Angela Jefferson - US grants

DESCRIPTION (provided by applicant): As the population continues to age, the incidence of dementia is dramatically increasing, resulting in an urgent need to identify risk factors for abnormal brain aging and dementia. Alterations in cardiac function influence systemic blood flow, which impacts cerebral blood flow homeostasis as demonstrated by animal models. Such changes in cerebral blood flow homeostasis may pose a risk for accelerating age-related brain injury. Our preliminary research suggests that cardiac function is related to markers of maladaptive brain aging. It is not yet clear if cardiac function accelerates neuroimaging or cognitive markers of cerebrovascular or Alzheimer's disease among aging individuals with mild cognitive impairment (MCI). Individuals with MCI are at increased risk for cognitive progression and susceptible to more rapid abnormal brain aging when concomitant vascular disease is present. Our proposed study will examine relations between cardiac function and maladaptive brain aging and provide important information for developing novel strategies to delay the progression from MCI to dementia. Using a prospective observational matched design, we will cross-sectionally and longitudinally relate cardiac function to neuroimaging and cognitive markers of early Alzheimer's disease and cerebrovascular changes among aging adults with MCI and age-, sex-, and race-matched cognitively normal adults. Clinical or subclinical cardiac dysfunction may be due to complex systemic mechanisms that are preventable or treatable, such as enhanced inflammatory markers and insulin resistance, or genetic factors, such as apolipoprotein E. Therefore, we will consider systemic and genetic factors as potential mediating mechanisms in relations between cardiac function and brain aging. The proposed study leverages an existing Alzheimer's Association funded study directed by the principal investigator, the participant registry of our NIA-funded Boston University Alzheimer's Disease Center, a recent American Recovery & Reinvestment Act supplement grant focused on African American recruitment and retention, and the unique resources afforded by our local Clinical and Translational Science Institute housing the General Clinical Research Unit.

DESCRIPTION (provided by applicant): As the population ages, cognitive decline and Alzheimer's disease (AD) are becoming increasingly important public health issues. Mild cognitive impairment (MCI) is considered a precursor to AD, and early identification of MCI and effective management of risk factors associated with conversion from MCI to dementia is an important step in managing the public health crisis of AD. Unfortunately, MCI is an unstable diagnostic construct, and key predictors of conversion and reversion are poorly understood. Multiple vascular factors and prevalent cardiovascular disease are known risks for the development of AD, so a plausible predictor of diagnostic fluctuations in MCI is the presence of concomitant micro vascular disease in the brain. This proposal will leverage the existing and robust dataset from the Alzheimer's Disease Neuroimaging Initiative to examine neuroimaging markers of micro vascular and microstructural tissue changes in the white matter with cognitive trajectory among cognitively normal older adults and individuals with MCI. We will (1) assess how stable versus progressive cerebral micro vascular disease and micro structural changes in white matter affect maladaptive cognitive aging over time and (2) assess the mediating effect of baseline systemic vascular disease (using a vascular health index) in the longitudinal relation between micro vascular and micro structural white matter changes and diagnostic conversion and cognitive trajectory. Insights regarding complex relations between systemic vascular disease and micro vascular or microstructural changes in the brain have important public health implications because they will contribute to early identification of a vulnerable population at high risk for cognitive progression. Furthermore, because vascular risk factors can be modified over the life course to reduce the burden of cerebrovascular disease in older adults, this vulnerable population would benefit most from novel strategies to delay or prevent progression, which is particularly valuable in light of the aging of the population and increasing prevalence of AD.

DESCRIPTION (provided by applicant): This proposal is a Midcareer Investigator Award in Patient-Oriented Research (K24) application for Angela Jefferson, PhD. Dr. Jefferson is a clinician-scientist whose interdisciplinary research program focuses on identification of early markers for mild cognitive impairment as well as hemodynamic factors contributing to the pathogenesis and clinical manifestation of Alzheimer's disease (AD). Dr. Jefferson is an Associate Professor of Neurology at Vanderbilt University Medical Center and the founding Director of the Vanderbilt Memory & Alzheimer's Center. In the 8 years since completing her training, Dr. Jefferson has demonstrated her commitment to professional education and mentorship and has established herself as a productive patient- oriented researcher in cognitive aging with strong NIH funding and a high-impact publication record. The proposed award will be instrumental in providing her protected time to expand her capabilities in cognitive aging patient-oriented research. In particular, she will gain new expertise and a practical skill set in the application of innovative biomarkers to better understand risk factors for accelerating the pathogenesis and clinical manifestation of AD. Furthermore, it will allow her to use her strong research program as a platform to mentor early career investigators, including graduate students, medical students, post-doctoral fellows, and junior faculty in patient-oriented research in cognitive aging. The proposal integrates the PI's interdisciplinary research team (including neuropsychology, cardiology, endocrinology, geriatrics, engineering, physics, neuroradiology, and biostatistics) with resources associated with the Vanderbilt Memory & Alzheimer's Center, the Vanderbilt University Institute of Imaging Science, and the Vanderbilt Institute for Clinical & Translational Research to offer a rich training environment for mentees. The training and research facilitated by this K24 mechanism will not only advance knowledge regarding early identification markers and vascular risk factors for AD, but it will also develop a cadre of next-generation cognitive aging researchers well-positioned to make meaningful contributions to the field.

As the population continues to age, cognitive decline and dementia are becoming increasingly important public health issues. While Alzheimer's disease is the most common cause of dementia, it is becoming increasingly evident that cerebrovascular mechanisms underlie cognitive impairment with mixed pathology accounting for at least half of all dementia cases. A majority of clinical research linking cerebrovascular mechanisms to cognitive impairment has focused on neuroimaging evidence of small vessel disease, such as white matter hyperintensities (WMHs) and silent lacunar infarcts. Less attention has been given to serum or cerebrospinal fluid (CSF) biomarkers that may be precursors to overt cerebrovascular disease evidence on neuroimaging. We propose to leverage an existing local cohort, the Vanderbilt Memory & Aging Project, to examine noninvasive serum and CSF biomarkers in relation to cognitive functioning and neuroimaging markers of small vessel disease, white matter integrity, and microcirculation in older adults. Since the Vanderbilt Memory & Aging Project cohort's inception in 2012, we have completed serial visits (baseline, 18-months, 36-months) with key covariate ascertainment, neuropsychological assessment, multimodal 3T brain MRI, and fasting blood and CSF acquisition, including maintaining a biosample repository on older adults free of clinical stroke and dementia at enrollment. Thus, we are very well positioned to examine proteomic serum and CSF biomarkers in relation to cross-sectional and longitudinal neuroimaging and cognitive outcomes. Results from this collaborative effort will provide a dynamic understanding of axonal injury, amyloid deposition, tau aggregation, and neurodegeneration associations with small vessel disease, white matter integrity, and microcirculatory health. Results will yield important applications for investigations examining the natural history, analytic epidemiology, prevention, clinical diagnosis, prognosis, and disease management of age-related and pathological changes in small vessel, white matter, and microcirculatory health.

As the population continues to age, cognitive decline and dementia are becoming increasingly important public health issues. While Alzheimer's disease is the most common cause of dementia, cerebrovascular pathology contributes to at least one third of all pathologically-confirmed cases of dementia and mixed pathology accounts for at least half of all clinical dementia cases. Cerebrovascular injury is in part driven by vascular risk factors, which also contribute to cardiovascular injury and disease. Alterations in cardiovascular function may pose a risk for accelerating age-related brain injury, independent of shared vascular risk factors. Our preliminary research suggests that subclinical cardiac dysfunction is related to maladaptive brain aging, such as cognitive impairment and incident dementia, including Alzheimer's disease. Despite extensive evidence that cardiovascular changes correspond to worse cognitive outcomes, the exact mechanism of injury linking subclinical cardiovascular changes to brain changes remains unclear. One plausible mechanism is subclinical small vessel disease. We propose to leverage legacy data from an existing cohort, the Vanderbilt Memory & Aging project, to evaluate systemic blood flow, cardiac contractility, and arterial stiffening in relation to cognitive progression and neuroimaging markers of small vessel disease. Since the Vanderbilt Memory & Aging Project cohort's inception in 2012, we have completed serial (baseline, 18-month follow-up, 36-month follow-up) visits with key covariate ascertainment, neuropsychological assessment, multi-modal brain MRI, cardiac MRI, and fasting blood acquisition on older adults free of clinical stroke and dementia at enrollment. For this award, we will post-process and code new variables from raw data unrelated to previous grant aims to test our hypotheses. Results from this interdisciplinary effort will yield important insights into mechanisms underlying the association between cardiovascular function and brain changes in older adults. Such insights will provide rich information regarding subclinical factors predisposing to cognitive impairment, Alzheimer's disease, and dementia, which will contribute to future novel strategies to delay or prevent cognitive impairment and progression.

The proposed T32 program will provide interdisciplinary, translational research training for pre-doctoral students and post-doctoral fellows in Alzheimer's disease (AD) and related neurodegenerative disorders. Leveraging the rich institutional resources of Vanderbilt University and interdisciplinary research strengths of the training faculty, the program will position the next generation of basic, translational, and clinical scientists to advance toward independence while making major contributions to the understanding of AD and its intersection with neurodegeneration and cerebrovascular disease. Through individualized mentorship, integrated curriculum, and involvement in cutting-edge research, the program will emphasize basic science and clinical fundamentals of AD and dementia focusing on (a) cellular stress responses and mechanisms of neuroprotection, (b) hemodynamic and neurovascular mechanisms of injury, (c) cellular regulation and membrane protein function, (d) mechanisms of memory function and dysfunction, (e) discovery and evaluation of therapeutic targets, and (f) clinical manifestations of disease. Trainees will develop essential research skills and professional skills for building a successful career along with a deep appreciation for the responsible conduct of research. Participation in a high quality interdisciplinary research experience will synthesize the trainee's knowledge base, research and professional skill set, and appreciation of research ethics. Each trainee's individualized training plan will be augmented by additional institutional or programmatic didactics and resources to foster academic excellence and scientific innovation during these early, formative periods of professional development.

Project Summary Of people admitted emergently to the Intensive Care Unit (ICU) in respiratory failure or shock, 50% to 70% develop delirium (by far the highest in any healthcare setting). The duration of this delirium independently predicts earlier death, longer hospital stay, and higher healthcare expenses annually. Delirium in ICU patients has been shown to be the strongest potentially modifiable risk factor for development of a long-term cognitive impairment, which resembles moderate to severe Alzheimer?s Disease and Related Dementias (ADRDs). Thus, medical and surgical ICU patients on ventilators or in shock are a prime population in whom to study the relationship between delirium and dementia. Our NIA-funded, NEJM published, and PAR-18-029 cited BRAIN- ICU-1 study [Bringing to light the Risk factors And Incidence of Neuropsychological dysfunction in ICU Survivors, 1st Study] showed over that one-third of ICU survivors (without preexisting dementia) emerged with new cognitive impairments or ADRD at 1 year. Some BRAIN-ICU-1 patients had cognitive resilience against ADRD, but others developed a persistent or progressive dementia-like illness. We are eager to develop interventions against this ICU-related dementia, but without knowing more about this form of brain injury, we are very limited. Now, we have pilot neuroimaging (MRI) data show that acute ICU delirium is associated with atrophy of the whole brain, frontal lobe, and hippocampus, but this problem requires an in-depth investigation. We know abnormal brain proteins (amyloid, tau) relate to Alzheimer?s disease, however, we know nearly nothing about protein pathology or other causes of this ICU-related dementia. It is critical to understand why ICU survivors are losing their jobs, and the leadership as matriarchs and patriarchs of their families. This BRAIN-ICU-2 study [Bringing to light the Risk factors And Incidence of Neuropsychological dysfunction (dementia) in ICU Survivors, 2nd Study] is in direct response to PAR-18-029 and will determine ICU patients? main paths to decline, maintenance, or recovery of brain function. We will answer gaps in knowledge about long-term outcome of post-ICU brain disease by following the remaining ICU survivors from the original BRAIN-ICU-1 study with complete cognitive testing for the first time ever to 14 years (AIM 1). We will consent and enroll 567 new ICU patients at Vanderbilt and Rush Universities (i.e., new ICU cohort) and determine how detailed neuroimaging and cerebrospinal fluid samples can help reveal locations and mechanisms of injury beyond what we learned from the clinical information collected in our original study (AIM 2). Importantly, we are partnering with the world-renowned Rush Alzheimer's Disease Research Center brain bank program so that all patients enrolled in Aims 1 and 2 will able to donate their brains to science for the first-ever in-depth pathological study of those who do and do not get post-ICU dementia to define this disease formally (AIM 3).

2019-nCoV; Acute; Administrative Supplement; Affect; Aging; Agitation; Alzheimer's Disease; Alzheimer's disease related dementia; Autopsy; Blood Coagulation Disorders; Brain; Brain region; Brain Stem; brain tissue; Case Study; Cerebral hemisphere; Collaborations; Communities; Conscious; COVID-19; COVID-19 pandemic; Critical Illness; data hub; Delirium; Dementia; Development; Encephalitis; experience; Functional disorder; Funding; Future; Grant; Guillain-Barré Syndrome; Headache; Impairment; in vivo; Incidence; indexing; Infection; Inflammation; inflammatory marker; Intensive Care Units; interest; Magnetic Resoce Imaging; Memory; National Institute on Aging; Nervous system structure; Neurodegenerative Disorders; neuropathology; Neuropathy; Neuropsychology; Parents; Patients; Publishing; ranpirnase; religious order study; repository; Research; Resource Sharing; Resources; response; Risk Factors; Seizures; Series; Signs and Symptoms; Structural defect; Survivors; Symptoms; Viral; viral RNA; Vision;

PROJECT SUMMARY ? OVERALL This P20 application seeks to establish the Exploratory Vanderbilt Alzheimer?s Disease Research Center (VADRC) at Vanderbilt University Medical Center and Vanderbilt University in Nashville, Tennessee. The VADRC will leverage and build upon the foundational elements of the Vanderbilt Memory and Alzheimer?s Center created in 2012, including established outreach and recruitment pipelines as well as clinical, neuroimaging, genetic, and biospecimen data collection, processing, storage, and dissemination protocols. Simultaneously, the VADRC will establish essential infrastructure appropriate for a future P30 Alzheimer?s Disease Research Center with a focus on identifying molecular factors that increase Alzheimer?s disease risk or promote resilience. The VADRC mission will be to enhance knowledge to solve the complexities underlying the pathophysiology, early identification, and treatment of Alzheimer?s disease and related dementias. Our mission and goals align with the 2011 National Alzheimer?s Project Act. During the P20 award, we will establish Administrative, Clinical, and Biomarker Cores that work in harmony to facilitate and enhance innovative basic, translational, and clinical science in Alzheimer?s disease and related dementia across Vanderbilt?s campus. This effort will leverage rich precision medicine techniques and tools available at Vanderbilt and innovative pathways to identify novel therapeutics while supporting faculty recruitment and retention, integrated team science, and mentorship at all levels. The P20 mechanism will provide essential research resources and foster a strong intellectual community to support existing studies and enable new opportunities for transformative research. Within the Clinical Core, we will complete comprehensive clinical, cognitive, neuroimaging, genetic and biospecimen assessment on a newly established research cohort of aging adults ranging from cognitively unimpaired to mild Alzheimer?s disease, including neuropathological analyses as participants come to autopsy. Cross-Core and interdisciplinary collaborations throughout campus and with national repositories (including the National Alzheimer?s Coordinating Center) will support data collection, sharing, and dissemination. The VADRC will also enhance clinical relationships, community partnerships, and educational opportunities to promote awareness, increase research participation, and provide an interdisciplinary training environment. The Center will serve as the institutional hub of all research and educational opportunities in Alzheimer?s disease. Simultaneously, the VADRC will contribute to national efforts to advance Alzheimer?s disease research, clinical care, and educational activities by establishing relationships with other Alzheimer?s Disease Research Centers, contributing to national initiatives, and enhancing collaborations to maximize contributions to the field. The Center will be the first of its kind in the region and would help to serve the growing population of Tennesseans and southern Americans suffering from Alzheimer?s disease and related dementias.

PROJECT SUMMARY As the population ages, Alzheimer's disease and dementia are becoming a public health crisis. In our initial cycle, the Vanderbilt Memory & Aging Project was established to examine cardiovascular function in relation to structural neuroimaging changes and cognition. We also tested whether associations were more prominent in clinically symptomatic individuals. We successfully enrolled several hundred participants age 60 and older, our data successfully supported multiple training grant opportunities (e.g., National Research Service Awards, Career Development Awards), and we published numerous papers. Our results suggest subclinical cardiovascular changes relate to worse cognition, white matter changes, and cerebral atrophy, especially in the hippocampus and other cortical regions primarily affected in Alzheimer's disease. Evidence to date supports our central hypothesis that well-established homeostatic mechanisms designed to protect cerebral blood supply become less effective with age, altering the integrity of cerebral hemodynamics, and lowering the threshold for neurodegenerative and cognitive changes. Interestingly, our preliminary associations between subclinical cardiovascular integrity and cerebral hemodynamics are stronger among carriers of the apolipoprotein E ?4 (APOE-?4) allele, an Alzheimer's disease genetic risk factor. Furthermore, findings are more prominent in cognitively unimpaired participants, suggesting subtle cardiac hemodynamic changes may act as an underrecognized precipitating contributor of neurodegeneration and corresponding cognitive decline, distinct from the exacerbating effects of overt cerebrovascular disease. In the next cycle, we propose to better characterize underlying mechanisms linking early cardiac hemodynamic changes to abnormal brain aging in cognitively unimpaired participants, and test whether APOE-?4 moderates the effect of vascular damage on brain health. We will follow the existing cohort and supplement it with enrollment of several hundred cognitively unimpaired participants to increase statistical power for more comprehensive analyses. The new participants will complete serial longitudinal assessments with identical procedures plus lumbar puncture for cerebrospinal fluid acquisition. Innovative translational efforts leveraging sophisticated neuroimaging and molecular biomarkers are critical to better detect early, asymptomatic cardiac hemodynamic changes, which may be more influential in initiating downstream cerebrovascular and neurodegenerative processes than previously recognized.

PROJECT SUMMARY Medical teams globally are consumed in caring for patients with respiratory failure and acute comorbidities caused by Coronavirus Disease 2019 (COVID-19). To understand the full impact of this pandemic on the lives of survivors and the magnitude of this emerging public health crisis, we must study the brain. We helped define the plague of disabling features suffered by millions of intensive care unit (ICU) survivors called Post-Intensive Care Syndrome (PICS), characterized by an acquired Alzheimer's disease and related dementia (ADRD), post- traumatic stress disorder (PTSD), and depression. Approximately 10% to 15% of COVID-19 patients develop hypoxemia requiring hospitalization, which can lead to acute respiratory distress syndrome and the need for life support, including mechanical ventilation. Up to 26% of hospitalized patients with COVID-19 require ICU admission. We hypothesize that COVID-19 survivors who are hospitalized will have a high burden of PICS- related acquired-ADRD, PTSD, and depression. To test this hypothesis, we propose this NIH Administrative Supplement to the BRAIN-ICU-2 Study (R01AG058639). This Administrative Supplement will allow us to use the BRAIN-ICU-2 long-term follow-up infrastructure to collect 6-month cognition, PTSD, and depression data for a NHLBI-sponsored randomized trial (ORCHID) that is evaluating hydroxychloroquine versus placebo on 15-day death, mechanical ventilation, or oxygen supplementation. We will ascertain these 6-month outcomes using a comprehensive phone battery that incorporates robust neuropsychological tests for memory, attention, language, reasoning, and executive function, and diagnostic evaluations for PTSD and depression. Our Administrative Supplement is titled ?Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease - Brain Outcomes and Psychological Distress (ORCHID-BUD)? and will conduct 6-month follow-up assessments in 270 adults who are hospitalized with COVID-19 infection and survive. ORCHID-BUD has the following specific aims: (1) To determine the epidemiology (i.e., prevalence) of cognitive impairment (i.e., acquired-dementia) at 6 months and if hydroxychloroquine administration is associated with improvement in these same outcomes; (2) To determine the epidemiology of PTSD and depression at 6-months, and if hydroxychloroquine administration is associated with improvement in these same outcomes, and (3) To identify modifiable risk factors (e.g., sedatives, isolation, intravenous fluids, pressor, ACE-inhibitor or ARB use, etc.) associated with worse long-term cognitive impairment, PTSD, and depression at 6 months. To our knowledge, this investigation will be the first ever to conduct robust neuropsychological assessments for SARS, MERS or COVID-19 survivors, and the first among COVID-19 to conduct diagnostic PTSD and depression assessments. This Administrative Supplement will leverage BRAIN- ICU-2 and ORCHID's resources to conduct a high impact and novel investigation at relatively low cost and help provide a comprehensive evaluation of COVID-19's effect on long-term cognitive and psychological outcomes.

PROJECT SUMMARY ? ADMINISTRATIVE CORE The Exploratory Vanderbilt Alzheimer?s Disease Research Center (VADRC) Administrative Core is central to achieving the overall mission of the VADRC and will leverage strong institutional resources to provide excellent administrative oversight for a scalable infrastructure to position Vanderbilt University Medical Center and Vanderbilt University for a future successful P30 application. Under the proven leadership of Dr. Angela Jefferson, supported by Associate Directors, Dr. Consuelo Wilkins and Dr. Charles Sanders, the Administrative Core is uniquely positioned to achieve this goal. Our interdisciplinary Core leadership will ensure that all programmatic objectives of the VADRC are accomplished by coordinating and integrating VADRC Cores and scaling these Center functions into a thriving P30-funded ADRC. Core leadership will drive the Center?s scientific direction emphasizing non-amyloid pathways of injury, including understanding vascular contributions to Alzheimer?s disease and related dementias, discovering novel disease pathways using advanced techniques, and improving pharmacological therapies for Alzheimer?s disease and related dementias. The Administrative Core will serve as the institutional hub for all local Alzheimer?s disease research activities by providing strategic planning, scientific direction, campus-wide integration, and essential infrastructure. Core leadership will identify opportunities for growth while harnessing strengths of existing programs. The Administrative Core will establish and facilitate administrative structure, Center governance, and oversight for Center operations. These functions include managing budgetary oversight, ensuring compliance with regulatory requirements, facilitating ongoing internal and external review and evaluation of VADRC activities, and coordinating fiscal, operational, and regulatory functions to ensure effective utilization of Center resources. The Administrative Core will actively support local research activities and contribute to collaborative national research initiatives and resource sharing to advance the goals of the National Alzheimer?s Project Act. Leadership will establish a scalable data sharing platform to support a future P30 Data Management and Statistical Core. Such infrastructure will promote coordinating and integrating VADRC activities for data transfer that serve local investigator needs and support national research efforts (e.g., National Alzheimer?s Coordinating Center, National Centralized Repository for Alzheimer?s Disease and Related Dementias). Additionally, the Administrative Core will support VADRC participation in multi-site clinical trials. Finally, the Core will be integral in fostering professional development of the next generation of clinicians and scientists in Alzheimer?s disease. Collectively, the VADRC Administrative Core will be instrumental in establishing and facilitating harmonized integration between all Center investigators, collaborators, Core functions, institutional resources, and national partners, which will facilitate a smooth transition to a future P30-funded VADRC.