Lane, Christopher A. S.; (2019) The influence of life course vascular risk on brain pathologies and cognition in later life - a neuroimaging study of the British 1946 birth cohort. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Vascular risk factors, particularly in midlife, confer risk for later-life dementia. The association is reported for both vascular dementia and Alzheimer disease (AD) dementia. The pathophysiological pathways by which vascular risk influences later-life dementia risk are not, however, well understood. This thesis examines the influence of vascular risk across the life course on brain pathologies, with a focus on cerebral small vessel disease (SVD) and b-amyloid burden at age ~70 years, and how these pathologies impact on brain structure and cognition, using data from Insight 46, a neuroscience sub-study of the MRC National Survey of Health and Development (NSHD) 1946 birth cohort. Key findings include demonstration of sensitive windows in early midlife when higher BP, and changes in BP, were associated with higher white matter hyperintensity volume (WMHV) and smaller brain volumes at age ~70 years. Increasing adiposity in later midlife was associated with smaller brain volumes. Being diabetic in early late-life was associated with smaller whole brain volume, and smokers had worse microstructural integrity in normal appearing white matter (NAWM). None of the vascular risk factors investigated was associated with b-amyloid burden. WMHV and b-amyloid burden had synergistic negative influences on NAWM microstructural integrity, but were not associated with brain volumes in this dementia-free cohort. WMHV and b-amyloid burden had independent influences on cognition: higher WMHV was associated with slower processing speed whilst amyloid positive individuals had lower performance IQ. Findings show that vascular risk factors influence late-life dementia risk through cerebral SVD and brain atrophy. Associations with AD dementia are unlikely to be mediated via amyloidogenic pathways, but instead relate to cerebral SVD lowering the threshold for clinical symptoms in individuals with co-existent b-amyloid pathology. From a public health perspective, findings reinforce the importance of vascular risk management, starting at least in midlife, for reducing late-life dementia risk.

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