From James Parkinson to Friederich Lewy: leaving landmarks for further research journeys.

It was in 1817 that James Parkinson first described in detail the features of the disease that was to take his name (first Paralysis agitans and subsequently Parkinson’s disease). It was not until 1912, however, that the most important pathological marker of this disease, a sort of neuronal inclusion body, was reported by Friederich H. Lewy in the dorsal motor nucleus of the vagus and in the nucleus basalis of Meynert, paving the way for new research strategies. Lewy was a brilliant scientist and an excellent clinician and neuropathologist. He trained with outstanding teachers: Nissl, Alzheimer and Spielmeyer in neuropathology; Oppenheim and Cassierer in clinical neurology; Magnus in neurophysiological research; and Kraepelin in psychiatry. In 1923 Lewy published his famous book about muscle tone and movement in which he described the pathological findings associated with Parkinson’s disease and tried to correlate them with the clinical features of the disorder. In this book he carefully detailed his original observation on the eosinophilic inclusion bodies and attempted to explain their development. He noted that axis cylinders become swollen and aggregated to produce compact basophilic cords. These swollen fibrils are then impregnated by eosinophilic cellular products and changed into elongated eosinophilic structures. Today, the Lewy body is again in the front line of research and it is emerging that this pathological entity indeed represents a structural manifestation of a cytoprotective cell response strategically designed to eliminate damaged cellular elements. Seven years after the first report by Lewy it was the turn of a student presenting his thesis at the University of Paris. It was this very young investigator, Trétiakoff, who actually established the basic pathological substrate of Parkinson’s disease: rather severe neuronal loss in the substantia nigra and the presence of the neuronal inclusions previously reported by Lewy – in the meantime named Lewy bodies – in surviving neurons. The description of the neuropathological basis of Parkinson’s disease was carefully completed by Greenfield and Bonsaquet (1953) and by Bethlem and Den Haltog Jager (1960), one and a half centuries after Parkinson’s original report. The features that characterise Parkinson’s disease are: marked depigmentation of the substantia nigra and locus coeruleus, and abiotrophic degeneration with scattered Lewy bodies in several brainstem and diencephalon nuclei including the substantia nigra and locus coeruleus. Indeed, Lewy bodies are also predominantly found in the hypothalamic nuclei, nucleus basalis of Meynert, dorsal raphe nucleus, superior central nucleus, dorsal vagal nucleus and intermediolateral nucleus. In addition, intraneuritic Lewy bodies occur in the sympathetic ganglia and in the intramural autonomic ganglia of the digestive tract. In the late 1970s, Kosaka and collaborators demonstrated Lewy bodies also in the cerebral cortex and basal ganglia, and in 1980 they proposed “Lewy body disease” as a distinct nosological entity. Lewy body disease was defined, at that time, as a chronic progressive neuropsychiatric disease whose clinical features were mainly parkinsonian symptoms with or without dementia. Patients were usually classified as senile or presenile and the disease rarely appeared in the young. Kosaka, when first proposing Lewy body disease, classified it in three types: a brainstem type, a transitional type and a diffuse type. While the brainstem type appears identical to Parkinson’s disease, Yoshimura (in 1983) proposed that the diffuse type, in which Lewy bodies are abundantly present in the cerebral cortex as well as in the basal ganglia, should be recognised as a distinct entity and termed diffuse Lewy body disease. Further steps towards understanding this entity were made in the 1980s by R. H. Perry and collaborators in Newcastle upon Tyne, UK. In two seminal papers published in 1989 and 1990 these authors proposed a type of Lewy body disease which