Gregory A. Jicha, Ph.D. - US grants

DESCRIPTION (provided by applicant): There is a great unmet need to distinguish clinically between the different causes of cognitive impairment in elderly individuals for the sake of early diagnosis and therapeutic intervention designed to improve outcomes for patients. The University of Kentucky Alzheimer's Disease Center (UK-ADC) has been at the forefront of studying the most prevalent causes of Non-AD MCI, demonstrating that over two-thirds of elderly patients have non-AD brain conditions that deleteriously affect cognition. We have chosen to focus on MCI due to cerebrovascular disease (MCI-CVD). This application focuses on defining the pathological underpinnings and relationships of specific risk factors to MCI-CVD, developing clinical diagnostic criteria for MCI-CVD using imaging, serum, and CSF biomarkers that will also allow longitudinal evaluation and assessment of therapeutic interventions in MCI-CVD. As such, the current application represents a comprehensive bench-to-bedside translational program designed to directly increase our understanding of and impact the major cause of cognitive decline in the elderly population today. The multidisciplinary team represents leaders in the field with proven track histories of scientific accomplishments and collaborative enterprise in the area of MCI. Successful completion of project aims will allow an integrated understanding of MCI-CVD with the potential for tremendous impact on one of the major healthcare crises facing the nation today. PUBLIC HEALTH RELEVANCE: Mild cognitive impairment (MCI) is often conflated with early Alzheimer's disease (AD) although a large proportion of individuals with MCI lack AD pathology. Especially among individuals beyond 85 years of age, the prevalence of non-AD brain diseases, such as cerebrovascular disease (CVD), surpasses that of advanced AD. We have chosen to focus on MCI due to cerebrovascular disease (MCI-CVD). The current application represents a comprehensive bench-to-bedside translational program designed to directly increase our understanding of and impact the major cause of cognitive decline in the elderly population today. The multidisciplinary team represents leaders in the field with proven track histories of scientific accomplishments and collaborative enterprise in the area of MCI. Successful completion of project aims will allow an integrated understanding of MCI-CVD with the potential for tremendous impact on one of the major healthcare crises facing the nation today.

DESCRIPTION (provided by applicant): Our preliminary data indicate that miR-107 plays an important role in AD pathogenesis. Fibrates (PPAR agonists) increase miR-107 expression, and down-regulated BACE1 protein, an essential enzyme contributing to AD, in cultured H4 cells. We plan to test our hypotheses and evaluate a potential therapy for Alzheimer's disease (AD) based on this novel microRNA (miRNA) pathway. Preclinical work in this area using animal models of AD has been thwarted by the species-specific hepatotoxicity not seen in humans. Thus, human clinical trials are necessary to test this important hypothesis on the disease modifying properties of fibrates in AD. Specifically, we propose an evaluation of the safety and efficacy of gemfibrozil administration on micro-RNA modulation of AD mechanisms in a parallel-design, double- blind, placebo-controlled study. We will evaluate both safety and target engagement of miR- 107 by gemfibrozil as well as alterations in relevant AD biomarkers. Gemfibrozil is a safe, orally- administered, FDA-approved drug for treatment of hyperlipidemia in aged individuals. The FDA has indicated IND exemption status for these studies. This study is designed to provide the foundation for future large-scale Phase II & III studies of fibrates in AD and AD prevention trials and represents the first attempt we are aware of designed to modulate disease progression in AD through influences on novel micro-RNA pathways. As such the proposed study represents a cutting-edge, data-driven, exploration of a novel disease relevant pathway that may hold promise for our global efforts targeting this major health priority among developing and developed nations.

DESCRIPTION (provided by applicant): There is a great unmet need to distinguish clinically between the different causes of cognitive impairment in elderly individuals for the sake of early diagnosis and therapeutic intervention designed to improve outcomes for patients. The University of Kentucky Alzheimer's Disease Center (UK-ADC) has been at the forefront of studying the most prevalent causes of Non-AD MCI, demonstrating that over two-thirds of elderly patients have non-AD brain conditions that deleteriously affect cognition. We have chosen to focus on MCI due to cerebrovascular disease (MCI-CVD). This application focuses on defining the pathological underpinnings and relationships of specific risk factors to MCI-CVD, developing clinical diagnostic criteria for MCI-CVD using imaging, serum, and CSF biomarkers that will also allow longitudinal evaluation and assessment of therapeutic interventions in MCI-CVD. As such, the current application represents a comprehensive bench-to-bedside translational program designed to directly increase our understanding of and impact the major cause of cognitive decline in the elderly population today. The multidisciplinary team represents leaders in the field with proven track histories of scientific accomplishments and collaborative enterprise in the area of MCI. Successful completion of project aims will allow an integrated understanding of MCI-CVD with the potential for tremendous impact on one of the major healthcare crises facing the nation today. PUBLIC HEALTH RELEVANCE: Mild cognitive impairment (MCI) is often conflated with early Alzheimer's disease (AD) although a large proportion of individuals with MCI lack AD pathology. Especially among individuals beyond 85 years of age, the prevalence of non-AD brain diseases, such as cerebrovascular disease (CVD), surpasses that of advanced AD. We have chosen to focus on MCI due to cerebrovascular disease (MCI-CVD). The current application represents a comprehensive bench-to-bedside translational program designed to directly increase our understanding of and impact the major cause of cognitive decline in the elderly population today. The multidisciplinary team represents leaders in the field with proven track histories of scientific accomplishments and collaborative enterprise in the area of MCI. Successful completion of project aims will allow an integrated understanding of MCI-CVD with the potential for tremendous impact on one of the major healthcare crises facing the nation today.

Project Summary/Abstract: Clinical Core The Clinical Core of the UK-ADC maintains a well-characterized, community-based cohort focused on normal aging and early transitional disease states, and follows individuals longitudinally until brain autopsy. We maintain a mandatory autopsy requirement for all subjects (with the exception of our Minority Gateway Clinic, where autopsy is promoted but not required), allowing major contributions in the area of clinical- pathological correlative studies, definition of early preclinical and pre-dementia disease state pathology, and basic translational research. The UK-ADC Clinical Core emphasizes: 1) collection of demographic, clinical, genetic, and autopsy data from large numbers of subjects, readily available as potential research subjects for current and future research needs, 2) provision of non-autopsy biospecimens including antemortem imaging and CSF biomarkers in a sub-cohort of subjects, and 3) efforts to further advance the discovery and development of novel therapeutics for AD. We are major contributors to national collaborative initiatives such as NACC, ADCS, ADNI, NCRAD, and ADGC. Our research cohort is strongly motivated to participate in research, as evidenced by 304 unique, active (living) subjects who have participated in clinical studies over the report period. The Clinical Core has supported 40 grants and affiliated projects focused on specific research questions beyond standard UK-ADC data collections, culminating in 64 direct and 18 indirect publications supported by Core activities. Antemortem biomarker collections over the current funding cycle include 361 clinical and 267 standardized research MRI scans, 229 CSF collections, and 90 A?-PET scans in order to more fully characterize our normal control and early transitional (MCI) cohort. Another major strength of our center lies in our robust minority outreach and engagement. Our efforts, in conjunction with the OR Core, have led to above-par, for local and regional area, minority engagement in ADC and affiliated studies. We have effectively engaged minority subjects in perceived invasive and therapeutic research efforts at a level of participation that has previously been considered untenable by most ADCs and non-NIA funded centers nationally (37.6% unique minority subjects engaged in interventional trials). These efforts and successes will continue in the next five years under the harmonized and integrated Clinical Core efforts that have proven successful at the UK-ADC. We will continue to play a leading role in clinical translational research and development of potential novel therapeutic strategies to prevent or modify pathogenesis of AD and related disorders. Overall, the Clinical Core will continue to provide an infrastructure and environment that will continue to contribute to our success in advancing multidisciplinary, innovative AD research supporting our center theme of Transitions & Translation.

Alzheimer's disease (AD) represents one of the most important public health issues our society is facing today. An estimated 5 million people age 65 and older in the United States (US) are currently living with AD, and this number may nearly triple by 2050. To address this impeding population burden, the National Alzheimer's Project Act (NAPA) 2015 report emphasized the need for identifying preventive strategies that can delay symptomatic disease onset. While much emphasis has been placed on developing and testing effective disease-modifying strategies targeting this asymptomatic preclinical phase of AD (pAD), little emphasis has been placed on currently available strategies that target cognitive reserve, resulting in (1) delaying symptom onset, (2) shortening the overall course of symptomatic disease, and (3) substantially reducing the financial and societal impact of AD. We hypothesize that targeted reductions in inappropriate medication use (Beers Criteria 2015), will bolster cognitive reserve in subjects at risk for AD, delaying the onset of clinical symptoms, and reducing the prevalence and duration of symptomatic disease. The impact of this strategy, if successful, includes a dramatic reduction in overall health care expenditures for the millions affected by AD by delaying the symptomatic phase of disease in accord with NAPA aims. Our specific aims are: Specific Aim 1. Conduct a 12-month, randomized, placebo-controlled trial to evaluate the impact of our patient- centered, pharmacist-physician team MTM intervention in reducing unnecessary and inappropriate medication use in community-dwelling, elderly, non-demented subjects. Primary outcome measures will include pre- to post- intervention measures of: (1) use of inappropriate medications as measured by the Medication Appropriateness Index (MAI); 2) Cognitive Reserve Change Score (CRCS) defined as the difference in the scopolamine- challenged vs unchallenged measures on the neurocognitive score. Specific Aim 2 Evaluate the impact of preclinical amyloid burden on cognitive reserve deficits and decline (measured as CRCS) to evaluate efficacy of delaying symptomatic disease progression in pAD. While not eliminating AD or shortening duration of biological disease, the delay in symptom onset and progression to functional decline resulting from reduction in inappropriate medication use could lessen AD prevalence and significantly reduce healthcare expenditures related to not only AD, but potentially all forms of dementia involving a prodromal asymptomatic period. Study results would enable the larger implementation of similar medication management strategies in clinical practice to address the need for multifaceted preventive strategies to maintain cognitive health in the aging population.

Abstract Vascular contributions to cognitive impairment and dementia (VCID) describes cognitive impairment resulting from cerebrovascular disease or dysfunction. VCID is a frequent co-morbidity with Alzheimer's disease (AD), as well as a single dementia-causing entity. The most common vasculopathy associated with cognitive impairment is cerebral small vessel disease (SVD). It is highly likely that SVD significantly contributes to the clinical manifestation of dementia, and therefore is a viable target for disease-modifying therapies, whether alone or in combination with AD-targeting therapies. One major obstacle for therapeutic development is the lack of biomarkers that are predictive of the presence and course of SVD-VCID. In this proposal we present candidate biomarkers for SV-VCID that will contribute to the consortium. We have identified MRI imaging modalities of 3D FLAIR, ASL, and DTI as our imaging candidate biomarkers. We have also identified IL-12 p70, TNF?, PIGF and VEGFD as our candidate fluid biomarkers that discriminate SVD well in the subset of our cohort that we have analyzed. In this application we have a plan for developing our candidate biomarkers and validating them through the UH2 phase an individual research group, and also through the UH3 part as a member of the consortium. In addition, we bring significant strengths that will help synergize and move the consortium as a whole forward in our collective goal of developing biomarkers that are ready for large scale clinical trials and FDA qualification in years 6-7 of the consortium. These strengths include a well characterized, longitudinal cohort supported through our ADC and other NIH initiatives, our long history of active participation in consortia providing the experience and infrastructure needed to ensure success in this UH2/UH3 mechanism, our history of data sharing, resource sharing including samples, recruitment of research participants for longitudinal studies, and our foundation in basic and translational science.

Abstract The proposed project is a pilot clinical trial investigating a potential treatment for hippocampal sclerosis of aging (HS-Aging). A major subtype of ?Alzheimer's disease and related dementia? (ADRD), HS-Aging affects 10-25% of all elderly individuals. HS-Aging is typically misdiagnosed as Probable AD or AD-type dementia in the clinical setting. Unfortunately, there currently is no validated biomarker to diagnose HS-Aging during life, and there is no known therapy. We will test the safety and efficacy of nicorandil for HS-Aging, based on our prior work elucidating a pharmacologically targetable mechanism underlying the disease. Nicorandil is a vasorelaxant drug, used clinically to treat chronic heart failure in the elderly population. Pharmacologically, Nicorandil is an agonist for a protein (SUR2) that is encoded by a gene that we found to be linked to HS-Aging risk. Primary specific aims follow: Specific Aim #1: Evaluate safety and neurodegenerative biomarkers linked to HS-Aging pathology in nicorandil vs. placebo treated subjects by: a. Conducting a double-blind, randomized, placebo-controlled, clinical trial of nicorandil in 62 participants (both sexes, >75 years old, CDR 0.5 or 1, with HS-Aging profile in CSF and MRI biomarkers [amyloid and phospho-tau negative, with evidence for hippocampal atrophy; A-/T-/N+]) over a 96-week treatment period; b. Evaluating the safety of nicorandil administration in the elderly at risk for HS-aging (this is the primary outcome measure) that will inform future trial design; and, c. Measuring structural MRI (3D-T1; hippocampal atrophy is the main efficacy outcome measure), cognitive tests, and CSF levels of nicorandil, tau, phospho-tau, and A?(1-42) at baseline and week 96. Specific Aim #2: Optimize and further explore HS-Aging biomarkers by: a. Refining MR imaging analysis (including hippocampal volumetric assays, arterial spin labeling (ASL), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS) techniques that may distinguish participants with probable HS-Aging from those with positive AD biomarkers; b. Performing proteomic discovery analysis in CSF to identify and evaluate potential HS-Aging biomarkers to complement the A/T/N framework utilizing our prospective cohort with A?(1-42), phospho-tau, and neurodegeneration markers and MR imaging as a control cohort for AD. This specific aim will directly test and enhance the clinical utility of the A/T/N framework for diagnosis of degenerative disease state; and, c. Following our published and replicated neurocognitive testing marker that is associated with HS-Aging pathology, we will optimize the clinical and neurocognitive criteria for disease diagnosis based on the prospects of a relatively long-running (96 week) early-phase clinical trial.

Project Summary/Abstract: Clinical Core The Clinical Core of the UK-ADRC maintains a well-characterized, community-based cohort focused on normal aging and early transitional disease states and follows individuals longitudinally until brain autopsy. We maintain a mandatory autopsy requirement for all subjects (with the exception of our Minority Gateway Clinic, where autopsy is promoted but not required), allowing major contributions in the area of clinical- pathological correlative studies, and definition of early preclinical and pre-dementia disease states. These efforts have been a driving force in our recognition of the heterogeneity of community-acquired dementia, including major contributions to the field in regard to LATE, PART, VCID, and the role these pathologic states play in conjunction with traditional AD, LBD, and FTLD disease states. A major focus of our work has also been on defining early clinical transitions involving the interplay of these disease states that has driven the widespread exploration of late-life multi-etiology dementia syndromes. To further such advances, the UK-ADRC Clinical Core emphasizes deep clinical, biomarker, genetic, and post-mortem phenotyping of a diverse cohort of elderly subjects at high risk for multi-etiology dementia. Major initiatives in the area of AD mimics and transitions from normal to late-life multi-etiology dementia are well-poised to continue to move the field forward in the areas of both diagnosis and translational interventional discoveries. We have introduced exciting new initiatives in our expansion of antemortem biomarker research allowing an even deeper clinical phenotyping of our participants as we work towards translational discoveries for multi-etiology dementia. The UK-ADRC will continue to constantly evolve in dynamic ways through our proposed specific aims. Aim 1: Maintain & longitudinally characterize a central longitudinal cohort enrolling cognitively normal subjects to facilitate our understanding of preclinical disease and early cognitive transitions to multi-etiology MCI & dementia. Aim 2: Maintain and expand our successful Minority Gateway Clinics to maintain and grow our (significantly) above-parity for population minority engagement. Aim 3: Further develop and maintain an infrastructure to support translational therapeutic development through all clinical trial phases in support of NIH, ADCS, ACTC initiatives, industry-sponsored drug trials, and investigator-initiated projects. Aim 4: Foster education and support of research participants and families to ensure that our efforts are clinically meaningful, both in novel prevention studies as well as treatment in established disease Overall, the Clinical Core will continue to provide an infrastructure and environment that will continue to contribute to our success in advancing multidisciplinary, innovative AD research supporting our center theme of Transitions from Normal to Late-Life Multi-Etiology Dementia.

Abstract The proposed project is a pilot clinical trial investigating a potential treatment for hippocampal sclerosis of aging (HS-Aging). A major subtype of ?Alzheimer's disease and related dementia? (ADRD), HS-Aging affects 10-25% of all elderly individuals. HS-Aging is typically misdiagnosed as Probable AD or AD-type dementia in the clinical setting. Unfortunately, there currently is no validated biomarker to diagnose HS-Aging during life, and there is no known therapy. We will test the safety and efficacy of nicorandil for HS-Aging, based on our prior work elucidating a pharmacologically targetable mechanism underlying the disease. Nicorandil is a vasorelaxant drug, used clinically to treat chronic heart failure in the elderly population. Pharmacologically, Nicorandil is an agonist for a protein (SUR2) that is encoded by a gene that we found to be linked to HS-Aging risk. Primary specific aims follow: Specific Aim #1: Evaluate safety and neurodegenerative biomarkers linked to HS-Aging pathology in nicorandil vs. placebo treated subjects by: a. Conducting a double-blind, randomized, placebo-controlled, clinical trial of nicorandil in 62 participants (both sexes, >75 years old, CDR 0.5 or 1, with HS-Aging profile in CSF and MRI biomarkers [amyloid and phospho-tau negative, with evidence for hippocampal atrophy; A-/T-/N+]) over a 96-week treatment period; b. Evaluating the safety of nicorandil administration in the elderly at risk for HS-aging (this is the primary outcome measure) that will inform future trial design; and, c. Measuring structural MRI (3D-T1; hippocampal atrophy is the main efficacy outcome measure), cognitive tests, and CSF levels of nicorandil, tau, phospho-tau, and A?(1-42) at baseline and week 96. Specific Aim #2: Optimize and further explore HS-Aging biomarkers by: a. Refining MR imaging analysis (including hippocampal volumetric assays, arterial spin labeling (ASL), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS) techniques that may distinguish participants with probable HS-Aging from those with positive AD biomarkers; b. Performing proteomic discovery analysis in CSF to identify and evaluate potential HS-Aging biomarkers to complement the A/T/N framework utilizing our prospective cohort with A?(1-42), phospho-tau, and neurodegeneration markers and MR imaging as a control cohort for AD. This specific aim will directly test and enhance the clinical utility of the A/T/N framework for diagnosis of degenerative disease state; and, c. Following our published and replicated neurocognitive testing marker that is associated with HS-Aging pathology, we will optimize the clinical and neurocognitive criteria for disease diagnosis based on the prospects of a relatively long-running (96 week) early-phase clinical trial.

ABSTRACT The MarkVCID consortium was established to discover and cross-site validate biomarkers of cerebral small vessel disease (cSVD) with an ultimate goal of developing a toolbox of biomarkers that will have diagnostic, disease stratification, and longitudinal tracking utility for future vascular contributions to cognitive impairment and dementia (VCID) clinical trials. The University of Kentucky (UK) was selected as one of the seven MarkVCID sites in its initial funding period in 2016. Being in the heart of the stroke belt, Kentucky is a state with a high prevalence of cardiovascular and cerebrovascular disease, and the University of Kentucky is a Center of Excellence for Stroke and Dementia, with UK being a designated Comprehensive Stroke Center and has an NIA Alzheimer's Disease Research Center (ADRC). During our current funding period, we successfully recruited a cohort of 126 individuals (exceeding our originally proposed 120) with varying levels of cardiovascular risk factors and a large proportion of whom have defined subjective memory complaints (SMCs), with some defined as mild cognitive impairment (MCI). All participants underwent the MarkVCID MRI battery, blood collection, and neuropsychological and clinical assessment, while one quarter also contributed CSF. Importantly, all participants have consented to autopsy; a requirement we initiated at the beginning of our MarkVCID recruitment. UK MarkVCID has fully participated in the validation of every biomarker kit except the OCT-A kit. We have also led two biomarker kits: the White Matter Growth and Regression kit and the CSF PlGF kit. In this renewal connected to UH3NS100606 under RFA-NS-16-020, we propose to expand our cohort to 200 individuals, with a particular focus on expanding recruitment of diverse populations and individuals with SMCs and MCI. Having participated in the harmonization, instrumental validation, and now biological validation, of all MRI and fluid biomarker kits, we are poised to make significant contributions in the continuation of the consortium. We have proposed three Specific Aims to achieve the goals laid out in RFA- NS-21-005: Specific Aim 1: Retain and expand a diverse cohort enriched for individuals with subjective memory complaints and cognitive impairment at high risk for cerebral small vessel disease. Specific Aim 2: Work with the consortium to facilitate data, imaging, and fluid sharing and accelerate our validation of the MarkVCID candidate biomarkers in our cohort. Specific Aim 3: Fully engage in leadership roles within the consortium and serve in a consulting capacity for both internal and external researchers seeking to explore biomarkers and or develop new clinical trials and interventional studies for the treatment of VCID.