William J. Jagust, MD - US grants

Positron emission tomography (PET) has increased understanding of Alzheimer's disease (AD) by demonstrating specific abnormalities of regional cerebral blood flow and metabolism. However, these studies have not generally been longitudinal and have been limited to small patient groups; thus questions remain regarding the progression of these changes over time, and their relationship to neuropathological abnormalities and clinical progression of the disease. This application propose to utilize the more practical and widely available technique of single photon emission computed tomography (SPECT) to follow a large cohort of patients with AD and Parkinson's disease (PD) in order to understand the evolution of regional blood flow changes, their relationship to neuropathology and clinical disease progression, and the relationship of the two diseases to each other. The project will enroll 30 new AD patients and 20 new PD patients per year for the first three years and follow them with yearly SPECT studies and neuropsychological evaluations for the 5 years of the study. A total of 90 patients with AD and 60 patients with PD will be evaluated. A group of 26 AD patients is already enrolled in a preliminary study and will continue to be followed and augmented, assuring a long period of observation. The blood flow tracer 123I-N-isopropyl-p-iodoamphetamine (IMP) will be utilized with the Cleon multidetector scanner for SPECT imaging. A subset of 20 patients from each group will be studied using PET with the quantitative blood flow tracer 122I-N,N,N'-trimethyl-N'- (2-hydroxy-3-methyl-5-iodobenzyl)-1,3-propanediamine (HIPDM) in order to validate the SPECT studies. A major hypothesis is that while patients with mild and moderate AD will show temporoparietal blood flow deficits (which will increase in severity as the disease progresses), severely demented patients will also show frontal lobe hypoperfusion. Patients with PD, on the other hand, are expected to demonstrate frontal deficits in early disease stages while a temporoparietal pattern of hypoperfusion will appear in some patients and predict the development of a severe dementia with Alzheimer neuropathological features. These physiological abnormalities are expected to correlate with both the cognitive abnormalities revealed on neuropsychological testing, and the regional histopathological abnormalities seen post-mortem. Of major potential clinical significance is the prospect that different perfusion patterns will identify different clinical subtypes, elucidating the pathophysiological mechanisms responsible for the clinical heterogeneity of these diseases.

Positron emission tomography (PET) has increased understanding of Alzheimer's disease (AD) by demonstrating specific abnormalities of regional cerebral blood flow and metabolism. However, these studies have not generally been longitudinal and have been limited to small patient groups; thus questions remain regarding the progression of these changes over time, and their relationship to neuropathological abnormalities and clinical progression of the disease. This application propose to utilize the more practical and widely available technique of single photon emission computed tomography (SPECT) to follow a large cohort of patients with AD and Parkinson's disease (PD) in order to understand the evolution of regional blood flow changes, their relationship to neuropathology and clinical disease progression, and the relationship of the two diseases to each other. The project will enroll 30 new AD patients and 20 new PD patients per year for the first three years and follow them with yearly SPECT studies and neuropsychological evaluations for the 5 years of the study. A total of 90 patients with AD and 60 patients with PD will be evaluated. A group of 26 AD patients is already enrolled in a preliminary study and will continue to be followed and augmented, assuring a long period of observation. The blood flow tracer 123I-N-isopropyl-p-iodoamphetamine (IMP) will be utilized with the Cleon multidetector scanner for SPECT imaging. A subset of 20 patients from each group will be studied using PET with the quantitative blood flow tracer 122I-N,N,N'-trimethyl-N'- (2-hydroxy-3-methyl-5-iodobenzyl)-1,3-propanediamine (HIPDM) in order to validate the SPECT studies. A major hypothesis is that while patients with mild and moderate AD will show temporoparietal blood flow deficits (which will increase in severity as the disease progresses), severely demented patients will also show frontal lobe hypoperfusion. Patients with PD, on the other hand, are expected to demonstrate frontal deficits in early disease stages while a temporoparietal pattern of hypoperfusion will appear in some patients and predict the development of a severe dementia with Alzheimer neuropathological features. These physiological abnormalities are expected to correlate with both the cognitive abnormalities revealed on neuropsychological testing, and the regional histopathological abnormalities seen post-mortem. Of major potential clinical significance is the prospect that different perfusion patterns will identify different clinical subtypes, elucidating the pathophysiological mechanisms responsible for the clinical heterogeneity of these diseases.

Chronic alcoholism is well known to affect cerebral function. Nevertheless, the nosology and pathophysiology of alcohol-related brain impairment syndromes remain confusing and incompletely understood. Classifications of such syndromes have characteristically distinguished Korsakoff's syndrome (KS), described as an amnestic disorder consequent to diencephalic pathology, from alcoholic dementia (AlcD), a global disturbance in cognition which is presumably due to diffuse cortical damage. However, the existence of AlcD as a distinct syndrome is controversial, and the overlap between KS and AlcD has become increasingly apparent since KS patients show evidence of cortical impairment and AlcD patients show evidence of subcortical damage. This project will apply the technique of positron emission tomography (PET) combined with careful clinical and neuropsychological characterization of patient groups, to the study of alcohol-related brain impairment syndromes. The PET600 tomograph (2.6 mm resolution) with the glucose metabolic tracer 2-[18F]-fluoro-2-deoxyglucose (FDG) will be used to quantitate regional cerebral metabolic rates for glucose (rCMRglc), thus providing a measurement of regional brain function. The objective of the project is the definition of the brain regions which show impaired function in different alcoholic neurobehavioral syndromes in order to better classify these syndromes as well as understand the mechanisms underlying memory impairment in chronic alcoholism. The study will include subjects from four groups: non-alcoholic controls, non-demented alcoholics, patients with AlcD, and patients with KS. All subjects will undergo a careful medical and neurological screening examination, and will have a battery of cognitive tests designed to characterize and quantitate intellectual deficits. Evaluation of anterograde and retrograde memory, temporal discrimination, and release from proactive interference will be an important part of the test battery. All subjects will have PET-FDG studies as well as magnetic resonance imaging of brain structure. A particular feature of the study is the determination of rate constants for glucose transport and phosphorylation in a subset of patients from each group. The core hypothesis of this project is the expectation that the relative metabolic impairment of cortical and diencephalic brain regions will define the clinical presentation of the alcoholic neurobehavioral syndromes and will be related to the specific character of memory disorders. This work will have important consequences for classification of the alcoholic neurobehavioral syndromes which will allow further investigations in the field to proceed on a firmer footing. Characterization of the metabolic bases of these behavioral deficits will also provide important insights into the neural basis of memory function in humans.

nervous system; hormones; spectrometry; Primates; Mammalia;

The University of California, Davis Alzheimer's Disease Center (UCD ACD) has evolved to focus upon the scientific theme of understanding factors that influence the expression and progression of Alzheimer's disease (AD) with the particular goal of understanding how cerebrovascular disease and minority ethnicity interact with the AD. This theme has developed as the research projects associated with the AD in the previous funding cycle resulted in new ways of thinking that have informed ADC activities. In addition, the ADC will continues its long- term commitment to supporting and developing the general field of AD research at UC Davis and throughout Northern California. The ADC is composed of six cores: Administrative, Clinical, Education and Information Transfer (EITC), Neuropathology, Biostatistics and Data Management, and Neuroimaging. The Administrative Core provides overall guidance for scientific, policy, and procedural aspects of the ADC in addition to ensuring collaboration and communication throughout the ADC program. The Clinical Core will evaluate patients and controls to provide two key resources: a large subject pool of AD patients with research diagnostic evaluations who are available for recruitment into specific studies, especially cross sectional studies, and a longitudinally followed cohort of AD patients emphasizing coexisting cerebrovascular disease, African American or Hispanic ethnicity who are annually evaluated, and followed to autopsy. Two already effective satellite clinics will employ a screening approach to augment minority patient recruitment. The Neuropathology Core will perform brain retrieval for subjects in the longitudinal cohort who have enrolled in the autopsy program, will characterize the extent and severity of Alzheimer and cerebrovascular pathology, and maintain and bank of fixed and frozen tissue and DNA. The EITC will provide education to both the community and professionals, as well as assist in recruitment of minority subjects to the longitudinal cohort. The Neuroimaging Core will acquire MRI data on members of the longitudinal cohort and provide quantitative and semi- quantitative data on white matter hyperintensities, hippocampal atrophy , and cerebral atrophy. The Biostatistics and Data Management core will provide both statistical support and consulting to ADC research, and will maintain the already operational database that links all components of the ADC to one another to facilitate cross disciplinary research and reporting requirements.

DESCRIPTION (provided by applicant): Over the past decade, approaches to the diagnosis of dementia have subtly shifted from one in which various disorders are "ruled out" to one in which characteristic findings may be used to support a specific dementia diagnosis. This transition has in large part been fueled by advances in brain imaging that show relatively specific molecular and biochemical changes in Alzheimer's disease (AD) using positron emission tomography (PET), and characteristic anatomical changes using magnetic resonance imaging (MRI). The recent development of a PET imaging compound that labels amyloid, N-methyl [11C]2-(4'- methylaminophenyl)-6-hydroxybenzothiazole, nicknamed "PIB" for Pittsburgh compound B, is another major advance for the field that may help differentiate different causes of dementia. In particular, a relatively common group of degenerative dementias collectively known as frontotemporal lobar degeneration (FTLD) may be difficult to differentiate from AD during life. We hypothesize that the combination of PIB imaging along with traditional glucose metabolic PET imaging with [18F]Fluorodeoxyglucose (FDG) will effectively differentiate the two disorders. We plan to recruit a group of 45 patients with AD and 45 patients with FTLD through the Memory and Aging center at the University of California San Francisco, a major center for the study of AD and FTLD. Individuals will receive an intensive clinical diagnostic evaluation including cognitive testing, genetic testing, and MR imaging. They will be followed in a longitudinal cohort with a brain donation program. Subjects will be studied with PIB-PET and FDG-PET and both qualitative ratings and quantitative measurements of PIB and FDG uptake will be utilized. These measures will be compared to clinical diagnosis and, over the long term, autopsy diagnoses to define the sensitivity, specificity, and discriminative ability of the two techniques relative to the highest quality clinical diagnosis possible, and to one another. The significance of this project is that there are no current laboratory tests to differentiate these two dementing disorders. PIB could become a diagnostic tool that is useful in diagnosing AD and FTLD during life. This will be especially important as new treatments for both disorders are developed.

[unreadable] DESCRIPTION (provided by applicant): Brain aging may result in the decline of cognitive functions subsumed under the category of frontal/executive systems. These abilities include working memory, a form of memory that is important in storing and manipulating information over relatively short times. Considerable evidence from both behavioral and imaging studies with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) shows that various aspects of working memory decline or change with aging. Working memory depends upon a neurochemical system that utilzes dopamine as a neurotransmitter, a system that also declines with advancing age. Although a variety of neural systems may compensate for this loss, compensation is incomplete, and there is considerable variability in behavioral and physiological measures of working memory with aging. The core hypothesis of this project is that this age-associated variability is related to different levels of dopamine innervation in older people. We will explore this hypothesis by relating PET measures of dopamine function to behavioral measures of working memory performance and fMRI measures of brain activation during a working memory task. The project will recruit 60 healthy older (age 55-85) and 30 healthy younger (age 25-35) individuals who will undergo PET with the tracer [18F]fluorometatyrosine (FMT) to measure presynaptic dopaminergic function. Cognitive tests will assess generalized cognition and working memory. During fMRI subjects will perform a working memory task with variable loads (the Sternberg task) that is designed to elicit activation in dorsolateral prefrontal cortex. We will relate measures of FMT uptake in striatum and cortex to patterns of brain activation and behavior, hypothesizing that older people with lower FMT uptake will show increased brain activation during fMRI and poorer working memory performance, while older subjects with higher FMT uptake will show patterns of fMRI activation and working memory that are similar to younger individuals. The project is significant because brain aging is a multifactorial process characterized by variable degeneration and compensation in different brain systems. Understanding the basis of these age-related changes could provide the ability to design neurochemically specific treatments for remediation, as well as ways of differentiating different etiologies of age-related cognitive decline from one another. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Breast cancer is the most common form of cancer in women. An increasing emphasis on early detection, along with more effective treatments, has resulted in increased survival rates. While it is recognized that chemotherapy can cause cognitive impairment, often termed "chemobrain", most of the studies done to date have limitations and few have focused on underlying brain mechanisms. We propose to use neuroimaging, both MRI and PET, along with cognitive testing to evaluate the acute and relatively long-term effects of chemotherapy on brain structure and function in breast cancer patients. Our long-term goal is to establish a cohort of breast cancer patients in which to longitudinally evaluate chronic effects of chemotherapy on imaging measures and cognitive function. Three groups of breast cancer patients will be studied: a group that will receive chemotherapy plus hormonal therapy, and a group that will be treated with hormonal therapy only, and a group that will receive chemotherapy only. We will also study a group of healthy women as control group. All subjects will receive a baseline PET scan, MRI and cognitive testing. The chemotherapy groups will receive additional scans and cognitive testing at one and 18 months post- treatment to evaluate both acute and relatively long-term effects of chemotherapy. The other groups will also be scanned and tested at the same intervals. We hypothesize that the patients who receive chemotherapy will show reductions in cerebral glucose metabolism that may be global or regional. MRI will be used to explore both cortical and subcortical structural changes, such as hippocampal volume, whole brain volume, and white matter hyperintensities (WMH). Previous studies suggest that we may see increased WMH patients who receive chemotherapy. We expect to see both acute and long-term cognitive deficits in the chemotherapy groups, involving multiple cognitive domains. The proposed studies may help to define the mechanisms of cognitive impairment following treatment for breast cancer. This project is relevant to public health because identifying the mechanisms of cognitive impairment may lead to different treatment strategies that do not negatively impact cognitive function. They are also relevant to the overall mission of the NIH because of the negative impact that cognitive dysfunction has on quality of life.

DESCRIPTION (provided by applicant): The cognitive aging field has long debated whether presymptomatic brain disease accounts for a proportion of what is considered to be normal age-related cognitive decline. This is most notable in relation to Alzheimer's disease (AD) not only because it is a highly prevalent age-associated condition, but also because several features of AD are seen in normal aging. In particular, decline in episodic memory, deposition of [unreadable]- amyloid plaques, and neurofibrillary tangle-related hippocampal atrophy are all aspects of AD that are also common in cognitively intact older people. However, the effects of AD pathology are not straightforward and are likely to be mediated by intervening factors that can be characterized as vulnerability and reserve. Within the past several years, scientific advances have allowed the measurement of the multiple processes that may be involved in this model of age-related memory loss. Thus, it is possible to measure [unreadable]-amyloid with positron emission tomography (PET) and the amyloid imaging agent [11C] Pittsburgh Compound B (PIB), to assess neurofibrillary tangle burden and hippocampal atrophy with magnetic resonance imaging (MRI), and to assess reserve processes with PET measures of glucose metabolism (using [18F]-Flurodeoxyglucose, or FDG) and with functional MRI (fMRI). In this project, a group of 125 older cognitively intact individuals will be recruited over 5 years, carefully characterized in terms of overall cognition and episodic memory, and studied with PIB- and FDG-PET imaging and structural MRI. A subgroup of 50 of these subjects, along with 50 healthy young subjects will be studied with fMRI and an event-related behavioral paradigm that contrasts brain activity during successfully remembered and forgotten items. A major question is whether, and how, older people without evidence of [unreadable]- amyloid deposition or hippocampal atrophy differ from older people with these characteristics, and from younger people. In addition key hypotheses will be tested in continuous multivariate models in which PET measures of [unreadable]-amyloid and MR measures of hippocampal atrophy are expected to be related to poorer episodic memory function, while resting prefrontal glucose metabolism will attenuate this relationship. Similar findings are expected during cognitive activity using fMRI, in which diminished brain activity in the medial temporal lobes may be related to [unreadable]-amyloid deposition, and better performance may be related to increased prefrontal cortical activation. Finally, a subgroup of subjects will be re-evaluated at a 2-year interval to see whether these measures predict change over time in cognition. In total, this project will both provide a description of optimal cognitive aging independent of brain amyloid deposition, and will begin to unravel the mechanisms associated with the loss and preservation of memory function in aging. PUBLIC HEALTH RELEVANCE: This project will assess whether and how Alzheimer's disease may account for the memory loss experienced by healthy normal older people. This is important both for understanding relationships between AD and normal aging, and for developing ways of optimizing brain function in aging.

DESCRIPTION (provided by applicant): This application requests a PET/CT imaging system for a group of investigators at the University of California Berkeley (UCB), Lawrence Berkeley National Laboratory (LBNL), University of California San Francisco and the University of California Davis. Ten major users are supported by 10 R01s, 2 P01s and considerable additional NIH, federal and foundation grants for PET research. The group has used the existing LBNL research-dedicated PET camera for years, and has collaborated on issues related to funding, operations, data analysis, and subject transportation. However, the current camera is outdated, no longer supported by the manufacturer, and suffers from frequent and prolonged downtime related to failures and difficulty obtaining parts. The request is for a modern camera that will support both the primary application of neuroscience research as well as multiple other applications. The scanner is configured to provide optimal image acquisition and research flexibility but without expensive clinical options that are unnecessary for the research program. The environment is strong, with existing complementary equipment including a 1.5T MR system and a SPECT/CT system at LBNL and a 3T MR system on the UCB campus. A medical cyclotron at LBNL operated by a radiochemistry research group, produces a wide variety of radiopharmaceuticals for human and animal use. The research group also has a long history of excellence in PET and imaging technology and has experience with the design, construction, operation, and maintenance of prototype PET cameras as well as PET data analysis. Use of the instrument will be overseen by an operations group comprised of technical staff and scientists who are expert in software support/data analysis, radiochemistry and hardware support. This group will operate the scanner, provide quality control, monitor usage, and assure training of all users as well as compliance with human, animal, and radioisotope regulations. A users group will assist in the development of protocols and will provide the interface between the operations group and users. The institution (LBNL) has committed support for any necessary renovations in siting the instrument, and will operate a recharge facility for financial administration. Current usage is adequate to support the cost of operations, a service contract, and minimal staffing with a relatively modest hourly charge. The entire project will be overseen by an executive committee with responsibility for ensuring access, promoting the use of the instrument, managing conflicts, ensuring training, and generation of continued extramural support. PUBLIC HEALTH RELEVANCE: Imaging with positron emission tomography (PET) has reached a level of maturity that permits the investigation of a host of biochemical processes that are related to human health and may reveal the fundamental processes underlying human disease. This PET scanner will permit a group of investigators to continue their productive research, and will help to create jobs through the continuing manufacture of scanners in the US as well as the development and support of a scientific infrastructure that employs technical and scientific workers.

DESCRIPTION (provided by applicant): Brain aging is a complex, multifactorial process that can involve aggregation of proteins such as b-amyloid (Ab) and tau, cerebrovascular disease, and alterations in neurochemical function. While many older people with cognitive decline may have Ab deposition related to presymptomatic Alzheimer's disease, in fact the majority of older people have little or no Ab in the brain. This project will specifically address a non-amyloid form of age- related cognitive decline that is associated with alterations in the brain's dopamine system. Dopamine is involved in frontal-striatal systems required for executive function. Executive dysfunction is a frequent hallmark of aging that is associated with fronto-striatal atrophy and which is manifest in tasks that require cognitive control, set-shifting, and attention. Our specific aims for this project are: (1) To recruit a sample of healthy individuals spanning ages 20-85; older subjects will have previously undergone PET scanning with [11C]PIB and will have no evidence of brain Ab. In these individuals we will characterize executive function with neuropsychological instruments and measure brain dopamine synthesis capacity using the PET tracer [18F]flurometatyrosine (2) To assess regional brain atrophy with structural MRI (3) To examine the interactions between large scale brain networks using MR measures of resting state functional connectivity and (4) To study brain activity using fMRI during a set-shifting task The overall framework guiding this study is that alterations in brain dopamine in aging produce adaptations that impair frontal-striatal executive function and produce cognitive inflexibility. We hypothesize that aging is associated with increased dopamine synthesis, resulting in overcompensation that disrupts cognition. We propose that older people will show regional atrophy in prefrontal cortex and striatum, and that greater atrophy will be associated with higher dopamine synthesis and poorer performance on neuropsychological tests reflecting executive function. Existing data in normal young people show that a frontoparietal control network (FPCN) is involved in directing attention to external or internal stimuli, and that it performs thi function by coupling to the default mode network (DMN) during internal processing or the dorsal attention network (DAN) during attention to external stimuli. We hypothesize that in aging, greater dopamine synthesis increases FPCN-DMN coupling, resulting in poorer performance on tests of executive function because of an inability to update or shift set in response to external stimuli. Finally, we propose that performance during a set-shifting task, requiring subjects to shift attention from internal to external stimuli, will be impaired in older subjects, and that thi will be associated with higher dopamine synthesis, reduced DMN deactivation during the task, greater FPCN-DMN coupling, and poorer performance on tests of executive function. These experiments will provide a new, neural systems approach to age-related cognitive decline that has major implications for underlying mechanisms and therapy.

PROJECT SUMMARY While late onset sporadic Alzheimer's disease (AD) is usually announced with amnesia, the aggregated proteins ?-amyloid (A?) and tau probably deposit in the brain for many years before symptom onset. This process occurs in the brain's episodic memory system, on a background of normal aging. Increasing evidence points to the spread of the tau protein out of the medial temporal lobe and into neocortical brain regions as crucial in the transition from normal aging to AD, possibly driven by A? and patterns of neural activity and connectivity. In this project we will specifically examine two subsystems of the episodic memory system, an anterior temporal (AT) system originating in lateral entorhinal cortex (LEC) specialized for object memory, and a posteromedial system (PM) system originating in medial entorhinal cortex (MEC) specialized for spatial memory. This is important for differentiating aging and AD because tau deposition begins in the LEC in older brains, while A? deposits in the PM system. The application builds upon on a longitudinal cohort consisting of almost 200 cognitively normal older people who have previously had baseline amyloid PET scanning with [11C]PIB, longitudinal structural MRI exams, and some of whom have had tau-PET imaging with [18F]flortaucipir. For this project, 120 participants will undergo a baseline examination of PIB-PET, flortaucipir- PET, structural MRI, and neuropsychological testing of memory and other cognitive abilities; these procedures will be repeated 1.5 and 3 years later. The baseline examination will also include a functional MRI experiment in which participants encode novel objects and scenes to define the AT and PM episodic memory systems. Neural activity will be examined using directed functional connectivity (directed-FC), an analytic approach employing Granger causality with assessment of neural activity directed from one region to another. This directed-FC will model the spread of tau through memory systems over the ensuing 3 years. Aim 1 will examine the overall pattern of tau spread in relation to the presence of A?, longitudinal cortical atrophy, and cognitive change. We hypothesize that A? will speed tau spread, which in turn will be associated with atrophy and memory decline. Aim 2 will examine tau spread through the AT and PM systems. We hypothesize that tau spreads predominantly in the AT system and, as such, reflects an enhancement of the processes that begin in the aged brain and not an anatomical or functional new condition. Aim 3 will use directed-FC to predict the spread of tau over time, with the hypothesis that brain regions most strongly connected to the entorhinal cortex will show the most rapid spread of tau pathology and this will be strongest in the AT system. How tau spreads through these systems and how A? and neural connectivity may drive this spread could help to differentiate the earliest stages of AD from normal aging, identify normal individuals at highest risk of progression, and provide new approaches to the selection of individuals for clinical trials.

PROJECT SUMMARY This overall goal of this application is to create an infrastructure for supporting and augmenting neuroimaging research in the National Institute of Aging?s Alzheimer?s Disease Centers (ADC) Program. The ADC program is comprised of 30 centers that pursue research goals dedicated to increasing our understanding of Alzheimer?s disease (AD) with a view towards improving diagnosis, care, and treatment of patients. Over the past decade, neuroimaging has played an increasingly important role in this mission, as new approaches to measuring brain structure, function, and biochemistry have produced biomarkers useful in diagnostic, mechanistic, and therapeutic studies. At the same time, methods for standardization of neuroimaging have become accepted, such that, despite the complexity and cost of imaging, we have the ability to combine images obtained at different centers in order to answer important questions about AD that require large datasets. This project will focus on standardizing approaches to magnetic resonance imaging (MRI) and positron emission tomography (PET) images. MR standardization will address structural and functional (task-free) MRI, and PET standardization will address amyloid, tau, and glucose metabolic imaging. We will work with the National Alzheimer?s Coordinating Center (NACC) to develop protocols for securely uploading and de-identifying all images at a NACC image repository, where a searchable database will also be available to researchers. We will develop standards for MR and PET image acquisition, and make these imaging protocols available to the ADC community. Uploaded images will undergo rigorous quality control and processing to permit merging of images obtained on different platforms and, for PET, at different resolutions. Laboratories that have specialized in image processing will produce numerical summary data of brain cerebrovascular pathology, brain volumes, perfusion, diffusion, and cortical thickness, amyloid and tau deposition, and glucose metabolism. These numerical variables will be stored at NACC where it will be linked to other ADC-related data on participants and made available to researchers. Additional aspects of the program will include a website with documentation, search functions, and user help functions. The administrative structure of the project will involve an executive committee with membership from the participating laboratories as well as representation from the NACC, the ADCs, and NIA. Leadership will remain apprised of changes in the neuroimaging landscape, and incorporate new MR and PET measures as they develop with the overall goal of standardizing and disseminating agreed- upon best practices while not stifling the development of new, innovative technical advances.