A definitive diagnosis of PD requires pathological confirmation of two invariant features: distinctive intraneuronal inclusions known as Lewy bodies (LBs) in regions of predilection, and reduced numbers of DA neurons in the substantia nigra pars compacta (SNc). PD is, for the most part, a sporadic disorder. Inhibitors,research,lifescience,medical Loose familial clustering, in which the pattern of inheritance is not apparent, occurs in up to 15% of cases. Forms of familial PD in which inheritance follows a mendelian pattern are

exceedingly rare, accounting for less than 1 % of all PD patients. Among all PD patients, the average age at symptom onset is 60. Except for the rare forms of familial PD with mendelian inheritance, Inhibitors,research,lifescience,medical the disease is rare in those under 40 years of

age. Thereafter, the prevalence rises rapidly, so that by the end of the seventh decade an estimated 1 person in 200 has the disease, and by the end of the eighth decade the proportion is 1 in 40.2 At this point, the annual rate of newly diagnosed cases has risen to about 1 for every 1000 persons of comparable age.3 In spite of tremendous improvements in the quality of life of PD patients since the introduction of levodopa, mortality rates continue to be increased in those with the disease, Inhibitors,research,lifescience,medical ranging from 1.5 to 2.3 times Inhibitors,research,lifescience,medical higher than rates for those without PD:4-6 In most series, the frequency

of PD is the same for both sexes.2 For nearly 150 years after the first clinical description of the disease in 1817 – An Essay on the Shaking Palsy by James Parkinson – little was known about the biology of PD. The landmark observation in 1960 that buy Regorafenib striatal DA levels were sharply reduced in PD patients led directly to a series of remarkable advances that greatly enriched our understanding of the pathophysiology of this disorder.7 Already known to be a precursor of DA and suitable for oral administration, levodopa was oxyclozanide Inhibitors,research,lifescience,medical promptly tested and found effective in treating the symptoms of PD. Chronic oral administration of levodopa became a mainstay of PD pharmacotherapy and remains so today8 – notwithstanding the current availability of effective direct-acting DA agonists, and mounting concerns about levodopa’s possible long-term toxic effects on DA neurons.9 A second breakthrough in PD research came in the early 1980s, with the serendipitous and insightful discovery of a toxin-induced model of PD in humans. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) was the unintended byproduct of an illicitly manufactured opiate whose users rapidly developed progressive, levodopa-responsive parkinsonism resembling that seen in sporadic PD.