The progression of pathology in Parkinson's disease.

To identify the progression of pathology over the entire course of Parkinson's disease, we longitudinally followed a clinical cohort to autopsy and identified three clinicopathological phenotypes that progress at different rates. Typical Parkinson's disease has an initial rapid loss of midbrain dopamine neurons with a slow progression of Lewy body infiltration into the brain (over decades). Dementia intervenes late when Lewy bodies invade the neocortex. Older onset patients (> 70 years old) dement earlier and have much shorter disease durations. Paradoxically, they have far more alpha-synuclein-containing Lewy bodies throughout the brain, and many also have additional age-related plaque pathology. In contrast, dementia with Lewy bodies has the shortest disease course, with substantive amounts of Lewy bodies and Alzheimer-type pathologies infiltrating the brain. These data suggest that two age-related factors influence pathological progression in Parkinson's disease--the age at symptom onset and the degree and type of age-related Alzheimer-type pathology.