Transcriptomic profiling reveals discrete poststroke dementia neuronal and gliovascular signatures

Poststroke dementia (PSD) is associated with pathology in frontal brain regions, in particular dorsolateral prefrontal cortex (DLPFC) neurons and white matter, remote from the infarct. We hypothesised that PSD results from progressive DLPFC neuronal damage, associated with frontal white matter gliovascular unit (GVU) alterations. We investigated the transcriptomic profile of the neurons and white matter GVU cells previously implicated in pathology. Laser-capture microdissected neurons, astrocytes and endothelial cells were obtained from the Cognitive Function After Stroke cohort of control, PSD and poststroke non-dementia (PSND) human subjects. Gene expression was assessed using microarrays and pathway analysis to compare changes in PSD with controls and PSND. Neuronal findings were validated using NanoString technology and compared with those in the bilateral common carotid artery stenosis (BCAS) mouse model. Comparing changes in PSD compared to controls with changes in PSND compared to controls identified transcriptomic changes associated specifically with dementia. DLPFC neurons showed defects in energy production (tricarboxylic acid (TCA) cycle, adenosine triphosphate (ATP) binding and mitochondria), signalling and communication (MAPK signalling, Toll-like receptor signalling, endocytosis). Similar changes were identified in neurons isolated from BCAS mice. Neuronal findings accompanied by altered astrocyte communication and endothelium immune changes in the frontal white matter, suggesting GVU dysfunction. We propose a pathogenic model in PSD whereby neuronal changes are associated with frontal white matter GVU dysfunction leading to astrocyte failure in supporting neuronal circuits resulting in delayed cognitive decline associated with PSD. Therefore, targeting these processes could potentially ameliorate the dementia seen in PSD

Axonal Preservation in Deep Subcortical White Matter Lesions in the Ageing Brain

Cerebral white matters lesions (WML) are seen in 94% of the population aged 64 and over and are associated with cognitive decline and depression. We used immunohistochemistry and stereological methods on post mortem brain samples derived from the Medical Research Council Cognitive Function and Ageing Study (MRC-CFAS) cohort to investigate the axonal density within deep subcortical lesions. There was no significant difference between the lesional and control white matter, therefore, we conclude that there is axonal preservation within these lesions that are characterized by demyelination

Stroke in Africa: Profile, progress, prospects and priorities

Funding text 1 R.O.A. is supported by the UK Royal Society/African Academy of Sciences FLAIR Grants FLR/R1/191813 and FCG/R1/ 201034, and a GCRF Networking Grant from the UK Academy of Medical Sciences. R.O.A., M.O.O., B.O. and F.S.S. are also supported by grants U54HG007479 and U01HG010273 from the US National Institutes of Health (NIH) as part of the H3Africa Consortium. M.O.O., B.O., R.O.A. and F.S.S. are further supported by NIH grant R01NS107900. R.N.K.’s research on elderly survivors of stroke has been supported by the Medical Research Council, RCUK Newcastle Centre for Brain Ageing and Vitality (MRC G0500247), Alzheimer’s Research UK, the Dunhill Medical Trust, UK, and the Newcastle National Institute for Health Research Biomedical Research Centre in Ageing and Age-Related Diseases, Newcastle upon Tyne Hospitals National Health Service Foundation Trust. Funding text 2 funds provided by the Wellcome Trust and the NIH. The NIH-funded SIREN study is exploring the genetic architecture of stroke among Indigenous Africans. More than 4,000 case–control pairs have already been recruited to the study and several publications on stroke phenom-ics and preliminary candidate gene analyses have been generated. The SIREN study has also undertaken the first-ever GWAS to unravel the genetic architecture of stroke in Indigenous Africans and the results are eagerly awaited. Stroke neurobanking resources consisting of blood fractions, extracted DNA, neuroimages and databases of clinical information are also being built in Africa and could facilitate data science-driven trans-omics research (including epigenomics, tran-scriptomics, proteomics and metabolomics) as well as the development of precision medicine products such as Afrocentric risk calculators, polygenic risk scores, biomarkers and drug targets23–25,227,307,308. The SIREN neurobiobank comprises a group of constantly monitored ultra-low-temperature (–86 °C) freezers located in Ibadan, Nigeria, constantly powered –20 °C chest freezers located in Ibadan and other recruitment sites, barcode scanners and printers, a laboratory information management system, a secure multi-terabyte server,Stroke is a leading cause of disability, dementia, and death worldwide. Approximately 70% of deaths from stroke and 87% of stroke-related disabilities occur in low-income and middle-income countries. At the turn of the century, the most common diseases in Africa were communicable diseases, whereas non-communicable diseases, including stroke, were considered rare, particularly in sub-Saharan Africa. However, evidence indicates that today, Africa could have up to 2–3-fold greater rates of stroke incidence and higher stroke prevalence than western Europe and the USA. In Africa, data published within the past decade show that stroke has an annual incidence rate of up to 316 per 100,000, a prevalence of up to 1,460 per 100,000, and a 3-year fatality rate greater than 80%. Moreover, many Africans have a stroke within the fourth to sixth decades of life, with serious implications for the individual, their family, and society. This age profile is particularly important as strokes in younger people tend to result in a greater loss of self-worth and socioeconomic productivity than in older individuals. Emerging insights from research into stroke epidemiology, genetics, prevention, care, and outcomes offer great prospects for tackling the growing burden of stroke on the continent. In this article, we review the unique profile of stroke in Africa and summarize current knowledge on stroke epidemiology, genetics, prevention, acute care, rehabilitation, outcomes, cost of care, and awareness. We also discuss knowledge gaps, emerging priorities, and future directions of stroke medicine for the more than 1 billion people who live in Africa. © 2021, Springer Nature Limited.Newcastle National Institute for Health Research Biomedical Research Centre in Ageing and Age-Related Diseases Newcastle upon Tyne Hospitals National Health Service Foundation Trust RCUK Newcastle Centre for Brain Ageing and Vitality Royal Society/African Academy of Sciences: FCG/R1/ 201034,FLR/R1/191813 National Institutes of Health (NIH): R01NS107900 Wellcome Trust (WT) Medical Research Council (MRC): G0500247 Dunhill Medical Trust (DMT) Academy of Medical Sciences: U01HG010273,U54HG007479 Alzheimer’s Research UK (ARUK

The Meta VCI Map consortium for meta-analyses on strategic lesion locations for vascular cognitive impairment using lesion-symptom mapping: design and multicenter pilot study

Introduction: The Meta VCI Map consortium performs meta-analyses on strategic lesion locations for vascular cognitive impairment using lesion-symptom mapping. Integration of data from different cohorts will increase sample sizes, to improve brain lesion coverage and support comprehensive lesion-symptom mapping studies. Methods: Cohorts with available imaging on white matter hyperintensities or infarcts and cognitive testing were invited. We performed a pilot study to test the feasibility of multicenter data processing and analysis and determine the benefits to lesion coverage. Results: Forty-seven groups have joined Meta VCI Map (stroke n = 7800 patients; memory clinic n = 4900; population-based n = 14,400). The pilot study (six ischemic stroke cohorts, n = 878) demonstrated feasibility of multicenter data integration (computed tomography/magnetic resonance imaging) and achieved marked improvement of lesion coverage. Discussion: Meta VCI Map will provide new insights into the relevance of vascular lesion location for cognitive dysfunction. After the successful pilot study, further projects are being prepared. Other investigators are welcome to join

ß-amyloid excitotoxicity in rat magnocellular nucleus basalis: Effect of cortical deafferentation on cerebral blood flow regulation and implications for Alzheimer's disease

Alzheimer's disease is the most common type of dementia with a still largely unclear etiopathology, One of the factors that may directly contribute to the development and progression of the disorder Is the abundant accumulation of beta-amyloid peptides (A beta) in senile plaques. In the present account we review coherent in vivo experimental evidence that A beta infusion into the rat magnocellular nucleus basalis (MBN) induces abrupt and persistent behavioral dysfunctions, perturbations of sensory information processing, storage, and retrieval. These substantial behavioral changes are due to the loss of cholinergic neurons in the MBN and their ascending projections to the frontoparietal cortex, Both neuroanatomical and neurochemical observations pinpoint that infusion of A beta into the rat basal forebrain significantly decreases choline-acetyltransferase and acetylcholinesterase activities and the population of-probably-M2 muscarinic acetylcholine receptors In the cerebral cortex. Neuropharmacological data indicate that A beta toxicity Is mediated by an excitotoxic cascade Involving blockade of astroglial glutamate uptake, sustained activation of N-methyl-D-aspartate receptors and an overt Intracellular Ca2+ influx, These changes are associated with increased nitric oxide synthase activity in cortical target areas that may directly lead to the generation of free radicals. Besides, as microvessels of the neocortex receive direct input from the MBN we assume that the loss of cholinergic innervation and hence that of tonic cholinergic vasoregulation ultimately leads to disturbances of vascular (endothelial) function and nutrient supply that may directly enhance neuronal vulnerability during aging and in Alzheimer's disease

Temporal lobe proteins implicated in synaptic failure exhibit differential expression and deamidation in vascular dementia

10.1016/j.neuint.2014.12.002Neurochemistry International8087-9