Rong Zhang, Ph.D. - US grants

ABSTRACT

OCE-0351383


The proposed research is to investigate the physical mechanisms of decadal variability in the North Atlantic ocean. Particularly, it focuses on exploring the hypothesis that Great Salinity Anomalies (GSAs) are a significant contributing factor to such variability, through their effect on the thermohaline circulation, deep western boundary current (DWBC), northern recirculation gyre (NRG) and the north-south shifts of the Gulf Stream path. Preliminary numerical experiments indicate that GSA events have as much if not more effect on decadal ocean variability than do changes in the wind forcing (e.g., variability in the North Atlantic Oscillation) and, on decadal timescales, have a much larger effect than do changes in radiative and surface heat flux changes due to increased greenhouse gases. Furthermore, the interaction between GSA events and the thermohaline circulation may lead to decadal variations of the cyclonic NRG, north-south shifts of the Gulf Stream path and thereby affect the climate of the east coast of the USA. The approach is to investigate these issues with a combination of numerical experimentation and theory, using both simplified and comprehensive numerical ocean models, coupled to slab sea-ice models and a simple model of the atmosphere. These numerical calculations will be supplemented by theoretical investigations of the nature of GSAs and how their interaction with the thermohaline circulation may lead to variations of NGR and north-south shifts of the Gulf Stream path, and hence decadal changes in the mid-latitude ocean circulation. In addition to climate variability, the proposed research addresses some physical-oceanographic problems of long-standing interest, namely the mechanism governing the Gulf Stream separation, the downstream path and the production of cyclonic NRG, and the importance (or otherwise) of the GSA events and their effect on the thermohaline circulation. In addition to an increased understanding of the fundamental nature and causes of ocean and climate variability, the research will lead to a better sense of whether and how high-latitude ocean monitoring is necessary in predicting and detecting decadal climate variability

ABSTRACT

OCE-0623345

Recent coupled climate model simulations show that changes in thermohaline circulation in the Atlantic Ocean can lead to a substantial response in the tropical Atlantic coupled climate system, which in turn can have an impact on global climate. If this proves correct, these modeling results can have tremendous implications on our understanding of the role of the ocean in global climate change. For this reason, it is critically important for us to gain a comprehensive understanding of the dynamical processes that link the changes in high latitudes to those in the tropics. The focus of this project is on the oceanic linkage. In particular, the investigators will explore how changes in the Atlantic Meridional Overturning Cell (MOC) can affect the pathways of the Sub-Tropical Cells (STCs), and how these changes in the STCs can affect the Sea Surface Temperatures (SSTs), and finally how these SST changes can affect the coupled climate variability in the tropical Atlantic. The investigation will be conducted via a hierarchy of coupled climate models in conjunction with observational analysis. An atmospheric model coupled to a 2.5-layer reduced-gravity-ocean model, perhaps the simplest and yet most efficient coupled model suited to investigate MOC/STC interaction and its effect on coupled climate variability, will be used to conduct extensive process-oriented experiments by varying the strength of the imposed MOC to shed light on the effect of the MOC on the Tropical Atlantic Variability (TAV). Then , an atmospheric circulation model coupled to a regional high resolution ocean circulation model capable of resolving mesoscale features in the tropical Atlantic circulation will be forced through its northern and southern open boundaries to allow a more complete look at the effect of the MOC/STCs on coupled feedback. Finally, the output of a comprehensive global coupled climate model used for IPCC assessment will be analyzed and used in conjunction with the other two model experiments to gain further understanding of the impact of Atlantic MOC change on global climate.

INTELLECTUAL MERIT: The anticipated outcome of this research will make an important contribution to the understanding of the fundamental ocean circulation physics in Atlantic climate variability and global climate change. A more refined theory of the connection between the different components of the Atlantic ocean circulation is expected to emerge from this study through hypothesis testing and systematic examination of the coupled model experiments. The modeling tools developed in this study will be valuable for future climate studies.

BROADER IMPACT: The proposed research addresses the issues pertinent to debates and discussions in climate change sciences. The proposed research will enhance our understanding of long-term climate variability in the tropical Atlantic sector, which has important social and economic impacts on countries in the region. The findings from this study will help educate the general public about the importance of the oceans in global climate change. The project will also help train the next generation of physical oceanographers and climate scientists by directly involving graduate students and postdoctoral researchers in research endeavors with faculty. Some of research results from this project will be integrated into the graduate courses at TAMU.

DESCRIPTION (provided by applicant): The overall objective of this proposal is to test the hypothesis that cerebrovasular function is impaired in patients with mild cognitive impairment (MCI) leading to brain hypoperfusion, brain atrophy, white matter lesions and cognitive impairment. Importantly, we will determine whether endurance exercise training improves cerebrovascular function and brain perfusion, thus ameliorating brain atrophy, white matter lesions and cognitive decline in patients with MCI. To accomplish these objectives, we will complete the following specific aims. Specific aim 1a: to determine whether baroreflex function is impaired, leading to enhanced blood pressure instability and thus hemodynamic challenges for brain perfusion in patients with MCI. Specific aim 1b: To determine whether cerebral autoregulation and cerebral vasomotor reactivity to CO2 are impaired in patients with MCI and whether cerebrovascular dysfunction is associated with atherosclerosis and arterial stiffness. Specific aim 2: To determine whether enhanced blood pressure instability in conjunction with cerebrovascular dysfunction leads to brain atrophy, white matter lesions and cognitive impairment. Specific aim 3: To determine whether exercise training improves cerebrovascular function, brain perfusion and ameliorates brain atrophy, white matter lesions and cognitive decline in patients with MCI and whether exercise training upregulates brain derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF). Cerebrovascualr function, brain perfusion, brain tissue volume and white matter lesions will be measured using magnetic resonance imaging (MRI) and transcranial Doppler (TCD). Cognitive function will be assessed using a comprehensive battery of neuropsychological tests focused on the executive and memory function. Multiple linear regression models will be used for statistical data analysis. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a devastating brain disorder imposing heavy burdens on the society with aging population. Existing therapies are at best, symptomatic and do not prevent or slow the progression of the disease. Mild cognitive impairment (MCI) is likely to be a transitional state between normal aging and AD, suitable for therapeutic interventions. The outcome of this project will provide in-depth understanding of important pathophysiological mechanisms for the control of brain perfusion in patients with MCI. Most importantly, this project will determine whether exercise training improves cerebrovascular function leading to improvement in brain structure and function in patients with MCI. The new knowledge will have significant impact on prevention or treatment of AD.

DESCRIPTION (provided by applicant): Advanced age is a major risk factor for cognitive decline. Accumulating evidence demonstrates the importance of physical activity for preserving brain health in older adults. However, at present, we know very little about the underlying mechanisms. Arterial stiffening and increases in central pulse pressure are the hallmark of arterial aging which may have significant impact on brain perfusion. The overall objective of this proposal is to test the central hypothesis that exercise training improves brain perfusion by modifying arterial aging and these changes lead to increases in regional brain volume and reductions in white matter lesions, and thus improvement in cognitive function in older adults over 65. The following specific aims will be accomplished: 1) to determine whether increases in arterial stiffness and central pulse pressure with age are associated with increases in cerebrovascular resistance/impedance, reduction in brain perfusion and cerebrovascular dysfunction;2) to determine whether exercise training improves brain perfusion by modifying arterial aging as indicated by reductions in cerebrovascular resistance/impedance, arterial stiffness, central pulse pressure and/or improvement in vascular endothelial function;3) to determine whether improvement in brain perfusion with exercise training leads to increases in regional brain volume, reductions in white matter lesions and improvement in cognitive function. To accomplish this goal, a cross-sectional study of the young, middle-aged and elderly individuals will be conducted for aim 1. Furthermore, a longitudinal study of aerobic exercise training and control (flexibility and balance training) will be conducted for one year in the elderly for aim 2 and 3. The state-of-the-art transcranial Doppler and magnetic resonance imaging will be used to measure changes in brain perfusion and structure. A comprehensive battery of neuropsychological testing sensitive to age will be used to measure changes in cognitive function. Advanced statistical methods of multiple variable regression and mediation model analysis will be used to determine the relationship between arterial aging, brain perfusion, structure and cognitive function. PUBLIC HEALTH RELEVANCE: Advanced age is a major risk factor for cognitive decline. With the growing share of older adults in the general population, the prevalence of age-related cognitive disorders, such as Alzheimer's disease (AD) and other types of dementia, is also on the rise. Thus, in-depth understanding of the mechanisms of brain aging and developing preventive interventions to maintain cognitive health is one of the biggest social and scientific challenges for the 21st century. This proposal will determine whether aerobic exercise training increases brain perfusion leading to improvement in brain structure and cognitive function in the elderly. Furthermore, we will determine whether these changes are mediated by modifying arterial aging. The new knowledge obtained will provide in-depth understanding the vascular mechanisms for exercise preserving brain health. Practically, the new findings are potentially important for developing new strategies to maintain cognitive vitality with age.

DESCRIPTION (provided by applicant): Maintaining cognitive vitality with aging and reducing the risks for Alzheimer's disease (AD) are urgent national health priorities. The goal of this revision is to strengthen the currently funded grant "Mild cognitive impairment: cerebrovascular dysfunction and exercise training" (R01 AG033106) to determine whether aerobic exercise training reduces brain amyloid burden and ameliorates chronic brain inflammation in patients with mild cognitive impairment (MCI) - a transitional stage between normal aging and AD. We will accomplish the following specific aims. Aim 1: To determine whether exercise training reduces brain amyloid burden in patients with MCI. Brain amyloid burden in patients with MCI before and after one year of aerobic exercise training will be measured with positron emission tomography (PET) amyloid imaging using 18F-AV-45 and immunoassay (ELISA) of cerebral spinal fluid (CSF) levels of A2, tau and phosphorylated tau. Aim 2: To determine whether exercise training ameliorates chronic brain inflammation in patients with MCI. Chronic brain inflammation in patients with MCI will be assessed using quantitative multiplex immunoassay methods to measure plasma and CSF levels of inflammatory biomarkers such as TNF-1, IL-12, and IL-6. Aim 3: To determine whether reductions in brain amyloid burden and/or inflammation are correlated with improvement in brain perfusion. Brain perfusion will be measured using non-invasive transcranial Doppler and perfusion MRI (via arterial spin labeling techniques). Together with the parent grant, we also will determine whether these changes in neuroimaging and inflammatory biomarkers are correlated with changes in cognitive function. Understanding the underlying mechanisms by which exercise improves brain health is essential for developing effective interventions to maintain cognitive vitality with aging and to prevent or slow Alzheimer's disease. PUBLIC HEALTH RELEVANCE: Maintaining cognitive vitality with aging and reducing the risks for Alzheimer's disease (AD) are urgent national health priorities. The goal of this study is to understand the underlying mechanisms by which exercise preserves or improves cognitive function in patients with mild cognitive impairment (MCI) - a transitional stage between normal aging and AD. The outcome of this study is potentially important for developing effective interventions to prevent or slow Alzheimer's disease.

DESCRIPTION (provided by applicant): Stress exposure stimulates the release of corticotropin releasing hormone (CRH) in the brain and activates the hypothalamus-pituitary-adrenal (HPA) axis, which is key mechanism of stress regulation. Research into the role of CRH in stress has advanced rapidly in the past 40 years since it was first characterized in 1981 (Vale et al., 1981). While the CRH-dependent HPA activation is undisputed, the role for CRH derived from sources other than the PVN remains largely unknown with inconsistent evidences. Recently, our lab has successfully generated the CRHflox mice which allow us to site-specifically delete the CRH through Cre recombinase, which provide us an elegant tool to clarify the role of CRH in different area. Our central hypothesis is that dysregulation of central amygdala (CeA) CRH is responsible for the stress-induced Depression by assessing the genetic and environmental risk factors. The hypothesis will be tested by the completion of 3 Specific Aims. Specific Aim 1 will test the hypothesis that CeA CRH system is required for the activation of HPA responsivity to psychogenic stressor but not systemic stressor. We predict that the loss of CRH from the CeA will attenuate the HPA responsivity to dirty cage exposure but not to hypoxia stress exposure. Specific Aim 2 will test the hypothesis that stress-induced insomnia is mediated through the CeACRH and noradrenergic pathway in LC is involved. We predict that deletion of the CeA CRH will attenuate the stress emotion-associated insomnia. Specific Aim 3 will test the hypothesis that CeA CRH is necessary for regulating stress-induced depression. This aim will assess the role of CeA CRH in acute stress responses (adaptation) and prolonged stress-associated vulnerability (maladaptation). The accomplishment of this study will illuminate the CRH-mediated neuronal circuitry underlying the depression, particularly for insomnia, a hallmark for affective diseases, and lead us to find a potential preventive or therapeutic approach to treat insomnia, thus, alleviate mental disorders. This Career Development Award (K01) will provide the candidate with the necessary skills to develop an independent research program focused on molecular mechanism of stress regulation. The training plan is designed to provide the candidate with skills in circadian biology and sleep regulation, psychophysiology and psychopathology, and genetic epidemiology which are critical in my chosen area of study. Specially, the candidate will acquire the knowledge and skills to 1) conduct the gene-modified research to identify the neuropathway underlying the mood and anxiety disorders 2) design, conduct and analyze stress-associated insomnia research. These skills will be developed through a combination of didactic training, guided readings and mentored research projects. Research results and training activities will be used to develop a R01 proposal for a prospective study that assesses both genetic and environmental risk factors and aims to identify the potential molecular targets for stress- related disease states.

DESCRIPTION (provided by applicant): Advanced age is a major risk factor for cognitive decline. Accumulating evidence demonstrates the importance of physical activity for preserving brain health in older adults. However, at present, we know very little about the underlying mechanisms. Arterial stiffening and increases in central pulse pressure are the hallmark of arterial aging which may have significant impact on brain perfusion. The overall objective of this proposal is to test the central hypothesis that exercise training improves brain perfusion by modifying arterial aging and these changes lead to increases in regional brain volume and reductions in white matter lesions, and thus improvement in cognitive function in older adults over 65. The following specific aims will be accomplished: 1) to determine whether increases in arterial stiffness and central pulse pressure with age are associated with increases in cerebrovascular resistance/impedance, reduction in brain perfusion and cerebrovascular dysfunction; 2) to determine whether exercise training improves brain perfusion by modifying arterial aging as indicated by reductions in cerebrovascular resistance/impedance, arterial stiffness, central pulse pressure and/or improvement in vascular endothelial function; 3) to determine whether improvement in brain perfusion with exercise training leads to increases in regional brain volume, reductions in white matter lesions and improvement in cognitive function. To accomplish this goal, a cross-sectional study of the young, middle-aged and elderly individuals will be conducted for aim 1. Furthermore, a longitudinal study of aerobic exercise training and control (flexibility and balance training) will be conducted for one year in the elderly for aim 2 and 3. The state-of-the-art transcranial Doppler and magnetic resonance imaging will be used to measure changes in brain perfusion and structure. A comprehensive battery of neuropsychological testing sensitive to age will be used to measure changes in cognitive function. Advanced statistical methods of multiple variable regression and mediation model analysis will be used to determine the relationship between arterial aging, brain perfusion, structure and cognitive function.

? DESCRIPTION (provided by applicant): We are facing one of the most significant challenges of the 21st century; how to maintain brain health and prevent dementia in our rapidly aging population. Alzheimer's disease (AD) is the most common type of dementia. Currently, there is no treatment to prevent or cure AD. Mounting evidence indicates that late-onset AD is an age-related, multi-factorial disease(s), which has a complex genetic background and the onset and progression of AD are influenced to a large extent by modifiable factors such as cardiovascular risk factors and physical inactivity. However, at present, there is no direct evidence that reducing these modifiable risk factors prevents or slows AD. The overarching goal of this proposal is to conduct a rigorously designed randomized controlled phase II trial to determine the independent and combined effects of Intensive pharmacological Reduction of Vascular Risk factors (IRVR, blood pressure and lipids) and Exercise (Ex) on neurocognitive function in older adults at high risk of AD (primary outcome). Furthermore, we will determine the effects of these interventions on the neuroimaging, blood, and CSF biomarkers of AD (secondary outcomes). We will enroll 640 cognitively normal older adults age 65 to 79 with a family history (FH) of AD who have hypertension (SBP?140 mmHg) and dyslipidemia (according to the new 2013 ACC/AHA guidelines). They will be randomized into 2-yr interventions of IRVR (SBP?130mmHg, lowering lipids with atorvastatin), Ex, IRVR+Ex, and a control arm of standard care (a 2 x 2 factorial design). Aim 1: Determine the independent and combined effects of IRVR and Ex on neurocognitive function. Hypothesis: IRVR and Ex will improve global cognitive function, while IRVR+Ex will provide a greater benefit than either IRVR or Ex alone. Neurocognitive function will be measured using well-validated tests at baseline, 6, 12, 18, and 24 months to optimize study power using linear mixed effects models for analysis. Aim 2: Determine the independent and combined effects of IRVR and Ex on brain structural and neural network plasticity. Hypothesis: IRVR and Ex prevent or slow hippocampal and whole brain atrophy and improve brain default-mode network (DMN) functional connectivity, while IRVR+Ex will provide greater benefits than either IRVR or Ex alone. Changes in brain volume, structural and DMN functional connectivity will be measured using MRI at baseline, 12 and 24 months. Aim 3: Explore the underlying mechanisms by which IRVR, Ex and IRVR+Ex impact brain structure and function. Hypotheses: 1) IRVR and Ex reduce AD pathology as indicated by the changes in cerebrospinal fluid (CSF) A?42, tau and phosphorylated tau (p-tau), and CNS inflammation; 2) increases in brain perfusion and/or brain-derived neurotrophic factor (BDNF) mediate changes in brain structure and function; 3) IRVR+Ex will have greater impacts on improving AD biomarkers than either IRVR or Ex alone. Novel transcranial Doppler ultrasonography (TCD) methods will be used to assess cerebral autoregulation.

Project Summary/Abstract Recent studies in rodents demonstrate the existence of a brain-wide glymphatic system, which transports bulk flow of cerebrospinal fluid (CSF) from the subarachnoid space into the brain parenchyma through the para- arterial and para-venous spaces. This CSF flow flushes out interstitial soluble A?, tau and other toxic proteins, ultimately influencing brain A? and tau protein homeostasis. The presence of intracranial pulsatility is recognized as the driving force for the convection of CSF through these pathways. However, whether this mechanism functions similarly in humans remains unknown. Hypertension accelerates brain aging and increases the risk of Alzheimer's disease (AD). The underlying mechanism(s) are not well understood. Our recent studies and others have demonstrated that elevated central pulsatility is associated with brain atrophy and white matter lesions. How changes in central pulsatility are transmitted downstream into cerebral microcirculation to generate intracranial pulsatility, and whether changes in intracranial pulsatility affect brain A? and tau homeostasis also remain unknown. The overarching goal of this project is to test the hypothesis that intensive antihypertensive treatment alters central and intracranial pulsatility which in turn affect brain A? and tau protein homeostasis. Furthermore, we will determine whether changes in intracranial pulsatility, A? and tau are associated with brain white matter integrity and neural network functional connectivity. To achieve this goal, we will enroll 120 older adults age 60-79. Of those, 40 have normal blood pressure (BP) (24-h BP<130/80 mmHg) and 80 have high systolic BP (24-h SBP ?140). Patients with hypertension will be randomized into a 12-month intensive treatment arm (24-h SBP?125) and a control arm of the standard care (24-h SBP?140). Aim 1: Determine the effects of hypertension on intracranial pulsatility, CSF A? and tau, brain white matter integrity, and neural network functional connectivity. Hypotheses: Hypertension is associated with: 1) augmented central pulsatility, but reduced intracranial pulsatility; 2) reductions in CSF soluble A?42, but increases in phosphorylated tau and total tau; 3) disruptions in brain white matter integrity inferred by diffusion tensor imaging, and functional connectivity by resting-state fMRI. We also will determine whether group differences in intracranial pulsatility, brain A?, and tau are associated with white matter integrity and neural network functional connectivity; Aim 2: Determine the effects of antihypertensive treatments on intracranial pulsatility, CSF A? and tau, brain white matter integrity and neural network functional connectivity. Hypotheses: compared to standard care, intensive treatment confers more benefits by: 1) reductions in central pulsatility, but increases in intracranial pulsatility; 2) increases in CSF A?42, but reductions in phosphorylated tau and total tau; 3) improvement in brain white matter integrity and neural network functional connectivity.

Model-based cerebrovascular markers extracted from hemodynamic data for non-invasive, portable and inexpensive diagnosis of MCI or mild AD and prediction of disease progression PROJECT SUMMARY The goal of the proposed multi-PI project is to establish proof of concept for the utility of a new class of cerebrovascular markers that may aid in the improved diagnosis and prediction of disease progression in Mild Cognitive Impairment (MCI) and mild Alzheimer's disease (AD). The means for obtaining these markers are non-invasive, inexpensive and portable, so that they can be used for screening in a primary-care setting. The scientific rationale for this new class of cerebrovascular markers is provided by the recent promising results of our group and the mounting evidence of a strong correlation between MCI/AD and cerebrovascular dysregulation. A recently published retrospective study on a large cohort of 1,171 subjects from the ADNI database utilized multi-factorial data-driven analysis to assess the relation between MCI/AD disease progression and commonly used biomarkers (obtained from MRI/PET and plasma/CSF) and concluded that cerebrovascular dysregulation is the earliest and strongest pathologic factor associated with AD progression, corroborating the hypothesis of cerebrovascular dysregulation. Quantification of cerebrovascular dysregulation in that large-cohort study was achieved through analysis of ASL-MRI data of cerebral perfusion. We propose instead to explore a novel integrative dynamic modeling approach that analyzes the cerebral hemodynamics of persons with no cognitive impairment and MCI/AD patients with a methodology that yields input- output predictive models of the dynamic relationships between changes in beat-to-beat cerebral blood flow velocity (via Transcranial Doppler) or cerebral tissue oxygenation (via Near Infrared Spectroscopy) in response to changes in arterial blood pressure and end-tidal CO2 data. The obtained data-based models are subsequently used to compute markers of the dynamics of cerebrovascular regulation. Initial results of the advocated approach have achieved statistically significant delineation between 46 MCI patients and 20 age-matched controls on the basis of a model-based marker of dynamic vasomotor reactivity (DVR). Evaluation of the DVR marker against established MRI-based and PET-based biomarkers, as well as neuropsychological test data, from the larger cohort of the proposed project offers the promise of portable, non-invasive, inexpensive and sensitive means for detecting cerebrovascular dysregulation at the early stages of MCI or mild AD, and monitoring disease progression. Important co-variates of this study include age, gender, education, ApoE genotype, site and amyloid burden.

PROJECT SUMMARY/ABSTRACT Each year in the United States, at least 2.8 million people sustain a traumatic brain injury (TBI) and 1.1% of the US population has lifelong disabilities as a consequence of TBI. Sustaining a moderate to severe TBI in middle age is associated with the acceleration of brain aging and increased risk of dementia. However, to date, there are no effective pharmacological agents for prevention or treatment of post-TBI cognitive deterioration. Conversely, mounting evidence suggests that aerobic exercise attenuates age-related cognitive decline linked to the preservation of brain tissue volume, white structural integrity, and cerebral perfusion. Our pilot study along with a few other small studies suggests that TBI persons may also benefit from aerobic exercise to improve cognitive function. Thus, a randomized controlled exercise clinical trial (RCT) is needed to provide evidence-based clinical decision-making regarding whether aerobic exercise training prevents or slows accelerated brain aging and cognitive decline after TBI. Therefore, the overarching goal of this proposal is to develop a study protocol to conduct a national multicenter exercise RCT assessing the efficacy of aerobic exercise training to improve cognitive function in mid-aged and older adults with moderate to severe TBI within the TBI model system (TBIMS) network (Primary outcome). We will address the following aims: Aim 1a: Identify potential barriers to exercise for middle-aged and older adults with moderate to severe TBI 1 year post-injury. We will conduct focus group and develop a survey to assess global neurocognitive function, and identify exercise barriers, as well as patterns of smartphone use among persons with moderate to severe TBI. Aim 1b: Develop a Personal Mobile Trainer ecosystem (PMT) to improve exercise compliance and reduce study burden. Using the Apple ResearchKit and CareKit, we will develop a cloud-based application ? ?PMT? to build in an individualized exercise-training protocol, collect exercise data, send reminders and video feedback, and conduct survey to improve the usability of PMT in persons with TBI. Aim 1c: Refine our individualized aerobic exercise- training program for persons with TBI in the North Texas TBIMS. We will: 1) tailor our exercise protocol to meet the individual needs of persons with TBI; 2) refine PMT based on participant?s feedback on the usability of the system. Aim 2: Establish the infrastructure to conduct a multicenter exercise RCT within the TBIMS. We will develop a RCT protocol, manual of operating procedures (MOP), establish the investigative team and define collaborative arrangements. This project will establish a solid infrastructure to conduct a phase II exercise RCT to promote regular aerobic exercise for improving brain health among middle aged and older adults with moderate to severe TBI.

Abstract Not applicable

Project Summary It is often hard to distinguish between Alzheimer?s disease (AD) and AD-related dementias (ADRD), including Vascular contributions to Cognitive Impairment and Dementia (VCID), due to a similar clinical presentation of memory loss and the presence of cardiovascular (CV) risk factors (e.g. hypertension, dyslipidemia). While CV risk factors have available drug therapies, increased physical activity also significantly lowers these co- morbidities. Unfortunately, evidence linking CV and exercise interventions to the prevention of cognitive decline is inconclusive, nor are biomarkers available to determine the efficacy of pre-dementia lifestyle interventions. This ancillary R01 will use plasma-based biomarkers and neuroimaging from subjects enrolled in our NIH- funded trial ?Risk Reduction for Alzheimer?s Disease (rrAD; NCT02913664).? This phase II randomized controlled trial will determine the independent and combined effects of Intensive pharmacological Reduction of Vascular Risk factors (IRVR; i.e. blood pressure, lipids) and aerobic exercise (Ex) on cognitive function. Participants were randomized into 2-year interventions (IRVR, Ex, IRVR+Ex, and a control arm of standard care (SC)) with plasma and neuroimaging collected at baseline and yearly. Of the 513 rrAD subjects (63% females; 34% aged 71-85; 13% African-American; 4% Hispanic/Latino), 41% of enrolled subjects have finished their 2-year follow-up. The rrAD trial is anticipated to be completed by the end of October 2021 with an overall attrition rate <15%. Banked longitudinal rrAD plasma samples will be used to test the hypothesis that 1) benchmark AD, 2) benchmark VCID, and/or 3) novel circulating brain-derived biomarkers can be modulated by positive lifestyle interventions. Aim 1 will test if the benchmark AD biomarkers A?42/A?40 ratio will increase, while pTau181 will decrease, with IRVR+Ex. Higher ratios and lower tau will be associate with our secondary outcome measure of preserved hippocampal volume measured by 3D T1-weighted MRI, as compared to SC. Aim 2 will test if primary benchmark endothelial VCID biomarkers will reveal effects of vascular and exercise interventions on cerebrovascular health. We will test if lower pathologic angiogenic proteins (i.e. VEGF-D, PlGF, bFGF) measured longitudinally decrease with intervention. Lower expression will coincide with secondary outcome measures of increased regional cerebral blood flow (i.e. arterial spin labeling, MRI) and fewer white matter hyperintensities (i.e. T2 FLAIR, MRI). Aim 3 will test if vascular and exercise interventions alter the neurotrophic cargo of circulating neuronal-enriched extracellular vesicles (EVs). We will test IRVR+Ex lowers pro- (i.e. uncleaved) brain-derived neurotrophic factor (BDNF) and increases mature BDNF in neuronal- enriched EVs. Higher BDNF will coincide with the secondary outcome measure of stronger resting-state functional MRI connectivity associated with the default mode network. We hypothesize that AD, VCID, and EV biomarkers not only identify individuals with high risk for AD/ADRDs but can also track efficacy of independent and combined lifestyle interventions that improve cerebrovascular health and delay dementia onset.