Brain communications最新文献

Individuals diagnosed with functional neurological disorder experience abnormal movement, gait, sensory processing or functional seizures, for which research into the pathophysiology identified psychosocial contributing factors as well as promising biomarkers. Recent pilot studies suggested that (epi-)genetic variants may act as vulnerability factors, for example, on the oxytocin pathway. This study set out to explore endogenous oxytocin hormone levels in saliva in a cohort of 59 functional neurological disorder patients and 65 healthy controls comparable in sex and age. First, we examined the association between salivary oxytocin levels with the genetic allelic variant (rs53576) of the oxytocin receptor gene (OXTR), its epigenetic changes indicated by methylation rates, and clinical variables-including childhood trauma. Second, due to previously reported effects of oxytocin changing the volume and functional connectivity of the amygdala, as well as the known involvement of the amygdala in the pathophysiology of functional neurological disorders, we further looked at both structural and functional imaging of the amygdala. While patients did not significantly differ from healthy control in their peripheral oxytocin levels, there was a specific interaction of OXTR methylation and peripheral oxytocin dependent on group: higher methylation rates correlated with higher salivary oxytocin in patients only, while this was not the case in healthy control [F(1109) = 8.92, P = 0.003, d = 0.541]. Moreover, patients with the AA-genotype (minor allele) of the rs53576 genetic variant of the OXTR gene presented with higher OXTR methylation levels [F(2106) = 10.25, P < 0.0001, d = 0.58]. Lastly, amygdalar connectivity to the hippocampus, the posterior cingulate cortex, the inferior parietal cortex and the inferior temporal cortex as well as smaller amygdalar volume were correlated to peripheral oxytocin levels in patients only [F(2,38) = 5.36, P  = 0.025,  d = 0.431], but not in healthy control. No significant interactions with childhood trauma were identified. Our study revealed a significant interplay between peripheral oxytocin and OXTR methylation in patients only, potentially influenced by genotype. One could hypothesize that higher peripheral oxytocin denotes a compensatory mechanisms for the increased methylation of the OXTR, which might affect amygdalar functional connectivity. These findings help to further understand underlying pathophysiological mechanisms, considering oxytocin's involvement in functional patients and could offer a potential site of treatment for future studies.

Extracellular beta-amyloid aggregation and inflammation are in a complex and not fully understood interplay during hyperphosphorylated tau aggregation and pathogenesis of Alzheimer's disease. Our group has previously shown that an immune challenge with tumour necrosis factor alpha can alter extracellular beta-sheet containing aggregates in human-induced pluripotent stem cell-derived cortical neurons carrying familial Alzheimer's disease-related presenilin 1 mutations. Here, using single-molecule detection and super-resolution imaging techniques, we quantified and characterized the intra- and extracellular beta-amyloid and AT8-positive tau aggregates. Our results indicate a pre-existing Alzheimer's disease-like pathology caused by the presenilin 1 mutation, with increased beta-amyloid aggregates in both the cell lysate and conditioned media compared to isogenic controls and also increased intracellular tau aggregates. The main effect of tumour necrosis factor alpha treatment on presenilin 1 neurons was the formation of larger intracellular beta-amyloid aggregates. In contrast, isogenic controls showed more significant changes with tumour necrosis factor alpha treatment with an increase in beta-amyloid aggregates in the media but not intracellularly and an increase in tau aggregates in both the media and cell lysate, suggesting a chronic inflammation-driven mechanism for the development of sporadic Alzheimer's disease. Remarkably, we also found significant morphological differences between intra- and extracellular beta-amyloid and tau aggregates in human-induced pluripotent stem cell-derived cortical neurons, suggesting these neurons can only clear aggregates when small, and that larger aggregates stay inside the neurons. While majority of the beta-amyloid aggregates were cleared into the media, a greater portion of the tau aggregates remained intracellular. This size-dependent aggregate clearance was also shown to be conserved in vivo, using soaked and homogenized mouse and human post-mortem Alzheimer's disease brain samples. As such, our results are proposing a previously unknown, size-dependent aggregate clearance mechanism, which can possibly explain the intracellular aggregation of tau and extracellular aggregation of beta-amyloid.

CSF concentrations of β-amyloid 42 (Aβ42) and phosphorylated tau (p-tau) are well-established biomarkers of Alzheimer's disease and have been studied in relation to several neuropathological features both in patients and in cognitively unimpaired individuals. The CSF p-tau/Aβ42 ratio, a biomarker combining information from both pathophysiological processes, has emerged as a promising tool for monitoring disease progression, even at pre-clinical stages. Here, we studied the association between the CSF p-tau/Aβ42 ratio with downstream markers of pre-clinical Alzheimer's disease progression including brain structure, glucose metabolism, fibrillary Aβ deposition and cognitive performance in 234 cognitively unimpaired individuals, who underwent cognitive testing, a lumbar puncture, MRI, 18F-fluorodeoxyglucose and 18F-flutemetamol PET scanning. We evaluated both main effects and interactions with Alzheimer's disease risk factors, such as older age, female sex and the apoliporoptein E (APOE)-ɛ4 allele, in a priori defined regions of interest and further examined the associations on the whole-brain using voxel-wise regressions. In addition, as the association between CSF Alzheimer's disease biomarkers and brain structure and function may be non-linear, we tested the interaction between the CSF p-tau/Aβ42 ratio and stages of pre-clinical Alzheimer's disease defined using the amyloid (A) and tau (T) classification. We found significantly positive associations between CSF p-tau/Aβ42 and both cortical Aβ deposition and regional grey matter volume while no effect was observed for brain metabolism. A significant interaction with age indicated that, for the same level of CSF p-tau/Aβ42, older individuals displayed both increased Aβ deposition and lower grey matter volume, in widespread cortical areas. In addition, we found that women compared with men had a greater Aβ fibrillary accumulation in midline cortical areas and inferior temporal regions, for the same level of the CSF biomarker. The impact of CSF p-tau/Aβ42 on grey matter volume was modulated by AT stages, with A+T+ individuals displaying significantly less positive associations in areas of early atrophy in the Alzheimer's continuum. Finally, we found that sex and APOE-ɛ4 modulated the association between the CSF biomarker and episodic memory as well as abstract reasoning, respectively. Our data indicate that the CSF p-tau/Aβ42 ratio is strongly associated with multiple downstream neuropathological events in cognitively unimpaired individuals and may thus serve as a potent biomarker to investigate the earliest changes in pre-clinical Alzheimer's disease. Given that its impact on both Aβ deposition and grey matter volume is modulated by specific risk factors, our results highlight the need to take into account such predisposing variables in both clinical practice and prevention trials.

Associate Editor Laurent Sheybani discusses how artificial intelligence (AI) could be both a risk and a solution for statistical reliability in scientific research in the context of the European Union AI act, which came into force in the summer of 2024.

[This corrects the article DOI: 10.1093/braincomms/fcad247.].

Syntactic processing and verbal working memory are both essential components to sentence comprehension. Nonetheless, the separability of these systems in the brain remains unclear. To address this issue, we performed causal-inference analyses based on lesion and connectome network mapping using MRI and behavioural testing in two groups of individuals with chronic post-stroke aphasia. We employed a rhyme judgement task with heavy working memory load without articulatory confounds, controlling for the overall ability to match auditory words to pictures and to perform a metalinguistic rhyme judgement, isolating the effect of working memory load (103 individuals). We assessed non-canonical sentence comprehension, isolating syntactic processing by incorporating residual rhyme judgement performance as a covariate for working memory load (78 individuals). Voxel-based lesion analyses and structural connectome-based lesion symptom mapping controlling for total lesion volume were performed, with permutation testing to correct for multiple comparisons (4000 permutations). We observed that effects of working memory load localized to dorsal stream damage: posterior temporal-parietal lesions and frontal-parietal white matter disconnections. These effects were differentiated from syntactic comprehension deficits, which were primarily associated with ventral stream damage: lesions to temporal lobe and temporal-parietal white matter disconnections, particularly when incorporating the residual measure of working memory load as a covariate. Our results support the conclusion that working memory and syntactic processing are associated with distinct brain networks, largely loading onto dorsal and ventral streams, respectively.

Familial hemiplegic migraine type 2 results from pathogenic variants in the ATP1A2 gene, which encodes for a catalytic subunit of sodium/potassium ATPase. This extremely rare autosomal dominant disorder manifests with a spectrum of symptoms, most commonly pure hemiplegic phenotype, epilepsy, and/or intellectual disability. In this study, we detail the clinical features and genetic analysis of nine patients from a large family spanning four generations, with all carrying a previously unreported likely pathogenic variant, p.Gly615Glu, in ATP1A2, compatible with a diagnosis of familial hemiplegic migraine type 2, fully penetrant with variable expressivity. This newly identified likely pathogenic variant primarily presented with psychiatric disturbances and a non-hemiplegic phenotype. Only one patient presented hemiplegic attacks, while seven were diagnosed with migraine with aura, including visual, sensory, and speech/language aura, and one with migraine without aura. The identification of the genes responsible for the more common forms of migraine, both with and without aura, remains a significant challenge in migraine genetics and is critical for advancing personalized medicine.

The prevalent belief that individuals with Huntington's disease exhibit selfish behaviour, disregarding the thoughts, feelings and actions of others, has been challenged by patient organizations and clinical experts. To further investigate this issue and study whether participants with Huntington's disease can pay attention to others, a joint memory task was carried out in patients with Huntington's disease with and without a partner. This study involved 69 participants at an early stage of Huntington's disease and 56 healthy controls from the UK, France and Germany, who participated in the international Repair-HD multicentre study (NCT03119246). Participants completed a semantic categorization task across three categories: animals, fruits and vegetables and manufactured objects. They performed the task either alone (Alone condition) or with the examiner acting as a partner (Pair condition). In the Pair condition, the participant was assigned one category, their partner was assigned another and one category was left unassigned. Afterwards, participants engaged in a surprise free recall task to remember as many words as possible. Words not assigned to anyone were considered socially irrelevant in contrast to the ones assigned to the participant and to the partner. Both groups demonstrated the expected self-prioritization effect, recalling their assigned words better than their partner's or unassigned words in both conditions. Additionally, a joint memory effect was observed, with better recall for the partner's assigned words than the unassigned words in the Pair condition (controls: difference = 0.45, P < 0.001; participants with Huntington's disease: difference = 0.34, P < 0.001). Socially relevant words were thus better recalled than irrelevant words. The number of recalled words correlated with cognitive performance (all P-values < 0.05) and MRI analysis revealed a negative correlation between the joint memory effect and right orbitofrontal grey matter density in participants with Huntington's disease. These findings challenge the notion that individuals with Huntington's disease display selfish behaviours because of disinterest in others. They show the ability to process information about their partners, implying that their social difficulties may arise from factors other than social cognition deficits. This opens the door for more ecological assessments of social cognition in patients with Huntington's disease.

PET is used to measure tau protein accumulation in Alzheimer's disease. Multiple biomarkers have been proposed to track disease progression, most notably the standardized uptake value ratio of PET tracer uptake in a target region of interest relative to a reference region, but literature suggests these region choices are nontrivial. This study presents and evaluates a novel framework, BioDisCVR, designed to facilitate the discovery of useful biomarkers, demonstrated on [¹⁸F]AV-1451 tau PET data in multiple cohorts. BioDisCVR enhances signal-to-noise by conducting a data-driven search through the space of possible combinations of regional tau PET signals into a ratio of two composite regions, driven by a user-defined fitness function. This study compares ratio-based biomarkers discovered by the framework with state-of-the-art standardized uptake value ratio biomarkers. Data used is tau PET regional measurements from 198 individuals from the Alzheimer's Disease Neuroimaging Initiative database, used for discovery, and 42 from the Mayo Clinic Alzheimer's Disease Research Center and Mayo Clinic Study of Aging (MCSA), used for external validation. Biomarkers are evaluated by calculating clinical trial sample size estimates for 80% power and 20% effect size. Secondary metrics are a measure of longitudinal consistency (standard deviation of linear mixed-effects model residuals), and separation between cognitive groups (t-statistic of the change over time due to being cognitively impaired). When applied to preclinical (secondary prevention with CU individuals) and clinical (treatment aimed at cognitively impaired individuals) trials on Alzheimer's disease, our data-driven framework BioDisCVR discovered ratio-based tau PET biomarkers vastly superior to previous work, both reducing measurement error and sample size estimates for hypothetical clinical trials. Our analysis suggests remarkable potential for patient benefit (reduced exposure to health risks associated with experimental drugs) and substantial cost savings, through accelerated trials and reduced sample sizes. Our study supports the leveraging of data-driven methods like BioDisCVR for clinical benefit, with the potential to positively impact drug development in Alzheimer's disease and beyond.