ABSTRACT
234Amyotrophic lateral sclerosis–parkinsonism dementia complex (ALS-PDC) has been termed the “Rosetta Stone” of neurological disease, due to its component amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease symptomatology and neuropathology. The largest and most-studied geographic focus of ALS-PDC is that of the island of Guam in the South Pacific. The consumption of the seeds of a local, indigenous species of cycad, Cycas micronesica, is thought to play a causal role in the development of ALS-PDC. Cycad contains many toxins, and traditional processing methods have therefore been developed with the aim of removing them. Water-soluble, cycad-specific toxins such as cycasin, macrozamins, and β-methylamino-l-alanine are removed by washing the cycad. This refutes early cycad theories of ALS-PDC that these toxins are causal in the development of ALS-PDC. Since cycad consumption still appeared to be linked to ALS-PDC, our laboratory has reexamined the cycad hypothesis. By feeding mice processed cycad flour, we have created a valid mouse model of ALS-PDC. This model allows us to analyze ALS-PDC in “four dimensions”: its behavioral deficits, biochemical changes, and morphological or pathological outcomes through time. Our “time course” project is an attempt to delineate the rate, type, and extent of disease progression as the subjects move from normal central nervous system state, through preclinical neurological damage, to clinical diagnosis, and, ultimately, arrive at the end state. This information, in conjunction with data on the effects of various genetic conditions, sex, and age, will allow us to template-match our findings against the human experience of ALS-PDC. This will allow us to distinguish between the disease’s causal, coincidental, and compensatory (successful or failed) components, and thus provide us with targeted therapeutics with which we can move from palliative to preventative care for patients suffering from ALS-PDC as well as those diagnosed with amyotrophic lateral sclerosis, Parkinson’s disease, or Alzheimer’s disease.
