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.
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.
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.
