Helena Chui, Ph.D. - US grants

The purpose of the proposed project is to explore the relationship between the clinical course and outcome of senile dementia of the Alzheimer type (SDAT) and impaired cholinergic and noradrenergic innervation of cerebral cortex. Patients referred for evaluation of dementia will be seen by a neurologist, (HCC), psychiatrist, and clinical psychologist. There will be a complete workup including: blood chemistries, electroencephalogram computed tomogram of the head, and formal psychological assessment. The clinical and neurological findings will be correlated with the post-mortem brain evaluation. A histopathological study will determine the type of dementia. Specimens of the substantia innominata (origin of some of the cholinergic axons terminating in the cerebral cortes), the locus ceruleus (origin of nearly all the noradrenergic axons projecting to the cerebral cortex), and the substantia nigra (origin of the dopaminergic innervation of the neostriatum) will be assessed. These specimens will be studiesd for the presence of cells containing catecholamines, acetycholinesterase, dopamine beta-Hydroxylase, cytoplasmic RNA, and lipofucsin using histological, histochemical and immunohistochemical techniques. Control brains from elderly patients without a history of dementia or with dementia due to causes other than SDAT will be similarly studied. This project will test the proposition that SDAT, in contrast to other dementias, involves abnormalities in at least two transmitter-specific nuclei of the forebrain and brainstem. Improved characterization of changes in these two neuronal populations in relation to clinical signs and symptoms will hopefully contribute to a better understanding and possible pharmacological treatment for Alzheimer's Disease.

mental disorder diagnosis; amyloid proteins; neurofibrillary tangles; brain mapping; neural degeneration; Alzheimer's disease; histopathology; image processing; immunocytochemistry; human tissue;

The main objective of this program project is to determine how structural changes in the cerebral vasculature affect brain function and behavior in elderly persons. The knowledge and understanding obtained from this project is intended to provide a solid base for developing effective treatment for highly prevalent and clinically significant disorders. Various changes in the cerebral vasculature (atherosclerosis, arteriosclerosis, amyloid angiopathy) will be systematically quantified in Project 4. The pathophysiology of chronic ischemia, which may play a particularly important role in persons with slowly progressive cognitive decline, will be examined in project 3. The metabolic, physiologic, and behavioral correlates of lacunar infarction and deep white matter changes will be investigated in projects 1, 2, and 3. Finally, questions related to natural history, clinico-pathologic correlation and diagnosis are addressed jointly by three Cores. The relationship between vasculature, ischemia, and behavior is complex; understanding requires a comprehensive inter-disciplinary approach. The program project represents a multi-institutional collaborative effort involving investigators at the University of Southern California and the University of California at Irvine, Los Angeles, San Francisco and Davis. Clinical recruitment and longitudinal follow-up will take place at 6 Alzheimer Disease Diagnostic and Treatment Centers (ADDTC) supported by the State of California. Whenever possible, provisions have been made to share resources (such as patients, protocols, data, and tissues) across the program. From both a thematic and logistical standpoints, we have attempted to create a highly-cohesive and cost-effective research program.

The objective of this multi-disciplinary prospective longitudinal study is to elucidate the pathophysiologic and functional significance of white matter signal hyperintensities (WMSH), a highly prevalent funding in brain MRI of normal and demented elderly persons. Evidence for two alternative pathophysiologic models will be examined: 1) WMSH are caused by chronic hypoperfusion of the deep white matter vs. 2) WMSH represent secondary demyelination that results from primary neuronal or axonal loss. A new visual-tactile motor reaction time paradigm has been developed to specifically test a neuroanatomical model for the functional significance of WMSH: namely, that WMSH causes slowing in responses that requires integration of sensory modalities across a distributed network. Four groups of 32 subjects each (n=128) will studied using a longitudinal repeated-measures design. The two major subgroups are comprised of normal elderly persons (CDR 0) and patients with cognitive impairment (CDR 0.5, 1 or 2). Each subgroup is further divided according to the severity of WMSH (mild vs moderate or severe). At baseline, the experimental reaction time paradigm, as well as volumetric studies of WMSH and grey matter will be performed for all subjects. Cerebral blood flow, glucose metabolism in areas of WMSH will be obtained using coregistered position emission tomography (PET) and MRI for a subset of patients with mild or severe WMSH severity. MRI studies, reaction time testing and PET will be repeated after 18 month intervals. Regional quantitative studies of white matter will be performed to test whether the pattern of demyelination corresponds better with the pattern of vascular perfusion or neuronal degeneration. Based upon regional patterns of selective vulnerability, we anticipate that patients with mild so moderate AD, as well as VaD, will be able to perform the visual-tactile motor paradigm. A longitudinal design has been chosen to clarify the temporal relationship between diminished cerebral blood flow and metabolism and to control for individual differences in the experimental variables. Thus, this study is designed to clarify the clinical importance and pathophysiology of WMSH in both AD and VaD.

The main objective of the Vascular Subcore is to provide the essential clinical and pathologic resources to study the contribution of cerebrovascular disease to dementia. Several pathogenetic mechanisms have been proposed to explain how vascular disease can lead to cognitive impairment, including: acute infarction, chronic ischemia and compromise of the blood-brain barrier. Various forms of cerebrovascular disease are highly prevalent in elderly persons and are often integral components of AD. These categories of patients, however, have traditionally been excluded from ADRC Clinical Cores. The unique mission of this Subcore is to recruit and follow patients with vascular or mixed dementias. The specific aims include: 1) recruitment of well-characterized subjects with ischemic vascular dementia, as well as appropriate controls (e.g. subjects with mixed dementia, AD or who are cognitively normal), 2) longitudinal follow-up of subjects, including enrollment in the Rancho Brain Research autopsy program; 3) post-mortem examination of patients including semiquantitative and quantitative characterization of vascular and degenerative lesions in the brain; and 4) distribution of autopsy tissues to ADRC investigators. The resources of this Subcore will support several other research projects, including a comprehensive investigation of neuronal degeneration in the AD visual system. In years 11 to 15, Rancho Los Amigos Medical Center (RLAMC) has been chosen to support these activities for several reasons. Rancho is the site of one of nine State-supported Alzheimer Disease Diagnostic and Treatment Centers (ADDTC) which provides clinical diagnoses and assessment for a variety of dementia patients (120 new patients per year). Approximately 25% of these new patients have mild to moderate dementia and would be appropriate for clinical studies of vascular dementia and vision. An autopsy program has been in smooth operation at Rancho since 1984 (previously, known as the ADRC Cell Quantimetric Core) and will provide neuropathologic data and tissues for research studies.

DESCRIPTION (provided by applicant): This is a competing renewal application for a multi-institutional Program Project Grant (PPG) that focuses on cognitive impairment due to small-vessel cerebrovascular disease (s-CVD). The long-term goals of this program Project are to 1) improve our understanding of the pathogenesis of subcortical ischemic vascular dementia (SIVD) and its interactions with Alzheimer's disease (AD), and 2) to develop and validate clinical and imaging markers that inform clinical diagnosis and prognosis. Previous findings from this Project have shown that both SIVD and AD are associated with changes in cerebral cortex, including atrophy, glucose hypometabolism, and loss of n-acetyl aspartate [NAA]. We hypothesize, however, that the mechanisms leading to these cortical and cognitive changes differ in these two disorders. Because s-CVD and Alzheimer disease frequently co-exist in persons over age 65 years, we propose to develop continuous, rather than binary, measures that describe the relative contributions of s-CVD and AD to cognitive impairment. Three Cores and four Projects are built around a prospective longitudinal study design and complementary multi-modal measures of brain structure and function. The Central Coordinating Core (CCC) recruits and follows over 500 subjects representing a spectrum of cognitive impairment attributed to either s-CVD or AD, as well as normal controls. The Imaging Core (Weiner) quantifies volumes of lacunes [L], white matter lesions [WML], cortical gray matter [cGM], and hippocampus [HV] over time. The Pathology Core (Vinters) determines the nature and severity of neurodegenerative, ischemic, and cerebrovascular pathology for each autopsy case. Project 1 (Reed) tests structural-functional-behavioral relationships associated with regional glucose hypometabolism (measured by FDG-PET) in the dorsolateral frontal vs. temporal-parietal lobes. Project 2 (Weiner) tests for differences in brain-metabolic-behavioral relationships in SIVD and AD, using N-acetylaspartate [NAA] and myoinositol from MRSI, as well as perfusion- and diffusion-tensor MR. Project 3 (Chui) seeks the pathological correlates of hippocampal and cortical atrophy, WML, and lacunes, using computerized co-registration of post-mortem brain with in vivo MRI. Project 5 (Mungas) uses multi-variate random effects analyses to model, over time, the neuropsychological and structural MRI correlates of dementia in s-CVD and AD. By integrating multidimensional data obtained using state-of the art methods, we propose to advance understanding of the pathogenesis of cognitive impairment associated with s-CVD and AD and to provide quantitative tools for diagnosis and prognosis.

Co-registration of clinical magnetic resonance imaging (MRI) and post- mortem brain, together with non-biased stereological cell-counting methods, will be utilized and to determine the pathological substrate of several cortical and subcortical neuroimaging changes in SIVD and AD. Specific Aim 1: Although hippocampal atrophy is an early hallmark of AD, it may also occur in subjects with SIVD. Hippocampal volume (HV), glucose metabolism (CMRglc), and N-acetyl aspartate [NAA] will be correlated with numbers and size of neurons in SIVD and AD. Specific Aim 2: Although SIVD is currently conceptualized as a subcortical disease, new findings during the initial funding period cortical changes (atrophy, decreased CMRglc and [NAA] also occur. Cortical gray matter volume, CMRglc, and [NAA[ will be correlated with number and size of cortical neurons to determine whether a) cortical changes in SIVD represent neuronal shrinkage secondary ti deafferentation, or b) primary neuronal loss due to ischemic injury or other factors. Specific Aim 3: Confluent white matter lesions (WML) are highly prevalent in SIVD, where they are believed to represent areas of myelin and axon loss due to ischemia. The volume and T1-signal intensity of WML will be correlated with numbers of oligodendrocytes, severity of demyelination and axon loss, and severity of microvascular disease. Specific Aim 4: Focal hyperintensities in proton density MRI of the subcortical gray matter (L) are considered to be lacunar infarcts. Because many of these lesions are clinically, the question is posed: Do all hyperintensities represent lacunar infarcts or possibly other types of pathology (e.g., gliosis or incomplete infarction? Specific Aim 3: According to the lacunar hypothesis, lesion location within frontal-subcortical loops is the key determinant of cognitive impairment. Patho-anatomical validation will be sought for a stereotaxic approach used in the Imaging Core to localized lacunes within key individual thalamic nuclei (e.g., anterior and dorsomedial thalamic nuclei. The goal of this project is to enhance our understanding 9of the pathology underlying SIVD and to improve the diagnostic utility of several highly prevalent neuroimaging findings.

The Central Coordinating Core (CCC) is responsible for clinical recruitment and follow-up, database management, administration, and strategic planning across the PPG. The CC implements the overall longitudinal design of the PPG. The goal is to recruit and to follow a sample of 500 subjects: 250 normal controls and 250 subjects with variable degrees of cognitive impairment attributed to subcortical ischemic vascular dementia (SIVD) or Alzheimer disease (AD). For normal controls, cognitive/functional status is assessed every 2 years and magnetic resonance imaging (MRI) is repeated every 4 years. For subjects, cognitive/functional status is followed every year, and MRI is repeated every 2 years and magnetic resonance imaging (MRI) is repeated every 4 years. For subjects, depend upon the CCC for classifying subjects and for ensuring the quality of key cognitive/functional data. Although the Pathology Core ultimately determines the likelihood of SIVD, AD, or mixed AD/SIVD, the CCC is responsible for obtaining consent and for coordinating the autopsy program. The CCC manages data from all three Cores (Clinical, Imaging, and Pathology). Key clinical variables include demographics, onset and duration of dementia, activities of daily living, mental status scores, neuropsychological test cores, clinical dementia rating (CDR), clinical diagnosis, and subject categorization. Key imaging data include the number, location, and size of lacunes, the volume of cortical gray matter, white matter; white matter hyperintensities (WML), ventricular and sulcal cerebral spinal fluid, and the volume of the hippocampi. The key pathological data include Braak and & Braak Staging, CERAD rating of neuritic plaques, and severity and distribution of ischemic brain injury and cerebrovascular disease. These data are utilized by all four of the research projects. PPG investigators work well together. In person meetings are held at least twice a year to review progress, set goals, ane to plan strategy. Monthly teleconferences and e-mail mitigate the geographic distances between campuses. Consultants and an external advisory group provides invaluable feedback and guidance. The PPG functions as a vital and cohesive whole.

[unreadable] DESCRIPTION (provided by applicant): The USC Alzheimer's Disease Research Center (ADRC) focuses on basic mechanisms and the cognitive/behavioral impact of Alzheimer's disease (AD) and cerebrovascular disease (CVD) among ethnically diverse populations. [unreadable] [unreadable] Administrative Core: (Helena Chui, Dir.; Caleb Finch, Co-Dir.; Elena Munoz, Admin.) Provides scientific direction and administration of Center, including solicitation of pilots, new investigators, and external advice. Data Management Core (Wendy Mack, Dir.) Responsible for Web-based database, resource for statistical design ant analytic support, sharing of data with National Alzheimer's Coordinating Center (NACC). [unreadable] [unreadable] Education Information and Transfer Core: (Margaret Gatz Dir.) Assists in minority subject recruitment, provides community education, and studies the conceptualization of dementia among minorities. [unreadable] [unreadable] Clinical Core: (Helena Chui M.D, Dir.; Lon Schneider, Co-Dir.) Evaluates, enrolls, follows, and refers subjects with AD, VD, and other dementias to research projects. [unreadable] [unreadable] Spanish-Speaking Satellite: (Xavier Salazar, Dir.) Evaluates, enrolls, follows, and refers Spanish speaking subjects with AD, VD, and other dementias to research projects. [unreadable] [unreadable] Pathology Core: (Carol Miller, Dir.) Provides neuropathological diagnoses, distributes tissues, and obtains genotypes. [unreadable] [unreadable] Imaging Core: (Manbir Singh, Dir.) Provides technical support to investigators, develops new techniques, refines methodologies, archives MRI. [unreadable] [unreadable] Project 16: Diffusion tensor tractography in AD and SVD (Manbir Singh, Dir.) Uses diffusion tensor MRI to map white matter pathways in AD and SVD. [unreadable] [unreadable] Project 17: Vascular risk and cognitive status in a Latino population (Wendy Mack Dir.; Rohit Varma, CoDir.) Defines the contributions of AD and VD to cognitive impairment in a community-based survey of a Mexican population. [unreadable] [unreadable] Project 18: Structural studies of a-synuclein and fibril assembly (Ralf Langen, Dir.) Uses site-directed spin labeling to define the structural characteristics of alpha-synuclein. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): The Latino population is an under-studied group in relation to epidemiological studies of cognitive impairment and dementia [Valle, 1994 #1103]. Utilizing the resources from our one-year ADRC supplement, we have incorporated a cognitive screening instrument (CASI-S) into an existing cohort study in Latino adults residing in La Puente, California (Supplement to NIA P50 AG05142). Our long-term objectives are to establish a cognitive component within this cohort to estimate incidence and prevalence of cognitive impairment and dementia in this Latino population, and to use identified incident cases for population-based epidemiological studies, with particular interest in vascular risk factors and dementia. Our short-term objectives for this one-year proposal (4-1-03 to 3-31-04) relate to methodological evaluation of our cognitive screening instrument in this Latino population and to establish feasibility for intensive cognitive follow-up. These research activities are essential steps to support future plans for a long-term cognitive follow-up study. [unreadable] [unreadable]

Adult; Advisory Committees; aging brain; alzheimer disease detection; Alzheimer's Disease; American; Asian Americans; Asians; Atherosclerosis; Basic Science; Blood Vessels; Brain; Caucasians; Caucasoid Race; Chinese American; Clinical; Clinical Data; Clinical Research; cognitive change; cognitive neuroscience; cohort; Communities; data management; Development; Doctor of Philosophy; Education; Evaluation; Eye; Faculty; Finches; Funding; genome wide association study; Gerontology; Grant; Health Sciences; Housing; Human Resources; human subject; human subject protection; Image; Impaired cognition; innovation; Institutes; Institutional Review Boards; Joints; Latino; Longitudinal Studies; Los Angeles; medical schools; meetings; mild neurocognitive impairment; Mission; neurogenetics; Neurosciences; neurosteroids; normal aging; novel; Pathology; Pharmacy facility; Pharmacy Schools; Philosophy; Pike fish; Pilot Projects; Population; Population Heterogeneity; pre-clinical; Process; Progesterone; programs; Protocols documentation; Recruitment Activity; Regenerative Medicine; Research; Research Personnel; Research Project Grants; Resource Sharing; Resources; Sampling; Schools; Staging; symposium; Tissues; Universities; Work;

The Clinical Core is responsible for maintaining a well-characterized pool of research subjects to support researcl in normal aging, Alzheimer disease (AD), vascular dementia (VD), and other dementias. It is also an essential resourc for obtaining autopsy consent, imaging data, and the Alzheimer Disease Center uniform data set. The Pharmacology Program is an integral component of the Clinical Core. Finally, the Clinical core serves as a training site for clinicians in the EIT core. The specific aims of the Clinical Core are: 1) Recruitment, evaluation, and diagnosis of ethnically-diverse subjects with mild cognitive impairment and dementia due to AD and VD, as well as normal elder b controls; la)Recruitment of subjects and referral to Pharmacology Program for clinical trials; lb) Referral of well-characterized subjects to Project #1 (M Singh, PI); lc) Maintenance of a research-subject registry ("pool") to support other ADRC affiliated research projects; 2) Repeat clinical evaluation and neuropsychological testing for subjects with normal aging, mild cognitive impairment (MCI) and AD dementia (Longitudinal Study); 3) Coordinatio_ of clinical components (with Pathology Core) of the Autopsy and Biological Tissue Program, including obtaining informed consent for autopsy, maintaining relevant clinical data, obtaining blood samples for apoE genotyping; 4) Coordination of the clinical components (with the Imaging Core) of an MRI Archive; 5) Submission of clinical data (with Data Management Core) to the National Alzheimer Coordinating Center (NACC). Clinical activities directed toward English-speaking subjects are described in the Clinical Core, while those for Spanish-speaking subjects are described in the Spanish Speaking Satellite (SSS).

The Central Coordinating Core (CCC) coordinates clinical research, database management, and strategic-planning across the PPG. The CCC implements the overall prospective longitudinal design of the program project (PPG) across three clinical sites. The goal is to recruit and to follow a sample of 450 subjects: 200 normal controls and 250 subjects with variable degrees of cognitive impairment attributed to subcortical ischemic vascular dementia (SIVD) or Alzheimer disease (AD). For normal controls < 80 years, cognitive/functional status is assessed every 2 years and magnetic resonance imaging (MRI) is repeated every 4 years. For subjects and older controls > 80 years, cognitive /functional status is followed every year, and MRI is repeated every 2 years. The research projects depend upon the CCC for classifying subjects and for ensuring the quality of key cognitive / functional data. Although the Pathology Core ultimately determines the likelihood of CVD, AD, or mixed AD/CVD, the CCC is responsible for obtaining consent and for coordinating the autopsy program. The CCC manages data from all three Cores (Clinical, Imaging, and Pathology). Key clinical variables include demographics, onset and duration of dementia, activities of daily living, mental status scores, neuropsychological test scores, clinical dementia rating (CDR), clinical diagnosis, and subject categorization. Key imaging data include the number, location, and size of lacunes, the volume of cortical gray matter, white matter, white matter hyperintensities (WML), ventricular and sulcal cerebral spinal fluid, and the volume of the hippocampi. The key pathological data include the overall likelihood ofAD, SIVD, or mixed AD/SIVD, numbers, size, and location of lacunar infarcts, and the severity of neurofibrillary tangles, neuritic plaques, white matter demyelination, and microvascular disease. These data are utilized by all four of the research projects. PPG investigators work well together. In person meetings are held at least twice a year to review progress, set goals, and to plan strategy. Monthly teleconferences are conducted to check progress and maintain course. Electronic communication tools, especially e-mail, mitigate the geographic distances between campuses. Consultants and an external advisory group provide invaluable feedback and guidance. The PPG functions as a vital and cohesive whole.

Coregistration of clinical magnetic resonance imaging (MR1) and post-mortem brain, together with non-biased stereologieal cell-counting methods, will be used to determine the pathological substrate of several cortical and subcortical neuroimaging changes associated with small-vessel cerebrovascular disease (CVD) and Alzheimer disease (AD). Specific Aim 1: To improve co-registration of post-mortem brain to clinical MRI by reducing geometric distortions and applying compensatory polynomial warping algorithms. Specific Aim 2: Although hippocampal atrophy is an early hallmark of AD, it may also occur in subjects with s-CVD. Hippocampal volume (HV), glucose metabolism (CMRglc), and N-acetyl aspartate [NAA] will be correlated with numbers and size of neurons in s-CVD and AD. Specific Aim 3: Although s-CVD is currently conceptualized as a subcortical disease, new findings during the initial funding period indicate that cerebral cortical changes (atrophy, decreased CMRglc and [NAA]) also occur. Cortical gray matter volume, CMRglc, and [NAA] will be correlated with number and size of cortical neurons to determine whether a) cortical changes in s-CVD represent neuronal shrinkage secondary to deafferentation, or b) primary neuronal loss due to ischemic injury or other factors. Specific Aim 4: Confluent white matter lesions (WML) are highly prevalent in s-CIVD, where they are believed to represent areas of myelin and axon loss due to ischemia. The volume and fractional anisotropy of WML will be correlated with numbers of oligodendrocytes, seventy of demyelination and axon loss, and seventy of microvascular disease. Specific Aim 5: Subcortical focal hyperintensities in proton density MRI (L) are considered to be lacunar infarcts. Because many of these lesions are clinically "silent," the question is posed: Do all hyperintensities represent lacunar infarcts or possibly other types of pathology (e.g., gliosis or incomplete infarction)? The goal of this project is to advance understanding of pathological changes and to clarify the diagnostic utility of several highly prevalent neuroimaging findings associated with s-CVD.

AD model; Accounting; Acquired brain injury; Address; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimer's disease model; Alzheimers Dementia; Alzheimers disease; Ammon Horn; Amyloid; Amyloid Substance; Apoplexy; Arteries; Arterioloscleroses; Arteriosclerosis; Arts; Atheroscleroses; Atherosclerosis; Atherosclerotic Cardiovascular Disease; Atrophic; Atrophy; Autopsy; Bleeding; Blood Vessels; Brain; Brain Infarction; Brain Injuries; Brain Vascular Disorders; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Disease; Cerebrovascular Disorders; Cerebrovascular Stroke; Cerebrovascular Trauma; Cerebrovascular accident; Cerebrum; Clinical; Cognition; Cognitive; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Cornu Ammonis; Coupled; Data; Dementia, Alzheimer Type; Dementia, Multi-Infarct; Dementia, Multiinfarct; Dementia, Primary Senile Degenerative; Dementia, Senile; Diagnosis; Dimensions; Disease; Disorder; Dissociation; Disturbance in cognition; Encephalon; Encephalons; Epidemiologic Research; Epidemiologic Studies; Epidemiological Studies; Epidemiology Research; Evolution; Goals; Health; Hemorrhage; Hippocampus; Hippocampus (Brain); Image; Impaired cognition; Impairment; Infarction; Inflammatory; Intracranial Vascular Disorders; Ischemia; Laboratories; Learning; Longitudinal Studies; MR Imaging; MR Tomography; MRI; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Measures; Mediating; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Memory; Modality; Modeling; Multi-Infarct Dementia; NMR Imaging; NMR Tomography; Nervous System, Brain; Neuropsychologies; Neuropsychology; Nuclear Magnetic Resonance Imaging; Numbers; P01 Mechanism; P01 Program; Pathology; Pathway interactions; Performance; Photography; Population; Prevention strategy; Preventive strategy; Primary Senile Degenerative Dementia; Principal Investigator; Process; Program Project Grant; Program Research Project Grants; Public Health; Recruitment Activity; Research Program Projects; Retinal; Risk; Risk Factors; Role; Sampling; Severities; Stroke; Structure; Testing; Thick; Thickness; Vascular Accident, Brain; Vascular Diseases, Intracranial; Vascular Injury, Brain; Vascular Trauma, Brain; Venous; Zeugmatography; atheromatosis; atherosclerotic vascular disease; blood loss; brain atrophy; brain attack; brain damage; brain lesion (from injury); cardiovascular risk; cardiovascular risk factor; cerebral atrophy; cerebral vascular accident; cognitive change; cognitive dysfunction; cognitive function; cognitive loss; cognitively impaired; cortical atrophy; dementia of the Alzheimer type; design; designing; disability; disease/disorder; executive control; executive function; gray matter; hippocampal; imaging; in vivo; infarct; intima media; long-term study; multifocal dementia; necropsy; neuroimaging; neuropathology; neuropsychologic; neuropsychological; novel; pathway; postmortem; primary degenerative dementia; public health medicine (field); recruit; senile dementia of the Alzheimer type; social role; stroke; substantia alba; substantia grisea; uptake; vascular; white matter; white matter change

The Administrative Core leads the development of the overarching goals and overall study design for the program project grant (PPG). The Core coordinates the flow of ideas, data, human subjects, tissues and other resources across the PPG. In addition, the Administrative Core is responsible for maintaining the PPG database, provides custom analytic datasets as needed, conducts statistical analyses, and provides consultation for study design and statistical analyses. For the renewal, the PPG has adopted the Uniform Data Set (UDS), developed by the National Alzheimer Coordinating Center, which will facilitate the dissemination of findings to the scientific community.The specific aims of the Core are two fold: 1. Administrative: a) Develop the overarching scientific goals and strategic plan of the PPG, and leverage outside resources, b) Organize the flow of information, subjects, tissues, and internal resources across the PPG (e.g., facilitate communication, disseminate information), c) Prioritize and monitor the utilization of resources (e.g..coordinate policy, administer the budget, review progress), d) Seek scientific review and guidance via an External Advisory Committee, .e)Ensure respect and safety for human subjects. 2. Statistical design and Data management: a) Provide expertise in study design and statistical analysis to the Cores and Projects, b) manage the PPG database assembled from the Clinical, Imaging, and Neuropathology Cores, c) Institute and maintain procedures for study protocol adherence and data quality assurance, d) Prepare and present specific reports (recruitment reports, follow-up schedules and oversight, data quality reports, data summary reports, final neuropathologic diagnosis), e) Facilitate sharing of data with the scientific community.

DESCRIPTION (provided by applicant): The overarching goal of this competitive renewal application is to examine the pleiotropic effects of arteriosclerosis (AS), on brain structure and function, either alone or in combination with Alzheimer disease (AD). We propose a prospective, longitudinal study of a convenience sample (231 current + 276 new = 507 subjects), selected using the Framingham cardiovascular risk profile (FCRP) to ensure representation of subjects ranging from little to severe arteriosclerosis (AS). The PPG includes 4 Cores (Administrative, Clinical, Imaging, and Pathology) and 4 Projects. Project 1 (Reed &Jagust) will use amyloid imaging (Pittsburgh Imaging B [PIB] compound) to identify in vivo a cohort of subjects representing the full spectrum of AS, with minimal AD pathology. Project 2 (Weiner, DeCarli, and Singh) will determine the extent to which arteriosclerosis (AS) is associated with changes of brain perfusion and volume and integrity of gray matter (GM) and white matter (WM) and the extent to which these associations relate to AD- vs. CVD-pathology. .Project 6 (Zarow &Vinters) seeks to improve the clinical diagnosis of hippocampal sclerosis and to clarify its pathogenesis. Project 7 (Chui &Mungas) will test the overarching hypothesis using data obtained in the Clinical, Imaging, and Pathology Cores.

ABSTRACT: ADMINISTRATIVE CORE The Administrative Core of the ADRC located at the University of Southern California (USC) is responsible for the overall scientific direction of the center and the coordination of six service cores, 2 research projects, and 2-3 pilot projects selected each year. The ADRC is an integral part of the national Alzheimer Disease Center (ADC) network, working closely with the National Alzheimer Coordinating Center (NACC), Alzheimer Cooperative Studies (ADCS), the Alzheimer Disease Genetics Consortium (ADGC), and Alzheimer Disease Neuroimaging Intiative (ADNI). Epidemiologic studies have long observed associations between highly prevalent and treatable vascular risk factors and an increased incidence of AD, yet the linking mechanisms are unclear. During the past 4 years, USC has made incremental strides in developing neuroselective steroids for the prevention and treatment of AD. A major Provost hiring initiative in neuroscience has brought together a critical mass of scientific talent in Alzheimer disease, especially knowledgeable about the cerebral vasculature and early Phase I/ II drug development. Thus, the USC ADRC has three unique overarching goals: 1) Elucidate vascular contributions to Alzheimer's disease (AD). 2) Catalyze local research in AD at USC (especially Phase I/Phase II clinical trials), and 3) Contribute expertise in vascular disease and imaging to national collaborative initiatives. The Clinical and ORE cores, together with the Huntington Medical Research Institute, will recruit and follow participants in a new vascular cohort (n-180) for Projects 1 and 2, and will refer well-characterized participants to clinical trials, the brain donation (autopsy) program, and other research projects. The capabilities of the Data and Imaging cores have been greatly expanded by the recruitment to USC of Arthur Toga and Paul Thompson to establish the Institute for Neuroimaging and Informatics. The Neuropathology core which prepares, stores, and shares brain tissues and biospecimens, now has the ability to perform a comprehensive assessment of CSF biomarkers. Project 1 and 2 have a complementary focus on the role of Neurovascular and Metabolic Factors on AD pathogenesis, and provide an intellectual cohesiveness to the Center as a whole. The projects build on innovations in assessing the integrity of the blood brain barrier with DCE-MRI, white matter tracts with DTI-MRI, and functional connectivity with fMRI. Imaging, biomarker, and clinical-pathological data from the vascular cohort will be shared openly with the scientific community online. The USC ADRC is thus prepared to serve as the nexus for translational research at USC and to bring unique expertise and tools to the national ADC research enterprise.

Model-based cerebrovascular markers extracted from hemodynamic data for non-invasive, portable and inexpensive diagnosis of MCI or mild AD and prediction of disease progression PROJECT SUMMARY The goal of the proposed multi-PI project is to establish proof of concept for the utility of a new class of cerebrovascular markers that may aid in the improved diagnosis and prediction of disease progression in Mild Cognitive Impairment (MCI) and mild Alzheimer's disease (AD). The means for obtaining these markers are non-invasive, inexpensive and portable, so that they can be used for screening in a primary-care setting. The scientific rationale for this new class of cerebrovascular markers is provided by the recent promising results of our group and the mounting evidence of a strong correlation between MCI/AD and cerebrovascular dysregulation. A recently published retrospective study on a large cohort of 1,171 subjects from the ADNI database utilized multi-factorial data-driven analysis to assess the relation between MCI/AD disease progression and commonly used biomarkers (obtained from MRI/PET and plasma/CSF) and concluded that cerebrovascular dysregulation is the earliest and strongest pathologic factor associated with AD progression, corroborating the hypothesis of cerebrovascular dysregulation. Quantification of cerebrovascular dysregulation in that large-cohort study was achieved through analysis of ASL-MRI data of cerebral perfusion. We propose instead to explore a novel integrative dynamic modeling approach that analyzes the cerebral hemodynamics of persons with no cognitive impairment and MCI/AD patients with a methodology that yields input- output predictive models of the dynamic relationships between changes in beat-to-beat cerebral blood flow velocity (via Transcranial Doppler) or cerebral tissue oxygenation (via Near Infrared Spectroscopy) in response to changes in arterial blood pressure and end-tidal CO2 data. The obtained data-based models are subsequently used to compute markers of the dynamics of cerebrovascular regulation. Initial results of the advocated approach have achieved statistically significant delineation between 46 MCI patients and 20 age-matched controls on the basis of a model-based marker of dynamic vasomotor reactivity (DVR). Evaluation of the DVR marker against established MRI-based and PET-based biomarkers, as well as neuropsychological test data, from the larger cohort of the proposed project offers the promise of portable, non-invasive, inexpensive and sensitive means for detecting cerebrovascular dysregulation at the early stages of MCI or mild AD, and monitoring disease progression. Important co-variates of this study include age, gender, education, ApoE genotype, site and amyloid burden.

Abstract The 3 overarching goals of the USC Alzheimer Disease Research Center (ADRC) are to: 1) Elucidate vascular contributions to Alzheimer disease (AD), 2) catalyze basic, clinical, and translational research in AD at USC, and 3) contribute expertise in vascular disease, biomarkers, and imaging to national collaborative initiatives. The ADRC is led by 3 multiple PD/PIs: Chui, Zlokovic, and Toga and comprised of 6 required cores, the required Research Education Component (REC), and 1 optional imaging core. The Administration Core (Chui, Zlokovic, Toga) provides administrative and scientific oversight across USC ADRC, including fostering development projects and supporting ADRC-affiliated studies. The Clinical Core (Schneider, Ringman, Chui) performs standardized evaluations and diagnoses using the NACC Uniform Data Set (UDS), enrolls and follows participants in our 2 primary ADRC cohorts: Vascular Cohort Study (VCS) and Brain Research Study (BRS). The Data Management and Statistical Core (Toga and Chen) oversees the NACC UDS database, provides study- and core-specific databases and curates our large imaging data sets as a local and national resource. The Neuropathology Core (Miller and Hawes) performs standardized neuropathological examinations, stores and distributes biological tissues to research investigators. The Outreach, Recruitment, and Engagement Core (Aranda) works closely with the Clinical Core to recruit and retain the primary ADRC cohort, focusing on under- represented minority groups (especially Latinx), and the development of a participant-caregiver dyad resource database. The Biomarker Core (Zlokovic) uses state of the art methods to determine cell-and system-specific biomarkers related to the neurovascular unit, as well as to measure standard AD biomarkers. The Imaging Core (Toga and Pa) provides high field (3T and 7T) MR imaging, as well as amyloid/tau PET scans. The Research Education Component (Yassine) is dedicated to mentoring post-doctoral students committed to the study of minority issues in Alzheimer disease and related disorders. The USC Health Science Campus is located near high Latinx catchment areas. Treatable vascular-metabolic risk factors (VMRF) are particularly prevalent among the Latinx population and dovetail with the research focus of the USC ADRC.