The Western Pacific Parkinsonism-
Dementia Complex (PDC) is a slowly progressive neurodegenerative

disease virtually endemic to the Western Pacific islands
such as Guam, the Kii peninsula of Japan, and West Papua, Indonesia. It closely
resembles the primary neurodegenerative disorders occurring throughout the
world with parkinsonism like Parkinson’s Disease and dementia reminiscent of
Alzhemer’s disease. Postmortem studies reveal underlying similar
neuropathological changes. PDC can manifest with parkinsonian features such as
tremor, rigidity, slow movement and cognitive decline as well as progressive
mental deterioration, memory deficits, and disorientation seen in Alzhemier’s
disease. Although age and genetic factors may play a role in PDC in Guam, the
sharp decline in disease prevalence over a short period of time, increasing age
of onset, and change in disease phenotype point to an environmental etiology. Many
environmental 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 leading
cause for the disease. Cycad consumption parallels the rise and subsequent fall
in PDC cases. The incidence of PDC peaked within several years of World War II
when 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.

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Cycads are palm-like gymnosperm plants
whose seeds contain toxic compounds that are traditionally

eaten by the Chamorro people. Its seeds, stem, roots, and
leaves have long been used as a source of dietary starch. The most common local
cuisine that has been studied is flour called fadang made from the seeds.
Although known to be acutely toxic, the Chamorro people routinely ingested it
and attempted to detoxify the flour through multiple washings. Major cycad
toxins include ?-D-glucoside (cycasin), which can be hepatotoxic and cause
nausea and vomiting and ?-N-methylamino-L-alanine
(BMAA) which is neurotoxic and damage motor neurons in the spinal cord and
brain producing behavioral changes (Boreinstein et al. 2007). It is thought
that chronic exposure to the toxins from harvesting, preparing, washing, and
consuming fadang precipitated PDC. In
addition, fruit bats were a popular delicacy item and consumed so often that it
resulted in severe declines in population. Cycad seeds are highly palatable to
fruit bats and like other herbivorous animals, are known to accumulate toxic
molecules in their adipose tissue and could have resulted in significant
ingestion of concentrated cycad toxins by the Chamorro people. Using stem
cells, we can explore how Guam’s environment and nutrition contribute to the
development of PDC (Cox et al. 2002).

Stem cells are primitive cells that
have the potential to differentiate and develop into many specialized

cell types and are important in living organisms for
several reasons. In an embryo, they give rise to the entire body of the
organism, producing specialized cell types and vital organs such as the heart,
lungs, skin, etc. Their application in medicine and research is in their unique
abilities to regenerate and repair damage tissues, and in offering insight for
treatment in diseases such as diabetes and heart disease. Without research in how
diseases work, treatment development is hindered (NIH Stem Cell Information).

Disease modeling using stem cells
allows us to reproduce disease pathology outside of the human

body. Induced pluripotent stem cells (iPSC) are adult
cells derived from skin or blood that have been reprogrammed back into an
embryonic-like pluripotent state and can differentiate into any cell just as in
its original embryonic state. In short, iPSCs are valuable in that they can act
as a source for cells that would otherwise be difficult to obtain such as brain
or heart cells. However, unlike embryonic stem cells, they are genetically
identical as the subject that they have been taken from and can be used to
recreate diseases to determine how a person’s genetics contribute to their
disease. This is a unique advantage for disease modeling. In addition, their
use allows insight in the earliest progression of a disease, long before
symptoms appear. Many diseases are often detected when symptoms first appear
and long after the disease process began in the body (NIH Stem Cell

Several studies have unsuccessfully
attempted to generate a comparable neurological disease in

experimental animals by feeding them cycad seeds. Although
mouse models for PDC mimicked key aspects of human neurodegenerative disorders,
they are not a sufficient model for human disease (Preedy et al. 2005). As
such, iPSCs can provide a more accurate representation of the effects that
environmental toxins can have on our health. We hypothesize that if cycad
toxins have a significant etiological role in PDC, then PDC-type phenotypic
changes such as accumulation of tau, deposition of b-amyloid, astrogliosis, etc. should greater in PDC neurons as well
as be reproducible in neurons and astrocytes from healthy Chamorro individuals
after exposure to suspect toxin agents. This research and others like it
furthers our understanding of the behavioral and neuropathological components
of disease progression in people. This knowledge may allow us to reverse
engineer neurological disease and suggest or create interventions that will
prevent, halt, or reverse the disease progression. More importantly, insight
into the mechanisms of cycad neurotoxicity may help to shed light on similar
nutritional toxicities around the world.