Overview of program project

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 native 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 ALS/PDC are in the Guam Patient Registry among an at-risk 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 pure dementia, and the age of onset of neurologic 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 program project, using epidemiologic, genetic, pathologic, and molecular biologic approaches, address 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 ALS/PDC, 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 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. 

Principal members of the research team

Ulla-Katrina Craig, DrPH Director, Micronesian Health & Aging Studies University of Guam	Daniel P. Perl, MD Professor of Pathology & Psychiatry Mt. Sinai School of Medicine, New York
Paul F. Good, PhD Assistant Professor of Pathology Mt Sinai School of Medicine, New York	Gerard D. Schellenberg, PhD Research Professor of Medicine, Neurology, and Pharmacology University of Washington, Seattle
Virginia M.-Y. Lee, PhD Professor of Pathology University of Pennsylvania School of Medicine, Philadelphia	John Q. Trojanowski, MD, PhD Professor of Neuropathology University of Pennsylvania School of Medicine, Philadelphia
W. Davis Parker, MD Professor of Neurology University of Virginia School of Medicine, Charlottesville	Douglas Galasko, MD, Principal Investigator Professor of Neurosciences University of California, San Diego

Examinations performed and tissue obtained

All participants have brief neuropsychological and general medical screening examinations and a blood sample is collected for routine chemistry and DNA analysis. Those categorized as potential patients, on the basis of the screening examination, undergo more detailed neuropsychological and neurological examinations. In addition, a risk factor questionnaire is administered and detailed family histories are obtained. Autopsies are performed on most deceased participants. 

Current status as of May 2000

Total participants	867
- Normal controls	560
- Patients	305
Screening neuropsychological examination	620
Detailed neuropsychological examination	229
Neurological examination	284
Risk factor questionnaire (control)	200
Risk factor questionnaire (patient)	385
DNA samples	580
Brain tissue
- fixed	40
- frozen	16