Brain communications最新文献

The extent to which glial cell turnover features in successful remyelination is unclear. In this study, the rat caudal cerebellar peduncle-ethidium bromide lesion model was used to profile oligodendroglial and microglial/macrophage cell death and proliferation dynamics over the course of repair. Lesioned and control tissue was co-labelled with antibody markers for cell identity, proliferation, and apoptosis (TUNEL assay), then imaged at full thickness using confocal microscopy and quantified using custom CellProfiler pipelines. Early remyelination time points were marked by an increased density of total proliferating cells, including oligodendrocyte progenitor cells. Late remyelination time points featured increased TUNEL+ oligodendrocyte progenitor cells: however, most TUNEL+ cells within remyelinating lesions were Iba1+ microglia/macrophages. These results indicate that repairing lesions are characterized by a high degree of glial cell death and suggest that monitoring cell death-related by-products might have clinical value in the setting of remyelination.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death, likely stemming from seizure activity disrupting vital brain centres controlling heart and breathing function. However, understanding of SUDEP's anatomical basis and mechanisms remains limited, hampering risk evaluation and prevention strategies. Prior studies using a neuron-specific Kcna1 conditional knockout mouse model of SUDEP identified the primary importance of brain-driven mechanisms contributing to sudden death and cardiorespiratory dysregulation; yet, the underlying neurocircuits have not been identified. Using the Emx1-Cre driver, we generated a new conditional knockout mouse model lacking Kcna1 in excitatory neurons of the cortex, hippocampus, amygdala and select vagal afferents. To test whether the absence of Kv1.1 in forebrain corticolimbic circuits is sufficient to induce spontaneous seizures, premature mortality and cardiorespiratory dysfunction, we performed survival studies and EEG, ECG, and plethysmography (EEG-ECG-Pleth) recordings. We demonstrate premature death and epilepsy in corticolimbic conditional knockout mice. During monitoring, we fortuitously captured one SUDEP event, which showed a generalized tonic-clonic seizure that initiated respiratory dysfunction culminating in cardiorespiratory failure. In addition, we observed that cardiorespiratory abnormalities are common during non-fatal seizures in conditional knockout mice, but mostly absent during interictal periods, implying ictal, not interictal, cardiorespiratory impairment as a more reliable indicator of SUDEP risk. These results point to corticolimbic excitatory neurons as critical neural substrates in SUDEP and affirm seizure-related respiratory and cardiac failure as a likely cause of death.

This scientific commentary refers to 'Intraspinal microstimulation of the ventral horn has therapeutically relevant cross-modal effects on nociception', by Bandres et al. (https://doi.org/10.1093/braincomms/fcae280).

The largest risk factor for dementia is age. Heterochronic blood exchange studies have uncovered age-related blood factors that demonstrate 'pro-aging' or 'pro-youthful' effects on the mouse brain. The clinical relevance and combined effects of these factors for humans is unclear. We examined five previously identified brain rejuvenation factors in cerebrospinal fluid of adults with autosomal dominant forms of frontotemporal dementia and sporadic Alzheimer's disease. Our frontotemporal dementia cohort included 100 observationally followed adults carrying autosomal dominant frontotemporal dementia mutations (M_age = 49.6; 50% female; 43% C9orf72, 24% GRN, 33% MAPT) and 62 non-carriers (M_age = 52.6; 45% female) with cerebrospinal fluid analysed on Somascan, and longitudinal (M_visits = 3 years, range 1-7 years) neuropsychological and functional assessments and plasma neurofilament light chain. Our Alzheimer's disease cohort included 35 adults with sporadic Alzheimer's disease (M_age = 69.4; 60% female) and 56 controls (M_age = 68.8, 50% female) who completed the same cerebrospinal fluid and clinical outcome measures cross-sectionally. Levels of C-C motif chemokine ligand 11, C-C motif chemokine ligand 2, beta-2-micorglobulin, bone gamma-carboxyglutamate protein (aka Osteocalcin) and colony stimulating factor 2 in cerebrospinal fluid were linearly combined into a composite score, with higher values reflecting 'pro-youthful' levels. In genetic frontotemporal dementia, higher baseline cerebrospinal fluid rejuvenation proteins predicted slower decline across cognitive, functional, and neurofilament light chain trajectories; estimates were similar across genotypes. In transdiagnostic analyses, higher cerebrospinal fluid rejuvenation proteins associated with better functional, cognitive, and neurofilament light chain outcomes in adults with sporadic Alzheimer's disease. Proteins with pre-clinical evidence for brain rejuvenation show translational clinical relevance in adults with Alzheimer's disease and related dementias and warrant further investigation.

This scientific commentary refers to 'Brain aging rejuvenation factors in adults with genetic and sporadic neurodegenerative disease', by Casaletto et al. (https://doi.org/10.1093/braincomms/fcae432).

Neuroinflammation impacts on the progression of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. Specialized pro-resolving mediators trigger the resolution of inflammation. We investigate the specialized pro-resolving mediator blood profile and their receptors' expression in peripheral blood mononuclear cells in relation to survival in ALS. People living with ALS (pwALS) were stratified based on bulbar versus limb onset and on key progression metrics using a latent class model, to separate faster progressing from slower progressing ALS. Specialized pro-resolving mediator blood concentrations were measured at baseline and in one additional visit in 20 pwALS and 10 non-neurological controls (Cohort 1). Flow cytometry was used to study the GPR32 and GPR18 resolvin receptors' expression in peripheral blood mononuclear cells from 40 pwALS and 20 non-neurological controls (Cohort 2) at baseline and in two additional visits in 17 pwALS. Survival analysis was performed using Cox proportional hazards models, including known clinical predictors and GPR32 and GPR18 mononuclear cell expression. Differential expression and linear discriminant analyses showed that plasma resolvins were able to distinguish phenotypic variants of ALS from non-neurological controls. RvE3 was elevated in blood from pwALS, whilst RvD1, RvE3, RvT4 and RvD1_{n-3 DPA} were upregulated in A-S and RvD2 in A-F. Compared to non-neurological controls, GPR32 was upregulated in monocytes expressing the active inflammation-suppressing CD11b⁺ integrin from fast-progressing pwALS, including those with bulbar onset disease (P < 0.0024), whilst GPR32 and GPR18 were downregulated in most B and T cell subtypes. Only GPR18 was upregulated in naïve double positive Tregs, memory cytotoxic Tregs, senescent late memory B cells and late senescent CD8⁺ T cells from pwALS compared to non-neurological controls (P < 0.0431). Higher GPR32 and GPR18 median expression in blood mononuclear cells was associated with longer survival, with GPR32 expression in classical monocytes (hazard ratio: 0.11, P = 0.003) and unswitched memory B cells (hazard ratio: 0.44, P = 0.008) showing the most significant association, along with known clinical predictors. Low levels of resolvins and downregulation of their membrane receptors in blood mononuclear cells are linked to a faster progression of ALS. Higher mononuclear cell expression of resolvin receptors is a predictor of longer survival. These findings suggest a lipid-mediated neuroprotective response that could be harnessed to develop novel therapeutic strategies and biomarkers for ALS.

This scientific commentary refers to 'Cerebrovascular reactivity and response times describe recent ischemic symptomatology in patients with moyamoya', by Han et al.  (https://doi.org/10.1093/braincomms/fcae381).

Brain serotonin dysregulation is associated with dementia and neuropsychiatric symptomology. However, the prognostic utility of circulating serotonin levels in detecting features of prodromal dementia including functional decline, cognitive impairment, mild behavioural impairment and brain atrophy remains unclear. In this prospective study of memory clinic subjects followed-up for ≤5 years, dementia-free subjects, classified as having no cognitive impairment or cognitive impairment, no dementia at baseline, underwent annual neuropsychological assessments including Montreal Cognitive Assessment, Global Cognition Z-scores and Clinical Dementia Rating Scale Global Scores (where a ≥ 0.5 increment from baseline denotes functional decline). Mild behavioural impairment was measured using baseline and annual Neuropsychiatric Inventory assessments, while brain atrophy was evaluated using cortical and medial temporal atrophy scores from baseline MRI scans. Baseline serum serotonin was then associated with the neuropsychological and neuroimaging measures cross-sectionally and longitudinally. Furthermore, associations of serum serotonin with cross-sectional brain atrophy scores were studied. Of the 191 elderly subjects included in the study, 63 (33.0%) had no cognitive impairment while 128 (67.0%) had cognitive impairment, no dementia. Fourteen subjects (9.0%) showed baseline mild behavioural impairment. Compared with the highest tertile, subjects within the lowest tertile of serotonin had greater Cortical Atrophy scores (adjusted odds ratio = 2.54, 95% confidence interval=1.22-5.30, P = 0.013). Serotonin levels were not significantly associated with cross-sectional neuropsychological or mild behavioural impairment scores (all P > 0.05). Of the 181 subjects with longitudinal cognitive follow-up (median duration 60.0 months), 56 (30.9%) developed functional decline, while incident mild behavioural impairment occurred in 26/119 (21.8%) subjects. Compared with the highest tertile, lower serotonin levels were associated with higher hazards of functional decline (lowest tertile: adjusted hazards ratio = 2.15, 95% confidence interval = 1.04-4.44, P = 0.039), and incident mild behavioural impairment (lowest tertile: adjusted hazards ratio = 3.82, 95% confidence interval = 1.13-12.87, P = 0.031, middle tertile: adjusted hazards ratio = 3.56, 95% confidence interval =1.05-12.15, P = 0.042). The association between the lowest serotonin tertile and functional decline was mediated via its effect on incident mild behavioural impairment (adjusted odds ratio = 3.96, 95% confidence interval = 1.15-13.61, P = 0.029). In conclusion, low circulating serotonin may be associated with cortical atrophy at baseline, as well as act as an early prognostic marker for functional decline and mild behavioural impairment in elderly, dementia-free subjects.

Primary progressive multiple sclerosis (PPMS) affects 10-15% of multiple sclerosis patients and presents significant variability in the rate of disability progression. Identifying key biological features and patients at higher risk for fast progression is crucial to develop and optimize treatment strategies. Peripheral blood cell transcriptome has the potential to provide valuable information to predict patients' outcomes. In this study, we utilized a machine learning framework applied to the baseline blood transcriptional profiles and brain MRI radiological enumerations to develop prognostic models. These models aim to identify PPMS patients likely to experience significant disease progression and who could benefit from early treatment intervention. RNA-sequence analysis was performed on total RNA extracted from peripheral blood mononuclear cells of PPMS patients in the placebo arm of the ORATORIO clinical trial (NCT01412333), using Illumina NovaSeq S2. Cross-validation algorithms from Partek Genome Suite (www.partek.com) were applied to predict disability progression and brain volume loss over 120 weeks. For disability progression prediction, we analysed blood RNA samples from 135 PPMS patients (61 females and 74 males) with a mean ± standard error age of 44.0 ± 0.7 years, disease duration of 5.9 ± 0.32 years and a median baseline Expanded Disability Status Scale (EDSS) score of 4.3 (range 3.5-6.5). Over the 120-week study, 39.3% (53/135) of patients reached the disability progression end-point, with an average EDSS score increase of 1.3 ± 0.16. For brain volume loss prediction, blood RNA samples from 94 PPMS patients (41 females and 53 males), mean ± standard error age of 43.7 ± 0.7 years and a median baseline EDSS of 4.0 (range 3.0-6.5) were used. Sixty-seven per cent (63/94) experienced significant brain volume loss. For the prediction of disability progression, we developed a two-level procedure. In the first level, a 10-gene predictor achieved a classification accuracy of 70.9 ± 4.5% in identifying patients reaching the disability end-point within 120 weeks. In the second level, a four-gene classifier distinguished between fast and slow disability progression with a 506-day cut-off, achieving 74.1 ± 5.2% accuracy. For brain volume loss prediction, a 12-gene classifier reached an accuracy of 70.2 ± 6.7%, which improved to 74.1 ± 5.2% when combined with baseline brain MRI measurements. In conclusion, our study demonstrates that blood transcriptome data, alone or combined with baseline brain MRI metrics, can effectively predict disability progression and brain volume loss in PPMS patients.