R01AG076660

Impact of Intensive Treatment of Systolic Blood Pressure on Brain Perfusion, Amyloid and Tau in Older Adults (IPAT-Study) - Impact of Intensive Treatment of Systolic Blood Pressure on Brain Perfusion, Amyloid and Tau in Older Adults (IPAT-Study)

Project Summary

Recently, the NIA-AA research framework has defined AD as a biological construct of abnormal accumulation of Aβ and tau proteins in the brain. Similarly, the importance of cerebrovascular contributions to AD pathogenesis is now well recognized. Hypertension is the leading cause of cerebrovascular disease; >70% of adults aged 65 or older have hypertension.

The SPRINT trial showed that intensive treatment of hypertension reduced risk of cognitive impairment or dementia. However, the underlying mechanisms are unclear. Hypertension and the associated arterial stiffening compromise regional cerebral blood flow (CBF), reduce brain white matter integrity, and impact brain amyloid and tau clearance via the brain glymphatic system.

Our studies also showed that high blood pressure and central arterial stiffness are associated positively with brain Aβ burden measured with PET and that the amplitude of low frequency fluctuations of blood-oxygen-level-dependent signal measured with rs-fMRI (BOLD ALFF) is correlated negatively brain amyloid burden in older adults, suggesting its role in brain Aβ regulation.

The overarching goal of this project is to determine whether intensive lowering of systolic blood pressure (SBP) to a target of <120 mmHg, compared with <140 mmHg, reduces brain amyloid and tau in older adults who are at high risk of dementia. Furthermore, we will determine the impact of BP lowering on CBF, arterial stiffness, BOLD ALFF, white matter hyperintensity (WMH), brain network connectivity, and neurocognitive function, as well as the relationships of these changes with brain amyloid and tau.

We will enroll 180 older adults age 60 to 80 years who have hypertension (SBP=130 mmHg), FH of dementia, and/or subjective memory complaints. Participants will be randomized into the intensive treatment (SBP<120 mmHg) or usual care (SBP<140 mmHg) arms and followed for 2 years to accomplish the following specific aims:

1) To determine the effects of intensive SBP lowering on brain amyloid, tau, and neurocognitive function. Hypotheses: Intensive SBP lowering, when compared with usual care, reduces the progression of brain Aβ and tau deposition; changes in tau are correlated with neurocognitive function.

2) To determine the effects of intensive SBP lowering on CBF, central arterial stiffness, and BOLD ALFF. Hypotheses: Intensive SBP lowering reduces central arterial stiffness and increases regional CBF and BOLD ALFF; changes in CBF, arterial stiffness, and BOLD ALFF are correlated with brain Aβ and tau.

3) To determine the effects of intensive SBP lowering on brain WMH, white matter microstructural integrity, and neural network connectivity. Hypotheses: Intensive SBP lowering reduces the progression of brain WMH, improves white matter microstructural integrity and brain network connectivity which are correlated with changes in brain Aβ and tau.

The new knowledge obtained will provide mechanistic insights into the relationship between hypertension, cerebrovascular function, and AD pathophysiology which is potentially important for development of multidomain strategies for dementia prevention and treatment.

The University Of Texas Southwestern Medical Center

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Dallas, Texas 753907208 United States

Single Zip Code

Early Stage Clinical Trials for the Spectrum of Alzheimers Disease and Age-related Cognitive Decline (R01 Clinical Trial Optional) (PAR-18-877)

Amendment Since initial award the total obligations have increased 300% from $2,369,453 to $9,488,371.