ReviewA timeline for Parkinson's disease☆,☆☆
Introduction
Support for the existence of a prodromal phase comes from imaging, neuropathology, and various clinical or epidemiological surveys. This has been surveyed in detail in an earlier publication [38] but in brief, the best evidence that derives from large prospective studies, many with pathological confirmation, relates to disorders affecting olfaction and the autonomic, including enteric, nervous systems (ENS) and depression[[5], [45], [57], [68]]. Several other prodromal features are described on the basis of retrospective or small studies, such as apathy or fatigue [20], altered colour vision[[9], [67], [76]] pain or paraesthesia [20], [89] but these await further confirmation. Estimates for the duration of the prodrome range from 2 to 50 years depending on the feature in question, duration of follow-up, accuracy of diagnosis, and individual variation, such as age of onset and gender as previously reviewed [38]. For this article a 20-year prodrome is presumed because it concurs broadly with clinical observations, imaging studies, olfactory deficit, sleep disorder and some pathological observations and would apply to the typical patient who presents during the seventh decade of life. The sequence of premotor events needs further evaluation both clinically and pathologically, but because the Braak staging is accurate in up to 80% of cases the expected symptoms will be based on this staging system. The following section should be read in conjunction with the proposed timeline in Fig. 1.
Section snippets
Braak staging for Lewy pathology in sporadic PD
This is a neuroanatomically based staging scheme, with 6 sequential and additive changes based on the presence of alpha-synuclein (αSN) deposits (Lewy pathology) in the brain [[11], [14], [15], [16]] heart [[30], [34], [84]] and cutaneous peripheral autonomic nerves [43], [69], [77]. The validity of this staging has gained in acceptance but it has been the subject of vigorous debate [17], [24], [35], [36], [47], [48], [49], [60], [66], [73], [74]. Overall, most neuropathologists support the
Discussion
Although this article makes many assumptions, it represents an attempt to integrate what is known of the neuropathology and clinical data in the prodromal and established phases of PD. Braak pathological staging provides a framework on which to build clinical correlations. Cognitive impairment is well recognised in the established phase of PD and even more prevalent in its variants but the exact point of onset of this is not clear. It may develop as early as Braak stage 2 given the changes in
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The review of this paper was entirely handled by the Co-Editor-in-Chief, Zbigniew Wszolek.
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Financial disclosure: This work was made possible in part by funding from the Deutsche Forschungsgemeinschaft (DFG) and Hilde-Ulrichs Foundation (Florstadt-Staden, Germany).
- 1
Conceived the timeline concept and was responsible for the main draft.
- 2
Supplemented and improved the text, referencing and timeline figure.