Brain communications最新文献

The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer's disease to explore the brain asymmetry within the Alzheimer's disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer's disease progression in autosomal dominant Alzheimer's disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

People with aphasia experience cognitive deficits in addition to their well-documented language impairments, with attention being a frequently affected domain. While numerous studies highlight the impact of attention deficits on language abilities in people with aphasia, research examining the neural correlates of these deficits and the influence of stimulus modality on attention performance remains limited. In this cross-sectional study, in Experiment 1, we investigated sustained attention deficits in people with aphasia using four matched tasks that varied by modality (visual versus auditory) and linguistic content (verbal versus non-verbal). In Experiment 2, we further explored whether the neural resources supporting sustained attention differ by modality. Participants included 56 people with aphasia following left-hemisphere stroke (Experiments 1 and 2), 14 individuals after right-hemisphere stroke and 23 age-matched healthy controls (only Experiment 1). Participants completed four sustained attention tasks. Structural MRI scans were obtained for stroke participants, and neural correlates of attention were explored in people with aphasia. Behavioural analyses revealed that people with aphasia, as a group and across subtypes, performed significantly worse on auditory tasks with notably slower reaction times compared to healthy controls, indicating sustained attention deficits, particularly in the auditory modality. Compared to individuals with right-hemisphere stroke, people with aphasia made significantly more errors only on the auditory verbal task, which may reflect the combined impact of language impairment and attentional demands. No significant differences were observed between non-fluent and fluent aphasia subtypes, indicating comparable sustained attention deficits across these groups. However, participants with non-fluent aphasia demonstrated slower reaction times across nearly all tasks compared to healthy individuals, while those with fluent aphasia showed slower reaction times only in the auditory modality. Lesion-symptom mapping analysis did not reveal distinct brain-behaviour associations specific to the auditory modality. However, for the visual verbal task, poorer performance was associated with lesions in the inferior and middle frontal gyri and underlying white matter fasciculi (inferior fronto-occipital fasciculus, uncinate fasciculus and corpus callosum), regions implicated in written word comprehension. Taken together, these findings suggest that people with aphasia exhibit modality-specific sustained attention deficits, particularly in the auditory domain, likely reflecting impaired processing of auditory information.

Mild traumatic brain injury can disrupt brain function and is associated with high morbidity and healthcare utilization. While many individuals recover from mild traumatic brain injury, a significant proportion experience long-term sequelae, collectively known as post-concussion syndrome. Symptoms of post-concussion syndrome include headache, dizziness, insomnia, cognitive processing difficulties and mental health disturbances. The disease burden is augmented by the current lack of objective measures to accurately predict long-term symptoms and deficits, providing an opportunity to utilize biomarkers in biofluids. A large proportion of available diagnostic clinical tools are subjective symptom scores. This review aims to explore current fluid biomarkers, grouped by clinical symptoms. With the available literature, we have discovered a wide range of fluid biomarkers that have been investigated for predicting post-traumatic headache, including neuropeptides; sleep disturbances, such as cortisol and melatonin; vestibular disturbances, including interleukin-6 and neurone-specific enolase; and vomiting, such as S100B. Along with physical symptoms, biomarkers investigated for predicting cognitive disturbances include inflammatory markers, S100B, neurofilament light chain, tau, microRNA and hormones. Biomarkers to predict mental health disturbances may include brain-derived neurotrophic factor, tau and cortisol. By utilizing such biomarkers, there is capacity to adopt a personalized medicine approach to facilitate early interventions for those most in need while also identifying individuals with a favourable prognosis who can safely return to their normal activities.

Epstein-Barr virus is now regarded as the critical risk factor for multiple sclerosis. However, Cytomegalovirus and human herpesvirus 6A have also been associated with altered multiple sclerosis risk, suggesting a multifactorial aetiology. Here, we present the first large-scale study of the association between human herpesvirus 7 and the risk of developing multiple sclerosis. A nested case-control study was performed by crosslinking Swedish registries and biobanks, identifying blood samples from 981 cases who later developed multiple sclerosis and 1278 matched controls. Serological testing was performed with a multiplex immunoassay. The association between viral serostatus and the risk of developing multiple sclerosis was analysed with conditional logistic regression, calculating an odds ratio with 95% confidence interval. Interactions between antibodies against human herpesvirus 7 and the Epstein-Barr virus nuclear antigen 1 regarding multiple sclerosis risk were analysed on the additive scale. Serological evidence of human herpesvirus 7 infection was associated with a higher risk of developing multiple sclerosis: odds ratio = 2.2 (95% confidence interval = 1.8-2.7), P < 0.001. The results remained similar when adjusting for cytomegalovirus, Epstein-Barr virus and human herpesvirus 6A serostatus. Synergistic interactions between human herpesvirus 7 and Epstein-Barr virus nuclear antigen 1 seroreactivity were observed: attributable proportion due to interaction = 0.51 (95% confidence interval = 0.34-0.68). These results suggest that human herpesvirus 7 could be a contributing factor in multiple sclerosis aetiology.

Developmental language disorder (DLD) is a common neurodevelopmental disorder that affects receptive and expressive language skills. In contrast to the wealth of evidence on acquired language disorders, we understand relatively little about the neural underpinnings of DLD. A recent meta-analysis across different types of structural brain analyses in DLD highlighted consistent anatomical differences in the anterior striatum, with other subcortical structures relatively spared. These findings are consistent with predictions from the procedural circuit deficit hypothesis (PCDH), namely that the anterior neostriatum differs in structure and function in DLD, whereas medial temporal lobe structures are unaffected and may act in a compensatory manner. Here, in a case-control study with a larger sample size than previous studies, we evaluated volume and microstructure of subcortical grey matter structures using T1-weighted images and diffusion imaging. Our predictions were partly in accord with those of the PCDH and the findings of the meta-analysis. Neuroimaging and behavioural measures were acquired in 156 children and adolescents (54 DLD; 74 typically developing (TD); 28 with a history of language difficulties) aged 10:0-15:11 years. As predicted by the PCDH, there were significant differences in the DLD group in volume and microstructure of the neostriatum (caudate nucleus, putamen). However, in contrast to our prediction, there were also significantly smaller structures in the DLD group across other subcortical structures evaluated: globus pallidus, thalamus and hippocampus. The hippocampal difference is of particular interest as it is hypothesized in the PCDH to be spared in DLD. Microstructural measures (diffusion tensor imaging and neurite orientation dispersion and density imaging) revealed differences in the caudate nucleus, thalamus and hippocampus. Multivariate machine learning analyses highlighted the relationship between the hippocampus and language skills but only in the TD cohort. We conclude that the subcortical correlates of DLD are in fact not limited to the neostriatum and represent important areas of further inquiry.

This study provides the first quantification of neurofilament light chain (NfL) kinetics in the human CNS using stable isotope labelling kinetics. NfL is elevated in CSF and blood across a range of traumatic, inflammatory and neurodegenerative diseases of the CNS, and has been increasingly included in clinical trials as a secondary or exploratory outcome measure of target engagement. Interpreting trajectories of NfL post-treatment has been challenging, prompting a greater need and focus on understanding its pathophysiology. We set out to measure NfL kinetics in the human CNS using stable isotope labelling kinetics. In human neurons derived from induced pluripotent stem cells, we show that NfL turnover is relatively slow, comparable to other long-lived proteins such as tau. We detected a delay of 3 to 6 days in the release of NfL into the media, unexpected for a passively released protein and supporting that controlled mechanisms of release could contribute to the appearance of NfL in the extracellular milieu. We optimized the kinetic NfL assay to measure the turnover of NfL in the human CNS. Participants with diagnosed primary tauopathies (n = 10) were recruited to the Human CNS Tau Kinetics in Tauopathies study and a cohort of cognitively unimpaired or with mild cognitive impairment (Clinical Dementia Rating score ≤0.5; n = 22) to the Tau Stable Isotope Labelling Kinetics study. Patients with suspected normal pressure hydrocephalus (n = 3) and primary tauopathy cases (n = 3) were examined to assess labelling in the brain parenchyma and ventricular CSF. In brain tissue, isotopically labelled in vivo and sampled ex-vivo and post-mortem, NfL is rapidly labelled but remains stable 18 months after, indicating very slow turnover and likely incorporation into very stable NfL networks. In line with a controlled mechanism of release in vivo, appearance of labelled NfL in CSF was detectable between 53 and 162 days post-labelling, during which NfL labelling did not reach its peak, suggestive of a half-life in CSF >3 months. These findings support the interpretation that acute rises in CSF NfL concentration are likely to be related to passive release or CSF clearance failure. We also show that active but delayed release of newly translated NfL can contribute to the concentration of NfL in CSF, but this would not be expected for at least 8 weeks. Clinical trials using NfL as an outcome measure will benefit from substantially longer follow-up periods and isotopic labelling to understand the NfL response to therapeutic intervention.

This scientific commentary refers to 'Systemic increase of AMPA receptors associated with cognitive impairment of long COVID' by Fujimoto et al. (https://doi.org/10.1093/braincomms/fcaf337).

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease involving progressive degeneration of upper and lower motor neurons. Beyond well-established grey and white matter pathology, alterations in cortical gyrification have recently been observed, yet their clinical relevance and molecular underpinnings remain to be understood. Here, we investigated this premise by examining its microstructural and transcriptional basis in 60 patients with amyotrophic lateral sclerosis (median age = 55, range = 25-72 years) and 60 matched controls (median age = 56, range = 27-72 years) using structural and diffusion MRI. Patients exhibited a significant reduction in local gyrification index within bilateral precentral and postcentral gyri, left middle frontal gyrus and left superior parietal lobule. This was accompanied by reduced fractional anisotropy in the white matter tracts, primarily involving the corticospinal tract and corpus callosum. Higher local gyrification index and fractional anisotropy values were associated with better motor function as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, and local gyrification index also showed positive associations with global cognitive status. A mediation analysis indicated that fractional anisotropy partially accounted for the relationship between local gyrification index and functional disability, suggesting that disrupted white matter pathways contribute to the clinical impact of gyrification changes. To explore underlying mechanisms, we integrated neuroimaging findings with transcriptomic data from the Allen Human Brain Atlas. Regions of reduced local gyrification index showed spatial convergence with cortical expression of amyotrophic lateral sclerosis-related genes such as TARDBP and C9orf72, enriched for biological processes related to protein aggregation, axon guidance and synaptic signalling. Together, these findings suggest that cortical gyrification abnormalities in amyotrophic lateral sclerosis are closely linked to white matter degeneration, functional impairment and genetic vulnerability, thereby offering an integrative window into the multiscale pathology of amyotrophic lateral sclerosis.

Brain atrophy is a natural consequence of ageing but can be accelerated by neurodegenerative diseases such as Alzheimer's disease. We apply an existing algorithm to identify new biomarkers that better track volumetric changes over time, i.e. atrophy. These new biomarkers are the volumetric ratio of two composite regions of interest, identified by an algorithm optimized to enhance the monitoring of Alzheimer's disease progression. The algorithm prioritizes biomarkers with less noisy trajectories (quantified by lower sample size estimates for clinical trials) and that capture disease signal by showing a greater rate of change in amyloid-positive versus amyloid-negative individuals, ensuring the biomarker effectively reflects Alzheimer's pathology. Data from 1381 individuals from the Alzheimer's Disease Neuroimaging Initiative database having multiple MRI scans were analysed. The new biomarkers outperformed traditional volumetric measures (whole brain, hippocampus and ventricles) across all metrics. This improvement was particularly pronounced in cognitively impaired individuals, where atrophy is more severe. Among the traditional measures, ventricular volume had the best performance. Results suggest that ratios of regional brain volumes could enhance disease progression tracking, as has been shown in other modalities like fluid biomarker ratios and standardized uptake value ratios from positron emission tomography.