Date Published: November 10, 2009
Publisher: Public Library of Science
Author(s): Fiona E. Matthews, Carol Brayne, James Lowe, Ian McKeith, Stephen B. Wharton, Paul Ince, Sam Gandy
Abstract: Researchers from the Medical Research Council Cognitive Function and Ageing Neuropathology Study carry out an analysis of brain pathologies contributing to dementia, within a cohort of elderly individuals in the UK who agreed to brain donation.
Partial Text: Assessment of brain pathology in the consensus protocols for pathological diagnosis of dementia has been based on semiquantitative methods –. These protocols aspire to distinguish demented and nondemented individuals using thresholds of plaques, neurofibrillary tangles (NFTs), infarcts, and Lewy bodies, so that pathology becomes the “gold standard” for diagnosis. This approach has progressed understanding of clinical phenotypes, genetics, biochemistry, and molecular pathogenesis associated with cognitive decline in older people. Trials of disease modifying therapies are already in progress and proponents of a vascular basis for cognitive dysfunction propose secondary prevention strategies in older people . The scale of the clinical and social problem presented by dementia in ageing populations presents an urgent need to assess the likely impact and cost effectiveness of new, potentially expensive, therapies, and to develop robust biomarkers for diagnosis and progression. Understanding the population impact of therapies that modify the pathobiology of dementia requires an understanding of the burden of cognitive dysfunction directly attributable to a particular pathology. Recently reported trials in Alzheimer disease (AD), alleging divergent outcomes for inhibition of amyloid gamma-secretase and tau aggregation, exemplify this need ,. These are issues about which conventional case-control cohorts and studies in secondary referral populations, memory clinics, or community volunteers are less informative than the population approach used here. Selection biases are associated with non–population-based studies of older people and lead to unknown effects so that their conclusions may not generalise to the whole population.
MRC CFAS shows that it is possible to set up and sustain a brain donation programme from a geographically dispersed, population-based study, which is not biased in terms of gender, social class, education, institutionalisation, or access to health care. The resulting brain donor sample is of sufficient size to generate meaningful estimates of AR at death associated with specific pathologies and contributes significantly to understanding the pathobiology of dementia on the basis of “epidemiological neuropathology.” It also allows the separation of factors that might be amenable to modification from others that may not. The main contributors to AR at death for dementia in MRC CFAS were age (18%), small brain (12%), neocortical neuritic plaques (8%) and neurofibrillary tangles (11%), small vessel disease (12%), multiple vascular pathologies (9%), and hippocampal atrophy (10%). Other significant factors include cerebral amyloid angiopathy (7%) and Lewy bodies (3%).