34 research outputs found
Assessing environmental features related to mental health: a reliability study of visual streetscape images.
BACKGROUND: An association between depressive symptoms and features of built environment has been reported in the literature. A remaining research challenge is the development of methods to efficiently capture pertinent environmental features in relevant study settings. Visual streetscape images have been used to replace traditional physical audits and directly observe the built environment of communities. The aim of this work is to examine the inter-method reliability of the two audit methods for assessing community environments with a specific focus on physical features related to mental health. METHODS: Forty-eight postcodes in urban and rural areas of Cambridgeshire, England were randomly selected from an alphabetical list of streets hosted on a UK property website. The assessment was conducted in July and August 2012 by both physical and visual image audits based on the items in Residential Environment Assessment Tool (REAT), an observational instrument targeting the micro-scale environmental features related to mental health in UK postcodes. The assessor used the images of Google Street View and virtually "walked through" the streets to conduct the property and street level assessments. Gwet's AC1 coefficients and Bland-Altman plots were used to compare the concordance of two audits. RESULTS: The results of conducting the REAT by visual image audits generally correspond to direct observations. More variations were found in property level items regarding physical incivilities, with broad limits of agreement which importantly lead to most of the variation in the overall REAT score. Postcodes in urban areas had lower consistency between the two methods than rural areas. CONCLUSIONS: Google Street View has the potential to assess environmental features related to mental health with fair reliability and provide a less resource intense method of assessing community environments than physical audits.There is no specific funding contributing to this study. Yu-Tzu Wu received a PhD scholarship from the Cambridge Trust, University of Cambridge. Fiona E. Matthews was supported by the Medical Research Council [grant number U105292687]This is the final version. It first appeared from BioMed Central via http://dx.doi.org/10.1186/1471-2458-14-109
Microglial immunophenotype in dementia with Alzheimer's pathology.
BACKGROUND: Genetic risk factors for Alzheimer's disease imply that inflammation plays a causal role in development of the disease. Experimental studies suggest that microglia, as the brain macrophages, have diverse functions, with their main role in health being to survey the brain parenchyma through highly motile processes. METHODS: Using the Medical Research Council Cognitive Function and Ageing Studies resources, we have immunophenotyped microglia to investigate their role in dementia with Alzheimer's pathology. Cerebral cortex obtained at post-mortem from 299 participants was analysed by immunohistochemistry for cluster of differentiation (CD)68 (phagocytosis), human leukocyte antigen (HLA)-DR (antigen-presenting function), ionized calcium-binding adaptor molecule (Iba1) (microglial motility), macrophage scavenger receptor (MSR)-A (plaque-related phagocytosis) and CD64 (immunoglobulin Fcγ receptor I). RESULTS: The presence of dementia was associated positively with CD68 (P < 0.001), MSR-A (P = 0.010) and CD64 (P = 0.007) and negatively with Iba1 (P < 0.001). Among participants without dementia, the cognitive function according to the Mini-Mental State Examination was associated positively with Iba1 (P < 0.001) and negatively with CD68 (P = 0.033), and in participants with dementia and Alzheimer's pathology, positively with all microglial markers except Iba1. Overall, in participants without dementia, the relationship with Alzheimer's pathology was negative or not significant, and positive in participants with dementia and Alzheimer's pathology. Apolipoprotein E (APOE) ε2 allele was associated with expression of Iba1 (P = 0.001) and MSR-A (P < 0.001) and APOE ε4 with CD68, HLA-DR and CD64 (P < 0.001). CONCLUSIONS: Our findings raise the possibility that in dementia with Alzheimer's pathology, microglia lose motility (Iba-1) necessary to support neurons. Conversely, other microglial proteins (CD68, MSR-A), the role of which is clearance of damaged cellular material, are positively associated with Alzheimer's pathology and impaired cognitive function. In addition, our data imply that microglia may respond differently to Aβ and tau in participants with and without dementia so that the microglial activity could potentially influence the likelihood of developing dementia, as supported by genetic studies, highlighting the complexity and diversity of microglial responses
Dementia in the older population is associated with neocortex content of serum amyloid P component.
Despite many reported associations, the direct cause of neurodegeneration responsible for cognitive loss in Alzheimer's disease and some other common dementias is not known. The normal human plasma protein, serum amyloid P component, a constituent of all human fibrillar amyloid deposits and present on most neurofibrillary tangles, is cytotoxic for cerebral neurones in vitro and in experimental animals in vivo. The neocortical content of serum amyloid P component was immunoassayed in 157 subjects aged 65 or more with known dementia status at death, in the large scale, population-representative, brain donor cohort of the Cognitive Function and Ageing Study, which avoids the biases inherent in studies of predefined clinico-pathological groups. The serum amyloid P component values were significantly higher in individuals with dementia, independent of serum albumin content measured as a control for plasma in the cortex samples. The odds ratio for dementia at death in the high serum amyloid P component tertile was 5.24 (95% confidence interval 1.79-15.29) and was independent of Braak tangle stages and Thal amyloid-β phases of neuropathological severity. The strong and specific association of higher brain content of serum amyloid P component with dementia, independent of neuropathology, is consistent with a pathogenetic role in dementia.NIH
Neuronal DNA damage response-associated dysregulation of signalling pathways and cholesterol metabolism at the earliest stages of Alzheimer-type pathology.
AIMS: Oxidative damage and an associated DNA damage response (DDR) are evident in mild cognitive impairment and early Alzheimer's disease, suggesting that neuronal dysfunction resulting from oxidative DNA damage may account for some of the cognitive impairment not fully explained by Alzheimer-type pathology. METHODS: Frontal cortex (Braak stage 0-II) was obtained from the Medical Research Council's Cognitive Function and Ageing Study cohort. Neurones were isolated from eight cases (four high and four low DDR) by laser capture microdissection and changes in the transcriptome identified by microarray analysis. RESULTS: Two thousand three hundred seventy-eight genes were significantly differentially expressed (1690 up-regulated, 688 down-regulated, P < 0.001) in cases with a high neuronal DDR. Functional grouping identified dysregulation of cholesterol biosynthesis, insulin and Wnt signalling, and up-regulation of glycogen synthase kinase 3β. Candidate genes were validated by quantitative real-time polymerase chain reaction. Cerebrospinal fluid levels of 24(S)-hydroxycholesterol associated with neuronal DDR across all Braak stages (rs = 0.30, P = 0.03). CONCLUSIONS: A persistent neuronal DDR may result in increased cholesterol biosynthesis, impaired insulin and Wnt signalling, and increased GSK3β, thereby contributing to neuronal dysfunction independent of Alzheimer-type pathology in the ageing brain
Implementation of multimodal computed tomography in a telestroke network : five-year experience
Aims: Penumbral selection is best-evidence practice for thrombectomy in the 6-24 hour window. Moreover, it helps to identify the best responders to thrombolysis. Multimodal computed tomography (mCT) at the primary centre—including noncontrast CT, CT perfusion, and CT angiography—may enhance reperfusion therapy decision-making. We developed a network with five spoke primary stroke sites and assessed safety, feasibility, and influence of mCT in rural hospitals on decision-making for thrombolysis. Methods: Consecutive patients assessed via telemedicine from April 2013 to June 2018. Clinical outcomes were measured, and decision-making compared using theoretical models for reperfusion therapy applied without mCT guidance. Symptomatic intracranial hemorrhage (sICH) was assessed according to Safe Implementation of Treatments in Stroke Thrombolysis Registry criteria. Results: A total of 334 patients were assessed, 240 received mCT, 58 were thrombolysed (24.2%). The mean age of thrombolysed patients was 70 years, median baseline National Institutes of Health Stroke Scale was 10 (IQR 7-18) and 23 (39.7%) had a large vessel occlusion. 1.7% had sICH and 3.5% parenchymal hematoma. Three months poststroke, 55% were independent, compared with 70% in the non-thrombolysed group. Conclusion: Implementation of CTP in rural centers was feasible and led to high thrombolysis rates with low rates of sICH. © 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd
The nuclear retention of transcription factor FOXO3a correlates with a DNA damage response and increased glutamine synthetase expression by astrocytes suggesting a neuroprotective role in the ageing brain.
The accumulation of reactive oxygen species leading to oxidative damage and cell death plays an important role in a number of neurodegenerative disorders. FOXO3a, the main isoform of FOXO transcription factors, mediates the cellular response to oxidative stress by regulating the expression of genes involved in DNA repair and glutamine metabolism, including glutamine synthetase (GS). Immunohistochemical investigation of the population-based neuropathology cohort of the Medical Research Council's Cognitive Function and Ageing Study (MRC CFAS) demonstrates that nuclear retention of FOXO3a significantly correlates with a DNA damage response and with GS expression by astrocytes. Furthermore, we show that GS expression correlates with increasing Alzheimer-type pathology in this ageing cohort. Our findings suggest that in response to oxidative stress, the nuclear retention of FOXO3a in astrocytes upregulates expression of GS as a neuroprotective mechanism. However, the activity of GS may be compromised by increasing levels of oxidative stress in the ageing brain resulting in dysfunctional enzyme activity, neuronal excitotoxic damage and cognitive impairment
A Reduced Astrocyte Response to β-Amyloid Plaques in the Ageing Brain Associates with Cognitive Impairment
Aims
β-amyloid (Aβ) plaques are a key feature of Alzheimer’s disease pathology but correlate poorly with dementia. They are associated with astrocytes which may modulate the effect of Aβ-deposition on the neuropil. This study characterised the astrocyte response to Aβ plaque subtypes, and investigated their association with cognitive impairment.
Methods
Aβ plaque subtypes were identified in the cingulate gyrus using dual labelling immunohistochemistry to Aβ and GFAP+ astrocytes, and quantitated in two cortical areas: the area of densest plaque burden and the deep cortex near the white matter border (layer VI). Three subtypes were defined for both diffuse and compact plaques (also known as classical or core-plaques): Aβ plaque with (1) no associated astrocytes, (2) focal astrogliosis or (3) circumferential astrogliosis.
Results
In the area of densest burden, diffuse plaques with no astrogliosis (β = -0.05, p = 0.001) and with focal astrogliosis (β = -0.27, p = 0.009) significantly associated with lower MMSE scores when controlling for sex and age at death. In the deep cortex (layer VI), both diffuse and compact plaques without astrogliosis associated with lower MMSE scores (β = -0.15, p = 0.017 and β = -0.81, p = 0.03, respectively). Diffuse plaques with no astrogliosis in layer VI related to dementia status (OR = 1.05, p = 0.025). In the area of densest burden, diffuse plaques with no astrogliosis or with focal astrogliosis associated with increasing Braak stage (β = 0.01, p<0.001 and β = 0.07, p<0.001, respectively), and ApoEε4 genotype (OR = 1.02, p = 0.001 and OR = 1.10, p = 0.016, respectively). In layer VI all plaque subtypes associated with Braak stage, and compact amyloid plaques with little and no associated astrogliosis associated with ApoEε4 genotype (OR = 1.50, p = 0.014 and OR = 0.10, p = 0.003, respectively).
Conclusions
Reactive astrocytes in close proximity to either diffuse or compact plaques may have a neuroprotective role in the ageing brain, and possession of at least one copy of the ApoEε4 allele impacts the astroglial response to Aβ plaques
Dementia prediction for people with stroke in populations: is mild cognitive impairment a useful concept?
Background: criteria for mild cognitive impairment (MCI) capture an intermediate cognitive state between normal ageing and dementia, associated with increased dementia risk. Whether criteria for MCI are applicable in the context of stroke and can be used to predict dementia in stroke cases is not known. Objectives: to determine the prevalence of MCI in individuals with stroke and identify predictors of 2-year incident dementia in stroke cases. Methods: individuals were from the Medical Research Council Cognitive Function and Ageing Study. MCI prevalence in individuals with stroke was determined. Logistic regression, with receiver operating characteristic curve analysis, was used to identify variables associated with risk of dementia in stroke cases including MCI criteria, demographic, health and lifestyle variables. Findings: of 2,640 individuals seen at the first assessment, 199 reported stroke with no dementia. In individuals with stroke, criteria for MCI are not appropriate, with less than 1% of stroke cases being classified as having MCI. However, in individuals with stroke two components of the MCI definition, subjective memory complaint and cognitive function (memory and praxis scores) predicted 2-year incident dementia (area under the curve = 0.85, 95% CI: 0.77-0.94, n = 113). Conclusion: criteria for MCI do not appear to capture risk of dementia in the context of stroke in the population. In stroke cases, subjective and objective cognitive performance predicts dementia and these variables could possibly be incorporated into dementia risk models for stroke cases. Identifying individuals with stroke at greatest risk of dementia has important implications for treatment and intervention
Predicting risk of 2-year incident dementia using the camcog total and subscale scores
Background: being able to identify individuals at high risk of dementia is important for diagnostics and intervention. Currently, there is no standard approach to assessing cognitive function in older aged individuals to best predict incident dementia. Objective: to identify cognitive changes associated with an increased risk of 2-year incident dementia using the Cambridge Cognitive Examination (CAMCOG). Design: longitudinal population representative sample aged 65+ years. Methods: individuals were from the Medical Research Council Cognitive Function and Ageing Study. Classification and Regression Tree analysis was used to detect the optimal cut-offvalue for the CAMCOG total, subscales and composite memory and non-memory scores, for predicting dementia. Sensitivity and specificity of each cut-offscore were assessed. Results: from the 2,053 individuals without dementia at the first assessment, 137 developed dementia at the 2-year follow-up. The results indicate similar discriminative accuracy for incident dementia based on the CAMCOG total, memory subscale and composite scores. However, sensitivity and specificity of cut-offvalues were generally moderate. Scores on the non-memory subscales generally had high sensitivity but low specificity. Compared with the CAMCOG total score they had significantly lower discriminative accuracy. Conclusion: in a population setting, cut-offscores from the CAMCOG memory subscales predicted dementia with reasonable accuracy. Scores on the non-memory scales have lower accuracy and are not recommend for predicting high-risk cases unless all non-memory subdomain scores are combined. The added value of cognition when assessed using the CAMCOG to other risk factors (e.g. health and genetics) should be tested within a risk prediction framework. © The Author 2013. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved
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Hippocampal sclerosis, hippocampal neuron loss patterns and Tdp-43 in the aged population
Hippocampal neuron loss is a common neuropathological feature in old age with various underlying etiologies. Hippocampal sclerosis of aging (HS-Aging) is neuropathologically characterized by severe CA1 neuronal loss and frequent presence of transactive response DNA-binding protein of 43 kDa (TDP-43) aggregations. Its etiology is unclear and currently no standardized approaches to measure HS-Aging exist. We developed a semi-quantitative protocol, which captures various hippocampal neuron loss patterns, and compared their occurrence in the context of HS-Aging, TDP-43, vascular and tau pathology in 672 brains (TDP-43 staining n = 642/672, 96%) donated for the population-based Cambridge City over-75s Cohort and the Cognitive Function and Ageing Study. HS-Aging was first evaluated independently from the protocol using the most common criteria defined in literature, and then described in detail through examination of neuron loss patterns and associated pathologies. 34 (5%) cases were identified, with a maximum of five pyramidal neurons in each of over half CA1 fields-of-view (x200 magnification), no vascular damage, no neuron loss in CA2-CA4, but consistent TDP-43 neuronal solid inclusions and neurites. We also report focal CA1 neuron loss with vascular pathology to affect predominantly CA1 bordering CA2 (Fisher's exact, P = 0.009), whereas neuron loss in the subicular end of CA1 was associated with TDP-43 inclusions (Fisher's exact, P < 0.001) and high Braak stage (Fisher's exact, P = 0.001). Hippocampal neuron loss in CA4-CA2 was not associated with TDP-43. We conclude that hippocampal neuron loss patterns are associated with different etiologies within CA1, and propose that these patterns can be used to form objective criteria for HS-Aging diagnosis. Finally, based on our results we hypothesize that neuron loss leading to HS-Aging starts from the subicular end of CA1 when it is associated with TDP-43 pathology, and that this neurodegenerative process is likely to be significantly more common than “end-stage” HS-Aging only.The Cambridge Human Research Tissue Bank is supported by the National Institute for Health Research Cambridge Biomedical Research Centre. CFAS is supported by grants (G9901400) from the UK Medical Research Council MRC CFAS was supported in part by: a Special Project grant and a Programme grant from the MRC and the Department of Health; the UK NIHR Biomedical Research Centre for Ageing and Age - related Disease Award to the Newcastle-upon-Tyne Hospitals Foundation Trust; the Cambridge Brain Bank is supported by the NIHR Cambridge Biomedical Research Centre; The Cambridgeshire and Peterborough NIHR CLAHRC; Nottingham University Hospitals NHS Trust; University of Sheffield and the Sheffield Teaching Hospitals NHS Foundation Trust; The Thomas Willis Oxford Brain Collection, supported by the Oxford Biomedical Research Centre; The Walton Centre NHS Foundation Trust, Liverpool. We would like to acknowledge the essential contribution of the liaison officers, the general practitioners, their staff, and nursing and residential home staff. Component projects within CFAS have been support by the Medical Research Council and by the Alzheimer's Research Trust (ART PG2006/6). This project was supported by an Australian NHMRC Project Grant (APP1042889) and The Addenbrooke's Charitable Trust; the later also supported SH. SRKH is supported by an Alzheimer's Research UK scholarship (ARUK-PhD2014–19). HADK is supported by an Australian NHMRC Training Fellowship (GNT568890). FEM is supported by the grant MRC.U.1052.00.013