Samuel N. Lockhart, Ph.D. - US grants

? DESCRIPTION (provided by applicant): Gradual, consistent cognitive declines commonly found with advancing age, even in the absence of clinical disease, are often ascribed to normal aging processes in the brain. Age-related differences in cognition have also been attributed to physiological mechanisms beyond the aging process, including degenerative diseases such as Alzheimer's disease (AD). Yet until recently the pathophysiological brain differences associated with preclinical AD have been difficult to study in vivo directly, and the effects of such preclinial biomarkers on cognition have received limited investigation in normal cognitive aging. With the advent of positron emission tomography (PET) ligands that bind biomarkers of the AD pathological cascade (e.g., tau, amyloid-beta [A?]), tools now exist to permit direct examination. We hypothesize that, among cognitively normal elderly, preclinical biomarker differences associated with AD are linked with disrupted glucose metabolism and cognition. In particular, increased age and increased fibrillar A? accumulation in diffuse neocortical regions will influence tau accumulation in and beyond MTL subregions, respectively, and tau will directly affect brain metabolism measured using FDG PET, and indirectly affect cognitive function. We will also examine, using approaches including mediation and path analysis, how tau may mediate the effect of A? on cognition, and how glucose metabolism may mediate the effect of tau accumulation on cognitive performance. Preclinical progression along the AD pathological cascade may be inadvertently conflated with normal aging processes in many studies investigating gradual cognitive decline late in life. Therefore, our goal is to investigate effectsof tau and A? accumulation on cerebral glucose metabolism, which itself is known to change in preclinical AD, and the relative effects of these brain differences on cognitive performance across multiple domains. The proposed research will contribute to a model of how preclinical AD-related differences, in otherwise normal elderly, disrupt brain function and cognitive performance. This research holds promise for impacting public health, through eventual clinical applications to age-related cognitive decline and disorders associated with A? and tau accumulation. My proposed research will provide training integral to my development as a translational cognitive neuroscientist of aging and dementia. I will gain valuable experience in PET and MRI imaging and in cognitive aging research during my training with Dr. William Jagust, and gain valuable mentorship from the collaborators whose letters are included with this application, taking advantage of the rich academic resources available through UC Berkeley and Lawrence Berkeley National Laboratory and through collaboration with UC San Francisco.

The proposed Neuroimaging Core (NIC) of the newly established Wake Forest Alzheimer?s Disease Core Center (ADCC) will provide biennial magnetic resonance imaging (MRI), amyloid positron emission tomography (11C-PiB PET) and tau PET (18F-AV-1451) to 200 ethnically diverse Clinical Core participants (100 normal older adults and 100 adults with mild cognitive impairment/MCI; 1/3 of each from underrepresented groups) using state of the art protocols optimized for sharing with the National Alzheimer?s Coordinating Center (NACC) and with other investigators. In addition, innovative specialized sequences to assess vascular integrity will be conducted, including multiphase pseudocontinuous arterial spin label (ASL) MRI, and controlled measures of hypercapnic cerebrovascular reactivity (CVR). Thus, the new NIC will enable Wake Forest to provide specialized resources to conduct high impact research examining the longitudinal interaction of AD and vascular pathologies in an ethnically diverse, deeply phenotyped cohort. To facilitate translational research, the NIC will also apply AD MRI protocols to non-human primates (NHP) who spontaneously develop age-related amyloid pathology and metabolic/vascular disease. The Core will leverage an extensive imaging infrastructure with dedicated research resources, including a 3T Siemens Skyra MRI scanner with a high-resolution 32- channel head coil, GE 16-slice PET/CT Discovery ST Scanner, GE PETtrace 10 Cyclotron Radiotracer Production System, and automated analytic pipelines. NIC members will also carry out educational and consultation activities to encourage the expansion of AD-related imaging research at Wake Forest. Led by neuroradiologist Christopher Whitlow, MD, PhD, Director of the Translational Imaging Program of the Clinical and Translational Science Institute (CTSI), and Sam Lockhart, PhD, a neuroimaging investigator with extensive published experience in MR and PET imaging related to AD, vascular pathology, and cognition, the NIC will: 1) conduct state of the art longitudinal MR, amyloid, and tau imaging in Wake Forest ADCC?s ethnically diverse Clinical Core, using protocols aligned with the national ADC network; 2) refine and implement sensitive MRI protocols for vascular integrity (ASL and CVR) that will facilitate understanding of the relationships between vascular and AD pathology and provide methodological innovations to enhance the reliability of multi-site vascular imaging; 3) develop and implement neuroimaging protocols for innovative translational NHP models; and 4) integrate quality-controlled imaging data with clinical and other biomarker data in a user-friendly relational database to facilitate dissemination and use by ADCC, NACC and other investigators.