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Principal Investigator  
Principal Investigator's Name: Daniel Nation
Institution: University of Southern California
Department: Psychology
Country:
Proposed Analysis: This proposal entails the investigation of a cerebrovascular biomarker, the cerebrovascular resistance index (CVRi), which may be related to vascular aging and has recently been described in patients with Alzheimer’s dementia (Nation et al., 2013). The index is calculated by dividing an individual’s pulse pressure (systolic – diastolic pressure) by the regional cerebral blood flow (rCBF) within the area of interest (CVRi = Pulse Pressure/rCBF). Pulse pressure elevation is a marker of vascular aging that has been shown to predict cognitive decline in older adults (Waldstein et al., 2008; Nation et al., 2010). It has also been associated with subclinical cerebrovascular disease in autopsy-confirmed Alzheimer’s disease (AD) patients (Nation et al., 2012). As the ratio of pulse pressure to rCBF, CVRi may provide a regional index of cerebrovascular aging. In patients with probable Alzheimer’s disease, CVRi elevation is found particularly within subcortical regions (thalamus and caudate), but also in cortical areas (medial temporal lobe, precuneus), relative to normally aging controls, and subcortical CVRi elevation correlates with increased white matter lesion volume and reduced dementia rating scale performance (Nation et al., 2013). We hypothesize that CVRi may be a marker of cerebrovascular aging that could play a role in the common cerebrovascular comorbidities observed in AD patients. More recent evidence suggests a role for pulse pressure elevation in the earliest AD biomarker changes, including amyloid beta deposition (Rodrigue et al., 2013; Langbaum et al., 2012) and tau phosphorylation (Nation et al., in revisions), even in cognitive normal older adults (Nation et al, in revisions). These findings raise the possibility that vascular aging may play a more direct role in the pathophysiology of AD, potentially starting with the earliest known phase of the disease. It remains to be seen whether CVRi will yield similar relationships with AD biomarkers, and whether there will be spatial correspondence between markers of cerebrovascular aging (e.g., subcortical CVRi) and AD (e.g., striatal amyloid retention). The current proposal will focus on leveraging neuroimaging (arterial spin labeling MRI) and blood pressure data from ADNI-GO and ADNI-2 to investigate the relationships among regional CVRi (pulse pressure / arterial spin labeling derived rCBF) and other AD biomarkers, including CSF- (amyloid and tau protein) and neuroimaging-based (amyloid retention) biomarkers, as well as apoE genotype, vascular factors (white matter lesions and vascular risk factors), cortical thinning, and cognitive function. It is expected that CVRi will exhibit regional associations with both markers of cerebrovascular disease (e.g., white matter lesions) and AD (e.g., amyloid retention, tau phosphorylation). The potential modification of these relationships by other factors, such as age, apoE genotype, vascular risk factors, and cortical thinning, as well as the associated cognitive differences will also be important aspects of this investigation. Improving our understanding of the relationship between cerebrovascular function and AD progression across the aging-AD continuum (i.e., normal aging, mild cognitive impairment, Alzheimer’s dementia) is an important goal of research into the clinical and pathophysiological aspects of AD. Furthermore, the need for an in vivo biomarker for the cerebrovascular contribution to cognitive decline and Alzheimer’s dementia argues for active investigation of novel indices of cerebrovascular function such as CVRi. Keywords: Blood pressure; cerebral blood flow References Langbaum , J.B., Chen, K., Launer, L.J., Fleisher, A.S., Lee, W., Liu, X., Protas, H.D., Reeder, S.A., Bandy, D., Yu, M., Caselli, R.J., Reiman, E.M. (2012). Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons. Neurobiology of Aging. 2012 33(4):827.e11-9. Nation, D.A., Delano-Wood, L., Bangen, K., Jak, A.J., Wierenga, C.E., Delis, D.C., Salmon, D., Bondi, M.W. (2012). Ante-mortem pulse pressure elevation predicts cerebrovascular disease in Alzheimer’s disease. Journal of Alzheimer’s Disease. 30(3):595-603. Nation, D.A., Clark, L., Wierenga, C.E., Delano-Wood, L., Bangen, K.J., Jak, A.J., Delis, D.C., Salmon, D.P., Liu, T.T., Bondi, M.W. (2013). Cortical and subcortical cerebrovascular resistance index in Alzheimer’s disease and MCI. Journal of Alzheimer’s Disease. 36(4):689-98. Nation, D.A., Jak, A.J., Wierenga, C.E., Delano-Wood, L., Delis, D.C., Salmon, D., Bondi, M.W. (2010). Elevated pulse pressure is associated with age-related decline in language functioning. Journal of the International Neuropsychological Society. 16(5):933-8. Rodrigue, K.M., Rieck, J.R., Kennedy, K.M., Devous MD Sr, Diaz-Arrastia R, Park DC. (2013). Risk factors for β-amyloid deposition in healthy aging: vascular and genetic effects. JAMA Neurology. 70(5):600-6. Waldstein SR, Rice SC, Thayer JF, Najjar SS, Scuteri A, Zonderman AB. (2008). Pulse pressure and pulse wave velocity are related to cognitive decline in the Baltimore Longitudinal Study of Aging. Hypertension. 51(1):99-104.
Additional Investigators  
Investigator's Name: Jean Ho
Proposed Analysis: We are evaluating the impact of specific antihypertensive medication classes on AD biomarkers.
Investigator's Name: Belinda Yew
Proposed Analysis: We are investigating the interactive effects of cerebral blood flow and cerebral amyloidosis in relation to cognitive decline and progression to dementia.
Investigator's Name: Anna Blanken
Proposed Analysis: We plan analysis of cluster-derived endophenotypes of Alzheimer's dementia and dementia risk. We predict that these patient subgroups will show distinct biomarker, brain atrophy and cognitive signatures that will have diagnostic and prognostic value for clinicians.
Investigator's Name: Shubir Dutt
Proposed Analysis: Study of brain stem atrophy patterns in preclinical and clinical AD.
Investigator's Name: Elissa McIntosh
Proposed Analysis: We plan analysis of diabetes status and use of diabetic medication in relation to cognitive decline and AD biomarker status.
Investigator's Name: Isabel Sible
Proposed Analysis: We plan to study the role of blood pressure variability in brain health and cognition across the AD spectrum