Epidemiological neuropathology of dementia - The Cognitive Function and Ageing Neuropathology Study

Lead Research Organisation: University of Sheffield
Department Name: Pathology

Abstract

Brain pathology is central to understanding dementia. For 18 years respondents in the MRC Cognitive Function and Ageing Study (CFAS), a major, prospective, longitudinal, population-based survey of mental health and frailty among older people, have donated their brains for research. The donor cohort has more than 500 completed brain examinations and provides an internationally acclaimed resource for research into the causes of dementia. In 2008 the MRC funded new clinical cohorts within CFAS (CFAS-II) to study how dementia has changed between those susceptible more than 20 years ago and today?s older people. Many changes in this period affecting lifestyles, health-care, nutrition and other factors raise the possibility that the pathology underlying dementia may evolve across generations. In an era when there is active development of innovative treatments to protect the brain and treat dementia we need as much information as possible about these changes with time. As the largest of only a handful of truly population-based studies of dementia in the world, and the only one with cross-generational cohorts, CFAS will uniquely be able to address these questions.
This study has two main objectives. One is to enrol a new cohort of potential donors from CFAS-II. The second is methodological, but of vital importance to the continuing relevance and future viability of brain pathology studies in CFAS. Until now the brains have been evaluated using a method developed 20 years ago (CERAD). There have been major scientific advances in the field of dementia across this time and the CERAD protocol does not capture a range of pathologies that are now considered to be very important. It is also very imprecise about what methods should be used to demonstrate the various pathologies. Recently colleagues in Europe have formed a consortium (BrainNet) which has resolved, through validation studies, the best way to look for and evaluate brain pathologies of relevance to dementia.
We propose to re-evaluate the CFAS-I donor brains, using the BrainNet protocols, to generate a new ?state-of-the-art? data set. We will also capture biochemical data which is important but not a part of standard pathology methods. We will investigate the hypothesis that this more comprehensive picture of brain pathology will significantly improve our ability to distinguish demented from non-demented people based on pathology. The data will also be invaluable to our wide range of collaborators currently using tissue from the CFAS brain donor resource.

Technical Summary

Dementia has come to be regarded as the product of distinct ?diseases? such as Alzheimer?s and Vascular Dementias. This paradigm derives from cohorts selected on the basis of clinical features and pathological examination at autopsy, an approach that has been validated over many years. There is no doubt that individual patients can be selected to conform to these diseases but recent work in population-based cohorts suggests that the clinical reality of dementia in the elderly is more complex. In comparison to population-based studies these selected cohort studies seriously underemphasise the prevalence of mixed pathologies and the impact of chronic vascular disease. Population-based studies are few in number (only 6 world-wide) and take many years to accumulate a cohort of brain donations with real statistical power. The MRC Cognitive Function and Ageing Study (CFAS) neuropathology study now has 525 brain donations from which we developed a new ?epidemiological neuropathology? approach to the relationship between cognition and brain pathology in older people. It is the largest, truly population-based, cohort in existence and is an essential resource in global research on dementia.
Two developments impact on this resource. Firstly there are major changes in the methodologies best suited to recognise and assign severity to brain lesions in older people. The pathology data are currently based on the CERAD protocol which is more than 17 years old. CERAD predates recognition of major pathological substrates (e.g. neuritic tau and synuclein, hippocampal sclerosis, TDP43) and does not provide a validated protocol for the assessment of important lesions like degenerative small vessel disease and amyloid angiopathy. Recent work within the EU Framework 6 BrainNet Europe consortium provides new, robust, validated approaches to the evaluation of Alzheimer-type and synuclein pathology based on modern immunocytochemical staining methods. Secondly the establishment of new CFAS cohorts in three centres (Cambridge, Newcastle upon Tyne, Nottingham) to investigate cohort effects in the epidemiology of dementia creates a unique opportunity to investigate changes the prevalence of pathological substrates arising from evolving socioeconomic factors. The proposed study will: 1) revaluate brain pathology in the CFAS1 donor cohort using validated, comprehensive measures, including biochemistry, to investigate hypotheses related to the role of pathology in cognitive decline and dementia, and for the numerous additional correlative studies ongoing in this cohort; 2) Establish a new donor cohort within CFAS2 to enable future inter-cohort comparison studies of the evolution of dementia substrates across time.

Publications

10 25 50
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Barker R (2013) Assessing white matter ischemic damage in dementia patients by measurement of myelin proteins. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

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EClipSE Collaborative Members (2010) Education, the brain and dementia: neuroprotection or compensation? in Brain : a journal of neurology

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Fahrenhold M (2018) TREM2 expression in the human brain: a marker of monocyte recruitment? in Brain pathology (Zurich, Switzerland)

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Franco Bocanegra DK (2018) Innate immunity in Alzheimer's disease: the relevance of animal models? in Journal of neural transmission (Vienna, Austria : 1996)

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Gebril OH (2011) Brain iron dysregulation and the risk of ageing white matter lesions. in Neuromolecular medicine

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Gomez-Nicola D (2015) Post-mortem analysis of neuroinflammatory changes in human Alzheimer's disease. in Alzheimer's research & therapy

 
Description ARUK Clinical Research Fellowship
Amount £213,317 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2014 
End 07/2017
 
Description ARUK PhD Scholarship
Amount £87,900 (GBP)
Funding ID ARUK PhD2016-1 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 08/2019
 
Description ARUK major grant
Amount £316,261 (GBP)
Funding ID ARUK-PG2012-8 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
End 12/2016
 
Description Developmental Pathway Funding scheme
Amount £750,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2011 
End 08/2013
 
Description Interdisciplinary research grant
Amount £237,984 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2014 
End 12/2016
 
Description Junior Fellowships
Amount £204,615 (GBP)
Organisation Alzheimer’s Society 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2015 
End 01/2018
 
Description MRC Research Grant
Amount £369,923 (GBP)
Funding ID G0900582 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 02/2011 
End 01/2014
 
Description PhD Scholarship
Amount £84,450 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 08/2019
 
Description Project Grant
Amount £413,000 (GBP)
Funding ID MR/J004308/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2012 
End 05/2015
 
Description Project grant
Amount £225,718 (GBP)
Organisation Alzheimer’s Society 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 09/2018
 
Description sensing-imaging-for-diagnosis-of-dementias
Amount £1,300,000 (GBP)
Funding ID EP/M006328/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 04/2015 
End 03/2018
 
Title Astrocyte microarray transcriptome 
Description Astrocyte transcriptome at low and high levels of Alzheimer's neuropathology. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2011 
Provided To Others? Yes  
Impact Transcriptome published on the GEO gene expression database - available to all researchers. Gene Expression Omnibus Repository accession GSE2652 
 
Title Gene expression microarray data associated with neuronal DNA damage 
Description Gene expression data deposited in the Gene Expression Omnibus, accession number GSE66333 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2016 
Provided To Others? Yes  
Impact Availability of data to bioinformatics community. 
 
Description Epidemiological neuropathology of dementia 
Organisation Harvard University
Department Harvard Medical School
Country United States 
Sector Academic/University 
PI Contribution We have been successful in obtaining funding to investigate microglial activation in the CFAS cohort. Using the CFAS cohort, we will investigate whether (i) microglial activation correlates with the presence of dementia and (ii) the role of APOE genotype on the risk of dementia. This project is funded by the MRC as a part of an MRC CFAS consortium "Epidemiological neuropathology of dementia - The Cognitive Function and Ageing Neuropathology Study" .
Collaborator Contribution This project is funded by the MRC as a part of an MRC CFAS consortium "Epidemiological neuropathology of dementia - The Cognitive Function and Ageing Neuropathology Study" (G0900582).
Impact This MRC CFAS consortium involves collaboration with Sheffield, Bristol and Cambridge. 2 papers in preparation
Start Year 2010
 
Description Epidemiological neuropathology of dementia 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution We have been successful in obtaining funding to investigate microglial activation in the CFAS cohort. Using the CFAS cohort, we will investigate whether (i) microglial activation correlates with the presence of dementia and (ii) the role of APOE genotype on the risk of dementia. This project is funded by the MRC as a part of an MRC CFAS consortium "Epidemiological neuropathology of dementia - The Cognitive Function and Ageing Neuropathology Study" .
Collaborator Contribution This project is funded by the MRC as a part of an MRC CFAS consortium "Epidemiological neuropathology of dementia - The Cognitive Function and Ageing Neuropathology Study" (G0900582).
Impact This MRC CFAS consortium involves collaboration with Sheffield, Bristol and Cambridge. 2 papers in preparation
Start Year 2010
 
Description Epidemiological neuropathology of dementia 
Organisation University of Cambridge
Department MRC Biostatistics Unit
Country United Kingdom 
Sector Public 
PI Contribution We have been successful in obtaining funding to investigate microglial activation in the CFAS cohort. Using the CFAS cohort, we will investigate whether (i) microglial activation correlates with the presence of dementia and (ii) the role of APOE genotype on the risk of dementia. This project is funded by the MRC as a part of an MRC CFAS consortium "Epidemiological neuropathology of dementia - The Cognitive Function and Ageing Neuropathology Study" .
Collaborator Contribution This project is funded by the MRC as a part of an MRC CFAS consortium "Epidemiological neuropathology of dementia - The Cognitive Function and Ageing Neuropathology Study" (G0900582).
Impact This MRC CFAS consortium involves collaboration with Sheffield, Bristol and Cambridge. 2 papers in preparation
Start Year 2010
 
Description Epidemiological neuropathology of dementia 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution We have been successful in obtaining funding to investigate microglial activation in the CFAS cohort. Using the CFAS cohort, we will investigate whether (i) microglial activation correlates with the presence of dementia and (ii) the role of APOE genotype on the risk of dementia. This project is funded by the MRC as a part of an MRC CFAS consortium "Epidemiological neuropathology of dementia - The Cognitive Function and Ageing Neuropathology Study" .
Collaborator Contribution This project is funded by the MRC as a part of an MRC CFAS consortium "Epidemiological neuropathology of dementia - The Cognitive Function and Ageing Neuropathology Study" (G0900582).
Impact This MRC CFAS consortium involves collaboration with Sheffield, Bristol and Cambridge. 2 papers in preparation
Start Year 2010
 
Description Epidemiological neuropathology of dementia 
Organisation University of Sheffield
Department Department of Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution We have been successful in obtaining funding to investigate microglial activation in the CFAS cohort. Using the CFAS cohort, we will investigate whether (i) microglial activation correlates with the presence of dementia and (ii) the role of APOE genotype on the risk of dementia. This project is funded by the MRC as a part of an MRC CFAS consortium "Epidemiological neuropathology of dementia - The Cognitive Function and Ageing Neuropathology Study" .
Collaborator Contribution This project is funded by the MRC as a part of an MRC CFAS consortium "Epidemiological neuropathology of dementia - The Cognitive Function and Ageing Neuropathology Study" (G0900582).
Impact This MRC CFAS consortium involves collaboration with Sheffield, Bristol and Cambridge. 2 papers in preparation
Start Year 2010
 
Description Prof James Nicoll 
Organisation Southampton University Hospitals NHS Trust (SUHT)
Department Department of Cellular Pathology
Country United Kingdom 
Sector Academic/University 
PI Contribution - Involved in the clinico-neuropathological follow-up of the AD patients actively immunised against Abeta42 (AN1792).
Collaborator Contribution - Bring the human neuropathology expertise, essentiel to the work - Co-applicant on other grants - Co-supervisor Mariko Taga (ART-PhD2011-22)
Impact See all publications
Start Year 2006
 
Description Prof James Nicoll 
Organisation University of Southampton
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution - Involved in the clinico-neuropathological follow-up of the AD patients actively immunised against Abeta42 (AN1792).
Collaborator Contribution - Bring the human neuropathology expertise, essentiel to the work - Co-applicant on other grants - Co-supervisor Mariko Taga (ART-PhD2011-22)
Impact See all publications
Start Year 2006
 
Description Prof Seth Love 
Organisation University of Bristol
Department Neuropathology
Country United Kingdom 
Sector Multiple 
PI Contribution - Access to the immunised AD cases
Collaborator Contribution - Access to the South West Dementia Brain Bank - Significant input into my research - Co-applicant on 3 grants.
Impact See publications
Start Year 2007
 
Description SAP in dementia - populatoin based study 
Organisation University College London
Department Centre for Amyloidosis and Acute Phase Proteins
Country United Kingdom 
Sector Academic/University 
PI Contribution We have recruited this collaborative group to provide data on brain SAP content in relation to other pathological and biochemical markers of dementia in the CFAS population representative brain donor cohort. We have provided temporal cortical tissue samples for a analysis from ~150 brains
Collaborator Contribution The partners are international experts on the analysis of SAP content in tissues. they are using this expertise to provide quantitative data on the CFAS cohort
Impact no outputs yet
Start Year 2012
 
Description aluminium 
Organisation Keele University
Department School of Life Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution provision of population representative human tissue cohort for elemental mass analysis
Collaborator Contribution elemental mass analysis
Impact peer reviewed publication in Metallomics. multidisciplinary - neuropathology, biostatistics, biometallic analysis, public health
Start Year 2010
 
Description Alzheimer's Research UK Public event 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The event included hands-on presentations by researchers who are using animal models of AD, as well as presentations by clinicians and academics within and outside the South Coast network. The interactive booths were particularly well received by the public.

Members of the public have requested to receive further information from upcoming events and the ARUK.
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013
 
Description Alzheimer's Society Network Volunteers Visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Visit by lay group. Talks given on the various projects we have underway.
Year(s) Of Engagement Activity 2016
 
Description Blog post 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Release of blog post about our Alz Soc funded diabetes grant, written by the post doc.
Year(s) Of Engagement Activity 2017
 
Description Journal promotion of one of our papers 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Promotion of our article on neuronal DNA damage response associated signalling changes.. by the publisher, Wiley to coincide with National Alzheimer's Awareness month.
Year(s) Of Engagement Activity 2016
 
Description insitute open days 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Up to 100 public attendees who were able to ask questions and then visit the laboratories to talk to the research team directly

Open day public feedback very positive. Attendees from dementia charities and support groups highly engaged locally
Year(s) Of Engagement Activity 2011,2013