep 1 (N1, 33/h) and least frequent during wakefulness (17/h) and REM sleep (9/h). The extent of IEDs during sleep was not reflected in the relative time in each sleep stage spent [REM% (P = 0.415), N1% (P = 0.668), N2% (P = 0.442), SWS% (P = 0.988)], and not associated with the arousal index (P = 0.317), apnoea-hypopnoea index (P = 0.846) or oxygen desaturation index (P = 0.746). Together, our observations suggest a multi-directional interaction between sleep, epileptiform activity and tau pathology in Alzheimer's disease.

Clinical variants of Alzheimer's disease and frontotemporal lobar degeneration display a spectrum of cognitive-behavioural changes varying between individuals and over time. Understanding the landscape of these graded individual/group level longitudinal variations is critical for precise phenotyping; however, this remains challenging to model. Addressing this challenge, we leverage the National Alzheimer's Coordinating Center database to derive a unified geometric framework of graded longitudinal phenotypic variation in Alzheimer's disease and frontotemporal lobar degeneration. We included three time point, cognitive-behavioural and clinical data from 390 typical, atypical and intermediate Alzheimer's disease and frontotemporal lobar degeneration variants (114 typical Alzheimer's disease; 107 behavioural variant frontotemporal dementia; 42 motor variants of frontotemporal lobar degeneration; and 103 primary progressive aphasia patients). On these data, we applied advanced data-science approaches to derive low-dimensional geometric spaces capturing core features underpinning clinical progression of Alzheimer's disease and frontotemporal lobar degeneration syndromes. To do so, we first used principal component analysis to derive six axes of graded longitudinal phenotypic variation capturing patient-specific movement along and across these axes. Then, we distilled these axes into a visualizable 2D manifold of longitudinal phenotypic variation using Uniform Manifold Approximation and Projection. Both geometries together enabled the assimilation and interrelation of paradigmatic and mixed cases, capturing dynamic individual trajectories and linking syndromic variability to neuropathology and key clinical end points, such as survival. Through these low-dimensional geometries, we show that (i) specific syndromes (Alzheimer's disease and primary progressive aphasia) converge over time into a de-differentiated pooled phenotype, while others (frontotemporal dementia variants) diverge to look different from this generic phenotype; (ii) phenotypic diversification is predicted by simultaneous progression along multiple axes, varying in a graded manner between individuals and syndromes; and (iii) movement along specific principal axes predicts survival at 36 months in a syndrome-specific manner and in individual pathological groupings. The resultant mapping of dynamics underlying cognitive-behavioural evolution potentially holds paradigm-changing implications to predicting phenotypic diversification and phenotype-neurobiological mapping in Alzheimer's disease and frontotemporal lobar degeneration.