Epidemiological neuropathology of dementia - The Cognitive Function and Ageing Neuropathology Study: Microglial studies in the CFAS cohort

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.