In this renewal of the program project Grant, we will continue to investigate neurodegenerative disorders on Guam, namely Parkinson-Dementia Complex (PDC), Amyotrophic Lateral Sclerosis (ALS) and late-life dementia. The unifying feature among these disorders is the pathological finding of neurofibrillary tangles. We hypothesize that interactions between aging, genetics and environment may determine which type of clinical phenotype results. We will use a multidisciplinary approach to determine rates of disease and risk factors, identify susceptibility genes and potential mechanisms of disease, investigate biochemical and radiological markers that may assist in early diagnosis and differential diagnosis, and carry out clinicopathological studies. There will be 3 cores: Administrative and Data core; Clinical core (on Guam and in San Diego), and: Neuropathology-Brain Bank core, in New York. There will be 4 research subprojects. Subproject by Galasko: 'Prevalence and incidence of dementia among elderly Chamorros' aims to measure the prevalence and incidence of PDC and dementia among Chamorros and assess risk factors. Subproject by Schellenberg: 'Genetic studies of ALS, PDC and Dementia on Guam' aims to perform genome-wide searches for genetic alterations associated with ALS and PDC, and to examine candidate genes for PDC and dementia. Subproject by Kaye: 'MRI of Neurodegenerative Disease among aging Chamorros' aims to carry out volumetric analyses of the hippocampus and other brain regions to identify markers of disease and assist in early diagnosis. Subproject by Lee: 'PHF-tau in neurodegenerative diseases of Guam' will assess oxidative markers related to brain lesions in ALS, PDC and dementia.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG014382-08
Application #
6738088
Study Section
Special Emphasis Panel (ZAG1-FAS-7 (J4))
Program Officer
Anderson, Dallas
Project Start
1997-03-01
Project End
2007-03-31
Budget Start
2004-07-15
Budget End
2005-03-31
Support Year
8
Fiscal Year
2004
Total Cost
$1,917,227
Indirect Cost
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Dombroski, Beth A; Galasko, Douglas R; Mata, Ignacio F et al. (2013) C9orf72 hexanucleotide repeat expansion and Guam amyotrophic lateral sclerosis-Parkinsonism-dementia complex. JAMA Neurol 70:742-5
Brunden, Kurt R; Ballatore, Carlo; Lee, Virginia M-Y et al. (2012) Brain-penetrant microtubule-stabilizing compounds as potential therapeutic agents for tauopathies. Biochem Soc Trans 40:661-6
Lee, Virginia M-Y; Brunden, Kurt R; Hutton, Michael et al. (2011) Developing therapeutic approaches to tau, selected kinases, and related neuronal protein targets. Cold Spring Harb Perspect Med 1:a006437
Yu, Chang-En; Bird, Thomas D; Bekris, Lynn M et al. (2010) The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration. Arch Neurol 67:161-70
Brunden, Kurt R; Ballatore, Carlo; Crowe, Alex et al. (2010) Tau-directed drug discovery for Alzheimer's disease and related tauopathies: a focus on tau assembly inhibitors. Exp Neurol 223:304-10
Crowe, Alex; Huang, Wenwei; Ballatore, Carlo et al. (2009) Identification of aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening. Biochemistry 48:7732-45
Brunden, Kurt R; Trojanowski, John Q; Lee, Virginia M-Y (2009) Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies. Nat Rev Drug Discov 8:783-93
Snyder, L R; Cruz-Aguado, R; Sadilek, M et al. (2009) Lack of cerebral bmaa in human cerebral cortex. Neurology 72:1360-1
Choi, Yoonha; Wijsman, Ellen M; Weir, Bruce S (2009) Case-control association testing in the presence of unknown relationships. Genet Epidemiol 33:668-78
Sieh, Weiva; Choi, Yoonha; Chapman, Nicola H et al. (2009) Identification of novel susceptibility loci for Guam neurodegenerative disease: challenges of genome scans in genetic isolates. Hum Mol Genet 18:3725-38

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