The 200-year journey of Parkinson disease: Reflecting on the past and looking towards the future.

It took almost 100 years before a meaningful advance occurred in any basic science understanding of Parkinson disease (PD) following James Parkinson's description in 1817. The Lewy body was described in 1912, and the substantia nigra was found to be depigmented with neuronal loss and gliosis in 1919. The link between dopamine and PD began in 1957, 140 years after Parkinson's Essay. Arvid Carlsson and Oleh Hornykiewicz were the major pioneers. The revolutionary therapeutic breakthrough was the introduction of high dosage levodopa therapy by George Cotzias in 1967. Following 40 years of the dopa/dopamine era, we have entered the era of alpha-synuclein, the protein present in Lewy bodies. Heiko Braak found that alpha-synuclein accumulates initially in the olfactory system and lower brainstem and then travels in an anatomic pattern to involve other regions of the brain and thereby cause progressive symptoms. Alpha-synuclein was somehow converted to a rogue protein. Where this originates and how it is propagated are under intense investigation. At the same time that the alpha-synuclein era was developing, clinical advances took place by recognizing PD as hosting a wide variety of nonmotor features with eventual cognitive impairment in many. Therapeutics has also evolved. Although the most effective therapy for the motor features remains levodopa, surgical approaches and drugs for nonmotor problems continue to expand our ability to treat people with PD. We can expect therapeutic advances in neuroprotection as the basic science discoveries uncovered in the alpha-synuclein era are translated into effective treatments.

100 years of Lewy pathology.

In 1817, James Parkinson described the symptoms of the shaking palsy, a disease that was subsequently defined in greater detail, and named after Parkinson, by Jean-Martin Charcot. Parkinson expected that the publication of his monograph would lead to a rapid elucidation of the anatomical substrate of the shaking palsy; in the event, this process took almost a century. In 1912, Fritz Heinrich Lewy identified the protein aggregates that define Parkinson disease (PD) in some brain regions outside the substantia nigra. In 1919, Konstantin Nikolaevich Tretiakoff found similar aggregates in the substantia nigra and named them after Lewy. In the 1990s, α-synuclein was identified as the main constituent of the Lewy pathology, and its aggregation was shown to be central to PD, dementia with Lewy bodies, and multiple system atrophy. In 2003, a staging scheme for idiopathic PD was introduced, according to which α-synuclein pathology originates in the dorsal motor nucleus of the vagal nerve and progresses from there to other brain regions, including the substantia nigra. In this article, we review the relevance of Lewy's discovery 100 years ago for the current understanding of PD and related disorders.