2000 — 2006 |
Galasko, Douglas R |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Age Related Neurodegenerative Diseases in Micronesia @ University of California San Diego
Amyotrophic lateral sclerosis (ALS), parkinsonism-dementia complex (PDC), and dementia, assumed to be a single disease entity, are highly prevalent, age-related neurodegenerative disorders among the people of Guam. Characteristically all show neuronal loss in the substantia nigra and/or anterior horn cells and severe hippocampal and neocortical neurofibrillary tangle formation. The tangles are identical to those encountered in Alzheimer disease (AD). Thus, clinically and pathologically this disease shows many aspects of the three major age- related neurodegenerative disorders encountered elsewhere in the world (ALS, AD, and Parkinson disease). Contrary to what has been reported, - the disease is not disappearing. Currently over 200 cases of ALSIPDC are in the Guam Patient Registry among an atrisk population of 17,000 individuals. However, the characteristics of the epidemic have changed. Fewer cases of ALS are seen, a greater proportion of patients present with presenile dementia, and the age of onset of necrologic impairment has increased by about 10 years. These changes support an environmental hypothesis with declining exposure, but other studies strongly suggest that an inherited gene(s) defect plays a significant role in susceptibility to this disease. The most likely model is that a gene- environment-interaction is responsible for ALS/PDC and dementia. The proposed program project, using epidemiologic, genetic, pathologic, and molecular biologic approaches, address i three major issues, 1) relevant genetic and environmental risk factors, 2) the pathogenesis and development of tau pathology, and 3) the potential role of oxidative stress and mitochondrial dysfunction. An important aspect involves the recognition that many relatively young Chamorros who die without a clinical diagnosis of ALSfPDC, show neuropathologic changes typical of ALS/PDC. This suggests that they have yet to accumulate a sufficient lesion burden to show clinical symptomatology. The study of brains of such individuals provides a truly unique opportunity to identify and characterize relevant pathogenetic features which are operative in the earliest phases of the disease. The proposed research will provide critical insights into the etiology and pathogenesis of this major public health problem for the people of Guam, while also serving as a model for the study of analogous conditions seen elsewhere in the world.
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1 |
2002 |
Galasko, Douglas R |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Prevalence /Incidence /Risk Factors For Dementia On Guam @ University of California San Diego
DESCRIPTION (provided by applicant): An extraordinarily high incidence rate of amyotrophic lateral sclerosis (ALS) and Parkinson's Dementia Complex (PDC) was documented in the 1950's among Chamorros living on Guam. ALS has declined markedly on Guam over the following 50 years but PDC has declined to a lesser degree. Among older Chamorros, late-life dementia clinically resembling Alzheimer's disease (AD) is now at least as common as PDC. We aim to carry out a population-based study to characterize the rates of dementia and PDC among Chamorros on Guam. Our overall hypothesis is that interactions between genetic and environmental factors and aging explain the complex pattern of neurodegenerative disorders seen on Guam and the rapid changes in patterns of disease. We hypothesize that the Chamorros have a genetic predisposition to form neurofibrillary tangles (NFT). When this predisposition is combined with a strong exposure to factors in the environment, ALS and PDC may result. When Chamorros escape these two disorders, factors associated with aging and the brain, particularly oxidative stress, may result in tangle formation and late-life dementia. Specific aims of project 1 of this renewal are: 1) To determine the prevalence of dementia ('pure' dementia, PDC and other causes) among Chamorros on Guam aged 65 and older; 2) To determine the age- and sex-specific incidence of dementia among Chamorros on Guam; 3) To examine the effect of putative risk factors on the prevalence and incidence of dementia and PDC. Potential risk factors include environment: (traditional Chamorro diet and lifestyle; sources of water); genetics (family history of ALS or PDC; ApoE e4 allele; tau polymorphisms and other candidate genes); risk factors for AD (education, head trauma, head circumference and others); biological measures (plasma levels of F-2-isoprostanes; cholesterol levels); 4) To characterize neuropathologic changes among elderly Chamorros who are cognitively normal and those who have clinical syndromes of dementia or AD. This project will draw on the Clinical core on Guam; Neurologists and a neuropsychologist at UCSD and OHSU; a Neuropathology core at Mt Sinai Hospital, New York, and Neuroepidemiologists at University of South Florida. The project is planned for 5 years.
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1 |
2002 |
Galasko, Douglas R |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Core--Clinical @ University of California San Diego
DESCRIPTION (provided by applicant): The Clinical core (core B) will continue to support studies into neurodegenerative disorders occurring on Guam, including amyotrophic lateral sclerosis (ALS), Parkinson's Dementia Complex (PDC) and late-life dementia clinically resembling Alzheimer's Disease (AD). Detailed clinical characterization of patients and controls on Guam, accurate clinical diagnoses, collection of data using standardized rating scales, obtaining blood samples (including DNA), obtaining longitudinal follow-up, coordinating structural MR studies of the brain, and arranging autopsy procurement of brain tissue are essential to support a variety of scientific projects investigating risk factors and mechanisms of disease. Specific aims of core B in this renewal are: 1) Recruit Chamorros aged 65 and older on Guam to support epidemiological and other studies; 2) screen subjects for cognitive, motor and functional abilities, conduct clinical, neurological and neuropsychological assessment of participants who meet criteria for detailed evaluation in the proposed prevalence and incidence studies; 3) establish clinical diagnoses; 4) Continue to follow existing patients with ALS, PDC and Marianas Dementia, and evaluate and follow new patients with these disorders; 5) Recruit subjects to undergo research MRI studies; 6) collect, store, and ship blood and CSF specimens; 7) obtain autopsy consent, and assist in brain autopsies and preparation of tissue, storage and shipment; 8) data acquisition and management.; 9) supervise staff and maintain quality assurance of procedures and data; 10) provide consultation for study participants and their families and caregivers; 11) liaison with health care providers and government agencies; 12) carry out education and training. core B will consist of staff based on Guam, directed by Ulla-Katrina Craig, whose activities are critical to the entire Program, including recruitment, screening, evaluation and follow-up of patients, and data entry. Neurologists and a neuropsychologist at UCSD and a neurologist at OHSU will travel to Guam regularly to perform neurologic and cognitive examinations.
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1 |
2002 |
Galasko, Douglas R |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Core---Administrative, Database, and Statistical @ University of California San Diego
DESCRIPTION (provided by applicant): Core A continues to administer the overall Program Project, and to manage the Database. This involves interacting with three cores, 4 subprojects, and with NIA officials and an External Advisory Board (in the US) and a Guam Community Advisory Board. The specific aims of core A are as follows: 1) Facilitate the overall goals of the program project, provide administrative support for all cores and projects, and maintain liaison with participating institutions on Guam, in San Diego, New York, Philadelphia, Seattle, Portland (OR) and Tampa (FLA), and with NIA program staff; 2) Monitor and maintain subject enrollment of subjects into the Clinical core and entry into research projects; 3) Maintain and manage a common database of all Clinical and Pathology core data and stored DNA and blood samples; ensure quality control and security; facilitate sharing of data between investigators; coordinate and provide support for data analyses; 4) Schedule communication and meetings between investigators, consultants, the executive committee, the External Advisory Committee and Guam Advisory Board; 5) Promote and facilitate sharing of resources and tissue with investigators outside the Program Project; 6) Review on an ongoing basis the scientific progress of the Program Project; 7) Review the utilization of funds; 8) Monitor and review all educational and training activities; 9) Monitor investigator and staff compliance with Human Subjects education and regulations.
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1 |
2003 — 2007 |
Galasko, Douglas R |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Biomarkers in Aging, McI and Alzheimer's Disease @ University of California San Diego
DESCRIPTION (provided by applicant): This proposal focuses on biological markers in cerebrospinal fluid (CSF) related to Alzheimer's Disease (AD). Biomarkers that are clearly related to the pathology of AD, namely A-beta42 (the major protein in plaques) and tau (found in tangles) can discriminate patients with AD from controls. Less is known about these and other biomarkers in mild cognitive impairment (MCI), which is often a prodromal stage of mild AD, and in relation to aging and to genetic and other risk factors for AD. In this proposal, 4 AD Research Centers will collaborate to obtain CSF and plasma samples from well-characterized subjects with AD, MCI and healthy controls spanning the age range 20-80. About 50% of subjects will contribute a set of serial CSF and plasma samples at 12 month follow-up. This project builds on an existing collaborative CSF and plasma bank, and aims to accrue and bank samples from over 500 subjects. A-beta processing, production, deposition and clearance are important factors in AD. These will be investigated by measuring levels of species of A-beta (A-beta 38, 40 and 42) and of secreted, cleaved forms of beta-amyloid precursor protein (APP), the parent molecule of A-beta, in CSF. Indices of neurodegeneration and tangle formation will be studied by quantifying CSF levels of tau and phospho-tau, and tau will be purified from CSF and sequenced. As indices of oxidative damage and inflammation, mechanisms implicated in neuronal damage in AD, biomarkers such as F-2 isoprostanes, S100B and alpha1ACT will be measured. The relationship between these biomarkers and age, sex, diagnosis (normal, MCI, mild AD), degree of cognitive impairment, and genetic risk factors for AD (apolipoprotein E [ApoE] and CYP46 genotypes) will be examined, and the extent of change in biomarkers over 12 months will be analyzed. Banked CSF and plasma will be available for further research into novel biomarkers, including broad-based proteomic studies.
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1 |
2006 — 2010 |
Galasko, Douglas R |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
A Trial of Ttp488 to Slow the Rate of Clinical Progression of Patients With Ad @ University of California San Diego
Project 3: A Trial of TTP488 to Slow the Rate of Clinical Progression of Patients with AD Currently FDA-approved drugs for Alzheimer's disease (AD) are primarily symptomatic and do not target pathogenic pathways. Deposition of amyloid beta protein (Ali) in plaques and inflammation may offer therapeutic targets. The receptor for advanced glycation endproducts (RAGE) is expressed in neurons and astrocytes and is upregulated in AD. RAGE interacts with multiple ligands, including AIJ, and may link AS to inflammation and neuronal dysfunction. Inhibition of RAGE/ligand interactions may slow the progression of neuropathological defects and cognitive changes induced by AH. TTP488 is a small molecule identified by a screening process, that binds to RAGE in vitro, and inhibits the interaction of RAGE with its ligands. In vivo, TTP488 crosses the blood brain barrier and, in transgenic mouse AD models, reduces brain amyloid load and behavioral dysfunction. The compound is well tolerated in healthy human subjects, including daily oral dosing for 1 month in elderly subjects, and longer safety studies in patients with AD are ongoing (data available in February 2006). We propose to carry out a randomized, double blind, multicenter trial in 350 patients with mild to moderate AD treated with one dose of TTP488 or placebo for 18 months. Subjects will be randomized 60:40 to receive active drug or placebo. The hypothesis is that treatment with TTP488, relative to placebo, will lead to slower clinical decline. Subjects will be followed at regular intervals to assess cognition, function, behavior, safety and tolerability. Primary outcome measures are the ADAS-cog and CDR Sum of Boxes (CDR-SOB). Secondary outcome measures are the ADCS-ADL and Neuropsychiatric Inventory (NPI). Drug levels and biomarkers will be measured in plasma. Standard therapy for AD will be permitted. The study has 90% power to detect a 41% or larger change on the ADAS-cog assuming a 3.8 point mean annual change in the placebo group, and has 80% power to detect a 35% change.
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1 |
2007 — 2008 |
Galasko, Douglas |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Testing the Role of Axonal Transport Disturbance in Ad? @ University of California San Diego
Our goal is to test the hypothesis that compromised axonal transport plays a causative or contributory role in CNS neurodegeneration associated with the development of Alzheimer's Disease (AD). We propose to test our hypothesis using genetic and biochemical approaches in the mouse and extending our work to humans. Specifically we propose: 1) To test the inter-related hypotheses that overexpression of APP generally causes axonal transport defects and that further reductions in anterograde axonal (and perhaps dendritic transport) generally enhance Abeta production and amyloid plaque deposition in mouse models of Alzheimer's Disease. While we have seen genetic enhancements with a single APP transgene (Tg-APPswe), it is critical to know whether enhancement of APP processing by reductions in motor protein dose and reduction in axonal transport is a general phenomenon. 2) To test the hypothesis that reductions in retrograde axonal (and perhaps dendritic transport) will suppress Abeta production and amyloid plaque deposition in mouse models of Alzheimer's Disease. In Drosophila, we have seen striking suppression of APP-induced phenotypes by reducing dynein and dynactin expression. We wish to test whether these findings can be extended to mammals. If so, this finding could lead to future novel therapeutic opportunities for AD. 3) To extend work on transport defects in Drosophila and mouse models to humans and to ask whether pathology characteristic of alterations in axonal transport in basal forebrain cholinergic neurons occurs as an early event in the development of Alzheimer's Disease. We will test whether pathologies characteristic of transport failure, i.e., swollen axons with organelle and vesicle accumulations, that are observed in the mouse and Drosophila models exist in the early stages of Alzheimer's Disease in humans.
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0.915 |
2007 — 2013 |
Galasko, Douglas R |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Alzheimer's Disease Research Center @ University of California San Diego
Alzheimer's Disease (AD), the most common cause of dementia in the elderly, is estimated to affect over 4 million Americans, a number projected to grow in the next few decades. Research progress has led to improved diagnostic accuracy for AD, the development of symptomatic medications, and provision of social and community care networks. However, current treatment options provide only temporary stabilization at best, and the overall cost for care of patients with AD in the USA exceeds $100 billion per year. Further research is essential to make progress in the fight against AD. The UCSD Alzheimer's Disease Research Center (ADRC) has contributed to much research progress in the past 25 years. In order to facilitate and conduct research into the causes, treatment and prevention of AD, the overall Specific Aims of this renewal application for the Center are: 1) To support research efforts by maintaining resources that include cohorts of subjects with normal cognition, AD and other dementias;neuropathology tissue from well-characterized subjects;biological samples and DMA;and to maintain a comprehensive database. 2) To coordinate pilot and research projects related to Alzheimer's Disease, aging or neurodegeneration. 3) To foster professional education and training, as well as educational outreach efforts in the community. 4) To collaborate with other ADCs, with NACC, and with national research efforts related to AD and dementia. The Center will consist of an Administrative Core, a Clinical Core (with a Hispanic Minority Satellite), a Neuropathology Core, a Data and Biostatistics Core, an Education and Information Core. Three research Projects are proposed: 1) Structural MRI analyses to distinguish patients with AD, Dementia with Lewy Bodies (DLB) and Controls. 2) Axonal transport of a-synuclein and the pathogenesis of DLB. 3) Psychometric prediction of the rate of progression of AD and DLB. Three Pilot Project awards will be issued each year. The Center will follow 500 subjects, using annual standard evaluations that include the Uniform Data Set components and will contribute to national research efforts by contributing data to the National Alzheimer's Coordinating Center, and to the Alzheimer's Disease Neuroimaging Initiative (ADNI). ADRC subjects will be offered participation in clinical trials organized by the Alzheimer's Disease Cooperative Study (ADCS) and by pharmaceutical companies. The Center will continue to support innovative research, to train new investigators, and to improve public knowledge and awareness about aging and AD, as well as to provide innovative support efforts for patients and families affected by AD.
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1 |
2009 — 2013 |
Galasko, Douglas R |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Clinical Studies of Nsaidss as Y-Secretase Modulators in Alzheimer's Disease @ University of California San Diego
Decreasing the production of Abeta may be beneficial in the treatment of Alzheimer's Disease (AD). Basic research carried out through Projects 1 and 2 previously identified that allosteric modulators of gamma- secretase selectively lower Abeta42, without affecting Notch processing, and screened several Nonsteriodal anti-inflammatory drugs (NSAIDS) as candidates. We designed and conducted'a clinical trial to determine :he safety, tolerability and pharmacokinetics of R-flurbiprofen in healthy older adults. The data was used by Myriad Pharmaceuticals, Inc.,to plan and implement phase 2 and an ongoing program of phase 3 clinical trials of R-flurbiprofen in AD. In this renewal of Project 3, we aim to optimize biomarker measurements of Abeta in CSF to characterize Abeta lowering effects of R-flurbiprofen. We also aim to test ibuprofen, an NSAID with gamma-secretase modulating activity and anti-inflammatory actions, by carrying out a controlled clinical trial in patients with amnestic Mild Cognitive Impairment (aMCI), the earliest clinically diagnosable stage of AD. This targets early intervention, before patients have developed extensive amyloid deposition and damage to neurons and synapses. We hypothesize that lowering Abeta42 very early in AD may have beneficial effects on imaging and biochemical biomarkers. We have 2 aims: (1) To evaluate CSF levels of Abeta42 after acute treatment with R-flurbiprofen at a high dose of 1600mg in healthy adults, using a lumbar CSF catheter to obtain CSF samples during 24 hours, and the technique of stable isotopic labeling to calculate Abeta synthesis rates. This will characterize the timing and duration of Abeta lowering actions. (2) To evaluate biomarker changes in CSF and brain atrophy measures on MRI,in 100 patients with aMCI who will be randomized to treatment with ibuprofen 800 mg three times per day (+ omeprazole 20 mg/day for gastroprotection), or to placebo, for 12 months. CSF and MRI will be obtained at baseline and 12 months and a brief neuropsychological test battery (NTB) and lADL-questionnaire will be given at baseline, 6 and 12 months. Primary outcome measures will be change in hippocampal and total brain volume (MRI); concentrations of total tau, phosphotau 181,Abeta42 and Abeta38, and F2-isoprostanes (CSF). Secondary outcome measures will be change in NTB and ADCS ADL-MCI scores. Significance: No treatment has been shown to have disease-modifying effects in AD. CSF biomarkers and MRI measures allow us to monitor whether treatment that targets modulation of gamma-secretase will (1) selectively lower Abeta42 in humans following acute treatment;(2) have beneficial effects on biomarkers related to Abeta and to damage from the resulting cascade of pathology in aMCI, the earliest clinical stage at which AD can be diagnosed. These results will support further efforts to develop gamma-secretase modulators for early clinical use.
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1 |
2009 — 2013 |
Galasko, Douglas R |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Clinical Core B @ University of California San Diego
The Clinical Core has characterized, followed and provided subjects and data, and has collected and banked biological specimens that have contributed to much research progress in the past 25 years in areas such as early and accurate diagnosis of AD, tracking the course of dementia, and testing new treatment approaches for AD. The Specific Aims are: (1) Maintain and follow a panel of 400 well characterized English-speaking subjects with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Parkinson's Disease with Dementia (FDD), Mild Cognitive Impairment (MCI), and age- and education-matched healthy control subjects. (2) Maintain and follow a panel of 100 well characterized Spanish and English-speaking Hispanic subjects with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Parkinson's Disease with Dementia (PDD), Mild Cognitive Impairment (MCI), and age- and education-matched healthy control subjects through our Hispanic Initiative. (3) Maintain a high autopsy rate (i.e., greater than 70%). (4) Perform annual detailed and standardized nursing, neurological, and neuropsychological evaluations of all subjects. (5) Maintain and augment banks of plasma, DNA, and CSF from subjects with AD, MCI, and healthy controls. (6) Share clinical data with the National Alzheimer's Disease Data Coordinating Center (NACC) Uniform Data Set (UDS) and with investigators performing other multi-center analyses of clinical data. (7) Participate in projects with other ADCs (e.g., NACC), in ADNI, and in multi-center therapeutic drug trials for AD. (8) Refine and evaluate clinical and neuropsychological assessment procedures for accurate identification of MCI and the transition to AD in very mildly impaired subjects. (9) Refine and evaluate clinical, neuropsychological, and laboratory assessment procedures for the accurate differentiation of AD from DLB, PDD, Frontotemporal dementia (FTD), and other dementing disorders. (10) Coordinate activities such as autopsy procurement and education with other Cores. RELEVANCE (See instructions): AD affects millions of Americans with its risk growing exponentially with age. The AD Centers Program fosters research related to AD and non-AD dementias. The ADRC will enhance the performance of innovative research on AD and related topics, including research that may lead to potential disease modifying therapies or behavioral treatments. It will provide an environment and core resources to enhance research, foster professional and community training, and coordinate interdisciplinary research.
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1 |
2009 — 2013 |
Galasko, Douglas R |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Administrative Core A @ University of California San Diego
The Administrative Core will provide scientific leadership to the ADRC, review and set priorities for general and specific research directions, and ensure that resources, infrastructure and feasibility are maintained to support ongoing and new research initiatives. The ADRC Director, Associate Director and Administrator will oversee the Cores and Projects, and the clinical sites in La Jolla and Chula Vista. The Core will promote interactions with researchers at UCSD, and with other institutes in San Diego, to foster ongoing and new research initiatives. Interactions with community organizations, including the Alzheimer's Association, and with lay representatives will enhance outreach efforts. An External Scientific Advisory Committee will visit and review the ADRC once per year and will review proposed Pilot Projects. Fiscal management of the Center will facilitate its smooth operation. The Administrative Core will also coordinate interactions with philanthropic donors to support Center activities, together with the UCSD Office of Planned Giving. ADRC staff will be expected to be knowledgeable about and compliant with regulations regarding human subjects, animal welfare, scientific integrity, data security, data and sample sharing, and financial policy, and will follow HIPAA-compliant procedures. The Administrative Core will interact with other AD Centers, the National Alzheimer's Coordinating Center and other researchers to develop and support research projects that cut across ADCs. Procedures will be maintained to ensure timely transmission of ADRC data sets, including the UDS clinical and neuropathology data, to the NACC. ADRC leaders will be responsible for liaison with NIA and NACC, and they, as well as representatives of Cores, will attend semi-annual meetings of the Centers. The Core will ensure that the ADRCC maintains an up to date website, which will assist with other efforts to ensure that ADRC research findings, resources and opportunities are publicized. RELEVANCE (Seeinstructions): AD affects millions of Americans with its risk growing exponentially with age. The AD Centers Program fosters research related to AD and non-AD dementias. The ADRC will enhance the performance of innovative research on AD and related topics, including research that may lead to potential disease modifying therapies or behavioral treatments. It will provide an environment and core resources to enhance research, foster professional and community training, and coordinate interdisciplinary research.
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1 |
2014 — 2018 |
Galasko, Douglas R |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Core a: Administrative Core @ University of California San Diego
CORE A: ADMINISTRATIVE - ABSTRACT The UCSD Alzheimer's Disease Research Center (ADRC) has contributed greatly to research progress in the past 30 years. Strong administrative management of the Center will be maintained during the renewal to set goals and direction, maintain a supportive environment for investigators, manage Cores, projects and personnel, and interact with University Administration, NIH, and researchers at other Centers. The ADRC will emphasize 3 research themes: 1) detailed phenotyping of early stages of AD, including Mild Cognitive Impairment (MCI) and preclinical AD; 2) research into non-AD dementias; 3) Basic studies of neurodegeneration in AD and related disorders, emphasizing translational research. Specific Aims of the Administrative Core include: 1) Provide overall scientific leadership to the ADRC and advance its mission, ensuring that resources are available. 2) Oversee and support Cores and Projects of the ADRC. 3) Build synergy and collaborations with clinicians and researchers at UCSD and VA Medical Center. 4) Continue and strengthen collaboration with researchers at other outstanding biomedical research institutions in San Diego. 5) Partner with community organizations and health care networks to advance education and enhance recruitment. This includes the Alzheimer Association and other patient organizations, and physicians at large San Diego HMOs. 6) Solicit Pilot research projects each year, arrange for review and submission to NIA. 7) Provide sound fiscal management for the Center. 8) Communicate and meet annually with our External Advisory Board. 9) Interact with other ADCs, NACC and ADCS to support multi-ADC projects and initiatives, including clinical trials. 10) Liaise with NIA and NACC and attend semi-annual national AD Center meetings. 11) Ensure that ADRC staff are knowledgeable about and comply with regulations. 12) Maintain a detailed and updated website to highlight ADRC research, for the public and researchers.
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1 |
2014 — 2019 |
Galasko, Douglas R |
U19Activity Code Description: To support a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach. A cooperative agreement research program generally involves the organized efforts of large groups, members of which are conducting research projects designed to elucidate the various aspects of a specific objective. Substantial Federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of award. The investigators have primary authorities and responsibilities to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations and conclusions of their studies. Each research project is usually under the leadership of an established investigator in an area representing his/her special interest and competencies. Each project supported through this mechanism should contribute to or be directly related to the common theme of the total research effort. The award can provide support for certain basic shared resources, including clinical components, which facilitate the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence. |
Csf Sampling Study @ University of California San Diego
There are many promising compounds in development for Alzheimer's disease, based on substantial preclinical evidence supporting efficacy in model systems and acceptable safety data to allow chronic human exposure. Guidance for developing a clinical trial program is often held back by the absence of pharmacokinetic/pharmacodynamic (pK/pD) data to support target engagement within the central nervous system (CNS) and to aid in dose selection. For small molecules that target secretases or other key biochemical pathways in AD, studies involving CSF and plasma sampling in humans are the best way to demonstrate that a drug crosses the blood-brain barrier and engages the relevant target, and to help establish the relationship between blood levels and CNS effects. Repeated sampling through a lumbar CSF catheter over 24-36 hours, and the technique of stable metabolic labeling to measure parameters such as fractional synthesis rate of amyloid beta protein (ABeta), have helped to guide the development of gamma-secretase inhibitors developed by Pharma, but have not been available to biotechnology companies and academic laboratories. To fill this need to increase the efficacy and speed of drug development, continued CSF and plasma sampling and SILK will be established at 6 academic sites with initial proposed studies evaluating 4 candidate drugs for future ADCS Phase II/III trials.
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1 |
2014 — 2021 |
Galasko, Douglas R |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Clinical Core @ University of California San Diego
CORE B: CLINICAL - ABSTRACT The Clinical Core clinically and neuropsychologically characterizes, and longitudinally follows, a cohort of cognitively-normal elderly control (NC) subjects and patients with Alzheimer's disease (AD), Mild Cognitive Impairment (MCI), Dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), Frontotemporal dementia (FTD) or other dementing disorders. It also banks biological specimens (e.g., plasma, DNA, fibroblasts, CSF) from these subjects and facilitates autopsy. Over the past 30 years, the Core has provided well-characterized subjects, clinical and cognitive data, and biological specimens to local, national and international research that has contributed to great progress in the areas of detection of AD in its earliest (even pre-clinical) stages, differential diagnosis of AD from other dementias, tracking the course of AD over time, and testing new treatment approaches for AD. The Specific Aims of the Clinical Core are to: (1) Maintain and follow a panel of about 500 well characterized English- or Spanish-speaking subjects with AD, MCI, DLB/PDD, or FTD, and age- and education-matched NC subjects. (2) Maintain a high autopsy rate (i.e., greater than 75%). (3) Perform annual detailed and standardized nursing, neurological, and neuropsychological evaluations of all subjects using Uniform Data Set (UDS) and supplemental procedures. (4) Maintain and augment banks of plasma, DNA, and CSF from subjects with AD, MCI, DLB/PDD and healthy controls. (6) Share clinical data with the NACC UDS and with investigators performing other multi-center analyses of clinical data. (7) Participate in projects with other ADCs, in ADNI, and in multi-center therapeutic drug trials for AD. (8) Refine and evaluate clinical and neuropsychological assessment procedures for accurate identification of the transition from normal cognition and pre-clinical AD to MCI to very mild AD dementia. (9) Refine and evaluate clinical, neuropsychological, and laboratory assessment procedures to differentiate AD from DLB/PDD, FTD, and other dementing disorders. The Core will also engage in innovative developmental research that will examine novel neuropsychological approaches to early detection of AD, assess subjective memory and other cognitive complaints, and assess attitudes and potential barriers to participation in primary prevention clinical trials. This will be enhanced by new recruitment of cognitively normal elderly with increased risk of AD (due to age and APOE genotype) and willingness to undergo typical AD trial procedures (including neuroimaging and plasma and CSF biomarkers). This cohort will provide important ecological validity in relation to enrollment for future primary prevention clinical trials.
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2014 |
Galasko, Douglas R Wagner, Steven Lee (co-PI) [⬀] |
R34Activity Code Description: To provide support for the initial development of a clinical trial or research project, including the establishment of the research team; the development of tools for data management and oversight of the research; the development of a trial design or experimental research designs and other essential elements of the study or project, such as the protocol, recruitment strategies, procedure manuals and collection of feasibility data. |
Translational Center For Alzheimer's Disease Target and Drug Discovery @ University of California San Diego
? DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia, a devastating disorder that affects over 35 million people worldwide. Our ultimate objective is to apply quantitative and systems pharmacology (QSP) approaches to AD drug discovery and development in order to deliver treatments capable of significantly attenuating the progression and/or preventing the disease. We will utilize this planning grant to integrate the necessary personnel, expertise and resources to assemble an infrastructure of cores across four San Diego medical research institutions (UCSD, the Salk Institute, the Scripps Research Institute and the Sanford Burnham Medical research Institute) and UCLA that are necessary for planning an AD Translational Center for Predictive Drug Development. This will be accomplished in part using a web-based platform that is currently under development (Systems Medicine Alzheimer's Research and Treatment or SMART) ://smart.ucsd.edu. Cataloging and integration of resources including cellular and animal models, reagents, chemical libraries of compounds, existing compounds in various stages of development, biosamples, postmortem brain tissue, methods such as high throughput screens and archiving and annotating of newly-generated multi-omics datasets (including existing data from cellular and animal models) as well as data from human longitudinal studies. A major focus will be the utilization of human iPSC (hiPSC) from extremely well phenotyped patients (including extreme phenotypes) to attempt to establish disease in a dish models. In addition we will capitalize on the local abundance of expertise in systems biology, biostatistics and bioinformatics bioengineering, pharmacology, neuropathology and clinical research to establish appropriate training programs in QSP for graduate students, medical trainees and postdoctoral scholars. Finally, we will identify processes to enable highly effective data sharing and establish strong collaborations with pharmaceutical companies.
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2014 — 2015 |
Galasko, Douglas R |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Ucsd Alzheimer's Disease Research Center P50 @ University of California San Diego
DESCRIPTION (provided by applicant): Alzheimer's Disease (AD), the most common cause of dementia in the elderly, affects over 4 million Americans, a number projected to grow in coming decades; current overall costs for their care exceeds $100 billion per year. Current treatment options at best provide only temporary stabilization. Failures of clinical trials in AD have led to a focus on intervening earlier, when there is less structural damage to the brain. Characterizing and intervening in pre-dementia stages of AD is a research imperative. The UCSD Alzheimer's Disease Research Center (ADRC) has contributed greatly to research progress in the past 30 years. To continue to facilitate and conduct research into the causes, treatment and prevention of AD and related disorders, overall aims of this renewal application are: 1) To support research efforts by maintaining resources that include cohorts of subjects with normal cognition, Mild Cognitive Impairment (MCI), AD and other dementias (particularly Lewy Body Disease); neuropathology tissue from well-characterized subjects; biological samples (DNA, plasma and CSF); MRI and other brain images; and to maintain a comprehensive database. This will be carried out by six well- integrated Cores: Administrative, Clinical, Hispanic Satellite, Pathology, Outreach/Recruitment/Education (ORE) and Data Management/Biostatistics. 2) To support 3 research Projects: i) APP trafficking and endosomal sorting. ii) Probing SORL1 Risk Factors with Human Induced Pluripotent Stem Cell Technology; iii) Disease Mechanisms in Frontotemporal Dementia Linked to C9orf72 Expansion. Three Pilot Project awards related to Alzheimer's disease, aging or neurodegeneration will also be issued each year. 3) Interact widely with researchers at UCSD, the VA Medical Center, and nearby research institutions (Salk Institute, Scripps Research Institute, Sanford-Burnham Institute, and San Diego State University). 4) To collaborate with other AD Centers, NACC, and other national research efforts. The ADRC will follow about 500 subjects, using annual standardized evaluations that include the Uniform Data Set components. The ADRC will provide data to the National Alzheimer's Coordinating Center, and DNA to NCRAD. ADRC subjects will be offered participation in clinical trials organized by the Alzheimer's Disease Cooperative Study (ADCS) and by pharmaceutical companies, and participation in biomarker studies such as ADNI and PPMI. We will share subjects, data, brain images and biosamples with other researchers. 5) To continue to support innovative research, and to train new investigators 6) To foster professional education and training, and to improve public knowledge and awareness about aging and AD, as well as to provide innovative support efforts for patients and families affected by AD.
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2021 |
Galasko, Douglas R Wagner, Steven Lee [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
A Single Ascending Dose / Multiple Ascending Dose Phase I Study of the Gsm 776890 in Healthy Normal Subjects @ University of California, San Diego
Scientific Abstract AD is currently a huge health problem that imposes a severe social and economic burden; in the absence of an effective disease modifying treatment it is projected to become a dominant source of health care expenditures over the next several decades. Unfortunately, existing treatments are palliative providing only temporary symptomatic benefit. Through an NIH Blueprint Neurotherapeutics (BPN) Network and U01 award we have discovered and developed a highly potent ? -secretase modulator (GSM), 776890 (also referred to as compound 2). Unlike semagacestat and other ? -secretase inhibitors (GSIs), GSMs do not inhibit gamma-secretase activity (e.g. Notch proteolysis) but rather allosterically enhance APP processing by reducing the net production of A?42 and to a lesser extent A?40 while concomitantly augmenting the production of A?38 and A?37. Compound 2 (776890), demonstrates excellent potency in vitro (IC50 = 4.0 nM), as well as in vivo (~55% lowering of brain and CSF A?42 levels and ~ 85% plasma A?42 levels in rats and mice at doses of 5 or 10 mg/kg p.o, respectively). In addition to showing robust dose-dependent in vivo efficacy in two different rodent species, 7-day dose-range finding toxicology studies in both rats and non- human primates (NHPs) has been completed and a no observed-adverse-effect-level (NOAEL) of >50 mg/kg was established in rats, resulting in a therapeutic index (safety margin) of >20. In addition, following 3-months of repeated daily (qd) oral dosing of compound 2 (25 mg/kg) showed no evidence of toxicity based on full body necropsy. Compound 2 is currently undergoing investigational new drug (IND)-enabling, good laboratory practice (GLP) 28-day safety and toxicity testing in rats and NHPs through the NIH BPN Network. Here we propose a single ascending dose (SAD) safety and tolerability study, to detail the pharmacokinetics (PK) following ascending doses (12.5, 50, 100, 200, 400 and 600 mg) and assess peripheral target engagement utilizing specific plasma biomarker MSD V-plex ELISA assays. In addition, we will perform a 14-day multiple ascending dose (MAD) safety and tolerability study, detailing the PK following multiple ascending doses (50 mg, 100 mg and 200 mg) and establishing engagement of mechanism via studies with plasma and CSF samples using a novel and innovative IP-MS analysis from 48 subjects treated with or placebo both at baseline and after ascending doses of treatment. Our collaborator in Sweden (Dr Kaj Blennow, MD, PhD) has developed a highly innovative immunoprecipitation - mass spectrometry (IP-MS) method using a QExactive instrument that enables accurate and rapid monitoring of all of the major A? isoforms in human CSF. Plasma concentrations of A?38, A?40, and A?42 will be measured using specific plasma biomarker MSD V-plex ELISA assays.
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