Oscar L. Lopez, M.D. - US grants

The purpose of this study is to identify the individuals with the highest risk to develop AD. To accomplish this goal we will conduct a longitudinal study on at-risk individuals who have been identified based on the presence of mild cognitive impairment (MCI). The subjects were part of the Pittsburgh cohort of the Dementia Study of the Cardiovascular Health Study (CHS). The CHS Dementia study ended in 1999, and the present study will follow those participants identified as MCI or normal control. Specifically, we study 142 MCI subjects and 218 controls with detailed neurobehavioral, neuroimaging, and neurological examinations. Each of these former CHS participants had clinical and neuropsychological exams, MRI studies, and blood samples in 1992-93 and 1997-98. In 1998-1999, each of these participants had detailed neuropsychological, psychiatric, and neurological testing that allowed us to identify a clear and well- characterized cohort of MCI and normal elderly individuals. Consequently, we are in the unique position to examine the natural history of the development of AD in a population-based sample. The study will make use of prospective structural and perfusion MRI- scans, genetic factors (e.g., apolipoprotein E epsilon4 allele), biological markers (e.g., inflamation markers [Inter-leukin-6, C- reactive protein, and Tumor necrosis factor alpha) and plasma beta amyloid level [Abeta1-40 and Abeta 1-40]), and specific neuropsychological measures as markers for the development of AD. We propose that there are two types of MCI: 1) The MCI amnestic- type, which represents a distinct entity, with a significantly increased risk to develop AD (10 percent per year). 2) the MCI multiple cognitive deficit-type, which represents a temporal elongation of the normal transition from aged to AD. Consequently, these participants will have a reduced risk to develop AD (5 percent per year).

[unreadable] DESCRIPTION (provided by applicant): The Cardiovascular Health Study-Cognition Study (CHS-CS), "Predictors of Alzheimer's disease (AD) in mild cognitive impairment (MCI)" (AG 20098) has carefully followed 532 CHS-CS participants over the past 4 years. These were 83% of the 924 eligible participants from the original CHS Pittsburgh Memory Study initially established in 1992-94. The participants have been followed with annual neuropsychological evaluations, information from informants and detailed clinical information. Data on risk factors are available since1988, when the parent CHS was initiated. By 2005, 32% of the normals (approximately 6% per year) and 63% of the MCls (approximately 16% per year) were demented; and 359 are alive in 2006, with a mean age of 86. This study has shown that most MCI convert to dementia, that many normals convert to dementia very rapidly, that the MRI findings are crucial for understanding risk, including vascular disease in the brain, global brain atrophy and focal brain abnormalities. The proposed 4-year renewal includes 3 years of follow up and repeat MRIs for the surviving cohort in order to evaluate the characteristics of individuals who survive free of dementia to determine the relationship of risk factors and MRI changes over an approximate 18-20 year follow up for the 924 participants, to analyze the relationship of lifestyles, genetic and MRI attributes to the risk of dementia, MCI and remaining normal. Most of the resources in this proposed follow up are dedicated to the detailed evaluation of the MRIs, to careful evaluation of the remaining survivors and for detailed final analysis. From the data gathered in the first 3 years of this project, we have developed a central hypothesis to guide our research questions. Specifically, that the pathological state of AD exists years prior to the development of the clinical signs/symptoms of the dementia syndrome. We view MCI as the transitional state between normal cognition and frank dementia, and that in the absence of other comorbid conditions, MCI is AD. In this context, our study of the variables that indicate the presence of neuropathological change (e.g., structural and perfusion MRI, plasma beta-amyloid) and the factors that modify the risk to express the clinical syndrome takes on an added importance. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The University of Pittsburgh Alzheimer's Disease Research Center (PITT-ADRC) has shown a clear scientific evolution over the past three decades. Since our inception, we have advanced the areas of AD neuropsychiatry, the natural history of AD, validation of clinical criteria, and clinico-pathological correlations. We have pioneered new PET techniques for amyloid imaging. We have used a multidisciplinary approach to better understand the transition from normalcy to dementia, have explored the biology of more aggressive forms of AD characterized by psychosis, and have made and contributed to new insights in genetics. This solid scientific background has allowed the PITT-ADRC to develop areas of excellence, which will serve as the basis for the future of the Center. These are reflected in the Center's cores and projects, and most notably in the large number of studies we support in Pittsburgh and at the national and international level. Equally important, the availability of a rich, multidisciplinary training environment along with dedicated, skilled mentoring creates the perfect laboratory to develop and advance young investigators. With our Projects, we are committed to remain at the forefront of the scientific efforts to understand the pathological processes involved in the etiology of AD. Project-1 takes a comprehensive neuroimaging approach to studying subjective cognitive decline (in the context of personality factors), with a focus on amyloid PET imaging as the putative earliest indicator of AD pathology. Project-2 will combine amyloid PET and tau PET (with T807) to examine fundamental characteristics of the T807 tracer with particular interest in the tau status of cognitively normal control subjects who are amyloid-negative but already show hypometabolism or hippocampal atrophy suggestive of suspected non-amyloid pathophysiology (SNAP). Project 3 will examine the pathological basis of psychotic symptoms in AD patients, which have a tremendous effect on the quality of life of the patients and their families, and are risk factors for rapid clinical progression of the disease and mortality. The PITT-ADRC, through its pilot projects, engages and involves as many clinical and basic researchers as possible. This extends to all aspects of research relevant to AD and related dementias. The PITT-ADRC is highly committed to leverage the strengths of the network of centers to provide large numbers of samples and standardized clinical data collection from our participants. The PITT-ADRC has designed novel methodology that improves the accessibility to its database to local and national researchers, and it has been a key player in multiple studies that advanced the understanding of AD pathology and its possible implications for the development of novel treatments and other symptoms. Therefore, we provide an excellent environment that enhances cutting-edge research by bringing together a multidisciplinary team of investigators to study AD and other dementias, and to improve health care delivery.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Cardiovascular Health Study-Cognition Study (CHS-CS), "Predictors of Alzheimer's disease (AD) in mild cognitive impairment (MCI)" (AG 20098) has carefully followed 532 non-demented participants over the past 3 years. These were 83% of the 924 eligible participants from the original CHS Pittsburgh cognition study initially established in 1992-94. The participants have been followed with annual neuropsychological evaluations, information from informants and detailed clinical information. By 2006, 32% of the normals (approximately 6% per year) and 63% of the MCIs (approximately 16% per year) will be demented;and 359 are alive in 2006, with a mean age of 86. This study has shown that most MCI convert to dementia, that many normals convert to dementia very rapidly, that the MRI findings are crucial for understanding risk, including vascular disease in the brain, global brain atrophy and focal brain abnormalities. The proposed 4-year renewal includes 3 years of follow up and repeat MRIs for the surviving cohort in order to evaluate the characteristics of individuals who survive free of dementia to determine the relationship of risk factors and MRI changes over an approximate 18-20 year follow up for the 924 participants, to analyze the relationship of lifestyles, genetic and MRI attributes to the risk of dementia, MCI and remaining normal. Most of the resources in this proposed follow up are dedicated to the detailed evaluation of the MRIs, to careful evaluation of the remaining survivors and for detailed final analysis. This is the only large population-based study for the foreseeable future with long term follow up, repeat MRIs and careful neuropsychological evaluation. From the data gathered in the first 3 years of this project, we have developed a central hypothesis to guide our research questions. Specifically, that the pathological state of AD exists years prior to the development of the clinical signs/symptoms of the dementia syndrome. We view MCI as the transitional state between normal cognition and frank dementia, and that in the absence of other comorbid conditions, MCI is AD. In this context, our study of the variables that indicate the presence of neuropathological change (e.g., structural and perfusion MRI, plasma beta-amyloid) and the factors that modify the risk to express the clinical syndrome takes on an added importance.

2-amino-4-mercaptobutyric acid; 21+ years old; APOE [{C0003595}]; Active Follow-up; Adult; Adverse Experience; Adverse effects; Adverse event; Age; Aged 65 and Over; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimers Dementia; Alzheimers disease; Amentia; Analysis, Data; Ancillary Study; Apo-E; ApoE; Apolipoprotein E; Appendix; B-Cell Differentiation Factor Gene; B-Cell Stimulatory Factor 2 Gene; BSF-2 Gene; BSF2 Gene; Blood Serum; Brain scan; Butanoic acid, 4,4'-dithiobis(2-amino)-; C-reactive protein; Cardiovascular; Cardiovascular Body System; Cardiovascular system; Cardiovascular system (all sites); Cessation of life; Clinic; Clinical; Clinical Trials Data Monitoring Committees; Cognition; Cognitive; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Complementary and alternative medicine; Computers; Consensus; DNA; Data; Data Analyses; Data Coordinating Center; Data Coordination Center; Data Monitoring Committees; Data and Safety Monitoring Boards; Death; Dementia; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Deoxyribonucleic Acid; Diagnosis; Diagnostic; Disturbance in cognition; Dose; Drugs; EGb-761; EGb761; Elderly; Elderly, over 65; Enrollment; Epidemic; Epidemiologic Research; Epidemiologic Studies; Epidemiological Studies; Epidemiology Research; Evaluation; Event; Folic Acid; Funding; GBE 761 ONC; Genotype; Gingkgo; Gingko; Ginkgo; Ginkgo biloba; HSF Gene; Haplotypes; Hepatocyte Stimulatory Factor Gene; Homocysteine; Homocysteine, L-Isomer; Homocystine; Human, Adult; Hybridoma Growth Factor Gene; IFNB2 Gene; IL-6 Gene; IL6; IL6 gene; Image; Impaired cognition; Incidence; Individual; Interferon, Beta-2 Gene; Interleukin 6 (Interferon, Beta 2) Gene; Interleukin-6 Gene; Investigators; MRI Scans; Maidenhair Tree; Maryland; Medication; Memory; Method LOINC Axis 6; Methodology; Mortality; Mortality Vital Statistics; N-(4-(((2-Amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl)amino)benzoyl)-L-glutamic acid; Nested Case-Control Study; Neurologic; Neurological; North Carolina; Organ System, Cardiovascular; Outcome; Outcome Study; PBO; Participant; Patient Self-Report; Persons; Pharmaceutic Preparations; Pharmaceutical Preparations; Phone; Placebos; Population; Preparation; Prevention; Primary Prevention; Primary Senile Degenerative Dementia; Programs (PT); Programs [Publication Type]; Proteins, specific or class, C-reactive; Proxy; Pteroylglutamic Acid; Publications; Randomized; Rate; Recruitment Activity; Research Design; Research Personnel; Research Resources; Researchers; Resources; Safety Monitoring Boards; Sampling; Scans, MRI; Scientific Publication; Score; Screening procedure; Self-Report; Serum; Sham Treatment; Site; Study Type; Study, Nested Case-Control; Study, Outcome; Target Populations; Telephone; Time; Treatment Side Effects; United States; Universities; Vascular, Heart; Vermiform Appendix; Vermont; Visit; Vitamin M; Washington; Work; adult human (21+); advanced age; base; cardiovascular risk; cardiovascular risk factor; case control; cerebrovascular; circulatory system; clinical research site; clinical site; cognitive dysfunction; cognitive function; cognitive loss; cognitively impaired; cohort; data management; day; decline in function; dementia of the Alzheimer type; design; designing; double-blind placebo controlled trial; double-masked controlled study; double-masked controlled trial; drug/agent; elders; enroll; follow-up; forest; functional decline; functional status; geriatric; imaging; late life; later life; mild cognitive disorder; mild cognitive impairment; mild neurocognitive disorder; neuropsychological; normal aging; older adult; older person; prevent; preventing; primary degenerative dementia; programs; randomisation; randomization; randomly assigned; recruit; screening; screenings; senile dementia of the Alzheimer type; senior citizen; sham therapy; side effect; study design; success; therapy adverse effect; treatment adverse effect; vitamin Bc

[unreadable] DESCRIPTION (provided by applicant): The Cardiovascular Health Study-Cognition Study (CHS-CS), "Predictors of Alzheimer's disease (AD) in mild cognitive impairment (MCI)" (AG 20098) has carefully followed 532 non-demented participants over the past 3 years. These were 83% of the 924 eligible participants from the original CHS Pittsburgh cognition study initially established in 1992- 94. The participants have been followed with annual neuropsychological evaluations, information from informants and detailed clinical information. By 2006, 32% of the normals (approximately 6% per year) and 63% of the MCIs (approximately 16% per year) will be demented; and 359 are alive in 2006, with a mean age of 86. This study has shown that most MCI convert to dementia, that many normals convert to dementia very rapidly, that the MRI findings are crucial for understanding risk, including vascular disease in the brain, global brain atrophy and focal brain abnormalities. The proposed 4-year renewal includes 3 years of follow up and repeat MRIs for the surviving cohort in order to evaluate the characteristics of individuals who survive free of dementia to determine the relationship of risk factors and MRI changes over an approximate 18-20 year follow up for the 924 participants, to analyze the relationship of lifestyles, genetic and MRI attributes to the risk of dementia, MCI and remaining normal. Most of the resources in this proposed follow up are dedicated to the detailed evaluation of the MRIs, to careful evaluation of the remaining survivors and for detailed final analysis. This is the only large population-based study for the foreseeable future with long term follow up, repeat MRIs and careful neuropsychological evaluation. From the data gathered in the first 3 years of this project, we have developed a central hypothesis to guide our research questions. Specifically, that the pathological state of AD exists years prior to the development of the clinical signs/symptoms of the dementia syndrome. We view MCI as the transitional state between normal cognition and frank dementia, and that in the absence of other comorbid conditions, MCI is AD. In this context, our study of the variables that indicate the presence of neuropathological change (e.g., structural and perfusion MRI, plasma beta-amyloid) and the factors that modify the risk to express the clinical syndrome takes on an added importance. The goals of this study are to examine the natural history of AD, from a normal cognitive state to dementia onset, with especial emphasis on the transitional phase (Mild Cognitive Impairment (MCI)). This analysis will be conducted in a context of a large cohort using detailed medical information, and it constitutes an integrative approach to truly understand the development of AD and MCI in the general population. [unreadable] [unreadable] [unreadable] [unreadable]

Core A: Administrative Core: Summary/Abstract: The University of Pittsburgh Alzheimer?s Disease Research Center (PITT-ADRC) Administrative (ADM) Core provides the organization and structure for planning and implementation of ADRC core and research activities. The core supervises all PITT-ADRC functions and the Clinical, Data Management & Statistics, Neuropathology, Biomarker and Neurogenetics, Neuroimaging, and Outreach, Engagement and Education Cores, as well as the Research and Education Component. The ADM Core monitors budgets to ensure fiscal responsibility; organizes the review and funding process for the Developmental Projects and for the philanthropically funded pilot studies. It monitors all PITT-ADRC research projects utilizing ADRC subjects or resources. This core determines new research directions, including the recruitment of new investigators to work in AD. Establishment of outreach efforts to the medically underserved and minority communities are directed and stimulated by the Core. The Core also oversees participation in multicenter studies, data transfer to NIA databases, tissue and DNA samples to NIA repositories, cross-ADC collaborations, and other national and international initiatives. Through the establishment of a comprehensive communications system the Core Leaders, investigators, and staff maintain an integrated, coherent and multidisciplinary focus. The goals of the ADM Core are achieved by the Executive Committee, which is comprised of the Director, Co-Director, Advisory Co-Director, Center Administrator, and Core and Project Leaders. It is aided in these tasks by advice of the Internal and External Advisory Committees, which is chaired by the Senior Vice Chancellor/Dean of the Medical School, and includes the Chairmen of Psychiatry and Neurology Departments, and the former Chair of Epidemiology at the University of Pittsburgh. They provide guidance on policy, administration, and scientific direction, as well as ensure that all schools of the Health Sciences and facilities of the University of Pittsburgh provide full cooperation in the execution of ADRC activities. The External Advisory Board is comprised of nationally respected researchers and clinicians with expertise in disciplines relevant to AD. They provide scientific critiques of research and operations of the PITT-ADRC, as well as recommendations for new initiatives. The ADM Core coordinates a well-established research infrastructure that will serve to the local, national, and international scientific community. We anticipate that the ADM Core will continue improving the ADRC data distribution. We have an exemplary record of data sharing and collaboration.

Alzheimer's disease (AD) is the most frequent form of dementia in the elderly, and its prevalence rises substantially between ages 65 and 85, doubling every 5 years such that one has a close to a 50% chance of expressing the disease by age 85. AD inexorably progresses to severe cognitive and functional states with subsequent increase risk of institutionalization and death. This proposal focuses on the understanding of the pathophysiological mechanisms that influence the rate of progression in the very early stages of the disease;the first year after the conversion from mild cognitive impairment (MCI) to AD. This is a cross-sectional and longitudinal study that will examine the relationship between sub-clinical vascular disease, structural and perfusion MRI, and in vivo amyloid cerebral deposition measures in subjects with early probable AD. Natural history studies as well clinical trials have shown a tremendous variability in the rates of progression of AD patients. However, we do not know why some patients with AD progress slowly or more rapidly. Whether this is related to a pathological heterogeneity of the disease, to the presence of comorbid factors, or both, still has to be determined. This study will test the hypothesis that vascular disease decreases grey matter volume and rCBF in limbic and paralimbic areas. This renders these individuals in their early stages of AD more vulnerable to a rapid clinical progression of the disease. These changes in brain structure and function will be due to tissue injury secondary to long-term effects of vascular disease, and they will be associated with altered kidney function and cardiovascular disease, which are also a general manifestation of vascular disease. In addition, this vulnerability state caused by cerebrovascular damage precludes the brain to mount compensatory mechanisms, especially in the early stages of the disease, and consequently, it needs less amyloid deposition for the expression and progression of the clinical symptoms. To accomplish the study objectives, we will obtain PET/PIB, structural MRI, arterial spin-labeled (ASL) MRI, and cardiovascular and kidney mesures (cystatin-C) in a group of subjects at the moment of the conversion from MCI to AD (n=20) and a group of normal controls (n=10). These subjects are part of a group of MCI patients and normal controls with PET/PIB and structural MRI completed through an on-going study conducted by Dr. W. Klunk (a co-investigator in this proposal), and who are being followed at the Alzheimer's Disease Research Center (ADRC).

PROJECT SUMMARY (See instructions): This proposal is oriented to examine the relationship between the two most important CNS pathologies that occur in the elderly (Alzheimer's disease [AD] and vascular disease) during the pre-symptomatic phase of AD. We will specifically test the hypothesis that the clinical effects of amyloid deposition detected in vivo in the brain of normal individuals who progress to mild cognitive impairment (MCI) and later to AD is modulated by sub-clinical vascular disease. The central hypothesis of this study is that cognitively normal subjects with systemic and cerebral vascular disease will be less likely to mount a compensatory response to amyloid deposition. Elderly subjects with vascular disease, in whom the neuropathological cascade leading to AD has already started, will be less likely to maintain normal cerebral metabolism; they will have a shorter latency period, and a greater incidence of MCI. By contrast, cognitively normal subjects with less vascular disease will have more amyloid deposition, since they will be able to compensate and maintain a longer 'latency period. This longitudinal study will examine the MRI, PET, and cerebral and systemic vascular characteristics of 70 cognitively normal subjects participating of the Ginkgo Evaluation of Memory Study (GEMS). The GEMS was conducted to determine effectiveness of ginkgo biloba versus placebo in lowering the incidence of all-cause dementia and AD in normal elderly subjects and those with MCI. The GEMS has conducted careful annual cognitive evaluations since 2001 (mean follow-up: 8.5 years) on 966 subjects in Pittsburgh, and the study was completed in 2008. As part of the last examination to be completed in 2010, all non-demented participants in Pittsburgh were invited to have an MRI of the brain and a PET scan with an amyloid ligand (Pittsburgh Compound B), and approximately 200 subjects will be entered in the last phase of GEMS. From this population, we will select 70 cognitively normal participants for the present study; 35 without and 35 with amyloid deposition. Consequently, by sampling from the GEMS, we will be in the unique position of examining the relationship between vascular disease, amyloid deposition and onset of cognitive changes in a normal elderly population.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Cardiovascular Health Study-Cognition Study (CHS-CS), "Predictors of Alzheimer's disease (AD) in mild cognitive impairment (MCI)" (AG 20098) has carefully followed 532 non-demented participants over the past 3 years. These were 83% of the 924 eligible participants from the original CHS Pittsburgh cognition study initially established in 1992-94. The participants have been followed with annual neuropsychological evaluations, information from informants and detailed clinical information. By 2006, 32% of the normals (approximately 6% per year) and 63% of the MCIs (approximately 16% per year) will be demented;and 359 are alive in 2006, with a mean age of 86. This study has shown that most MCI convert to dementia, that many normals convert to dementia very rapidly, that the MRI findings are crucial for understanding risk, including vascular disease in the brain, global brain atrophy and focal brain abnormalities. The proposed 4-year renewal includes 3 years of follow up and repeat MRIs for the surviving cohort in order to evaluate the characteristics of individuals who survive free of dementia to determine the relationship of risk factors and MRI changes over an approximate 18-20 year follow up for the 924 participants, to analyze the relationship of lifestyles, genetic and MRI attributes to the risk of dementia, MCI and remaining normal. Most of the resources in this proposed follow up are dedicated to the detailed evaluation of the MRIs, to careful evaluation of the remaining survivors and for detailed final analysis. This is the only large population-based study for the foreseeable future with long term follow up, repeat MRIs and careful neuropsychological evaluation. From the data gathered in the first 3 years of this project, we have developed a central hypothesis to guide our research questions. Specifically, that the pathological state of AD exists years prior to the development of the clinical signs/symptoms of the dementia syndrome. We view MCI as the transitional state between normal cognition and frank dementia, and that in the absence of other comorbid conditions, MCI is AD. In this context, our study of the variables that indicate the presence of neuropathological change (e.g., structural and perfusion MRI, plasma beta-amyloid) and the factors that modify the risk to express the clinical syndrome takes on an added importance.

Core A: Administrative Core Abstract: The University of Pittsburgh Alzheimer's Disease Research Center (PITT-ADRC) Administrative Core provides the organization and structure for planning and implementation of ADRC core and research activities. The core supervises all PITT-ADRC functions and the Clinical, Data Management & Statistics, Neuropathology, Neurogenetics, Neuroimaging, and Outreach, Recruitment and Education Cores. The Administrative Core monitors PITT-ADRC budgets to ensure fiscal responsibility; organizes the review and funding process for pilot studies, and monitors ADRC research projects, pilot projects and studies utilizing ADRC subjects or resources. This core determines new research directions, including the recruitment of new investigators to work in AD. Establishment of outreach efforts to the medically underserved and minority communities are directed and stimulated by the Core. The Core also oversees participation in multicenter studies, data transfer to NIA databases, tissue and DNA samples to NIA repositories, cross-ADC collaborations, and other national and international initiatives. Through the establishment of a comprehensive communications system including, the Core Leaders, project investigators, and staff will maintain an integrated, coherent and multidisciplinary focus. The goals of the Administrative Core are achieved by the Executive Committee, which is comprised of the Director, Co-Director, Associate Director, Center Administrator, and Core and Project Leaders. It is aided in these tasks by the guidance of the Internal (IAC) and External (EAC) Advisory Committees. The IAC is composed of the Dean of the School of Medicine, Chairs of Neurology and Psychiatry and former Chair of Epidemiology and provides guidance on policy, administration, and scientific direction, as well as ensure that all schools of the Health Sciences and facilities of the University of Pittsburgh provide full cooperation in the execution of ADRC activities. The EAC is comprised of nationally respected researchers and clinicians with expertise in disciplines relevant to AD. They provide scientific critiques of research and operations of the ADRC, as well as recommendations for new initiatives. Since the inception of the PITT-ADRC, the Administrative Core has shaped and coordinated a well- established research infrastructure that has served the local, national, and international scientific community. By continually updating and improving our mechanisms for data and sample distribution the Administrative Core has helped the PITT-ADRC achieve an exemplary record of data sharing and collaboration.

Project-1 Summary/Abstract: Our group has been testing the hypothesis that systemic and cerebral vascular diseases are risk factors for Alzheimer's disease (AD), and that vascular disease modulates the onset of the cognitive syndrome. That is, there is a vascular-related vulnerability state that alters brain structure and regional blood flow, which interferes with the brain's ability to compensate for the development of the AD pathology, and thus reducing the clinical latency period for the onset of MCI and later clinical AD. However, in the process of testing this hypothesis, we have found that there is close relationship between A? deposition and vascular disease, and that the pathological events leading to clinical dementia may be more complex and heterogeneous than previously thought. These new findings indicate that vascular disease has a double role in the pathophysiology of AD; as a factor that alters brain structure and as a contributor to A? deposition. We believe that is essential to compare and contrast the relative merits of two hypotheses: 1) vascular disease, A? deposition and neurodegeneration are independent predictors of dementia, and increased vascular disease increases the risk of earlier manifestation of cognitive symptoms by increasing a vulnerability state and interfering with vascular-related compensatory mechanisms, and 2) vascular disease accelerates the A? deposition, and consequently, this interaction accelerates the onset of clinical symptoms. While there are subtle differences between them, the implications of the two are critically different, and this can affect our understanding of the pathophysiology of dementia in old age, and by extension, its preventive treatments. In order to achieve the study aims, we will complete the follow-up of 191 individuals at high risk for AD (age 85+) who were followed with detailed annual clinical evaluations since 2000, had C11 Pittsburgh compound B (PiB) PET and brain MRI studies, and measures of inflammatory markers in 2009, and structural and perfusion MRI and PiB PET, and vascular studies between 2010-11 and 2015. In this proposal, we will complete annual neuropsychological and neurological exams on all participants, repeat structural and arterial spin-labeled MRI, and PiB PET scans to identify abnormalities in CNS structure, function and A? deposition, repeat carotid Doppler, EKG, and measures of arterial stiffness to determine severity of systemic sub-clinical vascular disease, determine the levels of inflammatory markers, and perform tau ligand scans using [F-18]AV-1451 PET to determine severity of tau protein deposition. At the end of the proposed study, we will have two decades of data, which include clinical evaluations, laboratory tests, incidence and prevalence of clinical and subclinical cardiovascular disease. This provides us with a unique opportunity to examine the pathological mechanisms that lead to abnormal cognition in the elderly.

ABSTRACT The University of Pittsburgh Alzheimer's Disease Research Center (PITT-ADRC) has shown a clear scientific evolution over the past three decades. Since our inception, we have advanced the areas of AD neuropsychiatry, the natural history of AD, validation of clinical criteria, and clinico-pathological correlations. We have pioneered new positron emission technology (PET) techniques for amyloid imaging. We have used a multidisciplinary approach to better understand the transition from normalcy to dementia, have explored the biology of more aggressive forms of AD characterized by psychosis, and have made and contributed to new insights in genetics. This solid scientific background has allowed the PITT-ADRC to develop areas of excellence, which will serve as the basis for the future of the Center. These are reflected in the Center's cores and projects, and most notably in the large number of studies we support in Pittsburgh and at the national and international level. Equally important, the availability of a rich, multidisciplinary training environment along with dedicated, skilled mentoring creates the ?perfect laboratory? to develop and advance young investigators. With our Projects, we are committed to remain at the forefront of the scientific efforts to understand the pathological processes involved in the etiology of AD. Project-1 takes a comprehensive neuroimaging approach to studying subjective cognitive decline (in the context of personality factors), with a focus on amyloid PET imaging as the putative earliest indicator of AD pathology. Project-2 will combine amyloid PET and a measure of synaptic density (11C- UCB-J) to examine pathological status of cognitively normal control subjects who are amyloid- negative but already show hypometabolism or hippocampal atrophy. Project 3 will examine the pathological basis of psychotic symptoms in AD patients, which have a tremendous effect on the quality of life of the patients and their families, and are risk factors for rapid clinical progression of the disease and mortality. The PITT-ADRC, through its pilot projects, engages and involves as many clinical and basic researchers as possible. This extends to all aspects of research relevant to AD and related dementias. The goal of this Revision application is to augment the acquisition of brain imaging data (both MRI and PET), standardize the analysis of all imaging data acquired from ADRC participants, and to make these data available to ADRC investigators, collaborators, and large data repositories (e.g., NACC, ENIGMA) for further analysis.  

ABSTRACT We have found that very few individuals survived to age 90+ free of dementia or disability, suggesting that almost the entire older population is at risk for incident dementia, especially Alzheimer's disease (AD). Further, it is now generally accepted that AD pathology starts decades prior to clinical onset, and the factors that alter the risk to express a clinical dementia are generally cumulative such that the presence of these factors in midlife are associated with dementia in old age. Therefore, it is imperative to understand the processes that lead to dementia at their very early stages, especially when both, vascular and AD pathology are emerging. This proposal will test the hypothesis that midlife systemic atherosclerotic and arteriosclerotic vascular disease, irrespective of subsequent treatment, is a major risk factor for the development of subclinical AD pathology, and its clinical expression. At the end of this study, we will know whether subclinical systemic vascular disease in midlife accelerates the presence of incident cerebral vascular disease and AD pathology in non-demented subjects, and whether the emerging vascular process leads to amyloid or tau protein deposition. In addition, we will be able to describe the compensatory mechanisms that allow a person to maintain normal cognition and function. If we can confirm our hypotheses, there will be strong evidence (esp., among middle aged individuals) for aggressive interventions to prevent the progression of vascular disease in order to ameliorate the development of subclinical AD pathology, and later the onset of its clinical symptoms. We will study non-demented individuals who are enrolled in an ongoing community-based Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study that began in 2003 and has collected a wealth of vascular measures over time. Approximately 1,400 participants are currently in the study; 43% are African- Americans. The subjects will be stratified in four groups based on the presence or absence of atherosclerosis (i.e., arterial endothelial dysfunction) or arteriosclerosis (i.e., pulse pressure) at study entry in 2003. Specifically, we will complete annual clinical evaluations (neuropsychological, neurological, psychiatric) on 500 non-demented subjects age 45-59 at the onset of HeartSCORE in 2003, and from this group, we will identify 400 who will undergo amyloid and tau ligand PET, structural and functional MRI scans, and cardiovascular evaluations (100 in each group); 45% of each group will be African-American. The PET, MRI, and cardiovascular exams will be repeated in a subgroup of 160 participants (40 in each group). Blood tests for cystatin C levels, lipid profile, and glucose levels will be obtained. Measures of physical activity and fitness will be obtained twice during the observation time. Using these data, we will address a series of linked hypotheses concerning the associations among subclinical vascular disease, changes in brain structure and perfusion, and subclinical AD pathology during the transition from middle age to old age.

Overall: Summary/Abstract: The University of Pittsburgh Alzheimer?s Disease Research Center (PITT- ADRC) has shown a clear scientific evolution over the past three decades. Since our inception, we have advanced the areas of AD neuropsychiatry, genetics, natural history of AD, validation of clinical criteria, and clinico-pathological correlations, and have pioneered the development of PET amyloid tracers, which have transformed AD research. We have used a multidisciplinary approach to better understand the transition from normal cognition to dementia, have explored the biology of more aggressive forms of AD characterized by psychosis, and have made and contributed to new insights in genetics. This solid scientific background and investment in junior investigators has allowed the PITT-ADRC to develop areas of excellence, which form the foundation of our Center going forward. These are reflected in the Center?s cores, and most notably in the large number of studies we support in these areas in Pittsburgh and at national and international level. The PITT-ADRC is committed to remain at the forefront of the scientific efforts to understand the pathological processes involved in the etiology of AD. Along with the high level of research conducted by the PITT-ADRC, we are also dedicated to developing strong training programs to promote the careers of young investigators, consolidate the career of midlevel investigators, and to create strong ties with the community through educational and support programs. The PITT-ADRC is highly committed to leverage the strengths of the network of Centers to provide large numbers of samples and standardized clinical data collection from our participants. The PITT-ADRC has designed novel methodology that improves the accessibility of its database to local and national researchers, and it has been a key player in multiple studies that advanced the understanding of AD pathology and its possible implications for the development of novel treatments and other symptoms. Therefore, we provide an excellent environment that enhances cutting-edge research by bringing together a multidisciplinary team of investigators to study AD and other dementias, and to improve health care delivery. The methodology proposed in this application will lead us to the creation of a unique and well-characterized cohort of patients and normal control subjects assessed with state of the art clinical and biomarker methods. This will allow us to test multiple scientific hypotheses and to examine the short- and long-term public health outcomes of the pathophysiology of cognitive disorders in the adult. We believe that the PITT -ADRC will be at the center of the new era of AD research that will require a wealth of clinical and biological data, highly sophisticated biomarker methodologies, close inter-relationship among centers and institutions, creation and optimization of human resources, and enhanced communication with patients and families.