Vascular risk and Aβ interact to reduce cortical thickness in AD vulnerable brain regions

Abstract

Objective: The objective of this study was to define whether vascular risk factors interact with b-amyloid (Ab) in producing changes in brain structure that could underlie the increased risk of Alzheimer disease (AD).Methods: Sixty-six cognitively normal and mildly impaired older individuals with a wide range of vascular risk factors were included in this study. The presence of Ab was assessed using [11 C] Pittsburgh compound B-PET imaging, and cortical thickness was measured using 3-tesla MRI. Vascular risk was measured with the Framingham Coronary Risk Profile Index.Results: Individuals with high levels of vascular risk factors have thinner frontotemporal cortex independent of Ab. These frontotemporal regions are also affected in individuals with Ab deposition, but the latter show additional thinning in parietal cortices. Ab and vascular risk were found to interact in posterior (especially in parietal) brain regions, where Ab has its greatest effect. In this way, the negative effect of Ab in posterior regions is increased by the presence of vascular risk. The prevalence of b-amyloid (Ab), the hallmark of Alzheimer disease (AD), is approximately 25% among cognitively normal elderly individuals, indicating that Ab alone might not be sufficient to drive brain changes and cognitive decline, and that other factors work with Ab to promote disease onset or progression. Vascular risk factors such as hypertension, dyslipidemia, and diabetes are known risk factors for dementia in persons with clinical syndromes suggesting AD pathology. Conclusion:1 One pathway by which vascular risk increases the likelihood of dementia is by causing vascular brain injury (VBI) (e.g., white matter lesions and infarcts). 1,2In vivo studies show that increased vascular risk is related to higher Ab burden. [3][4][5][6] Other work suggests that VBI per se is not associated with elevated Ab, and that the effects of VBI and Ab on brain structure and cognition are independent. 7,8 Together, these findings suggest that vascular risk factors may have independent effects on Ab and VBI, and therefore increase AD risk through multiple pathways.Integrity of the cerebral cortex is a major determinant of cognitive function. 9 A better understanding of the interplay between vascular risk and Ab pathology in relation to cortical thickness might yield insight into the factors that drive the development of AD. In this study, we assessed how Ab and vascular risk, alone and together, affect cerebral cortex, specifically evaluating

Structural Imaging Measures of Brain Aging

“…Prominent frontal and anterior temporal atrophy shown in Fig. 3 are remarkably similar cross-sectional cortical thickness patterns seen in amyloid negative group by Villeneuve et al (2014), suggesting that processes underlying progressive atrophy in this region is likely be unrelated to Alzheimer’s disease pathology and may be related to other factors such as vascular disease or age-related degeneration.…”

“…Despite numerous studies of vascular factors on regional brain and gray matter volumes (Debette et al 2011; DeCarli et al 1999; Raz et al 2005,2007; Salerno et al 1992; Seshadri et al 2004; Swan et al 2000, 1998), only limited work has been done on the relationship between vascular risk factors and cortical thickness (Villeneuve et al 2014). This study consisted of 66 individuals with normal or mildly impaired cognitive ability, but included individuals with hypertension, hypercholesterolemia, diabetes, stroke and myocardial infarction.…”

Increased levels of plasma amyloid-beta are related to cortical thinning and cognitive decline in cognitively normal elderly subjects

“…Accumulated evidence suggests that soluble Ab oligomers precede plaque formation and constitute the principal instigators of synapse loss and neuronal injury in AD patients (Selkoe, 2008;Walsh and Selkoe, 2007;Zahs and Ashe, 2013). Furthermore, the association between higher cerebral Ab load and cortical thinning of AD regions reinforces the idea that increased Ab levels might lead to synaptic deficits and neuronal loss in asymptomatic elderly subjects (Villeneuve et al, 2014). Therefore, given that plasma enzyme-linked immunosorbent assays mainly detect soluble Ab, a straightforward prediction for the present study is that cognitively normal older adults with increased plasma Ab levels should also show worse cognitive functioning and thinner cortex than those with lower plasma Ab levels.…”

Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease

“…Sequences included T 1 -weighted magnetization prepared rapid gradient echo (MP-RAGE) for structure and fluid attenuation inversion recovery (FLAIR) to assess cerebrovascular disease [ (Villeneuve et al, 2014;Ossenkoppele et al, 2015a), see specifications in Supplementary material]. MP-RAGE sequences were processed using FreeSurfer 5.1 (Fischl et al, 2002) to define native-space reference regions and cortical regions of interest.…”