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.

Digital cognitive testing using online platforms has emerged as a potentially transformative tool in clinical neuroscience. In theory, it could provide a powerful means of screening for and tracking cognitive performance in people at risk of developing conditions such as Alzheimer's disease. Here we investigate whether digital metrics derived from an in-person administered, tablet-based short-term memory task-the 'What was where?' Oxford Memory Task-were able to clinically stratify patients at different points within the Alzheimer's disease continuum and to track disease progression over time. Performance of these metrics compared to traditional neuropsychological pen-and-paper screening tests of cognition was also analysed. A total of 325 people participated in this study: 49 patients with subjective cognitive decline, 57 with mild cognitive impairment, 63 with Alzheimer's disease dementia and 156 elderly healthy controls. Most digital metrics were able to discriminate between healthy controls and patients with mild cognitive impairment and between mild cognitive impairment and Alzheimer's disease patients. Some, including Absolute Localization Error, also differed significantly between patients with subjective cognitive decline and mild cognitive impairment. Identification accuracy was the best predictor of hippocampal atrophy, performing as well as standard screening neuropsychological tests. A linear support vector model combining digital metrics achieved high accuracy and performed at par with standard testing in discriminating between elderly healthy controls and subjective cognitive decline (area under the curve 0.82) and between subjective cognitive decline and mild cognitive impairment (area under the curve 0.92), while performing worse in classifying between mild cognitive impairment and Alzheimer's disease patients (area under the curve 0.75). Memory imprecision was able to predict cognitive decline on standard cognitive tests over one year. Overall, these findings show how it might be possible to use a digital memory test in clinics and clinical trial contexts to stratify and track performance across the Alzheimer's disease continuum.

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease with no current disease-modifying treatments approved. Longitudinal research and clinical trials for PSP are ongoing and require reliable measures that are sensitive to disease progression. Despite susceptibility to subjective limitations, clinical and cognitive assessments are the most used instruments in therapeutic trials in PSP. The objective of this review was to identify measures that have been studied longitudinally as measures of progression and are suitable for use as clinical trial endpoints. We reviewed the measures currently used as trial endpoints, identifying the clinical, cognitive, fluid and imaging measures that have previously been studied longitudinally, and discuss current diagnostic and emerging measures that are yet to be studied longitudinally but that may be sensitive to disease progression. We found that many fluid and imaging measures require further research to validate their use as longitudinal measures of change, including emerging measures that have not yet been studied specifically in PSP. We also summarize the sample size estimates required to detect changes in a two-arm, 52-week therapeutic trial and found that specific MRI volumes require the smallest sample sizes to detect change.

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.

Previous research has revealed patterns of brain atrophy in subjective cognitive decline, a potential preclinical stage of Alzheimer's disease. However, the involvement of myelin content and microstructural alterations in subjective cognitive decline has not previously been investigated. This study included three groups of participants recruited from the Compostela Aging Study project: 53 cognitively unimpaired adults, 16 individuals with subjective cognitive decline and hippocampal atrophy and 70 with subjective cognitive decline and no hippocampal atrophy. Group differences were analysed across five MRI biomarkers derived from multi-component T2 relaxometry, each sensitive to variations in cerebral composition and microstructural tissue integrity. Although no significant differences in myelin content were observed between groups, the subjective cognitive decline with hippocampal atrophy group exhibited a larger free-water fraction, and reduced fraction and relaxation times of the intra/extracellular water compartment in frontal, parietal and medial temporal lobe brain regions and white matter tracts as compared with the other groups. Moreover, both subjective cognitive decline groups displayed lower total water content as compared with the control group and the subjective cognitive decline with hippocampal atrophy group showed lower total water content as compared with the subjective cognitive decline without hippocampal atrophy group. These changes are likely related to microstructural tissue differences related to neuroinflammation, axonal degeneration, iron accumulation or other physiologic variations, calling for further examinations.

The subthalamic nucleus is thought to play a crucial role in controlling impulsive actions. Networked among the basal ganglia and receiving input from several cortical areas, the subthalamic nucleus is well positioned to influence action selection when faced with competing and conflicting action outcomes. The purpose of this study was to test the dissociable roles of the dorsal and ventral aspects of the subthalamic nucleus during action conflict in patients with Parkinson's disease undergoing intraoperative neurophysiological recording and to explore a potential mechanism for this inhibitory control. We hypothesized that modulations of neurophysiological activity during action conflict would be more pronounced in the dorsal subthalamic nucleus compared with the ventral subthalamic nucleus, due to the dissociation of cortical afferents to subthalamic nucleus subregions and previous findings of deep brain stimulation targeting subthalamic nucleus subregions in Parkinson's disease. We recorded neurophysiological activity while 10 participants with Parkinson's disease performed the Simon task during deep brain stimulation surgery. Response-locked local field potentials in the theta and beta band (associated with conflict control and movement inhibition, respectively) were analysed across subthalamic nucleus subregions and hemispheres relative to the motor response (ipsilateral/contralateral). In the presence of action conflict, the dorsal subthalamic nucleus, connected to cortical motor regions, exhibited larger theta power relative to the ventral subthalamic nucleus subregion, which is linked to the limbic circuits (P < 0.05). This evidence supports independent subregion function in conflict control. However, both subregions had relatively increased beta power for conflict trials compared with non-conflict in the hemisphere ipsilateral to the motor response. The conflict-related beta modulation was not present in the contralateral hemisphere. This indicates the importance of the ipsilateral hemisphere in the inhibition of incorrect action impulses. Additionally, higher intertrial beta power in the ventral subregion correlated with reduced accuracy on conflict trials, which we propose, could serve as a biomarker for impaired task performance. The results of the study support the existence of a functional dissociation within subthalamic nucleus subregions, emphasizing the role of the dorsal subthalamic nucleus in modulating action conflict.

Alzheimer's disease (AD) is characterized by the accumulation of protein aggregates, which are thought to be influenced by posttranslational modifications (PTMs). Dehydroamino acids (DHAAs) are rarely observed PTMs that contain an electrophilic alkene capable of forming protein-protein crosslinks, which may lead to protein aggregation. We report here the discovery of DHAAs in the protein aggregates from AD, constituting an unknown and previously unsuspected source of extensive proteomic complexity. We used mass spectrometry-based proteomics to discover 404 sites of DHAA formation in 171 proteins from protein aggregate-enriched human brain samples, 6-fold more sites than observed in the soluble protein fractions. The DHAA modifications are observed both directly and in the form of conjugates after reacting with abundant cellular nucleophiles or crosslinking to nucleophilic amino acid residues. We report 11 such crosslinks, including three in the Tau protein, which are 10-fold more abundant in AD samples compared with age-matched controls. Many of the proteins found to contain DHAAs and their conjugates are involved in protein aggregation or pathways dysregulated in AD. DHAAs are prevalent modifications in the AD brain proteome and give rise to protein crosslinks that may contribute to protein aggregation.

Early-onset Alzheimer's disease constitutes ∼5-10% of Alzheimer's disease. Its clinical characteristics and biomarker profiles are not well documented. To compare the characteristics covering clinical, neuropsychological and biomarker profiles between patients with early- and late-onset Alzheimer's disease, we enrolled 203 patients (late-onset Alzheimer's disease = 99; early-onset Alzheimer's disease = 104) from a Chinese hospital-based cohort, the Shanghai Memory Study. A full panel of plasma biomarkers under the amyloid/tau/neurodegeneration framework including plasma amyloid beta 40, amyloid beta 42, total-tau, neurofilament light chain and phosphorylated tau 181 were assayed using ultra-sensitive Simoa technology. Seventy-five patients underwent an amyloid molecular positron emission tomography scan whereas 43 received comprehensive amyloid, Tau deposition and hypometabolism analysis. Clinical features, plasma and imaging biomarkers were compared cross-sectionally. Compared to those with late-onset Alzheimer's disease, patients with early-onset Alzheimer's disease presented more severe impairment in language function, lower frequency of APOE ɛ4 and lower levels of plasma neurofilament light chain (all P < 0.05). The plasma phosphorylated tau 181 concentration and phosphorylated tau 181/amyloid beta 42 ratios were higher in early-onset Alzheimer's disease than in late-onset Alzheimer's disease (all P < 0.05). More severe Tau deposition as indicated by ¹⁸F-florzolotau binding in the precuneus, posterior cingulate cortex and angular gyrus was observed in the early-onset Alzheimer's disease group. Plasma phosphorylated tau 181 was associated with earlier age at onset and domain-specific cognitive impairment, especially in patients with early-onset Alzheimer's disease. We concluded that patients with early-onset Alzheimer's disease differed from late-onset Alzheimer's disease in cognitive performance and biomarker profile. A higher burden of pathological tau was observed in early-onset Alzheimer's disease and was associated with earlier age at onset and more profound cognitive impairment.

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).

Movement dysfunction after stroke is largely due to the inability of cortical motor neurons to activate spinal motor neurons via transmission of descending motor commands along the corticofugal projection from the primary motor cortex. Pathophysiological processes that ensue following injury have mostly resolved and white matter volume within the remodelled tract has mostly stabilized by the chronic stage many months to years after symptom onset. Where along the cranial course of the residual corticofugal projection white matter microstructure explains potential to activate muscles weakened by stroke at this stage is still not well understood. Here, diffusion spectrum imaging was used to reconstruct the descending corticofugal projection and quantify its microstructure in stroke survivors (n = 25) with longstanding hand impairment (7.7 ± 6.5 years). Portions of the residual tract overlapping with abnormalities on structural images were defined as the 'Overlap' compartment, and portions above and below this compartment were defined as 'Rostral' and 'Caudal' compartments, respectively. Maximal precision grip force and size of motor-evoked potentials elicited by transcranial magnetic stimulation were used to quantify activation of paretic hand muscles. Coherence of fibre anisotropy and directional diffusivities between tracts in either cerebral hemisphere was reduced in stroke survivors relative to neurologically-intact controls, with most abnormal asymmetries observed in the 'Overlap' compartment. While differences in fibre anisotropy and diffusivity between residual and intact tracts were detected most prominently in the 'Overlap' compartment, the overall magnitude of unrestricted diffusion within the 'Caudal' compartment was most closely linked to paretic muscle activation. The ability of cortical motor neurons to access spinal motor neuron pools long after stroke onset is therefore associated with microstructural integrity in portions of the residual corticofugal projection subject to secondary degeneration. These findings expand knowledge on white matter adaptation in response to neurological injury and may inform applications that seek to reverse brain pathology long after stroke onset when movement dysfunction tends to persist.