Leon J. Thal, MD - US grants

cholinergic agents; brain disorder diagnosis; Alzheimer's disease; dementia; neuropharmacology; human subject;

This research will investigate the ability of a large protein, called nerve growth factor, to promote functional recovery in rats who have undergone specific brain lesions. After producing injury to acetylcholine-containing brain neurons, nerve growth factor will be administered into the brain. Its effects on both brain biochemistry and on abnormal behavior produced by the lesioning will be examined. This work is important because it will provide information about how specific chemicals may work to promote recovery of function after brain damage.

The enclosed application represents the development of a consortium of investigators who will carry out multicenter drug trials in Alzheimer's disease (AD). This consortium, containing 30 Alzheimer Disease Study Units (ADSUs), will critically examine existing instruments for the evaluation of AD patients participating in clinical drug trials. When appropriate, new instruments will be developed for use by this group. Specific drug trials proposed are a pilot study to examine the safety of nerve growth factor administered to a small number of AD patients. If safe, a multicenter double-blind, parallel, placebo-controlled trial examining both short- and long-term administration of nerve growth factor in 150 subjects is proposed. A second study examining the ability of deprenyl, a selective monoamine oxidase-B inhibitor, to slow the rate of decline in AD is also proposed. The second study will be a two-year, parallel, double-blind, placebo-controlled trial in 300 subjects. Additional drug trials are proposed for Years 4 and 5 of this grant. The specific drug trials included in this proposal are examples of trials that might be carried out by this consortium. Final decisions regarding which drugs are tested will be made in consultation with NIA and the NIA-appointed Oversight Committee.

The enclosed application represents the development of a consortium of investigators who will carry out multicenter drug trials in Alzheimer's disease (AD). This consortium, containing 30 Alzheimer Disease Study Units (ADSUs), will critically examine existing instruments for the evaluation of AD patients participating in clinical drug trials. When appropriate, new instruments will be developed for use by this group. Specific drug trials proposed are a pilot study to examine the safety of nerve growth factor administered to a small number of AD patients. If safe, a multicenter double-blind, parallel, placebo-controlled trial examining both short- and long-term administration of nerve growth factor in 150 subjects is proposed. A second study examining the ability of deprenyl, a selective monoamine oxidase-B inhibitor, to slow the rate of decline in AD is also proposed. The second study will be a two-year, parallel, double-blind, placebo-controlled trial in 300 subjects. Additional drug trials are proposed for Years 4 and 5 of this grant. The specific drug trials included in this proposal are examples of trials that might be carried out by this consortium. Final decisions regarding which drugs are tested will be made in consultation with NIA and the NIA-appointed Oversight Committee.

This proposal is for a five-year renewal of the Alzheimer's Disease Research Center (ADRC) at the University of California at San Diego in consortium with the Salk Institute. The major objective of our ADRC is to understand the pathogenesis and pathophysiology of AD with the ultimate goal of understanding the etiology sufficiently to be able to prevent it or slow its course. This center is focused on structure- functional relationships, made possibly by the close links between the Clinical and Neuropathology Cores. We will carry out a series of specific clinical pathological correlations complemented by studies of molecular events in AD in order to understand the disease. The ADRC provides an invaluable clinical and neuropathological resource to both ADRC and other AD investigators and to the San Diego community as a whole by making available a well characterized clinical cohort of both Caucasian and Hispanic volunteers who undergo annual evaluations and are willing to participate in clinical research. We also supply brain tissue, fibroblasts, serum, DNA and cerebrospinal fluid to numerous investigators. The Clinical Core also recruits special subjects and controls to support the special needs of many of the individual projects. These cohorts are subjects also participate in both multicenter drug trials and registries such as CERAD. The ADRC provides a setting to facilitate research training of AD investigators and information is transferred to the professional and lay communities through our mini- residency program, conferences and other educational activities. We foster interdisciplinary research activities through collaborations, seminars, feasibility and pilot projects. Our specific research projects in this renewal include research into: The Role of Glutamate Receptor Activation in AD; Beta Amyloid Protein Metabolism in vitro; A novel Amyloid Component; Synaptic Alterations in Rodent Models of AD; Early Brain Structural Changes in Subjects at Risk for proposed including: Human Fetal Neuronal Cultures for AD; Bilingualism and Dementia; Quantitative MRI Analysis of Psychosis in AD; the Deterioration of Semantic Networks in Patients with AD; and the Biological Activity of the Secreted Form of APP-751.

DESCRIPTION (Investigator's Abstract): We hypothesize that altered protein phosphorylation reactions are deleterious to neurons and might be involved in neurodegeneration in Alzheimer's disease (AD). It is now well recognized that protein phosphorylation is a key biochemical reaction required for the regulation of cell growth and cell survival. Thus, it is possible that aberrant phosphorylation reactions play an important role in the neuronal degeneration. There are age-associated declines of some protein kinases. Therefore, it is possible that the neurodegeneration observed in AD which is an age-associated disease, might be at least partly explained by the altered protein phosphorylation reactions. In affected neurons, there are neurofibrially tangles composed of cytoskeletal proteins, ubiquitin, and still unknown molecules. Immunohistochemical studies have revealed that the constituents of tangles as well as proteins in neurons at risk are excessively phosphorylated. Our in vitro phosphorylation study has supported the notion that the phosphorylation cascade reactions are aberrant in AD. We have identified protein kinase C (PKC), casein kinase II (CK-ll), and protein tyrosine kinase (PTK) as altered in AD. Interestingly, PKC alteration might be associated with neuritic plaque pathology in AD and CK-ll alteration with neurofibrillary tangle pathology. In the current proposal, we extend this study to their substrate proteins employing biochemical and immunohistochemical techniques. Furthermore, we attempt to identify an unknown protein kinase, the activity of which, measured with exogenous histone lll-S, is increased in AD, and a phosphoprotein, P60, which was found by in vitro phosphorylation of AD cytosol. In addition, possible phosphorylation of t, a tangle constituent, by CK-ll and other kinases will be studied. The purpose of the project is to pull all the altered molecules of protein phosphorylation into a cohesive cascade of AD pathology. To this end, we will study the localization of various components of protein phosphorylation.

clinical research; human therapy evaluation; human subject; cooperative study; brain disorder chemotherapy; Alzheimer's disease;

This proposal is for a five-year renewal of the Alzheimer's Disease Research Center (ADRC) at the University of California San Diego in consortium with The Salk and The Burnham Institutes. The major goals of the Center over the next five years will be to expand our efforts into early clinical identification of Alzheimer's disease (AD) and studying mechanisms of neurodegeneration and repair. Projects will focus on semantic memory in AD, potential mechanisms of neurodegeneration in AD, alpha-synuclein biology, and mechanisms whereby hormones or environment may enhance neuronal survival. In addition, we will continue to carry out detailed clinicopathological correlations and studies of the course of AD. This Center will continue to maintain extremely strong Clinical and Neuropathology Cores. The Clinical Core will continue to longitudinally characterize a cohort of approximately 475-500 subjects to study early changes in cognition and semantic memory, and to provide other AD investigators and the San Diego community as a whole with a well- characterize clinical cohort of both Caucasian and Hispanic volunteer who undergo annual evaluations and are willing to participate in clinical research. The Clinical Core will also recruit special subjects and controls to support the special needs of many of the individual projects. Subjects will also participate in multi-center drug trials. Data derived from subjects will be used in collaborative research. We will place increasing emphasis in identifying genetic influence that either accelerate or protect individuals from the development of AD. In addition, we will continue to focus our studies on the 15-20% of individuals with AD who also have Lewy bodies in their cortex and represent the second most common form of dementia in the United States. The Neuropathology ore will continue to refine the diagnosis of AD and LBD, provide diagnoses, clinicopathological correlations, and brain tissue. The Center as a whole will continue to provide brain tissue, fibroblasts, plasma, DNA, and cerebrospinal fluid to investigators upon request. The ADRC provides a setting to facilitate research training of investigators and will transfer information to the profession and lay communities through our mini-residency program, conferences and other educational activities. The Biostatistics Core will continue to modernize the database and will: 1) maintain the database for the Center, 2) transmit data as requested for the Alzheimer's Disease Data Coordinating Center, 3) provide consultations and statistical expertise for projects emanating from the cores, projects and pilots. Our specific research projects in this renewal include: the role of caspase cleavage in neurodegenerative disease (Bredesen), regulation of neurogenesis in the adult mammalian hippocampus (Gage), NACP/alpha-synuclein and the mechanism of neurodegeneration in Lewy body disease (Masliah), cognitive studies of semantic memory in AD (Salmon), and estrogen mediated neuronal plasticity in the brain (Tuszynski). A mechanism is also outlined for the awarding of pilot feasibility studies.

The principle objective of the Clinical Core will be to maintain a panel of 375-400 volunteer patients and controls at the ADRC, and 100 volunteer patients & controls as part of our Hispanic initiative at our satellite clinic in Chula Vista, and to recruit new D subjects with a mild degree of cognitive impairment (defined as DRS>109, many of whom will leave MMSE >24/30 to replace subjects who have become more impaired. During the period of this competing renewal we will increase our recruitment of specific groups of patients and controls to meet research needs. Particular emphasis will be to recruit controls over the age of 80 in order to meet the need for a greater number of autopsies of elderly control brains for clinical-pathological correlations and to meet for a greater number of autopsies of elderly control brains for clinical-pathological correlations and to meet the needs of those studying genetic markers (since the effect of Apo-Eepsilon4 as the major susceptibility factor for AD diminishes after age 80). Annual participant evaluations will include demographic, historical, medical, neurological, psychiatric and neuropsychological examinations to aid in diagnosis and to track yearly changes in cognitive and neurological progression. The evaluations provide a behavioral data base that can be used by the various research projects associated with the ADRC and in addition, provide detailed longitudinal data on the course and progression of AD. The Clinical Core maintains banks of fibroblast cultures, DNA, plasma samples, and CSF that are used by a variety of investigators. The Clinical Core provides the sources that permits participation multicenter trials and collaboration data and genetic analysis, as well as supply a well characterized cohort to other D investigators in San Diego. Finally, developmental work will be undertaken to improve our ability to diagnose AD early and to improve the diagnosis of other dementias such as dementia associated with Lew bodies and fronto-temporal dementia.

DESCRIPTION: (adapted from applicant's abstract) Lesions of the cholinergic basal forebrain (CBF) system in animals using an immunotoxin produce robust behavioral deficits and mimic some aspects of Alzheimer's disease (AD). This model is useful for testing both the role of acetylcholine in cognitive processes and new therapeutic strategies such as gene therapy. The ability to control gene expression is an important requirement of this technology for clinical application. The vector systems being explored in this proposal may be exogenously regulated. This proposal will investigate mechanisms of restoring neurotransmitter function in animals with CBF immunotoxin lesions by 1) enhancing ACh release postgrafting via choline supplementation, and 2) transplanting cells capable of repressing or inducing the transgene for choline acetyltransferase (ChAT). The repressible system (tetracycline), and the inducible system (eccdysteroid), modulates gene expression of ChAT in a rapid, reversible and highly specific fashion. In the first series of experiments, the investigators will determine whether different doses of exogenously administered choline can augment the production and release of acetylcholine from genetically engineered fibroblasts grafted to the cortex and hippocampus of rats following immunotoxic lesions of the CBF. Once an increase in release has been determined, behavioral effects of this augmented release will be determined. For the second and third series of experiments, they will use the regulatable cell lines that either induce or repress ChAT expression after administration of doxycycline or Muristerone A, respectively. In their immunotoxin lesion they will demonstrate that acetylcholine released from these cells after grafting to the neocortex and hippocampus is both necessary and sufficient for behavioral recovery. The effects of these regulatable genes will be tested in a spatial and non-spatial task after determining the dose and duration of the exogenous compound needed to induce or repress gene expression. If successful, the experiments will demonstrate that release of ACh can be exogenously controlled in animals and results in significant behavioral improvement. The control of transmitter release is necessary before grafting or direct gene insertion experiments can be entertained in humans in order to be able to safely terminate delivery of the gene product. These approaches will not only be applicable for AD, but other neurodegenerative disorders and for delivering other transgenes of interest.

The purpose of this Mentored Clinical Scientist Development Program is to support the career development of outstanding physician trainees in an aging-related neuroscience discipline, leading to research independence. Training will be conducted as a joint program taking advantage of the diverse and extensive resource of the local neuroscience community, including the University of California-San Diego, Scripps Research Foundation, the Salk Institute, and the Burnham Foundation. Outstanding applicants for the program will be recruited both locally and graduating residents of the clinical neurology program in the Department of Neurosciences at UCSD, and from neurology training programs nationally. 2 slots per year are requested for a 5 year period, totaling training positions. The program will be administered by the Department of Neurosciences, a joint basic science clinical department. The faculty possesses considerable strength in the genetic, molecular, cellular systems, behavioral and modeling aspects of nervous system and aging research. The training program will provide appointees three types of academic experiences to lead to research independence. 1) Basic neuroscience training, accomplished by formal Neuroscience Graduate Program course work and laboratory research rotations, 2) a 3-4 year period of intensive mentored research, and 3) a continuous curriculum of symposia, coursework in aging, and lectures. Trainees who do have a Ph.D. degree will have the opportunity to enroll in the UCSD Neuroscience Graduate Program and early a Neuroscience doctoral degree. The training program intends to expose the trainees to a breath of neuroscience topics that are required to approach aging-related questions from a comprehensive and scholarly vantage point, ranging from the study of gene expression to whole systems/behavioral approaches. Individual trainees will then choose a discipline within which to focus and foster a career research topic.

This proposal is for a five year renewal (years 11 through 15) of the Alzheimer's Disease Cooperative Study (ADCS). This consortium of 34 academic medical centers and 65 participating sites is proposing to continue to carry out clinical drug trials for promising to continue to carry out clinical drug trials for promising new agents designed to ameliorate behavioral symptoms, improve cognition, slow the rate of decline or delay the appearance of Alzheimer's disease (AD). We will also expand our efforts in the recruitment of minority groups into AD clinical trials. Development of instruments will now shift to developing instruments suitable for data collection in primary prevention trials where data can be collected efficiently in a subjects home and returned by mail with minimal use of interviewer time, allowing for cost-effective, large prevention trials. Subjects in our trials will range from normal individuals to individuals with moderate dementia. Trials will range in size from small 1A trials involving 15 subjects to a very large primary prevention trials with a planned enrollment of 2,700 normal elderly. As a follow-up to our previous vitamin E trial and ongoing MCI trial, we are proposing a primary prevention trial to test the theory that the use of cellular and mitochondrial antioxidants, both alone and in combination, will prevent the development of AD in normal elderly. Our new protocols will also include the development of two new molecules (a neuroactive peptide [NAP] and indole-3 propionic acid [IPA], a potential anti-oxidant) that will be tested in Phase 1 trials. We will also test a combination of vitamins (folate/B6/B12) that have been demonstrated to reduce homocysteine levels, a risk factor for AD on the theory that this will lead to a slowing in the rate of decline. A trial of a drug designed to lower cholesterol will follow up on new data suggesting that lower cholesterol decreases the deposition of beta amyloid. We also are including a new trial design employing divalproex sodium to block the emergence of behavioral symptomatology.

[unreadable] DESCRIPTION (provided by applicant): This proposal is for a five-year renewal of the Alzheimer's Disease Research Center (ADRC) at the University of California San Diego in consortium with The Buck Institute. The major goals of the Center over the next five years will be to expand our efforts into studying the conversion from normal aging to dementia through the intermediary step of Mild Cognitive Impairment (MCI) and to study mechanisms of neurodegeneration Projects will focus on functional MRI of the elderly at risk for Alzheimer's disease (Bondi, Project 1), testing of the role of axonal disturbances in Alzheimer's disease (Goldstein, Project 2), and studying the cytoplasmic domain of APP and its interacting proteins in synapse damage (Koo, Project 3). This Center will continue to maintain extremely strong Clinical and Neuropathological Cores. The Clinical Core will continue to longitudinally characterize a cohort of approximately 500 subjects to study early changes in cognition and semantic memory, and to provide other investigators and the San Diego community as a whole with a well characterized clinical cohort of both Caucasian and Hispanic volunteers. The Clinical Core will also recruit subjects and controls to support the special needs of many of the individual projects. The Center will also continue its participation in collaborative projects with other ADCs funded through the NACC or directly from NIA. Subjects will also participate in multi-center drug trials. Data derived from subjects will be used in collaborative research. In addition we will continue to carry out detailed clinicopathological correlations in Alzheimer's disease and other related neurodegenerative diseases: Lewy Body Variant of AD and fronto-temporal dementia. The Neuropath Core has taken a lead role in this endeavor. The Center as a whole will continue to provide brain tissue, plasma, serum, DNA, and cerebrospinal fluid to investigators upon request. The ADRC provides a setting to facilitate research training of investigators and will transfer information to the professional and lay communities through our miniresidency program, conferences and other educational activities. The Data Management and Biostatistics [unreadable] Core will continue to provide statistical design and analysis services to ADRC investigators, prepare the minimum data set for submission to the NACC, as well as coordinate the entry, quality control, management and analysis of data generated by the Clinical and Neuropathology Cores. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Partial support is requested to host a research conference on the "Epidemiology of Alzheimer's Disease" to be held on April 27-28, 2006 in San Diego, CA. In April 1976, Robert Katzman published a seminal editorial "The Prevalence and Malignancy of Alzheimer Disease: A Major Killer" in the Archives of Neurology. 30 years later, we feel it is timely to review progress, challenges, and future opportunities in Alzheimer's Disease (AD) epidemiology by holding a conference. The major goals are to 1) review scientific progress in the field; 2) provide a forum to discuss hot topics in epidemiology including: minority populations/risk factors and education/literacy and brain reserve; 3) facilitate interaction and collaboration between junior researchers and leaders in the field; and 4) reach a population of minority healthcare providers who might not otherwise have access to this information. Conference sessions will be organized by types of epidemiological studies: Descriptive studies will include prevalence and incidence studies of both mild cognitive impairment and AD in different ethnic groups both in the US and worldwide. Analytical studies will describe both risk and protective factors, including genetic, cardiovascular and lifestyle risk factors, diet, medications, and cognitive stimulation. Experimental studies will review current and completed prevention clinical trials. Special presentations will provide a historical perspective on the epidemiology of AD, a discussion of the urgency to prevent AD due to numbers and cost and a discussion of lessons we have learned from pathology. Moderated panels will discuss our hot topics to encourage meaningful interactions among speakers and the audience. Outreach to targeted racial and ethnic healthcare providers may improve health disparities in groups with high representation of putative risk factors. Researchers attending the conference will obtain a critical review, update, and information about controversial questions as well as research opportunities. This small conference will facilitate exchange of ideas and concepts. Partial support is requested to defray travel costs of invited speakers and to provide travel awards to minority healthcare providers, junior faculty, postdocs and students. [unreadable] [unreadable] [unreadable]