Bruce L. Miller, MD - US grants

The long term aim of this project is to study certain aspects of choline metabolism in the pathogenesis of dementia of the Alzheimer type (DAT). The strategy will be to investigate some abnormalities for erythrocyte choline transport which have been demonstrated in some patients with DAT with the hypothesis that this dysfunction reflects similar abnormalities occurring in the central nervous system. In addition, the peripheral and central nervous systems of animals made hypocholinergic with a false choline (Ch) analogue will be studied and compared to patients with DAT. More specifically, choline transport and metabolism will be studied in erythrocytes from patients with Alzheimer's disease using stable isotopic tracer techniques. Red blood cell (RBC) Ch levels will be measured in patients with DAT and compared to age-matched demented and normal controls. Influx and efflux of Ch between erythrocytes and medium as well as Ch release and uptake from erythrocyte membrane will be calculated. An attempt will be made to discriminate between a plasma factor and an inherent RBC defect by cross-incubation studies in which plasma from DAT patients with abnormal erythrocyte choline and influx will be incubated with erythrocytes from normal subjects and from patients with DAT who show no erythrocytic abnormalities. If the normal erythrocytes develop abnormal Ch levels or influx, it would suggest that this abnormality in DAT patients is due to a plasma factor. An attempt to characterize this factor would be attempted. Families with an autosomally dominant inherited pattern of DAT will be studied. Families members with DAT will be compared to unaffected relatives at risk to see if abnormal erythrocyte Ch is a marker for DAT throughout life or increases as the disease deteriorates clinically. A potential animal model of Alzheimer's disease will be studied using the false choline analogue N-amino, N,N-dimethyl-aminoethanol(NADe). This will be fed to young rats on a choline-deficient diet, which leads to the incorporation of this false precursor into both acetylcholine (ACh) and membrane phospholipids (unpublished data). Erythrocyte flux, neurochemical parameters, and behavioral and histopathological studies will be conducted in these rats, and compared to control animals fed a diet containing an equal concentration of choline instead of NADe.

Due to the spread of AIDS, distinguishing infectious from neoplastic lesions has become a major problem at many urban medical centers. It is not possible to separate CNS toxoplasmosis (Toxo) from CNS lymphoma on the basis of clinical, serologic or magnetic resonance (MRI) findings. The medical treatment for these two conditions is distinct and the currently utilized "empiric" therapy for Toxo can delay appropriate therapy. A non-invasive technique for identifying and separating these lesions would be helpful in the management of AIDS patients and is the goal of this proposal. We hypothesize that CNS Toxo can be differentiated from CNS lymphoma utilizing 1H NMR and postulate that these lesions can be distinguished by measuring a ratio of lactate to choline which will be 1 with Toxo and 1 with lymphoma. We further hypothesize that the Lac/Cho ratio will be useful in separating other brain infections such as cryptococcal granuloma from brain tumors. Finally, we speculate that loss of NAA and elevation of Cho seen with tumor, will normalize with successful treatment of these lesions. We will utilize 1H NMR to determine the in-vivo concentration of NAA creatinine (CR), Cho and Lac in patients with CNS Toxo, CNS tumors, and control subjects within the focal mass and compare it to normal appearing brain in the contralateral hemisphere 20 patients in each group will be remeasured after they have been successfully treated and the mass has regressed. In 20 patients with Toxo and 20 with lymphoma we will compare in-vivo 1H NMR measurements with in-vivo chemical measurements.

Due to the spread of AIDS, distinguishing infectious from neoplastic lesions has become a major problem at many urban medical centers. It is not possible to separate CNS toxoplasmosis (Toxo) from CNS lymphoma on the basis of clinical, serologic or magnetic resonance (MRI) findings. The medical treatment for these two conditions is distinct and the currently utilized "empiric" therapy for Toxo can delay appropriate therapy. A non-invasive technique for identifying and separating these lesions would be helpful in the management of AIDS patients and is the goal of this proposal. We hypothesize that CNS Toxo can be differentiated from CNS lymphoma utilizing 1H NMR and postulate that these lesions can be distinguished by measuring a ratio of lactate to choline which will be 1 with Toxo and 1 with lymphoma. We further hypothesize that the Lac/Cho ratio will be useful in separating other brain infections such as cryptococcal granuloma from brain tumors. Finally, we speculate that loss of NAA and elevation of Cho seen with tumor, will normalize with successful treatment of these lesions. We will utilize 1H NMR to determine the in-vivo concentration of NAA creatinine (CR), Cho and Lac in patients with CNS Toxo, CNS tumors, and control subjects within the focal mass and compare it to normal appearing brain in the contralateral hemisphere 20 patients in each group will be remeasured after they have been successfully treated and the mass has regressed. In 20 patients with Toxo and 20 with lymphoma we will compare in-vivo 1H NMR measurements with in-vivo chemical measurements.

functional magnetic resonance imaging; cocaine; racial /ethnic difference; abnormal psychology; methamphetamine; brain disorders; drug abuse; gender difference; Asians; neuropsychology; neuroanatomy; physical chemical interaction; African American; Hispanic Americans; behavioral /social science research tag; brain imaging /visualization /scanning; neuropsychological tests; human subject; clinical research;

human therapy evaluation; brain disorder chemotherapy; Alzheimer's disease; human middle age (35-64); carnitine; outcomes research; disease /disorder prevention /control; clinical trials; clinical research; human subject;

To investigate the medicine Rilutek as a possible treatment for Frontotemporal Dementia. Rilutek is currently approved by the FDA for treatment of amyotrophic Lateral Sclerosis. FTD is a cortical degenerative disorder that often occurs in association with ALS. The relationship between ALS and FTD is unexplained but needs further study. Patients with FTD between the ages of 40 and 90 years of age, Patients will have their memory and thinking tested, will have an MRI, SPECT and EMG performed and will have blood drawn at every visit to monitor ...

The existing resource of longitudinal data from the NHLBI Twin Study, the relatively large sample size, the use of comprehensive and state-of-the-art measures of brain function and structure will provide us with an unprecedented opportunity to examine previously unexplored associations between CVD risk factors and indices of brain aging in older twins. 1. Conduct a fourth exam in an estimated 641 individuals including, 120 monozygotic (MZ) and 120 dizygotic (DZ) intact pairs, that will repeat a core battery of assessments given in previous examinations and add new neuropsychological tests and cerebral NM scanning. 2. Evaluate the prospective and cross-sectional relationships of cardiovascular risk factors collected over 23 to 25 years of follow-up (e.g., blood pressure, lipids, obesity, smoking) and MRI indices of brain morphology assessed at the fourth exam. 3. Determine the extent that twins discordant for essential hypertension or non-insulin dependent diabetes mellitus (NIDDM) or cardiovascular disease (CVD) show different MRI profiles. 4. Characterize the neuropsychological changes In performance from Exam 3 to Exam 4 and determine the contribution of genes and the environment to stability or change. 5. Use the data from exams I to 3 to investigate prospective relationships between CVD risk factors and decline in cognitive performance from Exam 3 to Exam 4. 6. Determine the heritability of the new measurements obtained for the first time at the fourth examination cycle [e.g., MRI measures of white matter hyperintensities (WMHIs), infarct area and location, and ventricular volumes]. 7. Conduct multivariate genetic analyses to determine the contribution of genes and the environment to the covariation among physical, physiological, and neuropsychological variables.

Frontotemporal dementia (FTD) encompasses a spectrum of clinical syndromes characterized by progressive impairment of behavior, language and motor functions caused by neurodegeneration within temporal and frontal brain networks. It is the most frequent cause of dementia under the age of 60. Project 4 of this PPG focuses on differential diagnosis of FTD, which, until recently, was thought to be undistinguishable form Alzheimer's disease (AD) during life. In the previous cycle we have concentrated on identifying distinctive features between FTD and AD and have incorporated our findings into novel research criteria for the behavioral variant (bvFTD), the language variants (primary progressive aphasia-PPA) and the mixed cognitive/behavioral and motor presentation (corticobasal syndromes or CBS) of the disease. The first aim of this application will focus on establishing sensitivity and specificity of these novel classification systems, combined with established PSP-S and amytrophic lateral sclerosis criteria, in predicting in vivo FTLD versus AD pathology. For this purpose we will consider pathology as the gold standard and we will have a large cohort of pathology-confirmed cases that have undergone our extensive clinical and cognitive evaluations. Project 4, and this PPG in general, have also contributed to the recent, discovery that FTD is associated with not only tau aggregates, but also with TDP-43 and FUS. Recognition that the clinical FTD syndrome is associated with a spectrum of diseases at the pathological level (called frontotemporal lobar degeneration-FTLD) poses a new challenge for differential diagnosis that will be tackled by this new project. The second and third aims of Project 4 apply all of the data acquired from the Cores, and some projects, into a multidimensional dataset comprised of clinical, neuroimaging and genetic data that will be analyzed with modern multivariate statistical methods in order to predict in vivo which pathological subtype patients will have, tau, TDP or FUS. By the year 2017 we predict we will have pathological and clinical data on about 250 FTLD cases, creating the largest FTD cohort in the world and allowing us to be at the forefront of diagnosing, and eventually treating, this devastating disease.

DESCRIPTION (provided by applicant): This program project represents an attempt to determine the genetic, imaging, emotional and diagnostic features of frontotemporal 1obar degeneration (FTLD). In project 1 we will positionally clone a locus on chromosome 15 for autosomal dominantly inherited frontotemporal lobar dementia-amyotrophic lateral sclerosis (FTLD-ALS); identify tau-linked sequence changes responsible for susceptibility to sporadic FTLD and progressive supranuclear palsy (PSP); map a susceptibility locus for FTLD that is not due to highly penetrant autosomal dominant loci; and identify and study pre-symptomatic individual and susceptibility mutations. In project 2 we will define the structural, spectroscopic and perfusion changes in FTLD, Alzheimer s disease (AD), PSP and controls. In project 3 we will use methods from behavioral research to evaluate differences and changes in emotional reactivity, regulation of knowledge, and personality in FTLD, AD, and normal controls; evaluate emotional and personality changes associated with tau mutations in families with FTLD; and evaluate behavior in FTLD, AD, and controls by studying dyadic interaction with spouses. In project 4 we will determine with a prospective design the sensitivity and specificity of clinical and quantitative methods for differentiating FTLD and AD; determine the longitudinal changes in basal ganglia and motor neuron function in FTLD compared to AD and healthy controls; and study the cognitive and behavioral features of PSP.

emotions; cognition; Alzheimer's disease; aging; tau proteins; genetic polymorphism; dementia; clinical research; human subject; nuclear magnetic resonance spectroscopy;

taste; preference; dementia; eating; behavioral /social science research tag; clinical research; human subject; electrophysiology;

DESCRIPTION (provided by applicant): The purpose of this proposal is to establish a new Alzheimer's Disease Research Center (ADRC) at the University of California, San Francisco (UCSF). The UCSF ADRC proposes to integrate basic science and clinical resources to investigate the clinical, molecular, neuropathological and neuroimaging features of Alzheimer's disease (AD), non-AD dementias, and mild-cognitive impairment (MCI). The proposed ADRC has two overarching aims: 1) to bridge the gap between laboratory and clinical studies in dementia and aging and 2) to explore the early, heterogeneous and overlapping presentations of different neurodegenerative disorders. The new ADRC will help integrate the strong UCSF basic science and clinical neurology programs in an effort to promote new discoveries. To address these aims, the ADRC will be organized around five Cores and three Projects. The Administrative, Education and Outreach Core will provide support overall management, training, and minority outreach. The Clinical Core will maintain well characterized cohorts of patients with AD, frontotemporal lobar degeneration, progressive supranuclear palsy, corticobasal degeneration, Creutzfeldt-Jakob disease, and MCI. Atypical presentations of AD and MCI will be studied, with special interest in patients with isolated language or executive symptoms. The Data Management and Biostatistical Core will assure standardized collection, validation, and novel statistical analysis of data. The Neuropathology Core will obtain autopsy material from the ADRC cohorts and facilitate clinicopathological studies. The Neuroimaging Core will use 4 Tesla MRI to investigate differential diagnosis of dementia. One Project will develop novel reagents to study PrPC structure and evaluate the ability of proteins to detect PrPsc in mice. A second Project will evaluate the relationship between cognitive deficits and calcium-dependent proteins in mice and humans. The final Project will use data from a unique cohort of 1061 MCI cases from the State of California's Alzheimer's Disease Centers to identify outcomes, risk factors, and MCI subtypes. This Project will also evaluate amnestic and nonamnestic (language, executive and mixed) MCI patients in an effort to better define the heterogeneity of MCI. The new ADRC will, therefore, build upon existing strengths at UCSF to promote unique studies of AD and non-AD dementias and MCI that will have an impact both locally and nationally.

single nucleotide polymorphism; neural transmission; pathologic process; cholinesterase inhibitors; Alzheimer's disease; Lewy body; clinical research; human subject;

Prion diseases are devastating illnesses of the central nervous system and the outcome is invariably lethal. Fusion proteins consisting of cellular prion protein (PrPc) and the Fc domain of immunoglobulin 1, designated PrP-Fc, will be employed for the molecular characterization and immunochemical studies of PrPsc, the disease causing PrP isoform. We propose to produce and characterize several variants of PrP-Fc including mutant PrP molecules. We plan to investigate the interaction between PrP c and PrP sc using PrPFc, which was recently reported by others to inhibit PrPsc formation in transgenic mice. Preliminary studies indicate that PrP-Fc binds to PrPsc in crude extracts prepared from brain. We plan to exploit this property sc and develop new approaches for the detection of PrPsc in tissues of prion-infected animals and humans. Whether PrP-Fc can be used for the measurement of PrPsc in infected tissues remains to be established. Mutants of PrP in the PrP-Fc fusion protein may prove particularly useful in these studies if the affinity for PrPsc can be substantially increased. Not only might such mutant PrP-Fc proteins prove to be useful for measuring PrPsc but such molecules might also form the basis for a novel therapeutic approach to prion diseases. If the foregoing studies yield the anticipated results, a similar approach might be applicable to developing an antemortem diagnostic test to Alzheimer's disease (AD).

brain morphology; neurogenetics; imagery; dementia; biomedical resource; emotions; clinical research;

The overarching goal of the Clinical Core is to provide well-characterized patients and controls for dementia research. This Core will recruit, evaluate, and maintain several research cohorts, including Alzheimer's disease (100), frontotemporal lobar degeneration (75), frontotemporal lobar degeneration with motor neuron disease (10), corticobasal degeneration and progressive supranuclear palsy (30), Creutzfeldt-Jakob disease (20), mild cognitive impairment (100), and healthy elderly controls (100). In addition, as part of a larger minority outreach effort, we will recruit and maintain a cohort of 100 Chinese-Americans (50 cognitively impaired, 50 controls). Each subject will receive state-of-the-art clinical assessments. These will include quantitative neurological examinations and clinical histories, functional assessments, evaluation of memory, language, executive function and other cognitive skills, social/personality function, neurobehavior, and functional abilities. Blood will be drawn in order to bank serum, DNA and cell lines. Subjects will be referred to the imaging Core. Subjects will be carefuUy followed longitudinally, with most components of the evaluation repeated annually. In conjunction with the Data Management and Statistics Core, subject data will be made available to researcher for hypothesis testing, subjects will be selected for enrollment into the ADRC RO1s, pilot studies, and other projects, and referrals to the Neuropathology Core will be facilitated.

DESCRIPTION (provided by applicant): Research in dementia has changed dramatically over the last two decades. There have been tremendous advances in clinical characterization of dementia subtypes, in behavioral neuroscience, and in our understanding of the biochemical and genetic abnormalities leading to neurodegenerative diseases. With continued progress, linkages between these different disciplines will become increasingly stronger. Genetic studies already rely heavily on thorough and accurate clinical characterization. Animal models of neurodegenerative diseases are beginning to be used to evaluate potential treatments. At the same time, physiologic techniques, such as fMRI, are now being investigated as tools for diagnosis and staging in dementia. However, as our knowledge in each of these disciplines expands, investigators studying dementia from any of these perspectives will need to incorporate data from the other areas of study into the design and interpretation of their experiments. This will require a clinician-researcher entering the field of dementia research, regardless of their specific focus, to obtain a basic grounding in three (3) key areas: 1) knowledge about the specific clinical features associated with different dementia subtypes, 2) current approaches to characterizing the biochemical, molecular, and genetic alterations that lead to neural degeneration, and 3) state-of-the-art knowledge of cognitive and behavioral neuroscience. This proposal describes a fellowship training program for clinician-researchers interested in any of these areas of study. The program will admit two (2) fellows per year and provide support for three (3) years of training. The first year will provide comprehensive clinical exposure to patients with dementia, as well as other behavioral and cognitive problems and, through directed study, acquaint the fellows with research issues in the three (3) areas of focus described above. The next two (2) years will be devoted to mentored research, with a focus in clinical research in dementia, behavioral neuroscience, or molecular/genetic mechanisms leading to neural degeneration. Individualized coursework will supplement the practical training, as necessary. The goal is to produce clinician-researchers with a well-developed research focus who can understand the significance of findings in other disciplines and incorporate these findings into their own research.

[unreadable] DESCRIPTION (provided by applicant): This proposal describes a plan for the UCSF Alzheimer's Disease Research Center (ADRC) to expand its educational offerings through the establishment of an independent Education and Information core. UCSF is committed to integrating current advancements in the understanding of dementia to support education and Dromote research collaboration. To further these commitments, UCSF proposes the creation of an online environment that will foster collaboration and communication between geographically distributed dementia and neurodegenerative disease research experts, improve the quality and quantity of our educational materials and share the benefits our improved educational materials with the greater research and clinical communities. To accomplish these goals, we plan to 1) augment our online compendium of videotaped behavioral neurological findings, 2) compile detailed online case studies, including videotaped clinical materials, digital textual histories, brain imaging, genetic pedigree, laboratory data and pathology (when available) and 3) enhance the value of both the neurological findings and the detailed case studies with expert commentary from researchers around the country. To support these offerings, we will implement a content management system to handle the unique media assets (video clips, digital text, digital images, digital audio, etc.). This widely-available system will enhance the reach and scope of our educational offerings. This system could be extended to support the digital collections of other ADRCs. The clinical materials managed by this system could easily be integrated with the variables collected for the ADRC Uniform Dataset (UDS) both within and across centers to add value to these measures. Additionally, this resource would provide the opportunity for enhancing collaboration among ADRCs. Experts from seven other ADRCs have already agreed to participate in online case teleconferences and provide commentary that will be catalogued with each corresponding case. By making distributed participation possible, this system would enhance distributed collaboration and allow for the joint development of educational materials, and ultimately enhance diagnostic reliability across dementia research centers by allowing researchers to compare diagnostic impressions on the same cases. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This program project grant will determine the imaging, emotional, social-cognitive, language, genetic and diagnostic features of frontotemporal lobar degeneration (FTLD) and related disorders including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) in contrast to Alzheimer's disease (AD) and healthy aging. In project 2 we will explore the imaging features of the three major FTLD syndromes and a new cohort of patients with ALS using a 4.0 Tesla magnet. This project will use new imaging techniques including tensor-based morphometry, perfusion and diffusion tensor imaging. In project three we will use methods derived from basic emotion research to evaluate emotional functioning (reactivity, regulation, knowledge) in all three FTLD subtypes compared to AD. Dyads interaction between patients and caregivers, low-level emotion processing and higher order reactions to these basic emotional stimulations will be determined. Project 4 will use all of the information captured through the clinical core, genetics core as well as new amyloid imaging and proteomics parameters to explore better separation of FTLD subtypes from each other and from AD, early diagnosis and better prediction of patients with FTLD-associated tau pathology from those with FTLD-ubiquitin pathology. A new project 5 explores brain-behavior relationships in FTLD using novel and innovative cognitive and social probes. Using 4.0 Tesla scans from project 2 the relationship between changes in the dorsal frontal regions and specific aspects of cognitive control of motor responses and regulation of emotion, the relationship between changes in the ventral and medial prefrontal regions and activation of the emotional systems for monitoring of behavior and the relationship between the anterior temporal lobe and comprehension of verbal and non-verbal stimuli will be explored. Project 1 which was focused upon finding novel genes associated with FTLD is replaced by a Genetics Core that will not only perform routine studies of apolipoprotein E, tau, and presenilin 1, but will also explore mRNA expression of tau-related and frontal lobe related genes. Through the Clincial Core novel assessment of 107 AD, 131 FTD, 67 SD, 56 PNFA, 43 CBD, 30 PSP, 59 ALS, and 89 controls will be completed by year 10. Neuropathology will be completed in 37 AD, 64 FTD, 25 SD, 23 PNFA, 23 CBD, 23 PSP and 27 ALS patients. This PPG represents one of the largest efforts to understand the clinical features of FTLD ever performed. PRINCIPAL INVESTIGATOR: Dr. Miller received his medical and neurologic training at the University of British Columbia. He then completed a post-doctoral fellowship in Behavioral Neurology at the University of California, Los Angeles (UCLA). His interest in Frontotemporal Lobar Degeneration (FTLD) began when he was at UCLA and it continues to be his primary interest. There are few research groups in the world that focus on FTLD, perhaps because it has been so difficult to reconcile its'heterogeneous clinical and neuropathologic presentation. Dr. Miller has assembled an interdisciplinary team of investigators with expertise in the clinical, behavioral, neuropathological, imaging and genetic issues related to FTLD. It is clearly one of the premier groups in the world working in this area. FTLD is an understudied, important and particularly challenging, area of investigation. Taken as a whole, this program project represents one of the best groups in the world attempting to understand and treat this patient population. REVIEW OF THE COMPONENTS CORE A - CLINICAL AND ADMINISTRATIVE;DR. BRUCE L. MILLER DESCRIPTION (provided by applicant): The Clinical and Administrative Core provides essential operational functions for the entire PPG. This Core will recruit patients with frontotemporal dementia (FTD), semantic dementia (SD), progressive non-fluent aphasia (PNFA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and normal control subjects. Each subject will receive a comprehensive evaluation measuring a broad range of neurological, neuropsychological, functional, neurobehavioral, and social-personality variables. In addition, subjects will be followed annually to collect longitudinal data and maintain high enrollment in our autopsy program. Administrative functions of this Core include the infrastructure for establishing policies and procedures, maintaining communication within the PPG and between the PPG and the scientific community, ensuring optimal utilization and monitoring of PPG resources, and ensuring the scientific and ethical integrity of all PPG practices. Once recruited into the Clinical and Administrative Core, subjects will be referred to Projects 2 (Imaging;Dr. Weiner), 3 (Emotion;Dr. Levenson), 4 (Clinical Diagnosis;Dr. Miller), and 5 (Brain-Behavior;Dr. Rosen). In addition, blood samples will be sent to the Genetics Core (Dr. Geschwind) and autopsy tissue will be sent to the Pathology Core (Drs. Trojanowski and Lee). The Clinical and Administrative Core will also interact extensively with the Data Management and Biostatistics Core (Dr. Fox) for data management, data quality, and data analysis functions.

Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, invariably fatal and untreatable neurodegenerative disease with a mean duration of about eight months. Beyond the debilitating cognitive and motor deficits that accompany CJD, the difficulty in treating behavioral and mood disturbances and the rapidity of its course compound its tragedy. Moreover, an epidemic of new variant CJD (nvCJD) in England has raised serious concerns regarding the safety of the world's beef supply; the possibility that prions might be passed through the blood has led to the banning of blood or tissue donations from individuals who have resided in England. The discovery of an effective therapy for prion diseases would have enormous human and economic implications. Recent results from experiments in Dr. Prusiner's laboratory show that, at physiological concentrations, the anti-malarial drug quinacrine permanently clears abnormal priori proteins from cell culture. The demonstrated efficacy of quinacrine in cell culture, its relative safety and well known side-effects in the clinical setting, and the universal fatality of CJD justify quinacrine as an immediate candidate for the treatment of CJD. We propose a treatment study for patients with sporadic CJD (sCJD) with racemic quinacrine. Over three years, 90 patients will be admitted to the University of California at San Francisco (UCSF) NIH-funded clinical research center where a diagnosis of sCJD will be determined and where patients will enter into a randomized, double-blinded, treatment study with quinacrine. Patients will be divided into two quinacrine arms, a high-dose titration (450 mg daily) and a low-dose titration (75 mg daily). They will be treated for one year and then be followed through to the end of the five-year study period. The dose of quinacrine may be increased or decreased in each patient depending on clinical deterioration or toxicity, respectively. Survival will be the primary outcome measure of this clinical study. Also, additional outcome measures will be used that assess activities of daily living, cognition, MRI and EEG. We hypothesize that patients in the high-dose quinacrine arm will have increased survival and a slower rate of neurological progression compared with patients in the low dose arm. By year four of this program project grant (PPG), we hope to begin a clinical study with a new compound, developed in other Projects in this PPG, that shows even greater efficacy than racemic quinacrine.

Prion diseases are devastating illnesses of the central nervous system and the outcome is invariably lethal. Fusion proteins consisting of cellular prion protein (PrPc) and the Fc domain of immunoglobulin 1, designated PrP-Fc, will be employed for the molecular characterization and immunochemical studies of PrPsc, the disease causing PrP isoform. We propose to produce and characterize several variants of PrP-Fc including mutant PrP molecules. We plan to investigate the interaction between PrP c and PrP sc using PrPFc, which was recently reported by others to inhibit PrPsc formation in transgenic mice. Preliminary studies indicate that PrP-Fc binds to PrPsc in crude extracts prepared from brain. We plan to exploit this property sc and develop new approaches for the detection of PrPsc in tissues of prion-infected animals and humans. Whether PrP-Fc can be used for the measurement of PrPsc in infected tissues remains to be established. Mutants of PrP in the PrP-Fc fusion protein may prove particularly useful in these studies if the affinity for PrPsc can be substantially increased. Not only might such mutant PrP-Fc proteins prove to be useful for measuring PrPsc but such molecules might also form the basis for a novel therapeutic approach to prion diseases. If the foregoing studies yield the anticipated results, a similar approach might be applicable to developing an antemortem diagnostic test to Alzheimer's disease (AD).

The Administrative Core shall continue to supply overall management, guidance, and direction to UCSF's ADRC. Simultaneously it will further solidify effective relationships between the Center and its parent institution, while facilitating interactions with the national ADC community. This core will provide the administrative infrastructure to guide interactions among the UCSF ADRC cores and projects, will facilitate the efforts to enrich the training of researchers and patient care providers at UCSF, and will develop programs to support patient participants and sustain dementia caregivers. The Administrative core will also continue to promote the goal of increasing participation of minority populations in the ADRC. RELEVANCE (See instructions): The Administrative Core provides the infrastructure for management and operations of the UCSF Alzheimer's Disease Research Center. It works closely with all Cores, Projects and Pilot studies to aid in successful fiscal and resource management as well as provide communication systems for integration and reporting.

DESCRIPTION (provided by applicant): We propose to establish a comprehensive, validated repository of adult human dermal fibroblasts and human induced pluripotent stem cell (hiPSC) lines from frontotemporal dementia (FTD) patients with genetically defined mutations and familial, non-mutation carrying controls. hiPSCs hold tremendous promise for the development of in vitro FTD models for studying disease pathogenesis in relevant human cell types that would otherwise be impossible to obtain, such as human neurons. Using an established, collaborative, multi- institutional approach, we will bank adult human dermal fibroblasts from FTD patients carrying common mutations in the genes currently known to cause FTD: tau (MAPT), C9ORF72, and progranulin (GRN). In Aim 1, we will recruit both FTD patients with defined genetic mutations and control subjects. Comprehensive and longitudinal clinical evaluations will be linked to each cell line, allowing us to correlate disease characteristics with molecular phenotypes. In Aim 2, we will reprogram fibroblasts into hiPSCs by non-DNA-integrating technologies with which we have had recent success. In addition, we will further create EGFP reporter lines for monitoring and standardizing differentiation protocols in FTD-relevant cell types such as forebrain neurons. We will also correct selective mutations to create isogenic control lines so that we can precisely differentiate mutation-specific phenotypes from the noise of inter-individual variability. In Aim 3, we will derive and validate human neurons to model and study FTD pathogenesis in culture and to deliver hiPSC lines with robust phenotypes for FTD research and drug development. Based on our previous research experience in RNA and Tau biology and pathophysiology, we will focus on human neurons with GGGGCC repeat expansions in C9ORF72 and MAPT mutations. All cell lines will be banked at the Coriell Institute and will be accessible to the worldwide FTD research and drug development community. These resources should significantly alter the FTD research landscape by accelerating discovery.

CORE A - ABSTRACT The UCSF Alzheimer's Disease Research Center (ADRC) Administrative Core is responsible for guiding the overall direction and management of the ADRC. This Core sets and implements program wide policies and procedures for sustaining scientific and ethical integrity and productivity across all cores and projects. It will ensure compliance with institutional, NIH and HIPAA policies and requirements related to human subjects and animal research. The Core will support and promotes the development of the ADRC by supplying tools for communication, planning and evaluation working to maintain an integrated, coherent and multidisciplinary focus. A key function is to maintain partnerships with key stakeholders both internal to the university and external partners. Guidance will be sought from advisory committees both within and external to the university. The Administrative Core will coordinate and provide an enriched training environment while stimulating creative research. One goal is to attract new investigators via pilot project funding. Reviews for these pilots utilize UCSF's Clinical Translational Scientific Institute campus-wide research Resource Allocation Program. The core provides fiscal accountability and business management expertise. The Administrative Core provides an extensive administrative infrastructure in a supportive and unique environment aimed at scientific discovery, therapeutic developments, and improving dementia care.

ABSTRACT The overarching goal of this project is to further improve the differential diagnosis of bvFTD and its underlying neuropathologies in the individual patient, addressing practical limitations to diagnosis both in the clinic and in clinical research settings. Despite substantial advances over the last decades in the clinical and bench science of bvFTD, there are still impediments to progress in this area. First, though in a research setting we have become expert at differentiating bvFTD from various amnestic and non-amnestic variants of AD, bvFTD and AD are still routinely mistaken for each other in both primary and tertiary care centers, demonstrating that community providers still need practical, clinically realistic approaches to differentiating bvFTD and AD. To this end, we will develop a brief, targeted clinical evaluation that is sensitive and specific for the clinical diagnosis of bvFTD versus AD. Second, identification of the molecule responsible for the bvFTD syndrome in an individual patient -- tau, TDP43, or FUS ? remains challenging, even in a research environment where advanced diagnostic tools are available. Thus we will study novel biomarkers such as tau imaging, CSF biomarkers, DNA polymorphisms and RNA expression patterns for their value for in-vivo separation of the bvFTD molecular subtypes. Finally, in both community settings and expert FTD centers, bvFTD and primary mood disorders (MD) such as major depressive disorder (MDD) and bipolar affective disorder (BD) are frequently mistaken for each other. Direct comparison is needed to guide their differentiation, thus we will systematically examine groups of MDD and BD patients with a comprehensive set of neurologic measures and compare them to our bvFTD patients. This will also be an opportunity to explore the clinical presentations of the subset of MD patients in whom biomarkers of neurodegeneration are found. To accomplish our goals, we propose the following aims and activities: AIM 1: Identify a set of measures that can discriminate bvFTD from AD at a high level of accuracy and combine them into a brief clinical assessment protocol that could realistically be adopted in clinic. The clinical, imaging, and laboratory data collected in the previous 14 years of this PPG will be analyzed and a standardized clinical battery will be developed that is sensitive to the diagnosis of bvFTD and to the separation of bvFTD from AD and from healthy older controls. Over the next four years this battery will be validated prospectively, using a tiered approach to model cut-points where shifts in sensitivity/specificity occur with the addition of specific clinical tests that incur additional financial and time costs. AIM 2: We will examine the benefit of more recently developed biomarker approaches to diagnosis in our bvFTD patients to determine which measures best segregate the molecular subtypes of bvFTD. AIM 3: Comprehensively evaluate patients with MD (MDD and BD), matched by age (40-70 years) to our bvFTD patients, to identify features differentiating bvFTD from MD. AIM 4: Determine the frequency of neurodegenerative biomarkers in MD patients and evaluate clinical differences in biomarker positive MD patients.

ABSTRACT Frontotemporal dementia represents a group of clinical syndromes that specifically target language, behavior, social, and motor systems. The overarching goals of this Program Project Grant have been to detail the pathologic, genetic, imaging, cognitive, emotional, and behavioral features of these syndromes. In this renewal application, the Administrative and Clinical Core continues to maintain the PPG's overall administrative infrastructure and provide well characterized subjects and biospecimens to the PPG Projects and other Cores. Our specific aims are to recruit patients with bvFTD (n=90), svPPA (n=40), nfvPPA (n=30), lvPPA (n=30), non- language AD (n=30), CBS/PSP (n=30), asymptomatic mutation carriers (n=20), major depressive disorder (n=100), bipolar disease (n=100), and normal controls (n=15), engage in deep behavioral phenotyping, follow subjects annually, obtain autopsy consent, integrate evaluation data with the Imaging, Genetics, and Neuropathology/Biospecimen Cores, and refer subjects to the individual, hypothesis-driven PPG Projects.

ABSTRACT This is the third renewal application requesting T32 funding for the UCSF Behavioral Neurology Training Program (BNTP), co-directed by Drs. Howard Rosen and Bruce Miller. The BNTP was established at UCSF in 1999 within the UCSF Memory and Aging Center (MAC) to train clinical researchers in behavioral neurology and neurodegenerative disease. Funded in 2005, this T32 program allows emerging researchers to gain an integrated understanding of the clinical, epidemiological, genetic, and molecular features of neurodegenerative diseases, and is one of the few programs in the world that provides intensive training on the non-Alzheimer?s dementias and non-amnestic forms of AD. The goal of the program is to train postdoctoral clinical researchers for a career in neurodegenerative research. The program is open to MD neurologists, geriatricians and psychiatrists who have completed a residency. A core element of our program is accurate classification of dementia subtypes and prediction of the specific proteins causing neurodegeneration. Our training is designed to impart fellows with the skills to evaluate and quantify the effects of various proteins and other biological factors that cause dementia using clinical assessment and laboratory methods. Training takes place over two years. The first year consists of research rotations through four clinical research programs at our center including our program project grant on frontotemporal dementia, our Alzheimer?s disease research program, our rapidly progressive dementia program and our clinical trials program. During this year, fellows begin development of their research project with one of the program mentors and develop skills in scientific writing, presentation, and in data analysis using archival data from our clinical and imaging databases. In the second year, fellows are given more unstructured time to continue their research project and plan for grant submissions to support their future career in clinical research. Over the years, our program has strengthened relationships with UCSF Psychiatry and Geriatrics, and this has influenced our research, recruitment, and approach to training. Twenty- nine fellows have been supported directly by this T32, but the infrastructure developed through the T32 program contributes to the education of many additional postdoctoral fellows. In the upcoming cycle the training program will include additional didactic sessions covering social determinants of health, health economics and policy, along with leadership training.

PROJECT SUMMARY/ABSTRACT Although dementia has a global impact, efforts to address ensuing challenges have come mostly from high- income countries (HICs). Whereas the prevalence and incidence of dementia appear to be stable or declining in such countries, an alarmingly opposite tendency typifies South American countries (SAC). This scenario proves even more challenging due to region-specific traits. First, the particular genetic and environmental backgrounds of SAC limit the generalizability of key findings from HICs. Moreover, the greater genetic diversity and impact of socioeconomic status (SES) of SAC remain markedly understudied. Of note, this is true of the four largest SAC (Brazil, Argentina, Colombia, and Peru), representing over 75% of the region?s population. In addition, SAC face a dearth of innovative, harmonized, and cross-regional studies on two of their most prevalent neurodegenerative disorders: Alzheimer?s disease (AD) and frontotemporal dementia (FTD). It is thus critical for SAC to join ongoing international efforts and develop a gold-standard approach for detecting disease-specific alterations in a context of methodological, genetic, and socioeconomic heterogeneity. Against this background, our long-term goal is to identify the unique genetic and SES factors that drive AD and FTD presentation in SAC relative to the US. To this end, we will establish a cohort to test large samples from the four abovementioned SAC, as well as the US (totaling > 3000 participants, including 1500 controls, 750 AD patients, and 750 FTD patients). We will combine standardized clinical assessments with innovative analytical techniques including multimodal machine learning to account for heterogeneity in these diverse populations. By combining standardized genetic, neuroimaging, and behavioral (SES-cognitive) measures, we will test the underlying hypothesis that there are unique risk factors for AD and FTD in SAC which do not prove significant in US populations. More particularly, we will aim to (a) establish genetic risk to AD and FTD in diverse SAC cohorts; (b) test whether patients from SAC and the US can be discriminated after accounting for how SES affects cognitive and brain imaging signatures; and (c) determine genetic, cognitive, cerebral, and socioeconomic factors that discriminate among SAC vs. US patients. Positive impacts of this work include a better understanding of the genetic and socioeconomic factors driving neurocognitive manifestations of dementia, and the identification of novel genetic targets for risk reduction and disease prevention in SAC. Our large multimodal, cross-sectional study will enable clinical assessment of understudied patient groups, extend and harmonize existing data sets, and prompt the development of novel measures and multimodal machine learning protocols. More generally, by establishing a collaborative framework which capitalizes on unique regional populations, our proposal can consolidate a SAC-based platform for future translational research and assessment.