Gene E. Alexander - US grants

DESCRIPTION:(adapted from applicant's abstract): Alzheimer's disease (AD) is characterized by a progressive loss of cognitive functions. Studies of apolipoprotein E (APOE) genotype have suggested that the presence of the c4 allele substantially increases the risk for developing AD and is associated with reductions in cerebral metabolism even prior to the onset of clinical symptoms. We propose a new approach for detecting the very early effects of AD in individuals with increased genetic risk with the e4 allele, but without clinical symptoms using computerized tasks as cognitive "stress tests" that systematically vary attentional load and perceptual difficulty. By increasing the attentional or perceptual demands of a task in an experimentally controlled manner, we hypothesize that cohort differences in genetic risk for AD may be detected through alterations in speed of information processing and that differences in task performance may be related to brain changes that have been previously observed with neuroimaging techniques in these non-demented, healthy subjects. In this study, 25 e4 homozygotes, 25 c4 heterozygotes, and 25 s4 non-carriers who are matched in age, gender, and educational level will be included. These subjects will be healthy volunteers, ages 50 - 65, who report a family history of Alzheimer's dementia and are participants in a separate longitudinal study of the neuroimaging effects of increased risk for AD with the E4 allele. An information-processing approach will be used to test their cognitive function in two experiments: 1) with visual attention tasks that experimentally vary the number of target-relevant distractors and 2) using a face-matching task in which perceptual difficulty is incrementally increased. Analyses will test group differences in performing the tasks and will relate subject differences in task performance to patterns of brain metabolism and atrophy using neuroimaging results obtained for these subjects from the separate longitudinal study. Determining under what conditions differences in such cognitive tasks occur in persons at risk for AD may aid efforts for early detection, for understanding the mechanism of cognitive dysfunction, and for evaluating prevention therapies in AD.

DESCRIPTION (provided by applicant): The goal of the current study is to investigate how individual differences in health status and genetic risk for cognitive impairment affect the regional distribution and severity of brain changes associated with aging and age-related cognitive decline. Previous studies have shown that the frontal cortex is preferentially affected in aging and is important for cognitive abilities that often decline with age, including working memory, attention, and executive functions. Several health and genetic risk factors have been specifically associated with declines in cognition and brain abnormalities in regions of the temporal, parietal, cingulate, and frontal cortices and white matter in otherwise neurologically healthy elderly. Among these factors include differences in blood pressure, aerobic fitness, and the presence of the apolipoprotein E (APOE) s4 allele, a common susceptibility gene for Alzheimer's disease. Health and genetic risks factors may interact with the effects of aging to account for the heterogeneity of cognitive decline and atrophic brain regions commonly observed among active elderly, living in the community. We plan to study 222 community dwelling, neurologically healthy elderly with baseline tests of ambulatory blood pressure and aerobic fitness, baseline and two year follow-up structural and diffusion tensor magnetic resonance imaging (MRI) scans, APOE genotyping, and baseline and two year follow up assessments of cognitive function using a battery of standardized neuropsychological tests. We will test hypotheses using regional univariate and multivariate network analysis methods with voxel-based MRI morphometry to identify the baseline and two year longitudinal changes in gray and white matter associated with aging;to determine how age interacts with three potentially modifying factors: a) blood pressure, b) aerobic fitness, and c) APOE genotype to alter the regional distribution and severity of baseline and two year longitudinal gray and white matter changes in aging;and to evaluate how specific brain regions identified by the interactive effects of aging with health status and genetic risk for cognitive impairment are associated with baseline and two year declines in cognition. It is expected that results from this study will significantly enhance our understanding of the brain changes associated with aging and related cognitive decline, help to identify those at greatest risk for age- related cognitive dysfunction, and provide a foundation to develop and test focused strategies to delay or prevent the brain changes that lead to cognitive decline in aging.

With high prevalence in the community-dwelling elderly population, hypertension may be an important factor influencing the development and progression of cognitive aging. Although hypertension is a major health problem that has been shown to affect cognition, very little is known about its effects on the molecular status, especially the epigenetic status, of brain regions critical to cognition. However, significant literature is accumulating describing effects of selective cognitive tasks on epigenetic mechanisms in rodents. The known effect of hypertension on cognition, and the accumulating literature on the epigenetic bases of selected cognitive capacities leads to the overarching hypothesis to be tested by this project: epigenetic changes induced in a rodent model of hypertension will mirror the known relationships between cognitive tasks and epigenetic mechanisms in rodents. We focus on epigenetic mechanisms since these are major factors in the regulation of gene expression. Specifically, this project is aimed at determining epigenetic changes induced by hypertension in subregions of the brain known to be important to cognition. We will study brains from 20 normotensive controls and 20 hypertensive behaviorally characterized rats, who have also received high resolution in vivo magnetic resonance imaging (MRl) scans of brain structure and white matter integrity. Male Fischer 344 rats have the cytochrome P450 promoter (Cyp1a1) inserted to up-regulate the expression of the mouse renin (Ren2) gene, Administration of 0,15% indole-3-carbinol {I3C) to the diet of these transgenic rats activates the Cyplal promoter to induce a gradual onset of hypertension. Dependent variables will be gene expression and the major epigenetic mechanisms, DNA methylation and histone modifications, as well as measures of cognitive performance and patterns of MRl gray and white matter integrity. Defined sub-regions, of the hippocampus will be isolated by laser capture microdissection. In order to obtain sufficient starting material successive sections from the same brain will be pooled. We will assess DNA methylation on a genome wide basis by bisulfite conversion, amplification and NimbleGen arrays. PCR will be used to assess DNA methylation of specific genes based on previous findings of others and array data produced by this project. We will assess selected histone modifications by chromatin immunoprecipitation followed by PCR of selected genes. The genes we select are those previously shown to be differentially expressed in brain regions, with an emphasis on hippocampus, in association with learning and memory. We will test our major hypothesis by statistical determination of hypertension-induced epigenetic changes in our model and then compare the resulting data with epigenetic changes associated with cognitive behaviors and MRl gray and white matter integrity. We will use multivariate analyses to estimate the extent to which epigenetic variables account for cognitive status in the experimental animals.

Core Project Summary/Abstract In this competitive revision we propose to establish a new Brain Imaging and Fluid Biomarkers (BI-FB) Core to support neuroimaging and biomarker efforts in the [Arizona Alzheimer's Disease Core Center (ADCC)] and the acquisition and analysis of neuroimaging data?including amyloid-? (A?) positron emission tomography (PET) using 11C Pittsburgh compound B (PiB) [and 18F Florbetapir], tau PET using [18F Flortaucipir], and magnetic resonance imaging (MRI)?and the collection, preparation, storage and analysis of fluid biomarkers (including [cerebrospinal fluid (CSF)] A?42, t-tau and p-tau). This proposed core will provide new neuroimaging and fluid biomarker support for the Arizona ADCC and [will maximally leverage the center's existing strengths in: 1) advanced neuroimaging methods and analysis; 2) the ADCC core resources providing clinically well- characterized and tracked participants with Alzheimer's disease (AD) and mild cognitive impairment (MCI), as well as cognitively unimpaired individuals; and 3) the ancillary core resource of cognitively unimpaired Brain Body Donation Program (BBDP) enrollees who have agreed to undergo postmortem neuropathological examination. The supplemental specific aims of the application include: 1) to provide access to standardized acquisition, processing, collection, and storage of amyloid-? (A?) and tau PET, MRI scans, and CSF and blood samples across the Arizona ADCC; 2) to make available for research neuroimaging data and fluid biomarker samples from clinically well-characterized AD, MCI, and cognitively unimpaired participants who have agreed to have postmortem neuropathological evaluations; 3) to provide a resource of expertise and support for the acquisition, processing, and analysis of brain images for use in research studies to support the goals and mission of the Arizona ADCC and the NIA ADCC program nationally; and 4) to foster collaborative research by working closely with and supporting researchers in each of the other Arizona ADCC Cores, as well as users of these core resources inside and outside Arizona]. This new core will significantly extend the aims of the ADCC and capitalize on its most unique and innovative strengths. It will also provide needed expertise and support for neuroimaging and fluid biomarker studies to enhance the mission of our ADCC to detect and track preclinical AD and ultimately to support the goal of finding effective AD prevention therapies.

ABSTRACT There is a great need for effective treatments and prevention therapies that can provide symptomatic and disease modifying benefits for those at risk for Alzheimer?s disease. The proposed multi-site collaborative project brings together research teams at the University of Florida (UF) and University of Arizona (UA) to test a novel, relatively low cost, low risk, and potentially high impact therapeutic intervention in older adults who are at increased risk for Alzheimer?s disease. The intervention involves transcranial and intranasal delivery of near infrared (NIR) light via light emitting diodes, aka photobiomodulation. Prior research in cellular and animal models suggest that red and infrared light are neuroprotective and thought to improve mitochondrial function by promoting increased production of intracellular ATP. Transgenic mouse models of Alzheimer?s disease demonstrate reduced beta-amyloid and neurofibrillary tangles in response to transcranial NIR versus sham stimulation. Preliminary human studies have also shown promising behavioral findings in young adults and those with TBI, aphasia, and Alzheimer?s disease. From our team, pilot phosphorous magnetic resonance spectroscopy (31P MRS) and cognitive data in older adults support this mechanism of action and provide compelling evidence for a Phase II clinical trial. To more fully determine whether this novel stimulation approach has potential for enhancing cognition in cognitively normal but ?at risk? individuals for Alzheimer?s disease, we plan to conduct a multi-site double blinded randomized sham-controlled Phase II clinical trial. Our overall hypothesis is that exposure to NIR stimulation will have beneficial effects on brain health via influence on mitochondrial function as measured by changes in 31P MRS-based markers of ATP, neural network changes in functional connectivity (rs-fMRI), and improved cognitive performance. To test this hypothesis, we plan to randomize 168 older adults with subjective cognitive complaints, and a first-degree family history of Alzheimer?s disease to sham or real treatment groups and evaluate neuroimaging and cognitive outcome measures, before and after a 12-week intervention involving transcranial and intranasal NIR-PBM. The protocol will involve ?lab? and ?home? sessions, and a 3 month post-intervention follow-up. This trial will determine: 1) whether NIR stimulation, relative to sham, improves performance on memory and executive tasks sensitive to hippocampal and frontal brain function in older adults with increased risk for Alzheimer?s disease; 2) whether NIR stimulation, relative to sham, enhances brain function and connectivity measured by changes in MRS phosphorous ATP and resting state functional connectivity; and 3) how differences in demographic, neuroimaging, and Alzheimer-related risk factors influence the brain response to NIR stimulation versus sham in older adults with increased risk for Alzheimer?s disease. Results will provide key insights into whether this novel NIR intervention can enhance cognition in older adults with increased risk for Alzheimer?s disease and will provide the necessary data for a future Phase III randomized clinical trial.

PROJECT SUMMARY/ABSTRACT - BIOMARKER CORE The Biomarker Core (BC) will provide access across the Arizona ADRC to advance brain imaging, fluid, and wearable/digital biomarker expertise, resources, data, and specimens for application with our center and complementary affiliated cohorts to support NIA ADRC program goals. The Arizona ADRC has a major thematic focus on advancing efforts in the use of blood-based biomarkers (BBBs) in the diagnosis, preclinical study and prevention of AD. The BC will facilitate this thematic focus by supporting ADRC researchers in their efforts to: 1) further clarify the cognitive and biological changes associated with preclinical AD; 2) validate and clarify the role of new brain imaging, CSF, and blood-based biomarkers in the early detection and tracking of AD and to evaluate the potential of wearable/digital technologies as behavioral AD biomarkers; 3) inform the design, endpoints, and statistical power of prevention trials in individuals at different levels of AD risk to support our goal of finding effective AD prevention therapies; and 4) provide a valuable shared resource for Arizona ADRC researchers, the NIA ADRC program nationally, and researchers around the world studying AD and related disorders. To achieve these goals, the BC will support the standardized acquisition, processing, and analysis of amyloid PET, tau PET, and MRI; the standardized collection, preparation, storage, and analysis of blood, CSF, and DNA samples; and the acquisition, processing, and analysis of wearable/digital behavioral biomarkers in clinically well-characterized ADRC participants, many of whom have also agreed to brain donation. The BC will maintain a strong relationship with NCRAD for the processing and banking of blood and CSF samples and will fully support the NIA SCAN initiative for the sharing and archiving of ADRC BC neuroimaging scans with NACC. The BC will provide expertise and support to help ADRC researchers fully utilize the core resources and will work with each of the Arizona ADRC Cores, as well as investigators within and outside Arizona, to advance AD-related research. The BC will address the following specific aims: 1) to provide access to amyloid and tau PET, MRI scans, CSF and blood samples, and wearable/digital activity data across the Arizona ADRC; 2) to make available for research neuroimaging data, fluid specimens and biomarkers, and wearable/digital activity data from clinically well-characterized ADRC participants; 3) to support the development, evaluation, and implementation of blood-based biomarkers for early detection and tracking of AD risk and pathology; 4) to provide a resource of expertise and support for brain image processing and analysis for use in AD-related research studies; and 5) to foster collaborative research by working closely with each of the Arizona ADRC Cores, as well as users of these core resources inside and outside Arizona.