the "Why": The key question as to WHAT TRIGGERS the abovementioned pathophysiological
changes remains unsolved. What is known is that PD is strongly associated in some cases with
inherited genes and environmental pollutants, in the majority of cases there is no identifiable external
trigger. Thus, it is not yet clear whether the syndrome of PD symptoms has one, or multiple etiologies.
Possible Triggers / Causes:
Aging: This is the strongest risk factor for PD, and risk of PD clearly increases with advancing age,
particularly after age 60. That said, even if many of the associated symptoms and pathological
processes are to some extent eventually manifested in the very elderly, the question remains as to
why this progression is greatly accelerated in those diagnosed with PD in middle age.
de Rijk MC, 2000
Gender and Race/Ethnicity: PD is nearly twice as prevalent in men than in women. It also varies by
race/ethnicity, being highest in Hispanics, followed by non-Hispanic whites, Asians, and African
VanDenEeden, SK, 2003
Genetic: A minority of PD cases are linked to genetic mutations, and the proteins encoded by these
mutations strongly suggest that improper protein processing, oxidative stress, and mitochondrial
dysfunction involvement in the pathophysiology.
Toulouse A, 2008; Gao HM, 2011
Environmental: The strongest evidence of an environmental trigger for PD is that of pesticide
exposure, especially to rotenone and paraquat, which disrupt mitochondrial activity and oxidative
Tanner CM, 2011
Other environmental factors that have been linked to PD are various
toxins and organic solvents, potable well water, and prior head injury.
Fang F, 2012; Noyce AJ, 2012; Gardner RC,
Diet and Lifestyle: PD patients can have increased iron deposits in the substantia nigra of PD and
increased iron levels in individual dopaminergic neurons. Since free iron can induce oxidative stress
and neuron death, investigators have focused on effects of dietary iron intake, reporting a 30%
increase in dietary non-heme iron associated with PD.
Logroscino G, 2008
Hypertension and high
cholesterol are also associated with increased risk of developing PD.
Hu G, 2008; Elbaz A, 2008
diets high in saturated fats have also been studied as possible correlates of PD.
D’Amelio M, 2009;
Schernhammer E, 2011
On the other hand, caffeine may be protective, via its weak antagonism of adenosine
A2A receptors and nonspecific additional effects. Smoking has somewhat surprisingly been
associated with reduced risk of PD, possibly through nicotine's inhibition of the monoamine oxidase
Kalda A, 2006; Rivera-Oliver M, 2014
However, a causal relationship has not yet been
Disease Progression: By the time of diagnosis of PD, an estimated 50% of dopaminergic neurons in
the substantia nigra have been lost,
Hawkes CH, 2008; Toulouse A, 2008; Mullin S, 2015
and neuronal degeneration is
found throughout the brain stem in non-dopaminergic neurons. Other evidence suggests that as early
as two decades before PD diagnosis, threshold motor symptoms and olfactory and sleep
disturbances are manifest.
Hawkes CH, 2008; Postuma RB, 2012
Individual variation in these symptoms makes it
difficult to use these symptoms as predictors, but nevertheless, it is clear that substantial disease
progression has occurred prior to the first therapeutic interventions. To the extent that interventions
help to maintain dopaminergic activity, they provide symptomatic relief, and allow patients to function
initially. However, they do not forestall the underlying, continued disease progression.