Review
A timeline for Parkinson's disease,☆☆

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Abstract

It is reasonably well established that prior to the motor phase of classical Parkinson's disease (PD) there is a prodromal period of several years duration. Once typical motor features appear, the disease continues up to 20 years depending on multiple variables. The clinical features of the prodromal and motor phases may be correlated with pathological changes in the central and autonomic nervous systems to allow a sequential plan of disease progression. We present a ‘best guess’ for a typical individual presenting with PD in their sixties and speculate that the disease will last approximately 40 years from the earliest non-motor features to death. Appreciation of this concept may allow better strategies for slowing or halting disease progression.

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

References (93)

  • K.A. Jellinger

    The morphological basis of mental dysfunction in Parkinson's disease

    J Neurol Sci

    (2006)
  • M.E. Kalaitzakis et al.

    Dementia and visual hallucinations associated with limbic pathology in Parkinson's disease

    Parkinsonism Relat Disord

    (2009)
  • A.A. Miasnikov et al.

    Behavioral memory induced by stimulation of the nucleus basalis: effects of contingency reversal

    Neurobiol Learn Mem

    (2009)
  • R.J. Rodgers et al.

    Dose–response effects of orexin-A on food intake and the behavioural satiety sequence in rats

    Regul Pept

    (2000)
  • U. Rub et al.

    Parkinson's disease: the thalamic components of the limbic loop are severely impaired by alpha-synuclein immunopositive inclusion body pathology

    Neurobiol Aging

    (2002)
  • M. Shibata et al.

    Cardiac parasympathetic dysfunction concurrent with cardiac sympathetic denervation in Parkinson's disease

    J Neurol Sci

    (2009)
  • E. Tolosa et al.

    The premotor phase of Parkinson's disease

    Parkinsonism Relat Disord

    (2007)
  • H. Yagi et al.

    Spontaneous and artificial lesions of magnocellular reticular formation of brainstem deteriorate avoidance learning in senescence-accelerated mouse SAM

    Brain Res

    (1998)
  • R.D. Abbott et al.

    Frequency of bowel movements and the future risk of Parkinson's disease

    Neurology

    (2001)
  • R.D. Abbott et al.

    Bowel movement frequency in late-life and incidental Lewy bodies

    Mov Disord

    (2007)
  • R.D. Abbott et al.

    Midlife adiposity and the future risk of Parkinson's disease

    Neurology

    (2002)
  • R.D. Abbott et al.

    Excessive daytime sleepiness and subsequent development of Parkinson disease

    Neurology

    (2005)
  • A. Alonso et al.

    Use of antidepressants and the risk of Parkinson's disease: a prospective study

    J Neurol Neurosurg Psychiatry

    (2009)
  • Y. Ben-Shlomo et al.

    Survival and cause of death in a cohort of patients with parkinsonism: possible clues to aetiology?

    J Neurol Neurosurg Psychiatry

    (1995)
  • J.L. Bosboom et al.

    Cognitive dysfunction and dementia in Parkinson's disease

    J Neural Transm

    (2004)
  • H. Braak et al.

    Stanley Fahn Lecture 2005: the staging procedure for the inclusion body pathology associated with sporadic Parkinson's disease reconsidered

    Mov Disord

    (2006)
  • H. Braak et al.

    Invited article: nervous system pathology in sporadic Parkinson disease

    Neurology

    (2008)
  • H. Braak et al.

    Stages in the development of Parkinson's disease-related pathology

    Cell Tissue Res

    (2004)
  • R.E. Burke et al.

    A critical evaluation of the Braak staging scheme for Parkinson's disease

    Ann Neurol

    (2008)
  • B. Buzas et al.

    Pain in Parkinson disease

    Neurology

    (2004)
  • H. Chen et al.

    Obesity and the risk of Parkinson's disease

    Am J Epidemiol

    (2004)
  • M. D'Amelio et al.

    Long-term survival of Parkinson's disease: a population-based study

    J Neurol

    (2006)
  • K. Del Tredici et al.

    A not entirely benign procedure: progression of Parkinson's disease

    Acta Neuropathol

    (2008)
  • Dickson DW, Uchikado H, Klos KJ, Josephs KA, Boeve BF, Ahlskog J, A critical review of the Braak staging system for...
  • R.L. Doty et al.

    Olfactory dysfunction in Parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration

    Neurology

    (1988)
  • L.L. Edwards et al.

    Gastrointestinal dysfunction in Parkinson's disease: frequency and pathophysiology

    Neurology

    (1992)
  • A. Elbaz et al.

    Survival study of parkinson disease in Olmsted County, Minnesota

    Arch Neurol

    (2003)
  • J.M. Fearnley et al.

    Ageing and Parkinson's disease: substantia nigra regional selectivity

    Brain

    (1991)
  • H.C. Fibiger

    The neurobiological substrates of depression in Parkinson's disease: a hypothesis

    Can J Neurol Sci

    (1984)
  • H. Fujishiro et al.

    Cardiac sympathetic denervation correlates with clinical and pathologic stages of Parkinson's disease

    Mov Disord

    (2008)
  • X. Gao et al.

    Erectile function and risk of Parkinson's disease

    Am J Epidemiol

    (2007)
  • E.G. Gonera et al.

    Symptoms and duration of the prodromal phase in Parkinson's disease

    Mov Disord

    (1997)
  • A. Haehner et al.

    Olfactory loss may be a first sign of idiopathic Parkinson's disease

    Mov Disord

    (2007)
  • G. Halliday et al.

    The progression of pathology in longitudinally followed patients with Parkinson's disease

    Acta Neuropathol

    (2008)
  • G.M. Halliday et al.

    Critical appraisal of brain pathology staging related to presymptomatic and symptomatic cases of sporadic Parkinson's disease

    J Neural Transm Suppl

    (2006)
  • C.H. Hawkes

    Parkinson's disease and aging: same or different process?

    Mov Disord

    (2008)
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    The review of this paper was entirely handled by the Co-Editor-in-Chief, Zbigniew Wszolek.

    ☆☆

    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.

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