Brain communications最新文献

Magnetic resonance elastography has emerged over the last two decades as a non-invasive method for quantitatively measuring the mechanical properties of the brain. Since the inception of the technology, brain stiffness has been the primary metric used to describe brain microstructural mechanics. However, more recently, a secondary measure has emerged as both theoretical and experimental significance, which is the ratio of tissue viscosity relative to tissue elasticity. This viscous-to-elastic ratio describes different but complementary aspects of brain microstructural health and is theorized to relate to microstructural organization, as opposed to stiffness, which is related to tissue composition. The relative viscosity of brain tissue changes regionally during maturation, aging and neurodegenerative disease. It also exhibits unique characteristics in brain tumours and hydrocephalus, and is of interest for characterizing traumatic head impacts. Most notably, regional measures of relative brain tissue viscosity appear to hold a unique role in describing cognitive function. For instance, in young adults, relatively lower hippocampal viscosity compared to elasticity repeatedly and sensitively relates to spatial, declarative and verbal memory performance. Importantly, these same trends are not found with hippocampal stiffness, or hippocampal volume, highlighting a potential sensitivity of relative viscosity to underlying cellularity that contributions to normal healthy brain function. Likewise in young adults, in the orbitofrontal cortex, lower relative viscosity relates to better performance on fluid intelligence tasks, and in the Broca's area of children ages 5-7, lower relative viscosity is indicative of better language performance. In these instances, this ratio shows heightened sensitivity over other structural MRI metrics, and importantly, provides a quantitative and intrinsic alternative to measuring structure-function relationships with task-based fMRI. There are ongoing efforts to improve the accuracy and repeatability of the relative viscosity measurement, and much work is needed to reveal the cellular underpinning of changes to tissue viscosity. But it appears clear that regionally measuring the viscous-to-elastic ratio holds the potential to noninvasively reveal an aspect of tissue microstructure that is clinically, cognitively and functionally relevant to our understanding of brain function and health.

Alzheimer's disease is the most prevalent form of dementia in the elderly, which is clinically characterized by a gradual and progressive deterioration of cognitive functions. The central and early role of β-amyloid in the pathogenesis of Alzheimer's disease is supported by a plethora of studies including genetic analyses, biomarker research and genome-wide association studies in both familial (early-onset) and sporadic (late-onset) forms of Alzheimer's. Monoclonal antibodies directed against β-amyloid demonstrate slowing of the clinical deterioration of patients with early Alzheimer's disease. Aducanumab, lecanemab and donanemab clinical trials showed slowing of Alzheimer's disease progression on composite scores by 25-40% based on the measure used. Anti-β-amyloid antibodies can cause side effects of bleeding and swelling in the brain, called amyloid-related imaging abnormalities. Amyloid-related imaging abnormalities typically occur early in treatment and are often asymptomatic, and though in rare cases, they can lead to serious or life-threatening events. The aim of this review is to evaluate the clinical meaningfulness of anti-β-amyloid therapies amidst amyloid-related imaging abnormalities concern in Alzheimer's disease.

Demyelinating diseases including multiple sclerosis are associated with prior infectious exposures, so we assessed whether SARS-CoV-2 infection is associated with subsequent diagnoses of non-multiple sclerosis demyelinating diseases and multiple sclerosis. All residents of Sweden aged 3-100 years were followed between 1 January 2020 and 30 November 2022, excluding those with demyelinating disease prior to 2020, comprising 9 959 818 individuals divided into uninfected and those who were infected were categorized into those with and without hospital admission for the infection as a marker of infection severity. Cox regression assessed the risk of two separate outcomes: hospital diagnosed non-multiple sclerosis demyelinating diseases of the CNS and multiple sclerosis. The exposures were modelled as time-varying covariates (uninfected, infection without hospital admission and infected with hospital admission). Hospital admission for COVID-19 was associated with raised risk of subsequent non-multiple sclerosis demyelinating disease, but only 12 individuals had this outcome among the exposed, and of those, 7 has an unspecified demyelinating disease diagnosis. Rates per 100 000 person-years (and 95% confidence intervals) were 3.8 (3.6-4.1) among those without a COVID-19 diagnosis and 9.0 (5.1-15.9) among those admitted to hospital for COVID-19, with an adjusted hazard ratio and (and 95% confidence interval) of 2.35 (1.32-4.18, P = 0.004). Equivalent associations with multiple sclerosis (28 individuals had this outcome among the exposed) were rates of 9.5 (9.1-9.9) and 21.0 (14.5-30.5) and an adjusted hazard ratio of 2.48 (1.70-3.61, P < 0.001). Only a small number of non-multiple sclerosis demyelinating disease diagnoses were associated with hospital admission for COVID-19, and while the number with multiple sclerosis was somewhat higher, longer duration of follow-up will assist in identifying whether the associations are causal or due to shared susceptibility or surveillance bias, as these diseases can have long asymptomatic and prodromal phases.

Connected speech samples elicited by a picture description task are widely used in the assessment of aphasias, but it is not clear what their interpretation should focus on. Although such samples are easy to collect, analyses of them tend to be time-consuming, inconsistently conducted and impractical for non-specialist settings. Here, we analysed connected speech samples from patients with the three variants of primary progressive aphasia (semantic, svPPA N = 9; logopenic, lvPPA N = 9; and non-fluent, nfvPPA N = 9), progressive supranuclear palsy (PSP Richardson's syndrome N = 10), corticobasal syndrome (CBS N = 13) and age-matched healthy controls (N = 24). There were three principal aims: (i) to determine the differences in quantitative language output and psycholinguistic properties of words produced by patients and controls, (ii) to identify the neural correlates of connected speech measures and (iii) to develop a simple clinical measurement tool. Using data-driven methods, we optimized a 15-word checklist for use with the Boston Diagnostic Aphasia Examination 'cookie theft' and Mini Linguistic State Examination 'beach scene' pictures and tested the predictive validity of outputs from least absolute shrinkage and selection operator (LASSO) models using an independent clinical sample from a second site. The total language output was significantly reduced in patients with nfvPPA, PSP and CBS relative to those with svPPA and controls. The speech of patients with lvPPA and svPPA contained a disproportionately greater number of words of both high frequency and high semantic diversity. Results from our exploratory voxel-based morphometry analyses across the whole group revealed correlations between grey matter volume in (i) bilateral frontal lobes with overall language output, (ii) the left frontal and superior temporal regions with speech complexity, (iii) bilateral frontotemporal regions with phonology and (iv) bilateral cingulate and subcortical regions with age of acquisition. With the 15-word checklists, the LASSO models showed excellent accuracy for within-sample k-fold classification (over 93%) and out-of-sample validation (over 90%) between patients and controls. Between the motor disorders (nfvPPA, PSP and CBS) and lexico-semantic groups (svPPA and lvPPA), the LASSO models showed excellent accuracy for within-sample k-fold classification (88-92%) and moderately good (59-74%) differentiation for out-of-sample validation. In conclusion, we propose that a simple 15-word checklist provides a suitable screening test to identify people with progressive aphasia, while further specialist assessment is needed to differentiate accurately some groups (e.g. svPPA versus lvPPA and PSP versus nfvPPA).

Technologies to study mRNA in post-mortem human brain samples have greatly advanced our understanding of brain pathologies. With ongoing improvements, particularly in formalin-fixed paraffin-embedded tissue, these technologies will continue to enhance our knowledge in the future. Despite various considerations for tissue and mRNA quality, such as pre-mortem health status and RNA integrity, the impact of the tissue fixation time has not been addressed in a systemic fashion yet. In this study, we employed RNAscope to assess mRNA detectability in human post-mortem brain tissue in relation to fixation time. Our results reveal a dynamic change in mRNA detection across varying fixation durations, accompanied by an increase in signal derived from the negative probe and autofluorescence background. These findings highlight the critical relevance of standardized fixation protocols for the collection of human brain tissue in order to probe mRNA abundancy to ensure reliable and comparable results.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons in the brain and spinal cord. Despite the crucial role of aberrant immune responses in ALS pathogenesis, studies investigating immunological profiles in the cerebrospinal fluid (CSF) of patients with ALS have reported inconsistent findings. Herein, we explored the intrathecal adaptive immune response and features of circulating T cells between CSF and blood of patients with ALS using single-cell RNA and T-cell receptor (TCR) sequencing. This study comprised a total of 11 patients with apparently sporadic ALS and three controls with non-inflammatory diseases. We collected CSF from all participants, and for three patients with ALS, we additionally obtained paired samples of peripheral blood mononuclear cells (PBMCs). Utilizing droplet-based single-cell RNA and TCR sequencing, we analysed immunological profiles, gene expression characteristics and clonality. Furthermore, we examined T-cell characteristics in both PBMC and CSF samples, evaluating the shared T-cell clones across these compartments. In the CSF, patients with ALS exhibited a lower proportion of CD4⁺ T cells (45.2 versus 61.2%, P = 0.005) and a higher proportion of CD8⁺  GZMK ^hi effector memory T cells (TEMs) than controls (21.7 versus 16.8%, P = 0.060). Higher clonality was observed in CD8⁺ TEMs in patients with ALS compared with controls. In addition, CSF macrophages of patients with ALS exhibited a significant increase in chemokines recruiting CD8⁺ TEMs. Immunohistochemical analysis showed slightly higher proportions of T cells in the perivascular and parenchymal spaces in patients with ALS than in controls, and CD8⁺ TEMs co-localized with neurons or astrocytes in the motor cortices of patients with ALS. Clonally expanded CD8⁺  GZMK ^hi TEMs primarily comprised shared T-cell clones between CSF and PBMCs. Moreover, the shared CD8⁺ TEMs of PBMCs exhibited gene expression profiles similar to CSF T cells. Patients with ALS showed an increase in proportion and clonality of CD8⁺  GZMK ^hi TEMs and activated features of macrophages in CSF. The shared T-cell clone between CSF and blood was mainly composed of expanded CD8⁺  GZMK ^hi TEMs. In conclusion, single-cell immune profiling provided novel insights into the pathogenesis of ALS, characterized by activated macrophages and clonally expanded CD8⁺ T cells potentially communicating with the central nervous system and peripheral circulation.

Traumatic brain injury represents a significant global health burden and has the highest prevalence among neurological disorders. Even mild traumatic brain injury can induce subtle, long-lasting changes that increase the risk of future neurodegeneration. Importantly, this can be challenging to detect through conventional neurological assessment. This underscores the need for more sensitive diagnostic tools, such as electroencephalography, to uncover opportunities for therapeutic intervention. Progress in the field has been hindered by a lack of studies linking mechanistic insights at the microscopic level from animal models to the macroscale phenotypes observed in clinical imaging. Our study addresses this gap by investigating a rat model of mild blast traumatic brain injury using both immunohistochemical staining of inhibitory interneurons and translationally relevant electroencephalography recordings. Although we observed no pronounced effects immediately post-injury, chronic time points revealed broadband hyperexcitability and increased connectivity, accompanied by decreased density of inhibitory interneurons. This pattern suggests a disruption in the balance between excitation and inhibition, providing a crucial link between cellular mechanisms and clinical hallmarks of injury. Our findings have significant implications for the diagnosis, monitoring, and treatment of traumatic brain injury. The emergence of electroencephalography abnormalities at chronic time points, despite the absence of immediate effects, highlights the importance of long-term monitoring in traumatic brain injury patients. The observed decrease in inhibitory interneuron density offers a potential cellular mechanism underlying the electroencephalography changes and may represent a target for therapeutic intervention. This study demonstrates the value of combining cellular-level analysis with macroscale neurophysiological recordings in animal models to elucidate the pathophysiology of traumatic brain injury. Future research should focus on translating these findings to human studies and exploring potential therapeutic strategies targeting the excitation-inhibition imbalance in traumatic brain injury.

Agitated depression (A-MDD) is a severe subtype of major depressive disorder, with an increased risk of suicidality and the potential to evolve into bipolar disorder. Despite its clinical significance, the neural basis remains unclear. We hypothesize that psychomotor agitation, marked by pressured speech and racing thoughts, is linked to disruptions in brain dynamics. To test this hypothesis, we examined brain dynamics using time delay estimation and edge-centre time series, as well as dynamic connections between the somatomotor network (SMN) and the default mode network in 44 patients with A-MDD, 75 with non-agitated MDD (NA-MDD), and 94 healthy controls. Our results revealed that the neural co-activity duration was shorter in the A-MDD group compared with both the NA-MDD and controls (A-MDD versus NA-MDD: t = 2.295; A-MDD versus controls: t = 2.192, all P < 0.05). In addition, the dynamic of neural fluctuation in SMN altered in the A-MDD group than in the NA-MDD group (t = -2.616, P = 0.011) and was correlated with agitation severity (β = -0.228, P = 0.011). The inter-network connection was reduced in the A-MDD group compared with the control group (t = 2.102, P = 0.037), especially at low-amplitude time points (t = 2.139, P = 0.034). These findings indicate rapid neural fluctuations and disrupted dynamic coupling between the SMN and default mode network in A-MDD, potentially underlying the psychomotor agitation characteristic of this subtype. These insights contribute to a more nuanced understanding of the heterogeneity of depression and have implications for differential diagnosis and treatment strategies.

Understanding the nature and onset of neurophysiological changes, and the selective vulnerability of central hub regions in the functional network, may aid in managing the growing impact of Alzheimer's disease on society. However, the precise neurophysiological alterations occurring in the pre-clinical stage of human Alzheimer's disease remain controversial. This study aims to provide increased insights on quantitative neurophysiological alterations during a true early stage of Alzheimer's disease. Using high spatial resolution source-reconstructed magnetoencephalography, we investigated regional and whole-brain neurophysiological changes in a unique cohort of 11 cognitively unimpaired individuals with pathogenic mutations in the presenilin-1 or amyloid precursor protein gene and a 1:3 matched control group (n = 33) with a median age of 49 years. We examined several quantitative magnetoencephalography measures that have been shown robust in detecting differences in sporadic Alzheimer's disease patients and are sensitive to excitation-inhibition imbalance. This includes spectral power and functional connectivity in different frequency bands. We also investigated hub vulnerability using the hub disruption index. To understand how magnetoencephalography measures change as the disease progresses through its pre-clinical stage, correlations between magnetoencephalography outcomes and various clinical variables like age were analysed. A comparison of spectral power between mutation carriers and controls revealed oscillatory slowing, characterized by widespread higher theta (4-8 Hz) power, a lower posterior peak frequency and lower occipital alpha 2 (10-13 Hz) power. Functional connectivity analyses presented a lower whole-brain (amplitude-based) functional connectivity in the alpha (8-13 Hz) and beta (13-30 Hz) bands, predominantly located in parieto-temporal hub regions. Furthermore, we found a significant hub disruption index for (phase-based) functional connectivity in the theta band, attributed to both higher functional connectivity in 'non-hub' regions alongside a hub disruption. Neurophysiological changes did not correlate with indicators of pre-clinical disease progression in mutation carriers after multiple comparisons correction. Our findings provide evidence that oscillatory slowing and functional connectivity differences occur before cognitive impairment in individuals with autosomal dominant mutations leading to early onset Alzheimer's disease. The nature and direction of these alterations are comparable to those observed in the clinical stages of Alzheimer's disease, suggest an early excitation-inhibition imbalance, and fit with the activity-dependent functional degeneration hypothesis. These insights may prove useful for early diagnosis and intervention in the future.