Cerebrovascular Pathologies (CVP) and Alzheimer's disease (AD) pathologies (ADP) (amyloid and tau) are the two principal processes that drive cognitive impairment in the elderly. Even though CVP features have been available for decades, there is no scheme that integrates the multiplicity of CVD features into a metric that has predictive power comparable to the AD biomarkers and correlates with cognitive functioning. The primary objective of this grant is to develop and validate an imaging based metric for quantifying CVP which we call the ?CVD scale? [CVD - Cerebrovascular Disease]. We will use a stepwise approach to develop several CVD scales based on incremental information going from simple to more complex MRI metrics - FLAIR (white matter hyperintensities (WMH), size and location of infarctions), T2* GRE (subcortical microbleeds), and DTI (Fractional anisotropy and mean diffusivity underlying WMH and surrounding WMH to measure white matter integrity). The models will be developed by weighting each of these imaging features according to their contribution to cognitive performance and the final CVD scale will be analytically selected based on its ability to predict cognition. We will use additional independent datasets to ensure the generalizability of our models and improve them if necessary. Since autopsy based scales for cerebrovascular lesions have not found to be predictive of cognition and/or difficult to evaluate antemortem, pathology outcomes will not be used for the development of the scale, but instead for confirmation. The secondary objective of the grant is to apply the CVD scale to understand a) the impact of sex, APOE4, and resilience measures (intellectual and physical activity lifestyle) on the evolution of CVP after accounting for traditional risk factors (diabetes, hypertension, dyslipidemia, atrial fibrillation, smoking), and b) investigate interactions between CVP and ADP. We will capitalize on the existing population-based and prospective Mayo Clinic Study of Aging (MCSA) cohort and acquire new imaging data (PIB PET, Tau PET, MRI) for the development of the CVD scale. The population- based nature of the MCSA sample is ideally suited for the development and generalizability of the scale because it captures the range of CVP. One of the strengths of the proposal is the planned dissemination of the CVD scale to the scientific community.
We believe that it is possible to develop a metric based on antemortem imaging features that achieves success by measuring the burden of cerebrovascular disease in a way to reflect its direct impact on cognition. This quantitation will improve our understanding of the role of cerebrovascular disease in the elderly both as a stand-alone etiology as well as its more prevalent role as a secondary ?player? to AD and other dementias. Both of these will aid in improving the quality of life of patients by establishing early prevention and treatment plans.
| La Joie, Renaud; Ayakta, Nagehan; Seeley, William W et al. (2018) Multisite study of the relationships between antemortem [11C]PIB-PET Centiloid values and postmortem measures of Alzheimer's disease neuropathology. Alzheimers Dement : |
| Botha, Hugo; Mantyh, William G; Murray, Melissa E et al. (2018) FDG-PET in tau-negative amnestic dementia resembles that of autopsy-proven hippocampal sclerosis. Brain 141:1201-1217 |
| Fatemi, Farzan; Kantarci, Kejal; Graff-Radford, Jonathan et al. (2018) Sex differences in cerebrovascular pathologies on FLAIR in cognitively unimpaired elderly. Neurology 90:e466-e473 |
| Vemuri, Prashanthi (2018) ""Exceptional brain aging"" without Alzheimer's disease: triggers, accelerators, and the net sum game. Alzheimers Res Ther 10:53 |
| Wennberg, Alexandra M V; Lesnick, Timothy G; Schwarz, Christopher G et al. (2018) Longitudinal Association Between Brain Amyloid-Beta and Gait in the Mayo Clinic Study of Aging. J Gerontol A Biol Sci Med Sci 73:1244-1250 |
| Arnold Fiebelkorn, Catherine; Vemuri, Prashanthi; Rabinstein, Alejandro A et al. (2018) Frequency of Acute and Subacute Infarcts in a Population-Based Study. Mayo Clin Proc 93:300-306 |
| Ramanan, Vijay K; Przybelski, Scott A; Graff-Radford, Jonathan et al. (2018) Statins and Brain Health: Alzheimer's Disease and Cerebrovascular Disease Biomarkers in Older Adults. J Alzheimers Dis 65:1345-1352 |
| Vassilaki, Maria; Aakre, Jeremiah A; Syrjanen, Jeremy A et al. (2018) Mediterranean Diet, Its Components, and Amyloid Imaging Biomarkers. J Alzheimers Dis 64:281-290 |
| Jack Jr, Clifford R; Wiste, Heather J; Schwarz, Christopher G et al. (2018) Longitudinal tau PET in ageing and Alzheimer's disease. Brain 141:1517-1528 |
| Vemuri, Prashanthi; Lesnick, Timothy G; Przybelski, Scott A et al. (2018) Development of a cerebrovascular magnetic resonance imaging biomarker for cognitive aging. Ann Neurol 84:705-716 |
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