The subsequent fall in PDC cases. The incidence

The Western Pacific Parkinsonism-Dementia Complex (PDC) is a slowly progressive neurodegenerative disease virtually endemic to the Western Pacific islandssuch as Guam, the Kii peninsula of Japan, and West Papua, Indonesia. It closelyresembles the primary neurodegenerative disorders occurring throughout theworld with parkinsonism like Parkinson’s Disease and dementia reminiscent ofAlzhemer’s disease. Postmortem studies reveal underlying similarneuropathological changes. PDC can manifest with parkinsonian features such astremor, rigidity, slow movement and cognitive decline as well as progressivemental deterioration, memory deficits, and disorientation seen in Alzhemier’sdisease.

Although age and genetic factors may play a role in PDC in Guam, thesharp decline in disease prevalence over a short period of time, increasing ageof onset, and change in disease phenotype point to an environmental etiology. Manyenvironmental risk factors have been considered including exposure to animals,fish poisoning, low calcium and high aluminum levels in soil and water, etc.However, exposure to food and medicine from Cycas,a plant indigenous to the tropics, remain as the main hypothesis as the leadingcause for the disease. Cycad consumption parallels the rise and subsequent fallin PDC cases. The incidence of PDC peaked within several years of World War IIwhen its level of consumption rose and declined as Guam became “Westernized”and cycad became a less significant part of the Chamorro diet (Boreinstein et al.2007).

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Cycads are palm-like gymnosperm plantswhose seeds contain toxic compounds that are traditionally eaten by the Chamorro people. Its seeds, stem, roots, andleaves have long been used as a source of dietary starch. The most common localcuisine that has been studied is flour called fadang made from the seeds.Although known to be acutely toxic, the Chamorro people routinely ingested itand attempted to detoxify the flour through multiple washings. Major cycadtoxins include ?-D-glucoside (cycasin), which can be hepatotoxic and causenausea and vomiting and ?-N-methylamino-L-alanine(BMAA) which is neurotoxic and damage motor neurons in the spinal cord andbrain producing behavioral changes (Boreinstein et al.

2007). It is thoughtthat chronic exposure to the toxins from harvesting, preparing, washing, andconsuming fadang precipitated PDC. Inaddition, fruit bats were a popular delicacy item and consumed so often that itresulted in severe declines in population. Cycad seeds are highly palatable tofruit bats and like other herbivorous animals, are known to accumulate toxicmolecules in their adipose tissue and could have resulted in significantingestion of concentrated cycad toxins by the Chamorro people. Using stemcells, we can explore how Guam’s environment and nutrition contribute to thedevelopment of PDC (Cox et al. 2002). Stem cells are primitive cells thathave the potential to differentiate and develop into many specialized cell types and are important in living organisms forseveral reasons. In an embryo, they give rise to the entire body of theorganism, producing specialized cell types and vital organs such as the heart,lungs, skin, etc.

Their application in medicine and research is in their uniqueabilities to regenerate and repair damage tissues, and in offering insight fortreatment in diseases such as diabetes and heart disease. Without research in howdiseases work, treatment development is hindered (NIH Stem Cell Information). Disease modeling using stem cellsallows us to reproduce disease pathology outside of the humanbody.

Induced pluripotent stem cells (iPSC) are adultcells derived from skin or blood that have been reprogrammed back into anembryonic-like pluripotent state and can differentiate into any cell just as inits original embryonic state. In short, iPSCs are valuable in that they can actas a source for cells that would otherwise be difficult to obtain such as brainor heart cells. However, unlike embryonic stem cells, they are geneticallyidentical as the subject that they have been taken from and can be used torecreate diseases to determine how a person’s genetics contribute to theirdisease. This is a unique advantage for disease modeling. In addition, theiruse allows insight in the earliest progression of a disease, long beforesymptoms appear. Many diseases are often detected when symptoms first appearand long after the disease process began in the body (NIH Stem CellInformation).

Several studies have unsuccessfullyattempted to generate a comparable neurological disease in experimental animals by feeding them cycad seeds. Althoughmouse models for PDC mimicked key aspects of human neurodegenerative disorders,they are not a sufficient model for human disease (Preedy et al. 2005).

Assuch, iPSCs can provide a more accurate representation of the effects thatenvironmental toxins can have on our health. We hypothesize that if cycadtoxins have a significant etiological role in PDC, then PDC-type phenotypicchanges such as accumulation of tau, deposition of b-amyloid, astrogliosis, etc. should greater in PDC neurons as wellas be reproducible in neurons and astrocytes from healthy Chamorro individualsafter exposure to suspect toxin agents. This research and others like itfurthers our understanding of the behavioral and neuropathological componentsof disease progression in people. This knowledge may allow us to reverseengineer neurological disease and suggest or create interventions that willprevent, halt, or reverse the disease progression. More importantly, insightinto the mechanisms of cycad neurotoxicity may help to shed light on similarnutritional toxicities around the world.



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