Functional disability may be defined as 'the loss of ability to carry out daily tasks unaided'. It has been estimated that 11% of men and 19% of women over the age of 65 years living in the UK are functionally disabled. The effects of disease and ageing on an individual's functional ability, and in particular their performance of activities of daily living, is one of the most common problems that has an impact on the health and quality of life in older people. A priori assumptions about the cause of functional disability in the absence of an established diagnosed disease could suggest the contribution of a subclinical burden of morbidities associated with physical dysfunction (e.g. arthritis, cardiorespiratory disease, cerebrovascular disease). However, neurodegeneration associated with ageing, most especially Parkinson's disease (PD), is a cause of impaired physical function. The brain regions involved in PD are also vulnerable to other degenerative processes and can show neuronal loss in the absence of neuronal lesions. We have therefore analysed data from a large prospective, population-based cohort to investigate potential relationships between functional disability and cerebral degenerative disease in key subcortical regions (medulla, pons, midbrain and basal forebrain).
The worldwide increase in longevity, and the concomitant rise in functional disability, demands an understanding of how brain function in ageing, and the neuropathological substrates that underlie age-related decline, impact on physical function. A number of neuropathological alterations have been observed in the brains of older people compared to those dying at younger ages. The occurrence of lesions characteristic of Alzheimer' s disease, neurofibrillary tangles (NFT) and amyloid plaques, is an underappreciated feature of the brain in cognitively intact elderly individuals. Several studies have shown that a substantial burden of Alzheimer-type pathology is found in aged individuals with normal cognitive function [4–9]. Pathological changes associated with Parkinson's disease, most notably the formation of Lewy bodies in the midbrain substantia nigra (SN), have also been reported in cognitively normal aged individuals. In Parkinson's disease, these lesions are associated with impaired gait initiation, limb rigidity and postural instability. Like Alzheimer's pathology, the prevalence of Lewy bodies has been shown to increase with age. In addition to NFT and plaques, neuronal loss is a characteristic feature of Alzheimer's disease and other neurodegenerative disorders. Neuronal loss may be associated with normal ageing, though research using different procedures for counting neurons suggests this may have been overestimated. Vascular disease is a known cause of dementia, but also causes physical disability, e.g. through stroke. Recently there is also increasing interest in the role of small vessel disease as a substrate for functional decline.
Clinicopathological studies are usually based on comparisons of clinically defined case series, such as Alzheimer's disease  or stroke, and often include a relatively healthy, control brain comparison group using criteria that include restricted neuropathological burden. Few have explored the relationship between neuropathology and gait, movement disorder or functional disability in an unbiased sample of the ageing population among whom a sub-clinical threshold of such symptoms is common. Associations between functional disability and pathologies typical of Alzheimer's disease (plaques and NFT), Lewy bodies and neuronal loss in subcortical areas have been reported in small, mainly retrospective studies based on highly selected individuals[17, 18]. It is important to see whether such findings extend to population-based cohorts, so that their relevance to the marked increase of functional disability in older age can be estimated. There has been some indication from imaging studies that vascular changes in subcortical regions are associated with a decline in physical ability [20, 21].
In this paper we compare functional disability and subcortical neuropathology in brain donations to the Medical Research Council Cognitive Functioning and Ageing Study (MRC-CFAS), a prospective, longitudinal, population-based study of dementia and physical frailty that includes a brain donation programme. We test whether loss of functional disability is associated with Alzheimer-type pathology, Lewy bodies, vascular disease, and neuronal loss across subcortical areas.