White matter and cognitive reserve White matter atrophy was highlighted in 1989 when, in a quantitative neuropathological study of elderly brains, it was found that people without cognitive decline but with some AD pathology had atrophy of white matter but not of grey matter, whereas those with dementia and more extensive AD pathology had both grey and white matter atrophy. It was suggested that selleck chemicals llc white matter atrophy may precede whole brain atrophy in ageing brains [27]. Neuroimaging has taken this concept further. O’Sullivan and colleagues [28] described reduced diffusional anisotropy, a measure of white matter integrity, and higher mean diffusivity in elderly people with normal cognitive performance for age compared with young control subjects.

Another early diffusion tensor imaging study identified reduced white matter integrity in the splenium of the corpus callosum, superior longitudinal fasciculus, and cingulum whereas the pyramidal tracts were spared [29]. Bartzokis and colleagues [30] found, using the transverse relaxation rate, that people who were ApoE4-positive, and therefore at increased risk to develop AD (though they performed cognitively normally when examined), had a reduced cognitive processing speed, which was significantly correlated with myelin breakdown in late myelinating white matter regions. Presymptomatic carriers of familial AD mutations have altered diffusion tensor imaging signal in white matter throughout the brain and particularly in the perforant pathways, the fornix, and orbito-frontal white matter [31].

It was suggested that the changes in the fornix in particular may provide a biomarker for early disease in sporadic AD. Andrews-Hanna and colleagues [32] used functional MRI signal correlations between regions within large-scale brain systems in young and old cognitively normal subjects (mean Mini-Mental State Examination in the elderly score of 28.8) and showed marked reductions with age in normally present functional correlations within two higher order brain systems. The Anacetrapib worst affected system was the anterior to posterior components within the default network. Reduced correlations were associated with loss of white matter integrity. Abnormalities in the default mode network were also detected selleck kinase inhibitor using resting state paradigms in mild cognitively impaired subjects [33]. The level of deactivation differed in the anterior frontal, precuneus and posterior cingulate in AD when compared to controls, and the level of deactivation was intermediate in mild cognitive impairment. Both studies suggest activity in the default mode network may provide a marker for early changes and indicate continuity between normal ageing and so-called pathological ageing.