Brain communications最新文献

Meningioma, a prevalent central nervous system tumour, presents a significant challenge in neuro-oncology. This study harnesses genome-wide association studies (GWAS) and transcriptomic analysis to illuminate the pathological underpinnings of meningioma and spearhead the discovery of novel drug targets. By employing summary-data-based Mendelian randomization (SMR), colocalization analyses and Mendelian randomization, we pinpointed four genes as pivotal therapeutic targets. The integration of bulk and single-cell RNA sequencing confirmed the upregulated expression of three of the genes (XBP1, TTC28 and TRPC6) in meningioma tissues, unravelling their cellular distribution and hinting at the tumour's intrinsic heterogeneity. Molecular docking further identified dexamethasone and levonorgestrel as potential modulators of these targets, paving the way for personalized meningioma treatment strategies. This research advances our understanding of meningioma's molecular landscape and illustrates the power of genomic and transcriptomic integration in the realm of precision oncology.

Polycystic ovary syndrome (PCOS) is characterized by excess androgens, ovulatory disorders and a higher prevalence of obesity and metabolic disturbances including Type 2 diabetes, hyperlipidaemia and hypertension, some of which are risk factors for neurodegenerative disorders such as Alzheimer's disease and brain atrophy. However, it is unclear whether brain ageing occurs more rapidly in women with PCOS compared with those without PCOS. Except for the hypothalamic-pituitary-gonadal axis involved in the conventional ovulatory process, little is known regarding the role of the grey matter in the pathogenesis of PCOS, and limited existing studies examining brain structures in PCOS have shown inconsistent results. This case-control study aimed to investigate the age-related differences in total and regional brain grey matter volume and average cortical thickness in young women with and without PCOS by using brain magnetic resonance imaging to understand whether women with PCOS exhibit distinctive patterns of brain ageing, and their association with factors including obesity, hyperandrogenism and metabolic disturbances. Seventy-six women diagnosed with PCOS and 68 age-matched women without PCOS (aged 20-35 years) underwent brain magnetic resonance imaging to measure grey matter volume and cortical thickness. Anthropometric, hormonal and metabolic measurements were conducted to assess their associations with the investigated brain structures. In women without PCOS, increasing age was significantly correlated with a decrease in global grey matter volume (r = -0.5598, P < 0.0001), while this association was not significant in women with PCOS (r = -0.1475, P = 0.204). The decline in grey matter volume with age differed significantly between the two groups regardless of obesity (body mass index exceeding 25 kg/m²), especially in the frontal, parietal, occipital and temporal regions. After adjusting for dehydroepiandrosterone sulphate (DHEAS) levels, the negative association between age and global grey matter volume became statistically significant in women with PCOS. Increasing age was also significantly associated with a decrease in global cortical thickness in women without PCOS, but not in women with PCOS. Such negative association between global cortical thickness and age was particularly stronger in women with obesity compared with those without. The negative association between age and global cortical thickness in women with PCOS became pronounced after adjusting for DHEAS levels. Women with PCOS experience a milder grey matter loss with age compared with women without PCOS. The neuroprotective effect of high DHEAS levels in women with PCOS may be implicated in this relationship.

RNA polymerase III transcribes essential non-coding RNAs, a process regulated by transcription factors TFIIIB and TFIIIC. Although germline variants in TFIIIC subunit genes have been described in a few patients with neurodevelopmental disorders, the associated pathogenesis and clinical spectrum are not yet well defined. Herein, we describe the identification of biallelic variants in GTF3C3, which encodes a key component of the TFIIIC subunit, in four patients from three unrelated families of different ethnicities collected through GeneMatcher. The patients exhibited microcephaly, developmental delay, intellectual disability and distinctive dysmorphic facies that appear recognizable in very young children. Their brain imaging showed brain atrophy with predominant cerebellar involvement, as well as hypoplasia of the frontal lobes and one patient had moderate to severe simplified gyral pattern. Seizures were observed in half of the patients. Exome/genome sequencing revealed four different GTF3C3 variants including three missense (p.Cys172Gly, p.Val427Phe and p.Ala509Thr) and one nonsense variant (p.Arg717Ter). Missense variants were not present in known genetic databases and occurred in highly conserved residues. Knockout of the GTF3C3 ortholog in zebrafish recapitulated the key clinical symptoms including microcephaly, brain anomalies and seizure susceptibility. We also observed reduced RNA polymerase III target gene expression in the zebrafish knockout model. This study describes a new neurodevelopmental syndrome in humans and zebrafish associated with biallelic GTF3C3 variants and underscores the need for further research into the biological impacts of variants in TFIIIC-linked genes and their contribution to RNA polymerase III-related pathologies.

Alzheimer's disease is the commonest form of dementia, but its cause still remains elusive. It is characterized by neurodegeneration, with amyloid-beta and tau aggregation. Recently, however, the roles of the vasculature and the neurovascular unit are being highlighted as important for disease progression. In particular, there is reduced microvascular density, and altered gene expression in vascular and glial cells. Structural changes naturally impact the functioning of the neurovascular unit, and the goal of the study was to quantify the corresponding changes in vivo, non-invasively. Our assessment is based on recordings of brain oxygenation, neuronal and cardiorespiratory activities, captured by functional near-infrared spectroscopy, electroencephalogram, electrocardiogram and respiration effort, respectively. Two groups were compared: an Alzheimer's disease group (N = 19) and a control group (N = 20) of similar age. The time-series were analysed using methods that can capture multi-scale and time-varying oscillations such as the wavelet transform power and wavelet phase coherence. The Alzheimer's disease group shows a significant decrease in the power of brain oxygenation oscillations compared to the control group. There is also a significant global reduction in the phase coherence between brain oxygenation time-series. The neurovascular phase coherence around 0.1 Hz is also significantly reduced in the Alzheimer's disease group. In addition, the average respiration rate is increased in the Alzheimer's disease group compared to the control group. We show that the phase coherence between vascular and neuronal activities is reduced in Alzheimer's disease compared to the control group, indicating altered functioning of the neurovascular unit. The brain oxygenation dynamics reveals reduced power and coordination of oscillations, especially in frequency ranges that are associated with vasomotion. This could lead to reduced oxygen delivery to the brain, which could affect ATP production, and potentially reduce amyloid-beta clearance. These changes in neurovascular dynamics have potential for early diagnosis, as a marker of disease progression, and for evaluating the effect of interventions.

Late-onset epilepsy has been linked with accelerated cognitive decline and a higher risk of dementia. In this study, we sought to characterize the cognitive profile of participants with late-onset unexplained epilepsy and compare their MRI findings to healthy controls, to better understand underlying disease mechanisms. We recruited participants with at least one new-onset unexplained seizure at age 55 or later, without cortical lesions on MRI, within 5 years of the first seizure. We administered a neuropsychological battery to generate Preclinical Alzheimer Cognitive Composite and composite scores for delayed verbal recall, processing speed and executive function. We held a consensus meeting to determine whether the participants fulfilled criteria for mild cognitive impairment. An MRI volumetric analysis of hippocampal, amygdalae, and white matter hyperintensity volume was performed and compared to 353 healthy controls from the Harvard Aging Brain Study. On late-onset unexplained epilepsy participants, we also obtained 24-h EEG recording. Seventy participants were recruited, mean age 71.0 ± 7.0 years, 49% female, 15.6 ± 3.0 years of education. Impaired cognition (z-score ≤ -1.5) for late-onset unexplained epilepsy included the following: 15.9% for Preclinical Alzheimer Cognitive Composite -5, 23.2% for delayed verbal recall, 15.6% for processing speed and 7.5% for executive function. Seventeen percent were found to have mild cognitive impairment. Late-onset unexplained epilepsy participants who were drug resistant were more likely to have cognitive impairment (50% vs. 9%). When controlling for age, sex and race, late-onset unexplained epilepsy group had lower left AV (%; β = -0.003, P = 0.0016), right AV (%) (β = -0.003, P = 0.01), and log-transformed WMV (mm³; β = -0.21, P = 0.03) compared with Harvard Aging Brain Study (HABS); there were no differences in left or right HV between groups. EEG captured epileptiform abnormalities in 49% late-onset unexplained epilepsy participants, with a left temporal predominance (54%). In this single-site study of prospectively enrolled participants with late-onset unexplained epilepsy, we show that individuals with late-onset unexplained epilepsy exhibit cognitive impairments, mostly in verbal memory, and temporal dysfunction with left-sided predominance. Neuroimaging, when compared with healthy controls, shows lower amygdalae and white matter hyperintensity but not hippocampal volumes suggesting that the amygdalae is one of the earliest sites involved in the disease. The results also highlight the importance of seizure control given the association between mild cognitive impairment and drug-resistant epilepsy. Future studies extending these findings to Alzheimer's disease biomarkers and longitudinal follow-up will inform predictors of cognitive decline.

For over half a century, the cingulum has been the subject of neuroanatomical and therapeutic investigations owing to its wide range of functions and involvement in various neurological and psychiatric diseases. Recent clinical studies investigating neurosurgical techniques targeting the cingulum, like deep brain stimulation of the anterior cingulate cortex and cingulotomy, have further boosted interests in this central 'hub' as a target for chronic intractable pain. Proper targeting within the cingulum is essential to achieve sufficient pain relief. Despite the cingulum being the centre of research for over a century, its structural and functional organization remains a subject to debate, consequently complicating neurosurgical targeting of this area. This study aims to review anatomical and connectivity data of the cingulum from a clinical perspective in order to improve understanding of its role in pain. For the current study, a systematic literature search was performed to assess the anatomy and functional and structural connectivity of the cingulate bundle and cortex. These outcomes focus on MRI and PET data. Articles were searched within the PubMed database, and additional articles were found manually through reviews or references cited within the articles. After exclusion, 70 articles remained included in this analysis, with 50, 29 and 10 studies describing human, monkey and rat subjects, respectively. Outcomes of this analysis show the presence of various anatomical models, each describing other subdivisions within the cingulum. Moreover, connectivity data suggest that the cingulate bundle consists of three distinct fibre projections, including the thalamocortical, cingulate gyrus and anterior frontal and posterior parietal projections. Further, the cingulum is responsible for a variety of functions involved in chronic pain, like sensory processing, memory, spatial functioning, reward, cognition, emotion, visceromotor and endocrine control. Based on the current outcomes, it can be concluded that the cingulum is a central 'hub' for pain processing, because it is a melting pot for memory, cognition and affect that are involved in the complex phenomenon of pain experience, memory, spatial functioning, reward, cognition, emotion, visceromotor and endocrine control. Variability in anatomical and connectivity models complicate proper and standardized neurosurgical targeting, consequently leading to clinicians often being reluctant on stimulation and/or lesioning of the cingulum. Hence, future research should be dedicated to the standardization of these models, to allow for optimal targeting and management of patients with chronic intractable pain.

Ring finger protein 213 (RNF213) p.Arg4810Lys (c.14429G > A) is associated with intracranial artery stenosis; however, its association with extracranial artery stenosis remains unknown. We aimed to elucidate the clinical significance and association of RNF213 p.Arg4810Lys with stroke subtypes, extracranial artery stenosis, and maximum intima-media thickness. A cohort of 600 patients with stroke prospectively collected over 1 year was assessed for the presence of RNF213 p.Arg4810Lys. A total of 1202 patients served as controls. The association of RNF213 p.Arg4810Lys with various stroke subtypes was studied. In sub-analyses, the association of RNF213 p.Arg4810Lys with intracranial artery stenosis/extracranial artery stenosis and maximum intima-media thickness were assessed. RNF213 p.Arg4810Lys was more common in patients with stroke (3.3%) than in those without stroke (1.1%). RNF213 p.Arg4810Lys was significantly associated with stroke. Among various stroke subtypes, large-artery atherosclerosis, both due to intracranial artery stenosis and extracranial artery stenosis, was most significantly associated with RNF213 p.Arg4810Lys. In the sub-analysis, intracranial artery stenosis-only, extracranial artery stenosis-only, and concurrent intracranial artery stenosis and extracranial artery stenosis groups were significantly associated with RNF213 p.Arg4810Lys, regardless of stroke type (adjusted odds ratio, 3.72; 95% confidence interval, 1.30-10.60; P = 0.014, adjusted odds ratio, 7.04; 95% confidence interval, 1.51-32.77; P= 0.013, adjusted odds ratio, 11.68; 95% confidence interval, 4.25-32.07; P 0.001, respectively). RNF213 p.Arg4810Lys was associated with increased maximum intima-media thickness, measured using carotid artery ultrasonography (multiple regression analysis β = 0.165; P = 0.004). These results were replicated in an independent validation cohort. In conclusion, RNF213 p.Arg4810Lys increases the risk of stroke. In addition to intracranial artery stenosis, RNF213 p.Arg4810Lys is associated with extracranial artery stenosis and maximum intima-media thickness. Evaluating RNF213 p.Arg4810Lys may help predict the incidence and type of stroke.

We assessed the association between leisure time physical activity patterns across 30 years of adulthood with a range of in vivo Alzheimer's disease-related neurodegenerative markers and cognition, and their interplay, at age 70. Participants from the 1946 British birth cohort study prospectively reported leisure time physical activity five times between ages 36 and 69 and were dichotomized into (i) not active (no participation/month) and (ii) active (participated once or more/month) and further derived into: (0) never active (not active); (1) active before 50's only (≤43 years); (2) active from 50's onwards only (≥53 years); (3) always active (active throughout). Participants underwent 18F-florbetapir Aβ and magnetic resonance imaging at age 70. Regression analyses were conducted to assess the direct and the moderating relationship between leisure time physical activity metrics, Alzheimer's disease-related neurodegeneration markers (including Aβ status, hippocampal and whole-brain volume, and cortical thickness in Alzheimer's disease signature regions) and cognition. All models were adjusted for childhood cognition, education and childhood socioeconomic position, and examined by sex. Findings drawn from 468 participants (49% female) demonstrated a direct association between being active before 50 years old (≤43 years) and throughout life (up to age 69 years), with larger hippocampal volume at age 70 (P < 0.05). There was little evidence that leisure time physical activity had direct effects on other brain health measures (all P > 0.05). However, leisure time physical activity patterns modified and attenuated the association between poorer cognitive functioning at age 70 and a range of Alzheimer's disease-related neurodegenerative markers (Aβ status; hippocampal and whole-brain volume; cortical thickness in Alzheimer's disease regions) (all P < 0.05). We found suggestive evidence that women with early markers of Alzheimer's disease-related neurodegeneration were most sensitive to leisure time physical activity patterns: a lifetime of inactivity in women exacerbated the manifestation of early Alzheimer's disease markers (Aβ and cortical thickness-related cognition), yet, if women were active across life or early in life, it mostly buffered these negative relationships. Engagement in leisure time physical activity in the life course is associated with better cognitive functioning at age 70, even in those with early markers of Alzheimer's disease. If causal, this is likely via multiple pathways, potentially through the preservation of hippocampal volume, as well as via cognitive resilience pathways delaying cognitive manifestations of early markers of Alzheimer's disease, particularly in women. Our findings warrant further research to shed light on the mechanisms of physical activity as a potential disease-modifying intervention of brain health and cognitive resilience.

Charcot-Marie-Tooth (CMT) neuropathies represent a broad and very heterogeneous group of disorders for which no therapies are yet available. Due to the huge genetic heterogeneity, therapeutical approaches that can benefit several forms independently of the unique pathogenetic mechanism have been sought. Niacin, nicotinic acid, is a vitamin used for many decades as anti-dyslipidaemic and anti-cholesterol drug product under the commercial name of Niaspan^®, the extended-release formulation of niacin. Of note, niacin can have other effects depending on the dose, formulation and physiology and it has been used to reduce inflammation, to promote angiogenesis and to protect neurons, muscle and axons by boosting nicotinamide adenine dinucleotide (NAD⁺) levels. Niacin also activates TNF-alpha convertase enzyme (TACE) secretase, which negatively regulates Neuregulin type I-mediated signalling in the peripheral nervous system and myelination. We previously postulated that niacin-mediated TACE activation can be effective in reducing aberrant excessive myelin associated with different CMT forms. Here, we explored efficacy of this strategy by performing a long-term preclinical trial and we provided evidence that a novel niacin-based long-lasting formulation ameliorates neurophysiology and reduces fibre degeneration in a model of Charcot-Marie-Tooth type 4B1 (CMT4B1) neuropathy, characterized by aberrant myelin. We also sought to determine whether this strategy might interfere with nerve regeneration, which is dependent on Neuregulin type I signalling. Surprisingly, we found that the Mtmr2 knockout mice, a model of CMT4B1, have a defect in nerve regeneration and that niacin-based treatment is not detrimental to nerve regeneration.