Mary Sano, PhD, City University of New York Graduate Center - US grants

DESCRIPTION: (Adapted from Applicant's Abstract) This is a clinical trial to determine if l-deprenyl can maintain or improve function in community dwelling elderly. The specific aims are to identify a population at-risk to deteriorate cognitively and functionally; to conduct a double-blind parallel- design placebo controlled clinical trial of l-deprenyl; and to assess meaningful outcome measures including progression to dementia and loss of independence in daily activities. The WHICAP project currently assesses residents in the North Manhattan area. Based on the WHICAP evaluation, those who demonstrate cognitive deficits and functional impairments will be asked to participate. Both Spanish and English speaking elderly will be invited to participate. Patients will complete informed consent. Screening and follow-up evaluation will be conducted at the general clinical research center or in the community when necessary. Patients (N=150) will be randomly assigned to one of two conditions; l-deprenyl (10 mgs. per day) or placebo. Assessment will be completed at three month intervals for one year and will include measures of functional independence, assessment of activities of daily living, and quality of life assessments. In addition, brief neuropsychological assessments will also be completed. Parametric and non- parametric techniques will be used to assess drug effect. Endpoint analysis will use progression to dementia and functional independence measures.

Twelve month study to evaluate the safety and efficacy of this antioxidant in three doses for treatment of Alzheimer's Disease.

This is a randomized, double-blind, placebo-controlled clinical trial to determine if estrogen can delay the onset of Alzheimer's disease(AD) and reduce memory decline. 900 healthy, non-demented, women, 65 years of age or older, with a family history of AD will be recruited in 18 months from 3 different cities (New York, NY, Baltimore, MD and Jacksonville, FL) over an 18 month period using 4 distinct methods: 1) healthy non-demented female relatives of patients with AD seen at each of the 3 participating AD centers; 2) women with a family history of AD contacted through community service providers surrounding each medical center, 3) women with a family history of AD identified through advertisement using local media (newspaper, television and radio) and; 4) women with a family history of AD identified from a regional sample of female Medicare recipients provided by the Health Care Finance Administration (HCFA). At study entry, family history of AD in a first degree relative will be confirmed and each participant will have a physical, neurological, neuropsychological and functional assessment to insure the absence of dementia, any other degenerative neurological disease or potentially fatal disorder. Exclusions include a history of breast, uterine or ovarian cancer, history of arterial or deep vein thrombosis, a history of breast cancer in a first-degree relative. Randomization to estrogen, estrogen with progesterone or identical placebo among eligible women will be stratified by site and hysterectomy status (hysterectomized women will be randomized to unopposed estrogen or placebo; non-hysterectomized women to opposed estrogen or placebo); non-hysterectomized women to opposed estrogen or placebo). Analyses will combine opposed and unopposed estrogen treatments into a single group and compare them to placebo. Patients will be followed over a 3 year (36-month) period, and will be examined at 6 month intervals to assess compliance, adverse events and general health status. Annual complete medical, gynecological, neuropsychological and functional assessments will occur during follow-up. Outcome measures will include incident dementia and memory decline. We will use an intent-to-treat analysis from the primary analysis. Secondary analysis will examine potential co-variates. Safety evaluations will be based on finding from annual assessments and reported adverse events. Participants who become demented will be informed of standard-of-care treatment and will continue to be followed at annual intervals for the length of the study.

Eighty week study to evaluate safety and efficacy of Exelon in open- label format for mild to severe Alzheimer's Disease. The medication is a cholinesterase inhibitor.

Double-blind, placebo controlled study to evaluate safety and efficacy of cholinesterase inhibitor in an attempt to improve cognition and behavioral performance.

This is a 14 month study of an oral agent to be used in the treatment of Alzheimer's disease. It is a double-blind study of 4 doses of Lazabemide compared to placebo (12.5, 25, 50 or 100mgm BID). Safety and efficacy will be evaluated in patients with mild to moderate Alzheimer's disease.

Acetyl-Carnitine is a compound which has two primary actions: it is possibly cholinergic agonist and it may enhance cerebral metabolism by activating mitochondrial activity. Its efficacy in Alzheimer's disease is suggested by animal studies and this is the first US clinical trial of this agent. A parallel double blind study of 25 subjects will take place as a preliminary study to determine whether a nation-wide trial should take place.

Eight week study to determine whether oral melatonin administration can improve sleep disturbances in patients with probable Alzheimer's disease. Secondary purpose are to compare the effects of high and low doses of melatonin on various measures of actigraph recorded sleep measures, also safety and tolerability

There is growing evidence that individuals with mild cognitive impairment (MCI) are at increased risk for Alzheimer's disease (AD). Consequently, clinicians are faced with the question of how to properly evaluate subjects with a mild cognitive impairment. Recent studies suggest that oxidative stress may play a role in the pathogenesis of AD. The potential importance of oxidative stress mechanisms in disease pathogenesis was also suggested by a recent clinical trial of vitamin E and selegiline in subjects with moderate AD. This clinical trial indicates that treatment with vitamin E(2,000I.U./day) delayed time to important functional endpoints and suggests that vitamin E may slow clinical progression of disease in subjects with moderately severe AD. The present study will determine if this dose of vitamin E will delay progression to clinical AD in individuals with MCI. AD is associated with reduced concentrations of the neurotransmissor, acetylcholine, in the cerebral cortex. Acetylcholine is important for attention and memory, 2 cognitive functions impaired in AD. Cholinesterase inhibitors were developed in an attempt to increase acetylcholine levels in brain and improve related cognitive functions. Donepezil, a cholinesterase inhibitor, was approved by the FDA in 1996 as a symptomatic treatment for mild and moderate AD. This study will determine if donepezil treatment will delay progression to AD in MCI subjects. The specific aims of this study are:1) to evaluate the efficacy and safety of vitamin E (2,000 IU/day) or donepezil (10mg/day) compared to placebo for the prevention of Alzheimer's disease in individuals with mild cognitive impairment; 2) to evaluate the efficacy of vitamin E and donepezil on cognition in MCI subjects.

Education and Information Transfer Core. This application for the Education and Information Transfer Core (EITC) of the ADCR will build on our strong history of providing research training to professionals, educating physicians about new directions in the diagnosis, treatment and management of Alzheimer's Disease and partnering with the community by providing clinical service and research opportunities. A primary goal of this EITC is conduct "needs assessments" using interview and survey techniques for gathering information about the knowledge base, interests and needs of professional trainees, community physicians, caregivers and community organizations. This information will be used to design a comprehensive, high-impact education program serving the needs of a culturally diverse patient population. We will also undertake an evaluation of our ongoing lectures, training programs, and other activities. This revaluation will be used to modify, adjust and amend these programs as needed to insure that they are maximally effective in educating their intended audience. We have six specific aims which address our plans to assess needs, design new educational materials (newsletters, CME courses, and our Web Pages), evaluate this educational product and readjust to insure efficient, effective educational materials. The ultimate goal of our education programs is to develop a well-informed partnership among scientists, clinicians, patients and caregivers leading to relevant research directions with maximal community participation.

This is a multi-center, randomized, double-blind, placebo-controlled clinical trial in nondemented women, 65 years of age or older, with a family history of AD to determine if estrogen (alone or combined with progesterone as appropriate)can delay the onset of Alzheimer's disease and prevent memory decline. At study entry, family history of AD will be confirmed and each participant will have a physical, neurological, neuropsychological and functional assessment to insure the absence of dementia, any other degenerative neurological disease or potentially fatal disorder, rule out a history of breast, uterine or ovarian cancer and those with a history of breast cancer in a first-degree relative. Randomization to estrogen, estrogen with progesterone, or identical placebo among eligible women will be stratified by site and hysterectomy status (hysterectomized women will be randomized to unopposed estrogen or placebo; nonhysterectomized women to opposed estrogen or placebo). Patients will be followed over a 3 year (36 months) period, and will be examined at 6 month intervals to assess compliance, adverse events and general health status. Annual complete medical, gynecological, neuropsychological and functional assessments will occur during follow-up. Outcome measures will include incident dementia and memory decline and will use an intent-to-treat analysis. APOE genotype, educational level and ethnic group are potential covariates for the secondary analyses. Safety evaluations will be based on findings from annual assessments and reported adverse events.

This application constitutes the fourth competitive renewal of the Mount Sinai School of Medicine Alzheimer's Disease Research Center. Its fundamental goals have not change since the first funding period, however it has expanded much since then. In this renewal the following cores and projects are propose: . Clinical Research Support Core/El hurst Satellite (D. Marin) . Information Transfer Core (R. Mohs) . Neuropathology Core (D. Perl) . Project: "Molecular Genetic Studies of Neurofilament Assembly and Function" (R. Lazzarini) . Project: "Quantitative Indices of Neuron Vulnerability in Dementia" (P. Hof) . Project: "Novel Presenilin Binding Proteins" (J. Buxbaum) . Project: "Vascular Localization and Function of Presenilin 1 Fragments (N. Robakis) . Project: "An alpha2 Agonist and Cholinesterase Inhibitor in AD" . Project: "Risk Factors in Very Late Onset AD" (J. Silverman)

DESCRIPTION (provided by applicant): This is a continuation of a double blind placebo controlled multi-center clinical trial to determine if estrogen can delay the onset of Alzheimer's Disease (AD) and reduce memory decline. The use of estrogen to prevent or delay AD is supported by biologic, epidemiologic and clinical studies. New data are available which demonstrate that estrogen does not have a role in prevention of heart disease and stroke. However, the mechanisms through which estrogens may have a benefit in dementia are not the same as those which may mediate vascular activity. In the original proposal we postulated that estrogen had an effect on cognition and dementia, that the trial to assess dementia in a cohort with high risk of dementia was feasible and that dementia prevention was a high priority. It was designed to answer the question in a population at risk for dementia. We have carefully selected women at high risk for dementia and by careful screening we have selected to reduce the risk of the known estrogen related adverse outcomes. We propose to continue this 5 year multicenter, randomized, double blind placebo controlled trial of estrogens (Premarin or Prempro) to assess its efficacy to prevent memory loss and dementia in 900 healthy, elderly women greater than or equal to age 65 with a family history of AD recruited at 27 sites. Subjects will be assessed at 6 month intervals for safety and compliance and at annual intervals for cognitive outcomes. We believe that this trial must be completed to answer this important question. We propose the following specific aims: 1) to continue the double-blind placebo controlled 5 year trial of Premarin (.625 mg/day) or Prempro to assess the efficacy to prevent memory loss and dementia in healthy elderly women with a family history of AD; 2) To assess the safety of this regimen in this cohort with specific attention to the recently established profile of vascular adverse events; 3) To assess our use of a very sensitive neuropsychotogical battery which may permit reliable, early detection of impaired cognitive health. In an aging society, with the increasing risk of Alzheimer's disease and memory loss, and in a world of growing technological complexity requiring intact cognition, it would be short-sighted to abandon studies of an agent which has the potential to prevent cognitive loss and AD. This trial may represent the very last chance to determine if estrogen can have a benefit in dementia prevention and memory protection.

The Education and Information Transfer Core has two central aims. The first central aim is to recruit subjects, disseminate information, and publicize the wide range of ADRC research activities and clinical services. Outreach efforts will be accomplished, in both English and Spanish, through the ADRC newsletter, the new ADRC website, joint publications with NYCARE for the Alzheimer's Association Newsletter, brochures, lectures, workshops, conferences, and health fairs. Information transfer activities are accomplished not only through close collaboration with ADRC investigators and the Clinical Core, but also through a broad network of alliances with local agencies (such as the Alzheimer's Association) and other Mount Sinai departments and programs (such as the Caregiver's Program and the Department of Geriatrics). The ongoing collaboration with the Alzheimer's Disease Assistance Center further allows the Core to continue educational programming and outreach that is specifically targeted to the large Hispanic community we serve. The second central aim is to provide effective educational programming regarding Alzheimer's disease diagnosis, treatment, management, and research advances and training, to a diverse audience. This audience includes staff, other healthcare professionals, medical students, residents, postdoctoral fellows, psychology interns, patients/caregivers, and the general public. This will be accomplished in several ways: through a translational lectures series to foster information sharing between clinical and basic science faculty in collaboration with the Neurobiology and Psychiatry departments; through NYCARE (the collaboration of the Education Cores of New York City's Alzheimer's Disease Centers and the New York City chapter of the Alzheimer's Association), community lectures/workshops, and CME programs. Surveys and questionnaires will be used to evaluate the effectiveness of our programs, in order that the Core may modify its activities based on feedback and needs assessment of the populations it serves.

DESCRIPTION (provided by applicant): The Mount Sinai Alzheimer Disease Research Center (MSADRC) continues its historic success in research by using its unprecedented resources and expertise to seize opportunities for innovative approaches to understand, treat, and ultimately prevent the earliest signs of cognitive loss due to Alzheimer's disease (AD) and other causes of dementia. We have conducted critical basic translational and clinical studies to characterize cognitive loss and dementia in the elderly. We have used the National Alzheimer's Project Act (NAPA) as a road map to focus our established strengths. We continue our commitment to therapeutic development with innovative and powerful systems biology approaches to establish networks that can identify new targets and select trial ready candidates through pharmacological repurposing and by using the novel opportunity offered by our role in the international stem cell consortium, to develop neural progenitors, approaches to find unique models for therapeutic targets. We will develop a trial ready registry of non- demented elders who are informed and eager to participate in prevention studies. We will expand our characterization of racially and ethnically diverse elders currently underrepresented in research, and ensure the opportunity for them to participate in clinical research fully, including genetic analysis, biomarker studies, and clinical trials. We will continue to collect brains from our well-characterized clinical populations and focus our efforts on the pathology associated with the transition from normal aging and cognitive impairment. Contributing to National Alzheimer's Coordinating Center resources with clinical, neuropathological, and neuroimaging data will be continued as well as our commitment to provide the National Cell Repository for AD with samples for every eligible participant in our cohort. In keeping with the recommendations of NAPA and the 2013 AD-Related Dementias Research Workshop to include in the study of AD- related disorders a specific focus on the contribution of vascular risks, we will build on our expertise by proposing 3 projects that focus on the intersection of type 2 diabetes (T2D) one of the most common comorbidities of the at risk age group of AD. In Project 1, we will characterize cognitive loss and dementia in T2D individuals, examining markers of AD and insulin resistance including inflammation and cerebrovascular disease to identify the individual contribution and interactive roles of each pathogenetic factor. Minority participation will be a major feature of ths project to assure that our findings are applicable to the most applicable and understudied individuals. In Project 2, our well-characterized participant cohorts and animal models will be used with stem cell technology to identify the contribution of insulin resistance through cell types. In project 3, we examine the effects of T2D and AD on angiogenesis and angiogenic complexes. Together these efforts are aimed at identifying targets for intervention and prevention of AD. The resources of the cores and opportunities of the projects support the multidisciplinary studies of the widest community of researchers in cognitive loss and dementia.

The Clinical Core performs comprehensive clinical and neuropsychological patient evaluations, coordinates data transfer to the Data Management Core, and conducts longitudinal follow up of Alzheimer's disease and non-demented individuals. The Clinical Core coordinated recruitment of subjects for the Mount Sinai ADRC, the Alzheimer's Disease Cooperative Study (ADCS), and other National Institute of Health funded studies, and non-funded pilot studies. In its ongoing efforts to serve a diverse population, the Clinical Core maintains a Satellite Diagnostic and Treatment Clinic. This core provides training to a wide range of individuals to assist in the collection of data, and it approaches all participants for the autopsy program. Educational and outreach activities are conducted in conjunction with the Education Information Transfer Core. Antemortem clinical information on all autopsied cases is provided to the Neuropathology Core through the data management core.

The goal of the recruitment core is to maximize efficient enrollment into the clinical trials of the ADCS. The ADCS has engaged in many activities to increase participation in the past, working with Project Directors, Local Sites and with the general public. While several trials have recruited rapidly and efficiently, others have been difficult to recruit. In this application we propose to organize our recruitment efforts across all projects. We propose to expand the type of efforts, evaluate both new and previously tried recruitment approaches, modify based on the evaluation and re-evaluate. These efforts will be developed within specific trials but will use assessment techniques across trials. Specific Aims are to identify a full range of recruitment activities, both previously tried and newly developed. Specific activities would include use of focus groups with targeted populations to establish how we package the message about each trial;Direct Mail to targeted audiences to maximize exposure, Web based communication that is designed to maximize ease of participation and toll Free phone numbers with automated answer. Other activities include study specific Public and Professional Endorsement via direct work with Site staff at 3 levels: 1) Identify activities for PI that are associated with high recruitment 2) Provide guidance for selecting effective recruitment staff and other study personnel 3) Provide staff development opportunities. All activities will be evaluated and modified based on feedback from the modification.

The Clinical Core performs comprehensive clinical and neuropsychological patient evaluations, coordinates data transfer to the Data Management Core, and conducts longitudinal follow up of elders with normal cognition, mild cognitive impairment and with Alzheimer's disease and other dementias. The Clinical Core coordinates recruitment of subjects for the Mount Sinai ADRC, the Alzheimer's Disease Cooperative Study (ADCS), the National Alzheimer's Coordinating Center (NACC) and other National Institute of Health funded studies, and non-funded pilot studies. In its ongoing efforts to serve a diverse population, the Clinical Core maintains a Satellite Diagnostic and Treatment Clinic for the recruiment of minorty poulations. This Core works on the development of method for research in Alzheimer's and provides training to a wide range of researchers to assist in the collection of data in related areas. The Core approaches all participants for the autopsy program. Antemortem clinical information on all autopsied cases is provided to the Neuropathology Core through the data management core. Educational and outreach activities are conducted in conjunction with the Education Information Transfer Core.

In the past, the ADCS has had an active and successful minority recruitment core. In this submission we have expanded the function of the recruitment core to improve recruitment to all protocols and to evaluate recruitment efforts at the site level as well as across all sites. The specific aims of the recruitment core are as follows: 1. Identify a full range of recruitment and retention activities, including both successful previously tried and newly proposed. 2. Review protocols with Project Directors to reduce barriers to recruitment. Aspects of the protocol to be reviewed include subject eligibility, study procedures, and schedule of events. The goal of the review will be to avoid unnecessary restrictions, and to minimize subject burden while maintaining scientific rigor. 3. Support and train site staff in recruitment and retention efforts. While the sites have been chosen for their expertise in evaluation and treatment of cognitive deficits and dementia as well as their commitment to conduct clinical trials, many are less familiar with communication techniques that can maximize recruitment. This mandatory training will provide an opportunity to introduce the techniques and methods and provide a dialogue for specific needs. The trial sites will be evaluated continually throughout the trial and lags in recruitment will lead to additional contact from the trial PI and the recruitment core leader, and a site-specific remedial program will be developed, implemented and monitored for success. 4. Maximize minority participation. We will continue our efforts to insure that our sites provide maximum opportunity for participation by minority populations. We will include training at the sites. In addition, we will continue our efforts to bring on selected sites which primarily serve minority populations.

Mount Sinai ADRC: Core A (Sano) | PROJECT SUMMARY The purpose of the Administrative Core of the MSADRC is to ensure execution of our mission to conduct cutting-edge research into the causes, diagnosis, treatment, and prevention of Alzheimer's disease and related disorders. This core is responsible for articulating the research agenda and ensuring that it is effectively accomplished. The Administrative Core accomplishes this through a structure that includes an Executive Committee (EC) led by the Director (Sano) and the two associate directors (Gandy and Hof). This EC provides both global and local perspectives so as to insure that the ADRC enjoys the widest access to resources and the most sustaining environment possible. The administrative structure has been adapted dynamically over the years of the existence of this center as recently exemplified by a restructuring so as to maximize the unique and extraordinary resources of the Icahn School of Medicine at Mount Sinai and of the newly expanded Mount Sinai Health System. The MSADRC is co-located at the James J. Peters VAMC, and MSADRC. It takes responsibility for the enhancements made available through clinical and research opportunities of the VA system, including resources of space, patient cohorts, and data systems. The Internal Advisory Board insures that the vibrant local clinical and research community is leveraged to the advantage of the MSADRC. An External Advisory Board provides guidance and review to the ADRC leadership and communicates to the NIA Program Staff. The leadership assures that the Center is aware of national and international commitments as well as of opportunities to maximize our effectiveness. Specific responsibilities include financial administrative and regulatory management. Also this Core is responsible for conducting a highly effective Pilot Program to identify, sponsor, and nurture new research efforts and investigators who are either at early stages in their careers or who are established investigators new to the field of AD research. This program has been strengthened by combining efforts with other institutional entities including the Mount Sinai CTSA, CCARP, VA MERIT review system, the Brain Imaging Core (BIC) of the Department of Psychiatry, and the Center of Technology, Innovation, and Entrepreneurship. This Core also oversees the growth of new faculty in the area of Alzheimer's disease and related dementias through joint appointments across departments and across the wider Mount Sinai Health System. In this submission, we have proposed three topically related projects on the intersection of type 2 diabetes, insulin resistance, and Alzheimer's disease. This Core will ensure that resources are available to serve Project goals, that Projects have maximal opportunity to interact, and that Projects progress according to timelines and meet benchmarks of accomplishment.

DESCRIPTION (provided by applicant): The Mount Sinai Alzheimer Disease Research Center (MSADRC) continues its historic success in research by using its unprecedented resources and expertise to seize opportunities for innovative approaches to understand, treat, and ultimately prevent the earliest signs of cognitive loss due to Alzheimer's disease (AD) and other causes of dementia. We have conducted critical basic translational and clinical studies to characterize cognitive loss and dementia in the elderly. We have used the National Alzheimer's Project Act (NAPA) as a road map to focus our established strengths. We continue our commitment to therapeutic development with innovative and powerful systems biology approaches to establish networks that can identify new targets and select trial ready candidates through pharmacological repurposing and by using the novel opportunity offered by our role in the international stem cell consortium, to develop neural progenitors, approaches to find unique models for therapeutic targets. We will develop a trial ready registry of non- demented elders who are informed and eager to participate in prevention studies. We will expand our characterization of racially and ethnically diverse elders currently underrepresented in research, and ensure the opportunity for them to participate in clinical research fully, including genetic analysis, biomarker studies, and clinical trials. We will continue to collect brains from our well-characterized clinical populations and focus our efforts on the pathology associated with the transition from normal aging and cognitive impairment. Contributing to National Alzheimer's Coordinating Center resources with clinical, neuropathological, and neuroimaging data will be continued as well as our commitment to provide the National Cell Repository for AD with samples for every eligible participant in our cohort. In keeping with the recommendations of NAPA and the 2013 AD-Related Dementias Research Workshop to include in the study of AD- related disorders a specific focus on the contribution of vascular risks, we will build on our expertise by proposing 3 projects that focus on the intersection of type 2 diabetes (T2D) one of the most common comorbidities of the at risk age group of AD. In Project 1, we will characterize cognitive loss and dementia in T2D individuals, examining markers of AD and insulin resistance including inflammation and cerebrovascular disease to identify the individual contribution and interactive roles of each pathogenetic factor. Minority participation will be a major feature of ths project to assure that our findings are applicable to the most applicable and understudied individuals. In Project 2, our well-characterized participant cohorts and animal models will be used with stem cell technology to identify the contribution of insulin resistance through cell types. In project 3, we examine the effects of T2D and AD on angiogenesis and angiogenic complexes. Together these efforts are aimed at identifying targets for intervention and prevention of AD. The resources of the cores and opportunities of the projects support the multidisciplinary studies of the widest community of researchers in cognitive loss and dementia.

Abstract This resubmission responds to ?PAR-16-365-Pilot Clinical Trials for the Spectrum of Alzheimer?s Disease and Age-related Cognitive Decline (R01)?. It will examine the efficacy of hyperbaric oxygen therapy (HBOT) in improving cognitive functioning in cognitively impaired elderly with diabetes (T2D), who have high risk for dementia. It is a collaboration of the Icahn School of Medicine at Mount Sinai, NY, the University of Wisconsin, the Sagol Center for Hyperbaric Medicine and Research at Asaf Harofeh Medical Center, Israel?one of the world?s largest and busiest hyperbaric units?and the Sheba Medical Center, Israel. HBOT is a treatment in which oxygen-enriched air (up to 100%) is administered to patients at a pressure above the ambient atmosphere. The combined action of hyperoxia and hyperbaric pressure leads to significant improvements in tissue oxygenation, resulting in cerebrovascular benefits with improved ischemic damage and cerebral blood flow. Recently, our group published compelling evidence from clinical trials indicating HBOT neurotherapeutic effects in stroke, with better cognitive function and elevated brain activity in SPECT. New preliminary data suggests potential neurotherapeutic effects of HBOT on T2D elderly with mild cognitive impairment (MCI), showing better cognitive performance and brain activity. We propose a randomized controlled clinical trial examining the short (12 weeks) and long-term (12 months) efficacy of HBOT. We will test hypotheses that HBOT compared to a sham condition improves cognitive function and increases cerebral blood flow and glucose utilization in MCI patients with T2D. Such patients are at high dementia risk and enriched in cerebrovascular disease, and thus have high potential for benefitting from HBOT. Aim 1 examines the potential beneficial effects of HBOT on cognition (with a primary composite measure of executive functions and episodic memory, both affected by T2D). Aim 2 examines effects of HBOT on ischemic injury which will be measured by CBF at the level of capillaries in gray matter (by MRI arterial spin labeling), and in macrovessels (by a novel 4D Flow MRI technology developed by our group). Aim 3 focuses on effects of HBOT on cerebral glucose utilization using [F18]FDG-PET. Finally, Aim 4 investigates mediation by the biomarkers, i.e. whether their inclusion in a mediation model will attenuate the effect of HBOT on cognition, suggesting them as underlying mechanisms. This study will be performed in Israel, where there is optimal infrastructure and expertise for all the study components at significantly lower costs. HBOT can be widely deployed in the US so if successful, this pilot study will provide the basis for a multi-center large-scale clinical trial for definitive evidence of its benefits to cognition in T2D patients at high dementia risk. Despite advances in our understanding of risk factors and the pathologic basis for dementia, treatments are of very limited effects. As the proportion of elderly increases, the accelerating prevalence of T2D and dementia amplifies this application?s public health impact.

DESCRIPTION (provided by applicant): Elderly patients undergoing anesthesia and surgery frequently suffer from postoperative cognitive dysfunction (POCD) and postoperative delirium (PD). The cause of these entities is unknown; specifically it is unclear what part the anesthetics play in the development of POCD and PD. We hypothesize that elderly patient's cognitive capacities recover more slowly after receiving general anesthesia, perhaps because they have more limited cognitive reserve. A more prolonged recovery would confound diagnoses of POCD and PD and potentially puts patients who are discharged on the day of surgery at risk of not understanding postoperative instructions. The trajectory of postoperative cognitive recovery has never been explored and elderly participants have been explicitly not included in any type of emergence research. To explore this vital area we propose to study young and elderly volunteers with a combination of two state of the art neuropsychological tests (postoperative quality of recovery scale and the NIH Toolbox) and magnetic resonance imaging. Starting from baseline, we will determine multiple cognitive domains and resting state networks, treat the volunteers with general anesthesia, and then explore the recovery of the cognitive domains and alterations in functional networks. The data acquired in this project will have both clinical and theoretical relevance. Apart from distinguishing immediate drug effects from POCD and PD, characterization of the trajectory of cognitive recovery in the elderly could affect changes in clinical practice vis a vis the criteria we employ to determine, for example, hospital discharge in this population. Currently many elderly patients are (perhaps inappropriately) sent home on the day of surgery. Furthermore, characterization of the trajectory of recovery in this population would enable us to better educate our patients and those who help care for them as to the proper expectations and time course for their recovery from anesthesia. Most fundamentally, the trajectory at which various patients recover from anesthesia is the most unappreciated confounding factor in this debate on the direct and indirect effects of anesthetic drugs. The effects of the anesthesia itself are theoretically (and as we propose here, practically) separable from those due to surgery, by studying the former in the absence of the latter we can delineate the trajectory of cognitive recovery from anesthesia itself, developing an understanding that is currently lacking and yet necessary to understand POCD and PD in general.

The Mount Sinai Alzheimer Disease Research Center (MSADRC) continues its historic success in research by using its unprecedented resources and expertise to seize opportunities for innovative approaches to understand, treat, and ultimately prevent the earliest signs of cognitive loss due to Alzheimer's disease (AD) and other causes of dementia. We have conducted critical basic translational and clinical studies to characterize cognitive loss and dementia in the elderly. We have used the National Alzheimer's Project Act (NAPA) as a road map to focus our established strengths. We continue our commitment to therapeutic development with innovative and powerful systems biology approaches to establish networks that can identify new targets and select trial ready candidates through pharmacological repurposing and by using the novel opportunity offered by our role in the international stem cell consortium, to develop neural progenitors, approaches to find unique models for therapeutic targets. We will develop a trial ready registry of nondemented elders who are informed and eager to participate in prevention studies. We will expand our characterization of racially and ethnically diverse elders currently underrepresented in research, and ensure the opportunity for them to participate in clinical research fully, including genetic analysis, biomarker studies, and clinical trials. We will continue to collect brains from our well- characterized clinical populations and focus our efforts on the pathology associated with the transition from normal aging and cognitive impairment. Contributing to National Alzheimer's Coordinating Center resources with clinical, neuropathological, and neuroimaging data will be continued as well as our commitment to provide the National Cell Repository for AD with samples for every eligible participant in our cohort. In keeping with the recommendations of NAPA and the 2013 AD-Related Dementias Research Workshop to include in the study of AD- related disorders a specific focus on the contribution of vascular risks, we will build on our expertise by proposing 3 projects that focus on the intersection of type 2 diabetes (T2D) one of the most common comorbidities of the at risk age group of AD. Together these efforts are aimed at identifying targets for intervention and prevention of AD. In this revision application we are adding a new Genetics and Genomics Core (Core F) to the P50. The main goals of this core are to provide a bank of biospecimens from ADRC participants and to centralize an integrated database of genomic data for ADRC subjects. Secondly, we will begin collecting longitudinal biospecimens for future biomarker studies in peripheral monocytes. The resources of the cores and opportunities of the projects support the multidisciplinary studies of the widest community of researchers in cognitive loss and dementia.

PROJECT SUMMARY/ABSTRACT The fastest growing segments of older adults include those from groups that have traditionally been underrepresented in research studies. Those conducting research in aging need understanding of how to engage with communities as partners to develop research proposals and recruitment strategies that motivate and sustain participants from these groups. Many approaches to recruitment focus on identifying large pools of potential participants and ?trial ready cohorts? of pre-screened individuals. These approaches do not yet have established success in aging populations and the platforms used to reach these large numbers may have limited value in aging and diverse cohorts, which depend on trusted sources to make decisions. Our project will develop, evaluate, and document a replicable process for creating the capacity and infrastructure for community-involvement necessary for ensuring enrollment goals of aging studies can be achieved and establishing the approaches by which to do so. Building on the established model for cultivating and leveraging collaboratory teams across scientific and non-scientific divides to address issues of equity in specific research areas, this project will develop, evaluate and disseminate a Recruitment Accelerator for Diversity in Aging Research, Cognitive Loss and Dementia (RADAR-CLD) at Mount Sinai and SUNY Upstate. Both the NYC and Syracuse sites have strong community partners and establishing the project in New York City and Syracuse allows an evaluation of the effectiveness of the Community Research Liaison (CRL) and Accelerator model in two distinct communities. The Accelerators will focus on the topic of recruiting and retaining diverse, older adults with or at risk for cognitive loss with application to NIH-funded studies. The project includes workforce development to create a novel professional, the CRL, not previously recognized in clinical trial staffing, who will be uniquely trained to maximize research participation by connecting the community and research partners through the Accelerator activities. The CRL will assemble collaborative teams including community seniors, patients, advocates, caregivers, families, clinicians, funders, public health and advocacy professionals, research teams and industry to be prepared with skills for effective group dynamics by the CRL and may create established networks for recruitment education and outreach. Accelerator meetings around specific NIH-studies will be organized and Accelerator-recommended, stakeholder-led projects will be supported by RADAR-CLD funds, with outcomes on recruitment, retention and participation diversity documented. Manuals of materials and methods for developing and sustaining the CRL professional and Accelerator infrastructure will be disseminated for implementation at other sites. Documentation of process and establishment of models of cost and time will allow appropriate allocation of budgets toward sustainability of the proposed CRL capacity, Accelerator infrastructure and innovative engagement activities for promoting diverse participation in aging research.