Imaging and neuropsychological correlates of neurodegeneration and cerebrovascular disease in elderly Australians: vascular risk factors, vascular pathology and β-amyloid positron emission tomography (PET)

© 2016 Dr. Paul Andrew YatesVascular risk factors increase risk for dementia, however whether they contribute to the dementia phenotype through the pathology of Alzheimer’s disease (AD) or cerebrovascular disease (CVD) is unclear. This thesis utilizes multimodal neuroimaging with 3-Tesla Magnetic Resonance Imaging, 11C-PiB and 18F-NAV4694 Positron Emission Tomography (β-amyloid PET), and Carotid Artery Ultrasound (Intima-Media Thickness) in a cohort of older Australians to characterize associations between vascular risk, vascular pathology and AD-biomarkers, and their relative contributions to cognitive change over time. The broad aims of the thesis are to determine the associations between vascular risk factors and vascular pathology with molecular and structural neuroimaging markers of Alzheimer’s disease in a cohort of pre-symptomatic older Australians, and to identify potentially-modifiable factors associated with increased AD-pathology or cognitive loss which could represent potential targets for intervention studies in the future. This thesis comprises three areas of study. In the first (Chapter 6 and 7), Susceptibility- Weighted Magnetic Resonance Imaging (SWI) was used to assess prevalence and incidence of asymptomatic cerebral microhaemorrhage, and their relationship with Aβ- burden, other imaging biomarkers, and cognitive changes. In older cognitively-normal controls, lobar microhaemorrhage were common (19.1%) and associated with presence of Aβ (PiB+ status) and age, but not vascular risk factors. In this cohort, microbleeds were not independently associated with poorer cognition at baseline, nor incident cognitive decline, after adjustment for covariates including baseline Aβ-burden. Longitudinally, incident microbleeds were associated with Aβ burden, and markers of vascular disease (baseline microbleeds, white matter hyperintensity severity and lacunar infarction). The second area (Chapters 8 and 9) examined the relationship between vascular risk factors and vascular disease (cerebrovascular disease, microhaemorrhage and CIMT) with in vivo neuroimaging biomarkers of AD (Aβ-burden and brain atrophy), both cross-sectionally, and over six years’ follow-up. Burden of vascular risk was associated with the presence of Aβ, and vascular risk burden and genetic risk (Apolipoprotein [APOE] ε4 status) interacted significantly to influence Aβ most strongly in APOE ε4 carriers. Important independent relationships with Aβ also emerged for hypertension, hypercholesterolaemia, insulin resistance, and body mass index, some of which were also influenced by genetic risk (APOE ε4 status). An interaction between APOE ε4 and CVD was associated with greater Aβ, such that APOE ε4 carriers with CVD had greater Aβ burden. However, as this finding was negated by controlling for presence of microbleeds, the finding may be explained by presence of cerebral amyloid angiopathy in these participants. Carotid artery disease (high CIMT) was not associated with higher Aβ overall or in APOE ε4 carriers, however high CIMT was associated with greater Aβ accumulation over time in APOE ε4 non-carriers. The final area of study (Chapter 10) sought to determine the relative contributions between (MRI-defined) cerebrovascular disease and Aβ (PET imaging) biomarkers to change in cognitive performance and incident dementia in preclinical and prodromal AD. In cognitively-normal controls, presence of Aβ and CVD were each independently associated with longitudinal performance in memory, visuospatial function, attention and processing speed, however an interaction between Aβ and CVD was seen for change in executive function. Second, in a non-demented cohort of controls and MCI participants, risk of incident cognitive decline and dementia were most strongly influenced by presence of Aβ, rather than CVD, with an additive, rather than synergistic association seen between the two pathologies. These chapters describe the relationships between markers of increased vascular risk, evidence of peripheral and cerebral vascular pathology, Alzheimer’s disease biomarkers, and cognitive changes. Taken together, the findings suggest that several risk factors for vascular disease may also be associated with Alzheimer’s disease pathology, and that genetic risk (APOE ε4 status), and timing of assessment may influence observed associations. Interventions to mitigate vascular risk are likely to prove beneficial to reduce the imposte of dementia on future generations and intervention trials targeting modifiable lifestyle factors will be vital in this regard. The thesis also confirms the benefit of multimodal neuroimaging in combination with longitudinal clinical assessment in providing new insights into the natural history of dementia due to Alzheimer’s disease, particularly its presymptomatic stages