The effects of amyloid-ß and white matter hyperintensity volume on rates of neurodegeneration remained similar in cognitively normal individuals when they were assessed together as predictors in the same model.
Longitudinal data from cognitively normal members of the 1946 British Birth Cohort showed that amyloid-ß (Aß) positivity and higher white matter hyperintensity volume (WMHV), a marker of presumed cardiovascular disease (CVD), were both independently related to faster rates of whole brain atrophy, ventricular expansion, and hippocampal atrophy.1
Lead investigator Sarah Keuss, MBChB, clinical research fellow, UCL Queen Square Institute of Neurology, and colleagues concluded that "these findings have implications for the use of MRI measures as biomarkers of neurodegeneration and emphasize the importance of risk management and early intervention targeting both pathways."
A total of 346 participants who were part of Insight 46, an observational population-based study, underwent brain MRI and florbetapir-Aß PET and were included in the analysis. Changes in whole brain, ventricular, and hippocampal volume were calculated from baseline and repeat volumetric T1 MRI using the Boundary Shift Integral. Resting systolic blood pressure (SBP) and an office-based Framingham Heart Study Cardiovascular Risk Score (FHS-CVS) were documented and assessed at ages 36, 53, and 69 years.
The mean age of baseline scan was 70.5 (SD, 0.6) years among the cohort. Compared with Aß-negative patients, being Aß positive was significantly associated with a 0.92 mL/year faster whole brain atrophy, 0.40 mL/year greater ventricular expansion and 0.016 mL/year faster hippocampal atrophy. There was an interaction between Aß and sex, with an associated 1.82 mL/year greater atrophy in Aß-positive women (95% CI, 0.64-3.00) and 0.31 mL/year faster atrophy in Aß-positive men (95% CI, –0.93 to 1.56).
Higher WMHV was associated with significantly greater rates of neurodegeneration: each 10 mL in additional WMHV was related to 1.09 mL/year faster whole brain atrophy, 0.32 mL/year greater ventricular expansion, and 0.014 mL/year faster hippocampal atrophy. There was no evidence of nonlinear associations and were no interactions between WMHV and sex (all P >.01).
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When assessed together as predictors in the same model, the effects of Aß and WMHV on rates of neurodegeneration remained similar. After accounting for WMHV, in addition to age, sex, and total intracranial volume, Aß status explained an additional 1.1% of the variance in whole brain atrophy, 2.6% of the variance in ventricular expansion rate, and 2.1% of the variance in hippocampal atrophy rate. WMHV explained an additional 3.3% of the variance in whole brain atrophy and ventricular expansion rate and 3.1% of the variance in hippocampal atrophy rate when accounting for the same variables. There were no interactive effects of Aß and WMHV (all P >.01).
A further aim was to investigate the contributions of APOE ε4 and vascular risk measured at different stages of adulthood to progression of neurodegeneration in later life. At the end of the analysis, APOE ε4 carriers demonstrated significantly greater rates of hippocampal activity (0.011 mL/year faster than noncarriers) as well as consistent but nonsignificant relationships with rates of whole brain atrophy (0.67 mL/year higher than noncarriers) and ventricular expansion (0.13 mL/year faster than noncarriers).
"The results of this study also have broader relevance to our understanding of the processes leading to dementia," Keuss et al wrote. "While this was a cognitively normal population, it is reasonable to infer that increased rates of neurodegeneration will have subsequent consequences for cognition, given that the two are known to be correlated. As such, our findings are in keeping with the idea that Aß and CVD predominantly influence risk of cognitive decline through distinct pathways, and that CVD does not contribute to the development of AD pathology per se, but may act by lowering the threshold for onset of dementia."
When evaluating the effects of exposure to vascular risk, there were no significant relationships of FHS-CVS or SBP with rates of neurodegeneration when assessed across the whole sample, and no evidence of nonlinear associations. Notably, higher FHS-CVS and SBP at age 53 years were initially found to be associated with faster rates of hippocampal atrophy in later life, but effects were too small and no longer significant after exclusion of an influential data-point.
Despite no interactions between SBP and Aß status at age 69 years, investigators did observe that higher FHS-CVS was related to significantly greater rates of whole brain atrophy (0.20 mL/year faster per 5% increment in FHS-CVS; 95% CI, 0.01-0.40) and hippocampal atrophy (0.004 mL/year faster per 5% increment in FHS-CVS; 95% CI, 0.001-0.006).