Gary W. Small, MD - US grants

The proposed research aims to clarify the relationship between the major histo-compatibility gene complex, HLA, and Dementia of the Alzheimer Type (DAT). Previous research has indicated that genetic and immunological factors are involved in DAT and that the HLA gene complex is related to immunological mechanisms and various neurological diseases of unknown origin. These studies led to preliminary research on the association between HLA typing and DAT. Although together the studies of DAT/HLA associations suggest a relationship between specific HLA antigens and DAT, some of the results are conflicting. Methodological difficulties may explain the discrepancies; for example patients with both dementia and depression (another psychiatric illness related to the HLA gene complex) are generally not segregated out or even identified. The proposed research will, therefore, investigate HLA typing in four groups of subjects as carefully defined as the state of the art permits: (1) patients with DAT; (2) patients with DAT and concurrent symptoms compatible with Major Depressive Disorder; (3) patients with Major Depressive Disorder alone; and (4) matched controls. In addition, first-degree relatives, when available, will be studied. A substantial number of subjects (group 2) will show features of both cognitive deficit and depression. Because no large-scale longitudinal studies have yet clarified these kinds of patients with overlapping symptoms, neuropsychological and psychosocial profiles will be collected to improve our understanding and clinical descriptions of such patients. The cause or causes of DAT remain(s) unknown; most likely they are multiple. The presence of HLA/DAT associations may be useful in distinguishing homogeneous subgroups among patients with DAT, homogeneity which could be of inestimable value with respect to treatment, outcome, and prediction of risk in as yet unaffected individuals. HLA associations with particular subgroups of patients with DAT offers, therefore, the possibility of refining our definition of a relatively global and heterogeneous syndrome into more specific disease entities.

The overall goal of this research program is to develop a non- invasive blood glucose monitor that can be used in the treatment and control of diabetes. This monitor will be based on near- infrared (NIR) spectroscopy and will allow direct measure of in situ blood glucose levels without penetrating the skin. Such an approach to glucose sensing requires new instrumentation capabilities in NIR spectroscopy coupled with state-of-the-art fiber optic technology and advanced computer-based data analysis. Before a long-term research effort toward this overall goal can be justified, the ability to measure glucose in the 1 to 20 MuM concentration range in a whole blood matrix with NIR spectroscopy must be established. The specific goal of this pilot study is to establish if such measurements are possible. If this novel approach is indeed possible, non-invasive NIR-based glucose monitors for patient home use will be designed. In addition, a NIR-based glucose monitor will be developed for application as a continuous sensor in an artificial pancreas.

The proposed project is designed to assess early diagnosis of a major form of mental impairment associated with aging: Alzheimer disease. The project will measure cerebral glucose metabolic patterns using positron emission tomography (PET) in people considered to be at high risk for developing familial Alzheimer disease (AD). This high risk group will consist of persons with Age-Associated Memory Impairment (AAMI) who have at least one first-degree relative with AD (familial AAMI or FAAMI group). PET measures, using the glucose analog 18F-fluorodeoxyglucose (FDG), will be obtained on FAAMI subjects at their initial assessment. These measures will be compared to those from age-matched controls and clinical profiles will be repeated at three-year follow-up evaluations to identify subjects who progress to probable AD. The study builds upon prior PET work at UCLA, which identified abnormal metabolic patterns in AAMI subjects who later developed nonfamilial AD. The proposed project aims to replicate these investigate the applicability of such metabolic patterns early in the course of familial AD. It is hypothesized that FAAMI subjects will show abnormal PET scan results compared to controls; and that FAAMI subjects will be more likely to develop AD in two years than will controls. Whether PET scan results predict which FAAMI patients develop AD in two years, as well as differences among AD subgroups, also will be explored. Early identification of patients with AAMI that progresses to AD is critical not only for guiding optimal clinical management and planning but also for identifying potential subjects who are most likely to benefit from experimental treatments. Because AD probably represents a multi-causal disorder, longitudinal refining diagnostic accuracy of homogeneous disease forms. Further study of such homogeneous subgroups would increase the likelihood of finding etiologies, which could eventually lead to specific treatments.

Previous research has indicated an association between the Histocompatibility Locus Antigen (HLA) A2 and men with the sporadic form of early-onset (less than 60 years) Alzheimer disease (AD). It is not known whether this finding can be generalized to a large sample, and the degree that lack of family history for AD defines the A2-positive subgroup: To fill such knowledge gaps, we propose to (1) perform HLA typing on 100 men with early-onset AD (50 with a family history of AD and 50 sporadic cases); (2) show that HLA-A2 and other relevant antigens have the expected-high frequency; and (3) determine if the A2 frequency is greater in sporadic than in familial AD. Thirteen of the National Institute on Aging AD Centers have agreed to provide blood from registered AD patients with research-level diagnoses. Enough blood will be drawn from each subject so that some will be stored for possible later DNA analyses, thus providing the basis for future studies exploring the molecular biology of A2 and closely linked genes. Because prior studies also indicate nongenetic factors influencing disease expression, differences among subgroups in frequencies of environmental risk factors will be explored. Identification of neurobiologically meaningful AD subgroups could facilitate future studies that elucidate disease etiology.

The proposed project is designed to assess early diagnosis of a major form of mental impairment associated with aging: Alzheimer disease. The project will measure cerebral glucose metabolic patterns using positron emission tomography (PET) in people considered to be at high risk for developing familial Alzheimer disease (AD). This high risk group will consist of persons with Age-Associated Memory Impairment (AAMI) who have at least one first-degree relative with AD (familial AAMI or FAAMI group). PET measures, using the glucose analog 18F-fluorodeoxyglucose (FDG), will be obtained on FAAMI subjects at their initial assessment. These measures will be compared to those from age-matched controls and clinical profiles will be repeated at three-year follow-up evaluations to identify subjects who progress to probable AD. The study builds upon prior PET work at UCLA, which identified abnormal metabolic patterns in AAMI subjects who later developed nonfamilial AD. The proposed project aims to replicate these investigate the applicability of such metabolic patterns early in the course of familial AD. It is hypothesized that FAAMI subjects will show abnormal PET scan results compared to controls; and that FAAMI subjects will be more likely to develop AD in two years than will controls. Whether PET scan results predict which FAAMI patients develop AD in two years, as well as differences among AD subgroups, also will be explored. Early identification of patients with AAMI that progresses to AD is critical not only for guiding optimal clinical management and planning but also for identifying potential subjects who are most likely to benefit from experimental treatments. Because AD probably represents a multi-causal disorder, longitudinal refining diagnostic accuracy of homogeneous disease forms. Further study of such homogeneous subgroups would increase the likelihood of finding etiologies, which could eventually lead to specific treatments.

Previous research has indicated an association between the Histocompatibility Locus Antigen (HLA) A2 and men with the sporadic form of early-onset (less than 60 years) Alzheimer disease (AD). It is not known whether this finding can be generalized to a large sample, and the degree that lack of family history for AD defines the A2-positive subgroup: To fill such knowledge gaps, we propose to (1) perform HLA typing on 100 men with early-onset AD (50 with a family history of AD and 50 sporadic cases); (2) show that HLA-A2 and other relevant antigens have the expected-high frequency; and (3) determine if the A2 frequency is greater in sporadic than in familial AD. Thirteen of the National Institute on Aging AD Centers have agreed to provide blood from registered AD patients with research-level diagnoses. Enough blood will be drawn from each subject so that some will be stored for possible later DNA analyses, thus providing the basis for future studies exploring the molecular biology of A2 and closely linked genes. Because prior studies also indicate nongenetic factors influencing disease expression, differences among subgroups in frequencies of environmental risk factors will be explored. Identification of neurobiologically meaningful AD subgroups could facilitate future studies that elucidate disease etiology.

disease /disorder proneness /risk; brain imaging /visualization /scanning; brain metabolism; aging; Alzheimer's disease; brain disorder diagnosis; family genetics; mental disorders; bioimaging /biomedical imaging; human subject; functional magnetic resonance imaging; clinical research;

The Education/Information Transfer core (E/ITC) is designed to provide education and information transfer to three domains -- the Alzheimer's Disease Center (ADC), the University, and the Community. During the first funding period, the E/ITC made considerable progress in each domain: (1) Regular Clinician Rater Training Sessions were conducted using several Clinical Core assessment instruments, with resultant inter-rater diagnostic agreements of > 90%. (2) A majority of previous fellows who participated in the ADC are now involved in clinical and research activities related to Alzheimer disease (AD). (3) Nearly 2,000 practicing physicians, fellows, and faculty were trained through conferences developed by or in collaboration with the E/ITC. During the next funding period, the E/ITC plans to continue enhancing clinical and research skills in AD and related dementias by training physicians and other professionals to provide research-level assessments and clinical diagnoses on subjects enrolled in the Clinical Core, using videotape technology to ensure inter- rater reliability. The E/ITC will also offer educational programs. Community education will be facilitated through liaisons with media representatives, and key local personnel will be included in ADC educational activities in coordination with other local universities (particularly the Los Angeles and Orange Counties ADRC Consortium), hospitals, and community agencies. Community professionals (especially primary care physicians), family members, and long-term care providers will also be addressed through a Speakers Bureau, Annual Conference, and newsletters. Activities will emphasize subject recruitment for the Clinical Lcore. The E/ITC will assist the Administrative Core in disseminating information about current research and education through a newsletter, Basic Science Guest Lectureship, and other programs. The E/ITC will also assist the Clinical and Neuropathology Cores by providing families with material relevant to postmortem tissue donation. The E/ITC will translate the community newsletter into Spanish and include minority representatives in educational activities, thus facilitating information transfer to ethnic minorities. Finally, systematic evaluation strategies will ensure that the E/ITC meets its objectives.

One of the pathologic hallmarks of Alzheimer's disease is a profound loss of cholinergic neurons in the forebrain. This neuronal loss has been strongly associated with the memory impairment and other cognitive deficits found in ad patients. In addition, positron emission tomography (pet) studies have identified a characteristic, specific pattern of cerebral metabolic changes in ad: bi-lateral reductions in glucose metabolism in parietotemporal areas, beginning early in the disease process, with reductions in frontal areas occuring later on.

This project is designed to assess the clinical and brain metabolic progression of age-related mental decline in the autosomal dominant form of familial Alzheimer disease (FAD). Families with autosomal dominant inheritance patterns for AD are rare, but such pedigrees provide information for linkage analysis of the FAD gene(s). Longitudinal investigation of "at-risk" relatives in these pedigrees is an efficient approach for studying early diagnosis and disease course because 50% of relatives eventually develop the disease. Our group already has recruited 21 FAD Pedigrees. with 410 living relatives potentially available for study. We propose to perform annual clinical and W neuropsychological assessments on relatives at risk for FAD. Positron emission tomography (PET) and magnetic resonance imaging scans will also be performed annually to explore relationships relating brain structure to clinical and L) metabolic decline. Our prior studies demonstrated parietal hypometabolism in patient s with mild dementias who later 5 developed probable sporadic (i.e.. nonfairnilial) AD, with more hypometabolism found in early-onset patients. The proposed project aims to replicate such findings in relatives at risk for FAD. We hypothesize that initial cerebral metabolic patterns (determined with PET) will predict clinical and metabolic decline. We also predict that PET data will improve accuracy of clinical diagnoses earl), in the disease course, thus defining neurobiologically homogeneous 5 FAD pedigrees. Our previous research has demonstrated that the genetic marker, apolipoprotein E type 4 allele (APOE-4) is correlated with the increased risk of Alzheimer disease (AD). While a variety of neuropsychological and functional imaging tests have been demonstrated to predict subsequent cognitive decline, such studies are unlikely to identify very early abnormalities because they: (1) assess brain function during a "resting" state when mental activity is poorly controlled and the specific mental processes showing impairment are not activated; (2) often include subjects without genetic risk for subsequent decline: and. most importantly (3) emphasize measures sensitive only to advanced disease and substantial neuronal loss. We propose to develop methods that detect the earliest signs of brain dysfunction when patients would be most likely to benefit from experimental interventions: before the onset of irreversible and debilitating cognitive impairment. 1a. Develop cognitive behavioral and fMRI procedures that demonstrate activation in brain regions associated with neuronal dysfunction and loss in AD. . 1b. Characterize the brain activation and objective behavioral performance seen in subjects with a clinical diagnosis of probable AD and in age-matched controls 2a. Identify and recruit a cohort of subjects at high risk for the subsequent development of AD, on the basis of genetic markers and pedigree. 2b.Characterize the general neuropsychological performance and baseline pattern of activation (using fMRI) and structure-specific brain volume in this population. 2c. Follow the performance in neuropsychological tests in this cohort in a longitudinal study. 3. Retrospect ively evaluate the fMRI structural and neuropsychological data, comparing the performance of those who did and did not show cognitive declines beyond normal age-associated memory impairment (AAMI).

This project will evaluate the effects of illicit drugs on central nervous system dopamine function. Positron emission tomography with 6- (18F)-L-DOPA(FD) will determine forward and reverse transport across the blood-brain barrier, decarboxylation to 18F-dopamine (FDA), and release and metabolism of FDA. One group of 81 individuals has been exposed to the dopaminergic neurotoxin MPTP. A second group of test subjects are chronic high-dose cocaine abusers.

The Imaging and Genetics Core builds upon existing strengths at UCLA in resources and talent in these two technologies, as well as initial successes in combining imaging and genetics in the study of milder forms of age-related memory loss. The Imaging and Genetics ore (Dr. Small, Leader) will include an Imaging Subcore (Dr. Mega, Leader) and a Genetics Subcore (Dr. Geschwind, Leader), which will bring together investigators and data from both scientific domains to provide a resource that will accomplish seen specific aims that include: (1) collecting longitudinal structural (MRI) and functional (FDG-PET) imaging data on an estimated 30 mild AD patients, 30 persons with minimal cognitive impairment, and 30 cognitively intact elderly controls every year; (2) providing digital access to the longitudinal imaging database for ADRC investigators with links to the clinical and genetic database; (3) providing the means for investigators to digitally analyze archived brain scans; (4) drawing blood to prepare genomic DNA for all ADRC patients with AD and fronto-temporal dementia (FTD); (5) Performing APOE genotyping on sporadic and familial AD and FTD patients, as well as controls; (6) completing a risk factor questionnaire for patients and controls to enhance the power of genetic and environmental risk factor analysis; and (7) facilitating recruitment of families with AD and FTD for ongoing linage studies in collaboration with investigators at other ADCs. The Core will support at least 13 identified protocols, in response to the last committee review. ADRC investigators will be able to access the database and identify appropriate subjects for further follow-up imaging analysis a specific dataset including 3T MRI and FDG- PET data. The Genetics Subcore will establish a genetics resource for the study of dementia at UCLA. This Subcore will provide another dimension of interface with neuropathological, imaging and clinical data, and support clinical and basic research efforts. Since sample collection is a major bottleneck for many genetic studies, the availability of DNA from a large number of sporadic and familial AD and FTD patients and controls will vastly improve the ability to rapidly replicate genetic findings and to test novel genetic hypotheses.

1. Perform a clinical trial with divalproex sodium, consisting of an open phase followed by double blind discontinuation in children and adolescents with BD. hypothesis: Divalproex sodium will show safety and efficacy in symptom response as measured by the Clinical Global Impressions Scale (CGI) and the Young/Fristad Mania Scale after 8 weeks of monotherapy in a group of children and adolescents diagnosed with bipolar illness. 2. Identify potential predictors of treatment response. hypothesis: There will be a significant correlation between change in cerebral GA13A concentration as measured by Magnetic Resonance Spectroscopy (IHMRS), and change in treatment response to divalproex sodium as measured by the CGI after two weeks of therapy. We hypothesize that a higher cerebral GABA concentration will be significantly related to a decrease in symptom response to divalproex sodium.

Several observational epidemiological studies indicate that anti- inflammatory treatments attenuate or prevent the symptoms of one of the most common mental disorders of late life, Alzheimer disease (AD). Neuropathological studies also support inflammatory or immune mechanisms in AD, including findings of reactive microglia within or near AD lesions. Such evidence, however, is circumstantial, and controlled, randomized drug trials are needed to determine efficacy. The proposed project is designed to determine if the commonly used non-steroidal anti-inflammatory drug (NSAID), ibuprofen, is efficacious in delaying progression of cognitive symptoms in people with age-related cognitive losses who are at risk for developing AD. A total of 135 subjects with age-associated memory impairment (AAMI) who are at risk for further cognitive decline (age 65 to 90 years, low scores on tests of verbal and visual memory and verbal fluency) will be randomized (double-blind design) to one of two treatment groups: ibuprofen (1200 mg/d) or placebo, and followed for two years for evidence of further cognitive decline. All randomized subjects will receive magnetic resonance imaging (MRI) scans and selective genotyping (apolipoprotein E [APOE] and human leukocyte antigen [HLA) to explore how baseline brain morphology (e.g., deep white matter disease hippocampal asymmetry and atrophy) and genetic risk for AD onset (e.g., APOE-4, HLA- A2) influence decline rates and treatment outcome. Subjects receiving ibuprofen are expected to show less evidence of cognitive decline than those receiving placebo. The proposed project builds upon our group's prior work on early detection of AD using brain imaging, genetic risk, and neuropsychological assessments. This project also is a logical follow-up to recent observation studies of a promising early intervention and will represent one of the first controlled, anti-inflammatory treatment trials for persons at high risk for age-related cognitive decline and the eventual development of AD.

This grant is a competitive renewal of prior 5-year grant, in which it was proposed that fMRI during a memory challenge, in combination with information regarding the presence versus absence of APOE-4, would predict future cognitive decline in the elderly. Studies from the prior funding period did indeed show different patterns of brain activation between the two sub-populations of elderly subjects, in areas known to be involved in Alzheimer's disease (hippocampus, parietal cortex, and dorsal prefrontal cortex); further, increased fMRI activity at baseline correlated with cognitive decline measured 2 years later. The renewal application seeks to expand on these findings by conducting longitudinal follow-up of the genotyped-subject groups, with functional and structural MRI, as well as neurocognitive assessments. New subjects will be added to the sample. Novel fMRI memory activation paradigms will be used and new cortical segmentation and unfolding techniques will be used. The goals of this project are to: define the natural history of changes in memory activation for the two subpopulations of elderly individuals (those with and without an APOE-4 allele); predict long-term outcome from baseline fMRI data; and delineate with greater precision the changes in function and structure of the hippocampus that distinguish elderly with an AD risk factor (APOE-4) from elderly without this AD risk factor.

Several observational epidemiological studies indicate that anti- inflammatory treatments attenuate or prevent the symptoms of one of the most common mental disorders of late life, Alzheimer disease (AD). Neuropathological studies also support inflammatory or immune mechanisms in AD, including findings of reactive microglia within or near AD lesions. Such evidence, however, is circumstantial, and controlled, randomized drug trials are needed to determine efficacy. The proposed project is designed to determine if the commonly used non-steroidal anti-inflammatory drug (NSAID), ibuprofen, is efficacious in delaying progression of cognitive symptoms in people with age-related cognitive losses who are at risk for developing AD. A total of 135 subjects with age-associated memory impairment (AAMI) who are at risk for further cognitive decline (age 65 to 90 years, low scores on tests of verbal and visual memory and verbal fluency) will be randomized (double-blind design) to one of two treatment groups: ibuprofen (1200 mg/d) or placebo, and followed for two years for evidence of further cognitive decline. All randomized subjects will receive magnetic resonance imaging (MRI) scans and selective genotyping (apolipoprotein E [APOE] and human leukocyte antigen [HLA) to explore how baseline brain morphology (e.g., deep white matter disease hippocampal asymmetry and atrophy) and genetic risk for AD onset (e.g., APOE-4, HLA- A2) influence decline rates and treatment outcome. Subjects receiving ibuprofen are expected to show less evidence of cognitive decline than those receiving placebo. The proposed project builds upon our group's prior work on early detection of AD using brain imaging, genetic risk, and neuropsychological assessments. This project also is a logical follow-up to recent observation studies of a promising early intervention and will represent one of the first controlled, anti-inflammatory treatment trials for persons at high risk for age-related cognitive decline and the eventual development of AD.

psychological aspect of aging; stress management; aerobic exercise; mental process; memory; body physical activity; diet therapy; human therapy evaluation; genetic susceptibility; emotions; antioxidants; frontal lobe /cortex; parietal lobe /cortex; temporal lobe /cortex; brain metabolism; brain imaging /visualization /scanning; glucose metabolism; omega 3 fatty acid; dietary carbohydrates; outcomes research; apolipoprotein E; functional magnetic resonance imaging; human subject; nutrition related tag; behavioral /social science research tag; positron emission tomography; clinical research;

positron emission tomography; amyloid proteins; early diagnosis; diagnosis design /evaluation; Alzheimer's disease; brain disorder diagnosis; brain imaging /visualization /scanning; cyanides; genetic susceptibility; cognition disorders; apolipoprotein E; deoxyglucose; patient oriented research; clinical research; human subject; bioimaging /biomedical imaging;

psychological aspect of aging; mental disorders; neuroanatomy; biomedical resource; aging; Alzheimer's disease; clinical research;

psychological aspect of aging; human therapy evaluation; mental disorder chemotherapy; memory disorders; piperidine; neuroanatomy; drug screening /evaluation; behavioral genetics; pathologic process; patient oriented research; human subject; clinical research;

The Imaging Core of the UCLA Alzheimer's Disease Research Center (ADRC) builds on extensive strengths at UCLA for brain imaging. The Imaging and Genetics Core of the past funded period has been reengineered to an Imaging Core that embraces both structural and functional imaging. During the past funded period, we have built a large archive of images of patients assessed cross-sectionally and have followed a cohort of patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and normal aged controls with longitudinal magnetic resonance imaging (MRI). Images have been used by investigators to construct a preliminary AD atlas. In the renewal period, these longitudinal studies will be extended to include patients with cognitive impairment not dementia (CIND) and patients with frontotemporal dementia (FTD). The Core will provide both structural (MRI) and functional (positron emission tomography; PET) assessments longitudinally. Patients will be assessed and followed for clinical data in the Clinical Core and genetic data will be collected in the Neuropathology and Molecular Genetics Core. The Imaging Core will: (1) collect high quality longitudinal (every two years) structural (MRI) imaging data on a total of 160 individuals consisting of 35 individuals with MCI, 35 with CIND, 20 with FTD, 10 with mild AD, and 40 cognitively intact healthy elderly; (2) collect functional (FDG-PET) imaging on the same cohort; (3) archive all cross-sectional imaging data (MRI, PET, and SPECT) obtained on ADRC subjects as part of their initial and/or follow-up assessments (approximately 1,000 individuals assessed cross-sectionally and 200 prospectively by the end of the renewal period); (4) provide the means for investigators to digitally analyze structural images; 5) develop a core resource for use by investigators to analyze functional images; 6) support other cores and investigators. The Core will interact with a network of related core activities and projects to advance drug development and neurotherapeutics for MCI, CIND, AD, and FTD.

Prior research indicates that evidence of brain aging (amyloid senile plaque [SP] and neurofibrillary tangle [NFT] accumulation, neuroreceptor decline) occurs decades before individuals reach the age at risk for dementia. Moreover, current methods for detecting pre-symptomatic dementia and differentiating types of dementia are imprecise. To address these issues, this project will clarify patterns of SP and NFT brain accumulation in cognitively intact individuals (ages 30 to 80 years), individuals with MCI, and patients with mild AD and frontotemporal dementia (FTD), using 2-(1-{6-[(2-[F-18]Fluoroethyl)(methyl)amino]-2- naphthyl}ethylidene)malononitrile ([18FJFDDNP-PET) scan imaging. Cerebral patterns of SP and NFT will be determined along with informative clinical, neuropsychological, and genetic risk measures, as well as measures of regional cerebral glucose metabolism, using flurodeoxyglucose ([18F]FDG)-PET. To further clarify patterns of neurodegeneration in subjects with AD, MCI, and older controls, serotonin receptor density will be determined, using [18F]MPPF-PET. At baseline, all subjects will receive [18F]FDDNP-PET, [18F]FDG-PET, and structural MRI (in order to co-register PET data for imaging analysis) scanning, as well as genetic risk testing (e.g., APOE, H1/H1 haplotype), and clinical, behavioral, and neuropsychological assessments. Older subjects also will receive [18F]MPPF scans to measure levels of 5-HT1A receptors. Cognitively intact middle-age and older subjects, individuals with MCI, and patients with AD will be followed longitudinally, and after two years, imaging, clinical, and neuropsychological assessments will be repeated. The aims of this project are to: (1) Determine how SP and NFT brain accumulation patterns differ according to age, dementia diagnosis, and genetic risk, and how these measures correlate with patterns of neuronal deterioration; (2) Measure 5-HT1A receptor levels throughout the brain, particularly in the medial temporal lobe, and compare these signals to [18F]FDDNP measures of plaque and tangle burden, as well as regional glucose metabolic rates; and (3) Determine whether [18F]FDDNP-PET patterns and/or [18F]MPPF-PET patterns predict future cognitive and metabolic decline, and SP and NFT accumulation in the brain. This project will lead to more effective diagnosis and differential diagnosis of dementia and age-related memory loss and will provide the groundwork for reliable methods of testing interventions designed to delay the onset of dementia and treat it once it develops.

model design /development

The Administrative and Clinical Core will provide the organizational underpinnings of this project and serve as the primary site for all human subject recruitment and screening for the research projects. It will be responsible for collecting demographic, genetic, clinical, neuropsychological, and structural MRI (used to co-register to PET for PET image analysis) data, as well as other relevant information needed to track and process subjects. Under Dr. Small's direction, the key personnel who will staff this core have worked together for the past decade, successfully providing clinical support for numerous grants funded by the NIH (R01) and other agencies, as well as collaborating with other personnel in the proposed program project. This core will be responsible for database management and statistical consulting; hosting and maintaining the centralized database for the entire program project and making those data available for appropriate project personnel; maintaining quality control and achieving projected project milestones; and serving as the central coordinating body for the entire project.

DESCRIPTION (provided by applicant): Amyloid senile plaques (SPs) and neurofibrillary tangles (NFTs) are neuropathological hallmarks of Alzheimer's disease (AD) that also accumulate in key brain regions in association with normal aging. Our group has synthesized a small molecule probe, 2-(1-{6-[(2-[F-18]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([18F]FDDNP), which provides excellent visualizations of NFTs, SPs, and diffuse amyloid in AD brain specimens using fluorescent microscopy, and in vivo human positron emission tomography (PET) studies show that [18F]FDDNP labels medial temporal cortex in AD patients. This program project grant is designed to determine whether this method of plaque and tangle PET imaging (1) correlates with the expected accumulation of neuropathological changes associated with aging and dementia (AD and frontotemporal dementia [FTD]); (2) predicts future decline in people at risk for AD and in patients with dementia; and (3) augments other informative imaging (e.g., structural and functional magnetic resonance imaging [MRI], FDG-PET measures of glucose metabolism, [18FJMPPF-PET measures of serotonin receptor density), neuropsychological, and genetic risk (apolipoprotein E-4 [APOE-4], H1 haplotype of the tau gene) measures in diagnosis and differential diagnosis of normal aging and dementia. An Administrative and Clinical Core, a Chemistry and PET Imaging Core, and an Image Analysis Core will support three proposed projects: (1) Visualizing brain A-beta, tau and serotonin receptor densities; (2) Clinical plaque and tangle imaging in aging and dementia; and (3) Multi-modal brain imaging in aging and dementia. This infrastructure will provide an opportunity to study transgenic animal models, neuropathological correlations, binding characteristics, and longitudinal PET, MRI, neuropsychological and genetic risk data in patients with AD and frontotemporal dementia, people with MCI, and younger and older adult controls. This project will expand an established program in early detection and prevention of AD, designed (1) to identify presymptomatic persons most likely to benefit from early intervention and (2) to provide an objective, noninvasive means to monitor therapeutic trials.

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. Our aim is to test 3 hypotheses: 1)PET imaging shows highest FDDNP concentrations in AD-affected brain regions in AD patients, intermediate concentrations in MCI, and lowest in age-matched controls. 2)FDDNP-PET and FDG-PET imaging patterns are inversely correlated. 3)Subjects with APOE-4 have greater FDDNP brain concentrations than those without this genetic risk for AD. These studies may eventually provide a safe, effective, and practical means for 1) early presymtomatic diagnosis, and 2) monitoring disease progression and efficacy of novel pharmacologic interventions.

APOE [{C0003595}]; Active Follow-up; Age; Age-associated cognitive decline; Age-associated memory impairment; Age-related cognitive decline; Aged 65 and Over; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimers Dementia; Alzheimers disease; Ammon Horn; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; Apo-E; ApoE; Apolipoprotein E; Atrophic; Atrophy; Attenuated; Benign senescent forgetfulness; Brain imaging; CRISP; Cognitive Disturbance; Cognitive Impairment; Cognitive Manifestations; Cognitive Symptoms; Cognitive decline; Cognitive function abnormal; Computer Retrieval of Information on Scientific Projects Database; Cornu Ammonis; Deep; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Depth; Development; Disturbance in cognition; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; Drugs; Early Diagnosis; Early Intervention; Early Intervention (Education); Elderly; Elderly, over 65; Epidemiologic Research; Epidemiologic Studies; Epidemiological Studies; Epidemiology Research; Funding; Genetic Risk; Genotype; Grant; HL-A Antigens; HLA Antigens; Hippocampus; Hippocampus (Brain); Hortega cell; Human Leukocyte Antigens; Ibuprofen; Immune; Impaired cognition; Inflammatory; Institution; Investigators; Lesion; Leukocyte Antigens; MR Imaging; MR Tomography; MRI; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Medication; Mental disorders; Mental health disorders; Microglia; Motrin; NIH; NMR Imaging; NMR Tomography; National Institutes of Health; National Institutes of Health (U.S.); Neurobehavioral Manifestations; Nuclear Magnetic Resonance Imaging; Onset of illness; PBO; Persons; Pharmaceutic Preparations; Pharmaceutical Preparations; Placebos; Primary Senile Degenerative Dementia; Psychiatric Disease; Psychiatric Disorder; Randomized; Rate; Research; Research Personnel; Research Resources; Researchers; Resources; Risk; Score; Sham Treatment; Signs and Symptoms, Neurobehavioral; Source; Symptoms; Testing; Treatment outcome; United States National Institutes of Health; Unspecified Mental Disorder; White Matter Disease; Work; Zeugmatography; advanced age; age dependent; age related; alpha-Methyl-4-(2-methylpropyl)benzeneacetic Acid; brain morphology; brain visualization; cognitive dysfunction; cognitive loss; cognitively impaired; dementia of the Alzheimer type; design; designing; disease onset; disorder onset; drug/agent; early detection; elders; follow-up; geriatric; gitter cell; hippocampal; late life; later life; mental illness; mesoglia; microglial cell; microgliocyte; neuropsychological; older adult; older person; p-Isobutylhydratropic Acid; perivascular glial cell; prevent; preventing; primary degenerative dementia; psychological disorder; randomisation; randomization; randomly assigned; senile dementia of the Alzheimer type; senior citizen; sham therapy; treatment trial; visual memory

DESCRIPTION (provided by applicant): Autopsy studies have shown that middle-aged adults with Down's syndrome (DS) exhibit the neuropathological hallmarks of Alzheimer's disease (AD): amyloid senile plaques (SPs) and tau neurofibrillary tangles (NFTs). Clinical, neuroimaging, and genetic risk studies demonstrate similarities between demented DS patients and AD patients. Because of the increased risk and earlier age at onset for dementia in people with DS compared with the general population, DS has been proposed as a model for the study of AD, which afflicts an estimated 4.5 million people in the U.S. Our pilot positron emission tomography (PET) studies of adults with DS show lower brain glucose metabolic rates (measured with flurodeoxyglucose or [18F]FDG) in subjects with evidence of dementia, as well as a significant correlation between older age and higher signals for a novel measure of SPs and NFTs: [18F]FDDNP. Other PET studies show that [18F]FDDNP can distinguish AD from mild cognitive impairment and normal aging and that brain regions showing high signals demonstrate high postmortem concentrations of SPs and NFTs. To elucidate such observations, we propose performing clinical, neuropsychological, and PET imaging ([18]FDG and [18]FDDNP) studies on 72 people age 45 and older with DS (36 demented and 36 non-demented) and 36 age-matched controls. We will also perform magnetic resonance imaging scans to assist with image analysis, apolipoprotein E (APOE) typing for AD genetic risk determinations, and repeat assessments and scanning after 2 years to test the following hypotheses: (1) [18F]FDDNP signals will be greater in demented subjects with DS than in non-demented ones, who will have higher signals than controls;(2) Parietal and temporal metabolic rates measured by [18F]FDG will be higher in controls and non-demented people with DS compared with demented people with DS. (3) Within each diagnostic group, age will correlate with greater [18F]FDDNP signals. (4) At 2-year follow-up, [18F]FDDNP signals will increase in subjects with DS (both with and without dementia) compared to controls. Within the subject group with DS, we will explore differences in [18F]FDDNP signal change after 2 years according to the presence or absence of dementia at baseline. (5) After two years of follow-up, [18F]FDG signals will decrease in those subjects with DS showing evidence of decline (including developing dementia or worsening dementia) than in other groups. In addition to these hypotheses, we will explore the influence of APOE-4 on [18F]FDDNP and [18F]FDG signals in people with DS. Over the 5-year study period, we anticipate that approximately 6 older DS subjects will die, and we will explore correlations between neuropathological features of these cases and in vivo scanning and neuropsychological measures. This project will lead to a better understanding of the clinical and neuroimaging correlates of dementia in people with DS and provide the groundwork for future studies designed to improve early detection, diagnosis, and treatment of DS and AD, and thus improve the quality of life for millions of patients and their families afflicted by these conditions. PUBLIC HEALTH RELEVANCE: This project will lead to a better understanding of the clinical and neuroimaging correlates of dementia in people with Down's syndrome and provide the groundwork for future studies designed to improve early detection, diagnosis, and treatment of Down's syndrome and Alzheimer's disease. Given the many people suffering from these neurodegenerative diseases, the potential impact of this study will be considerable, possibly improving the quality of life for millions of patients and their families.

This project will study neuroimaging, blood, and CSF to measure neurodegeneration associated with AD. Few studies have focused on multiple measures of neurodegeneration in the same subjects by combining informative neuroimaging and peripheral biomarkers to provide a "biosignature," in order to improve early diagnosis and treatment monitoring. Neuroimaging studies will include PET scans using probes of amyloid plaques (PIB) and amyloid plaques and tau in tangles (FDDNP), and MRI measures of myelin and white matter tract integrity. Plasma measures of signaling proteins and cerebrospinal fluid (CSF) levels of proteins associated with plaques and tangles (e.g., elevated phosphorylated tau and low Abl-42) and demyelination (e.g., sulfatide) will also be obtained. The UCLA Clinical Core will recruit 80 subjects (40 AD patients and 40 older cognitively-intact controls), and the Center's Imaging and Biomarker Core will assist with data storage and analysis. All subjects will receive neuropsychological testing, scans, and blood tests (apolipoprotein E genotyping and plasma signaling proteins), and an estimated 50 will agree to lumbar punctures for CSF measures. We will test the following hypotheses: (1) Plasma signaling protein biomarkers will differentiate AD patients from controls. (2) CSF Ab and phosphorylated tau will differentiate AD patients from controls. Within the AD and control subject groups, CSF Ab biomarkers will correlate with PIB signals, while both Ab and phosphorylated tau CSF biomarkers will correlate with FDDNP signals. (3) MRI measures of myelin integrity will differentiate AD and control groups. We will also explore possible associations of these MRI measures with CSF sulfatide values. (4) While both FDDNP and PIB signals will differentiate AD from controls, binding patterns will differ. FDDNP will label regions predicted to show tangle as well as plaque deposition;PIB will label predicted plaque-rich regions. Within the AD and control groups, we will also explore correlations between cognitive measures and PET binding signals. We will explore research questions on how well a potential combined-measure or biosignature predicts clinical decline and whether stratifying subjects according to apolipoprotein E genotype influences findings. This project would lay the groundwork for better quantification and understanding of these critical neurodegenerative biomarkers.

The overarching goal of the Neuroimaging and Biomarkers Core (NIBC) will be to bring together neuroimaging, plasma, cerebrospinal fluid (CSF), and other potentially relevant biomarkers to facilitate ADRC research projects and other ongoing studies, assist in initiating new projects, and encourage new investigators to benefit from the strengths in these areas at UCLA and at other institutions. Our ultimate goal - manifested in targeting subjects with pre-clinical cognitive changes and the interaction with Projects 1 and 2 - is to develop image acquisition, archiving, and analysis technologies to the point that they are valuable tools in the effort to support treatments that can delay, prevent, or slow the progression of degenerative brain diseases. The NIBC specific aims are: (1) Collect and archive longitudinal high-resolution structural MRI data on ADRC subjects. (2) Provide support for imaging analysis for longitudinal amyloid plaque and tau tangle (FDDNP) and Pittsburgh Compound-B (PIB) PET imaging on subjects enrolled in Project 2. (3) Interact with the Clinical Core and the Neuropathology Core in collecting plasma and tissue samples for planned proteomic and genomic studies, (plasma and CSF) (4) Provide the means for investigators to obtain rapid and reliable quantification and diagnostic interpretation of imaging data acquired from subjects or patients evaluated for mild cognitive dysfunction or dementia. (5) Support the other cores and projects of the ADRC, and promote the Therapeutic Imperative theme, activities, and mission of the ADRC. The Core is designed to leverage UCLA's current imaging research strengths, particularly in the development of new imaging methods and PET radioligands, and the DMSC has special biomarker systems support devoted to NIBC. Moreover, we recognize the critical importance of integrating informative imaging data with other relevant biomarkers. Given the important role of neuroimaging and biomarkers in current AD research within the ADRC and elsewhere, the NIBC will have a pivotal role in these investigations. The Core will interact with and support Project 1 (MRI biomarkers of incipient AD) and Project 2 (using both FDDNP and PIB and plasma and CSF biomarkers), as well as with the on-going research of the Jim Easton Consortium for Alzheimer's Drug Discovery and Biomarker Development at UCLA.