Brain最新文献

Annexin A11 mutations are a rare cause of amyotrophic lateral sclerosis (ALS), wherein replicated protein variants P36R, G38R, D40G and D40Y are located in a small helix within the long, disordered N-terminus. To elucidate disease mechanisms, we characterized the phenotypes induced by a genetic loss-of-function and by misexpression of G38R and D40G in vivo. Loss of Annexin A11 results in a low-penetrant behavioural phenotype and aberrant axonal morphology in zebrafish homozygous knockout larvae, which is rescued by human wild-type Annexin A11. Both Annexin A11 knockout/down and ALS variants trigger nuclear dysfunction characterized by Lamin B2 mislocalization. The Lamin B2 signature also presented in anterior horn, spinal cord neurons from post-mortem ALS ± frontotemporal dementia patient tissue possessing G38R and D40G protein variants. These findings suggest mutant Annexin A11 acts as a dominant negative, revealing a potential early nucleopathy highlighting nuclear envelope abnormalities preceding behavioural abnormality in animal models.

Reward positivity (RewP) is an event-related brain potential component that emerges ∼250-350 ms after receiving reward-related feedback stimuli and is believed to be important for reinforcement learning and reward processing. Although numerous localization studies have indicated that the anterior cingulate cortex (ACC) is the neural generator of this component, other studies have identified sources outside of the ACC, fuelling a debate about its origin. Because the results of EEG and magnetoencephalography source-localization studies are severely limited by the inverse problem, we addressed this question by leveraging the high spatial and temporal resolution of intracranial EEG. We predicted that we would identify a neural generator of rthe RewP in the caudal ACC. We recorded intracranial EEG in 19 patients with refractory epilepsy who underwent invasive video-EEG monitoring at Ghent University Hospital, Belgium. Participants engaged in the virtual T-maze task, a trial-and-error task known to elicit a canonical RewP, while scalp and intracranial EEG were recorded simultaneously. The RewP was identified using a difference wave approach for both scalp and intracranial EEG. The data were aggregated across participants to create a virtual 'meta-participant' that contained all the recorded intracranial event-related brain potentials with respect to their intracranial contact locations. We used both hypothesis-driven (focused on ACC) and exploratory (whole-brain analysis) approaches to segment the brain into regions of interest. For each region of interest, we evaluated the degree to which the time course of the absolute current density (ACD) activity mirrored the time course of the RewP, and we confirmed the statistical significance of the results using permutation analysis. The grand average waveform of the scalp data revealed a RewP at 309 ms after reward feedback with a frontocentral scalp distribution, consistent with the identification of this component as the RewP. The meta-participant contained intracranial event-related brain potentials recorded from 582 intracranial contacts in total. The ACD activity of the aggregated intracranial event-related brain potentials was most similar to the RewP in the left caudal ACC, left dorsolateral prefrontal cortex, left frontomedial cortex and left white matter, with the highest score attributed to caudal ACC, as predicted. To our knowledge, this is the first study to use intracranial EEG aggregated across multiple human epilepsy patients and current source density analysis to identify the neural generator(s) of the RewP. These results provide direct evidence that the ACC is a neural generator of the RewP.

Genetics and other data modalities indicate that microglia play a critical role in Alzheimer's disease progression, but details of the disease-driving influence of microglia are poorly understood. Microglial cells can be parsed into subtypes based on their histological appearance. One subtype of microglia, termed dystrophic microglia, is characterized structurally by fragmented processes and cytoplasmic decay, and their presence has been associated with ageing and neurodegeneration. Recent studies suggest that the interaction between tau proteins and amyloid-β might induce dystrophic changes in microglia, potentially linking amyloid-β and tau pathologies to their effects on these microglia. We developed a study of human brains to test the hypothesis that dystrophic microglia are involved in Alzheimer's disease progression. We speculated that if their presence is unique to Alzheimer's disease neuropathological change, they would be substantially more common in Alzheimer's disease neuropathological change than in neurodegenerative diseases characterized by other proteinopathies, e.g. α-synuclein or transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology. Our analyses used histologically stained sections from five human brain regions of 64 individuals across six disease states, from healthy controls to advanced Alzheimer's disease stages, including comparative conditions such as Lewy body disease and limbic-predominant age-related TDP-43 encephalopathy neuropathological change. Using stereological sampling and digital pathology, we assessed populations of ramified, hypertrophic and dystrophic microglia. We found a significant increase in dystrophic microglia in areas affected early by Alzheimer's disease neuropathological change, suggesting a disease-specific role in neuropathology. Mediation analysis and structural equation modelling suggest that dystrophic microglia might impact the regional spread of Alzheimer's disease neuropathological change. In the mediation model, tau was found to be the initiating factor leading to the development of dystrophic microglia, which was then associated with the spread of amyloid-β and tau. These results suggest that a loss of the protective role of microglia could contribute to the spread of Alzheimer's disease neuropathological change and indicate that further research into preserving microglial function might be warranted.

Developmental dyslexia (DD) is one of the most common learning disorders, affecting millions of children and adults worldwide. To date, scientific research has attempted to explain DD primarily based on pathophysiological alterations in the cerebral cortex. In contrast, several decades ago, pioneering research on five post-mortem human brains suggested that a core characteristic of DD might be morphological alterations in a specific subdivision of the visual thalamus-the magnocellular lateral geniculate nucleus (M-LGN). However, due to considerable technical challenges in investigating LGN subdivisions non-invasively in humans, this finding was never confirmed in vivo, and its relevance for DD pathology remained highly controversial. Here, we leveraged recent advances in high resolution MRI at high field strength (7 T) to investigate the M-LGN in DD in vivo. Using a case-control design, we acquired data from a large sample of young adults with DD (n = 26; age 28 ± 7 years; 13 females) and matched control participants (n = 28; age 27 ± 6 years; 15 females). Each participant completed a comprehensive diagnostic behavioural test battery and participated in two MRI sessions, including three functional MRI experiments and one structural MRI acquisition. We measured blood oxygen level-dependent responses and longitudinal relaxation rates to compare both groups on LGN subdivision function and myelination. Based on previous research, we hypothesized that the M-LGN is altered in DD and that these alterations are associated with a key DD diagnostic score, i.e. rapid letter and number naming. The results showed aberrant responses of the M-LGN in DD compared to controls, which was reflected in a different functional lateralization of this subdivision between groups. These alterations were associated with rapid letter and number naming performance, specifically in male DD. We also found lateralization differences in the longitudinal relaxation rates of the M-LGN in DD relative to controls. Conversely, the other main subdivision of the LGN, the parvocellular LGN (P-LGN), showed comparable blood oxygen level-dependent responses and longitudinal relaxation rates between groups. The present study is the first to unequivocally show that M-LGN alterations are a hallmark of DD, affecting both the function and microstructure of this subdivision. It further provides a first functional interpretation of M-LGN alterations and a basis for a better understanding of sex-specific differences in DD with implications for prospective diagnostic and treatment strategies.

There is a rich tradition of research on the neuroanatomical correlates of spoken language production in aphasia using constrained tasks (e.g. picture naming), which offer controlled insights into the distinct processes that govern speech and language (i.e. lexical-semantic access, morphosyntactic construction, phonological encoding, speech motor programming/execution). Yet these tasks do not necessarily reflect everyday language use. In contrast, naturalistic language production (also referred to as 'connected speech' or 'discourse') more closely approximates typical processing demands, requiring the dynamic integration of all aspects of speech and language. The brain bases of naturalistic language production remain relatively unknown, however, in part because of the difficulty in deriving features that are salient, quantifiable and interpretable relative to both speech-language processes and the extant literature. The present cross-sectional observational study seeks to address these challenges by leveraging a validated and comprehensive auditory-perceptual measurement system that yields four explanatory dimensions of performance-Paraphasia (misselection of words and sounds), Logopenia (paucity of words), Agrammatism (grammatical omissions) and Motor speech (impaired speech motor programming/execution). We used this system to characterize naturalistic language production in a large and representative sample of individuals with acute post-stroke aphasia (n = 118). Scores on each of the four dimensions were correlated with lesion metrics, and multivariate associations among the dimensions and brain regions were then explored. Our findings revealed distinct yet overlapping neuroanatomical correlates throughout the left-hemisphere language network. Paraphasia and logopenia were associated primarily with posterior regions, spanning both dorsal and ventral streams, which are critical for lexical-semantic access and phonological encoding. In contrast, agrammatism and motor speech were associated primarily with anterior regions of the dorsal stream that are involved in morphosyntactic construction and speech motor planning/execution, respectively. Collectively, we view these results as constituting a brain-behaviour model of naturalistic language production in aphasia, aligning with both historical and contemporary accounts of the neurobiology of spoken language production.

Mitochondrial and synaptic dysfunction are pathological features of brain ageing and cognitive decline. Synaptic mitochondria are vital for meeting the high energy demands of synaptic transmission. However, little is known about the link between age-related metabolic changes and the integrity of synaptic mitochondria. To this end, we investigated the mechanisms of advanced glycation end product (AGE)-mediated mitochondrial and synaptic stress and evaluated the strategies to eliminate these toxic metabolites. Using aged brain and novel transgenic mice overexpressing neuronal glyoxalase 1 (GLO1), we comprehensively analysed alterations in accumulation/build-up of AGEs and related metabolites in synaptic mitochondria and the association of AGE levels with mitochondrial function. We demonstrated for the first time that synaptic mitochondria are an early and major target of AGEs and the related toxic metabolite methylglyoxal (MG), a precursor of AGEs. MG/AGE-insulted synaptic mitochondria exhibit deterioration of mitochondrial and synaptic function. Such accumulation of MG/AGEs positively correlated with mitochondrial perturbation and oxidative stress in ageing brain. Importantly, clearance of AGE-related metabolites by enhancing neuronal GLO1, a key enzyme for detoxification of AGEs, reduces synaptic mitochondrial AGE accumulation and improves mitochondrial and cognitive function in ageing and AGE-challenged mice. Furthermore, we evaluated the direct effect of AGEs on synaptic function in hippocampal neurons in live brain slices as an ex vivo model and in vitro cultured hippocampal neurons by recording long-term potentiation (LTP) and measuring spontaneously occurring miniature excitatory postsynaptic currents (mEPSCs). Neuronal GLO1 rescues deficits in AGE-induced synaptic plasticity and transmission by full recovery of decline in LTP or frequency of mEPSC. These studies explored crosstalk between synaptic mitochondrial dysfunction and age-related metabolic changes relevant to brain ageing and cognitive decline. Synaptic mitochondria are particularly susceptible to AGE-induced damage, highlighting the central importance of synaptic mitochondrial dysfunction in synaptic degeneration in age-related cognitive decline. Thus, augmenting GLO1 function to scavenge toxic metabolites represents a therapeutic approach to reduce age-related AGE accumulation and improve mitochondrial function and learning and memory.