Brain最新文献

Although neuropsychiatric symptoms are not part of diagnostic criteria for sporadic Creutzfeldt-Jakob disease (sCJD), a few retrospective studies and our clinical experience have suggested they are prominent and often occur early. The objective of our study was to assess prospectively the neuropsychiatric features in sCJD (and their impact on caregivers) and compare them with five other neurodegenerative diseases: Alzheimer's disease (AD), dementia with Lewy bodies (DLB), progressive supranuclear palsy, behavioural variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia. The Neuropsychiatric Inventory (NPI) was given at the first UCSF research visit to caregivers of 789 serial patients evaluated at the UCSF Memory and Aging Center from January 2000 through November 2016 who met the diagnostic research criteria for one of these six neurodegenerative disorders. All subjects underwent a Mini-Mental State Examination, and demographic data (age, sex, years of education) were collected. We hypothesized that sCJD has a very prominent behavioural and neuropsychiatric profile, which might help to distinguish it from other neurodegenerative diseases. Of our sCJD cohort (n = 92), 97% exhibited at least one and 50% at least six of the 12 symptoms on the NPI at the time of their first research visit. The most common behavioural symptoms, which occurred in >50% of the sCJD patient cohort, were: appetite/eating disturbances (68%), apathy/indifference (66%), night-time behaviour disturbances (53%), aberrant motor behaviour (53%) and anxiety (52%). Even the least common behaviour, disinhibition, occurred in 19%. Compared with DLB and bvFTD, two conditions with very prominent behavioural features that are included in their diagnostic criteria, sCJD had significantly higher mean NPI frequency × severity scores for night-time behaviour disturbances and delusions. Patients with sCJD scored higher for hallucinations and dysphoria than bvFTD patients and higher for appetite/eating disturbances, aberrant motor behaviour and agitation than patients with DLB. sCJD resulted in significantly worse frequency × severity scores than AD in nine of the NPI symptom domains, with our data revealing sCJD to be a highly behavioural syndrome. No neuropsychiatric symptom is pathognomonic for sCJD, but specific symptoms may enable the differentiation of sCJD from other neurodegenerative diseases. Our findings support the inclusion of behavioural symptoms in sCJD diagnostic criteria.

Severely brain-injured patients may enter a spectrum of conditions collectively known as disorders of consciousness. This spectrum includes clinical conditions such as unresponsive wakefulness syndrome or minimally conscious state, where the behavioural assessment of consciousness can often be deceptive. To bridge this dissociation, neuroimaging techniques are employed to identify the residual brain functions. Each neuroimaging modality imperfectly captures distinct aspects of brain preservation-functional, anatomical, or both. In this study, we adopt a comprehensive approach by integrating the neurophysiology and neuroimaging modalities available from the standard and advanced clinical assessments through interpretable machine learning. The electrophysiological modalities included high-density EEG (resting state and task), whereas neuroimaging modalities included anatomical and resting-state functional MRI, diffusion MRI and 18F-fluorodeoxyglucose PET. Our investigation reveals that specific modalities, such as functional assessments, provide comprehensive insights into the currently evaluated state of consciousness, the diagnosis of the patients. Conversely, structural modalities offer valuable information about the patient's evolution within the consciousness spectrum. We validate the proposed analysis with data coming from other centres with different acquisition parameters. Importantly, we demonstrate that model performance improves with an increase in the number of modalities. We observe a higher inter-modality disagreement for minimally conscious state patients and those patients who improve. Lastly, we observe a difference in feature importances between diagnosis and prognosis, with an interaction between modality and anatomical structures: some subcortical markers tend to contribute more to prognosis, while other cortical markers are more informative for diagnosis. This integrative multimodal and machine learning methodology presents a promising avenue for a more nuanced understanding of disorders of consciousness, contributing to enhanced diagnostic precision, prognostic capabilities and the personalization of rehabilitative strategies in clinical practice.

Parkinson's disease (PD) is a common multisystem movement disorder characterized by accumulation of neurotoxic Lewy body (LB) aggregates, neuronal loss, and gliosis of vulnerable populations. The gene encoding α-synuclein (SNCA) is the greatest genetic risk factor for sporadic PD. Misfolding and overexpression of SNCA (α-Syn) underlie pathognomonic features of PD, including insoluble LB aggregates and midbrain dopaminergic (mbDA) neurodegeneration. We recently identified an SNCA intronic sequence that harbors variation associated with PD risk and demonstrated its role as a neuronal cis-regulatory element (CRE). CRISPR-mediated engineering was used to establish a mouse model lacking this intronic CRE sequence (SncaEnh+37). Single molecule fluorescent in situ hybridization (smFISH) was used to assess changes on Snca transcription in mbDA neurons. Intrastriatal injection of α-Syn preformed fibrils (PFF) was used to seed PD pathology (or PBS vehicle) in these mice. Cohorts of mice harboring two, one or zero CRE deleted alleles of SncaEnh+37 were evaluated for motor deficits in standard assays (pole descent, rotarod, grip strength). Immunohistochemistry, unbiased stereology and western blotting were employed to evaluate the impact of neuronal integrity, LB acquisition and glial activation in the substantia nigra. Mice deficient in SncaEnh+37 exhibit significantly reduced Snca transcription in mbDA neurons. In animals challenged with intrastriatal delivery of α-Syn PFF, SncaEnh+37 deficient animals are largely protected from motor deficits. Further, we demonstrate that mice lacking this Snca enhancer are protected against PD-relevant histopathology, including DA neurodegeneration, LB acquisition and evidence of neuroinflammatory response. By targeting a cell-dependent Snca CRE, we directly reduce the onset, severity and progression of PD pathology in mice. The demonstration that cell-type-dependent modulation of key genes in disease progression can be leveraged to mitigate risk introduces a potentially powerful therapeutic avenue for PD.