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NEUROLOGICAL REVIEW

SECTION EDITOR: DAVID E. PLEASURE, MD

When Does Parkinson Disease Start?
Rodolfo Savica, MD, MSc; Walter A. Rocca, MD, MPH; J. Eric Ahlskog, PhD, MD

T

here is convincing evidence that the Parkinson disease neurodegenerative process begins many years before the onset of motor manifestations. Initial estimates based on nigral neuropathological findings or striatal dopamine imaging suggested a 5- to 6-year
preclinical period. However, more recent evidence of Lewy body pathology in other neuronal populations preceding nigral involvement suggests that the preclinical phase may be much longer.
Epidemiologic studies of nonmotor manifestations, such as constipation, anxiety disorders, rapid eye
movement sleep behavior disorder (RBD), and anemia, suggest that the preclinical period extends at
least 20 years before the motor manifestations. Olfactory impairment and depression may also precede the onset of motor manifestations; however, the lag time may be shorter. Recognition of a nonmotor preclinical phase spanning 20 or more years should guide the search for predictive biomarkers and the identification of risk or protective factors for Parkinson disease.
Arch Neurol. 2010;67(7):798-801.
Parkinson disease (PD) is a neurodegenerative disorder that results in progressive
extrapyramidal motor dysfunction primarily related to loss of dopaminergic nigrostriatal function. Longevity has substantially improved with dopamine replacement
therapy1; however, advanced-stage PD motor symptoms respond incompletely to levodopa or related drugs and are now recognized to be caused by nondopaminergic
mechanisms.2 Although the dopaminergic nigrostriatal pathway may still hold
clues, research on the causes of PD has now
extended beyond this system.
Clues relating to the causes of PD are
crucially time dependent because causal
factors may surface and disappear at any
time during the patients’ lives; however,
some component causative factor(s) must
be present before the first evidence of PD
onset. Thus, dating the true onset of PD
is important to properly direct research of
predictive biomarkers and risk and protective factors.
Author Affiliations: Division of Epidemiology, Department of Health Sciences
Research, (Drs Savica and Rocca), and Department of Neurology (Drs Savica,
Rocca, and Ahlskog), College of Medicine, Mayo Clinic, Rochester, Minnesota.

(REPRINTED) ARCH NEUROL / VOL 67 (NO. 7), JULY 2010
798

NEUROPATHOLOGIC
AND IMAGING DATA
Until recently, the dopaminergic nigrostriatal system has been assumed to be fundamental to PD, and the length of the preclinical phase has been estimated by
backward extrapolation from the known
rate of nigrostriatal loss from autopsy studies (Table). Extrapolation from series of
postmortem brains with Lewy body pathology in the substantia nigra predicted
a preclinical stage of approximately 5
years.3 Similarly, striatal fludeoxyglucose 18 dopamine positron emission tomography studies4-6 estimated a 6-year preclinical phase.
However, the studies of Braak and colleagues17-19 emphasize that Lewy body pathology is much more widespread than
previously acknowledged. The substantia nigra appears to be relatively spared
early in the disease course, whereas other
regions, including the lower brainstem, olfactory bulb, and autonomic nervous system, are already accumulating Lewy body
pathology.17-20 Therefore, the previous es-

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Summary of Studies Suggesting a Long Premotor Phase of Parkinson Disease Approximate Length of Premotor Type of Study Phase. In summary.7 These findings were extended to women by a casecontrol study in Olmsted County. The purpose of this article is to compile clinical and epidemiologic studies that have a bearing on the preclinical phase in PD in order to better estimate the PD timeline. In an extension of that study. First. individuals with constipation who died without PD had significantly lower substantia nigra neuronal densities.archneurol. the Mayo Clinic Cohort Study of Personality and Aging11 showed that patients with high scores on the anxiety scale or the composite neuroticism scale of the Minnesota Multiphasic Personality Inventory had a significantly increased risk of PD. In addition. Importantly.7 2001 Savica et al.14 2007 Stiasny-Kolster et al.17 Patients with isolated RBD have reduced dopamine in the striatum. constipation may precede the motor symptoms of PD by at least 10 and perhaps more than 20 years (Table). the number corresponds to the observed mean or median length. and the mean interval from bowel-movement questionnaire to PD symptoms was 10 years (12 years to diagnosis). and constipation is probably the most common manifestation.com at .23 Although these investigations focused on substantia nigra and locus caeruleus. Constipation relates to impaired colonic motility and is not simply attributable to medications. . All rights reserved. some epidemiologic studies have suggested the occurrence of early manifestations of PD outside the central or peripheral nervous systems (Table). but animal studies28 localize it to the region of the pontine subcaeruleus nucleus. including not only PD but also dementia with Lewy bodies and multiple system atrophy. This finding was borne out in the Honolulu-Asia Aging Study. Table. Finally.23 in which men without PD or dementia were prospectively followed up after completing a bowel-movement questionnaire.6 1998 Constipation Abbott et al. on June 4. 38 d Case-control 20 e a Approximate length of premotor phase.3 1991 Neuroimaging Hilker et al. the association remained significant when restricted to constipation documented 20 or more years before the onset of PD motor manifestations. even when analy- Case-control 5b Clinical series Clinical series Clinical series 5.1 b 7b Cohort Case-control 10 b ⱖ20 c Cohort Case-control Cohort ⱖ4 c ⱖ20 c ⱖ20 c Cohort Single case Single case Clinical series 12.5 1996 Morrish et al.29 (REPRINTED) ARCH NEUROL / VOL 67 (NO.21 Previous authors22 have commented that constipation may sometimes precede the initial motor manifestations of PD.26 In fact. e Median. d Number of years between RBD and the onset of Parkinson disease in each of the 3 individuals described in the study. in a population-based.10 anxiety diagnoses documented in historical medical records were significantly associated with later PD. anxiety and neuroticism may predate motor PD by more than 20 years (Table).8 2009 Anxiety disorders Weisskopf et al. as shown by imaging.5% of individuals without it. Incidental Lewy body pathology was present in nearly one-fourth of individuals with constipation (⬍1 bowel movement daily) compared with 6.6 b 3.9 2003 Shiba et al. the Health Professionals Follow-up Study9 showed that “phobic anxiety” was a significant risk factor for the development of PD within 4 years.timates of the PD premotor phase that focused solely on substantia nigra now appear to be gross underestimates.12 1996 Uchiyama et al. CONSTIPATION Symptoms of dysautonomia develop in most patients during the course of PD.8 In summary. case-control study. b Mean.25 Several case-control or cohort studies suggested that anxiety may be 1 of the earliest manifestations of PD. RBD has been associated with ␣-synucleinopathies in general. suggesting preexisting manifestations well beyond 20 years before PD.10 2000 Bower et al. 7). other studies18.ARCHNEUROL. RAPID EYE MOVEMENT SLEEP BEHAVIOR DISORDER Rapid eye movement sleep behavior disorder (RBD) is common in PD and is recognized by clinicians to often precede PD motor symptoms. Second. this region is at a brainstem level consistent with early Braak stages. Minnesota.7 b 15-20 c 15-20 c 14. as reported by the authors. ANXIETY DISORDERS Anxiety is common among patients with PD. 16. it sometimes responds to dopamine replacement therapy. y a Source CLINICAL AND EPIDEMIOLOGIC DATA Neuropathology Fearnley and Lees. c Range. For some studies.15 2005 Anemia Savica et al.13 1995 Boeve et al. ses were restricted to 20 or more years before PD. 2011 ©2010 American Medical Association.11 in press Rapid eye movement sleep behavior disorder (RBD) Schenck et al. JULY 2010 799 WWW.4 2005 Morrish et al. that showed an association between earlier-life constipation documented in medical records and subsequent risk of PD. The association with neuroticism remained significant when analyses were restricted to individuals who completed the Minnesota Multiphasic Personality Inventory between 20 and 39 years of age. men with constipation had a significantly greater risk of subsequent development of PD.24 have documented Lewy body pathology in the autonomic nervous system of individuals without PD. Further studies in the Honolulu-Asia Aging cohort allow estimation of a timeline between constipation and later PD. Thus.COM Downloaded from www.16 2009 Epidemiologic studies have suggested that certain neurologic or psychiatric manifestations may precede the traditional motor manifestations of PD by long periods.27 The precise neuroanatomical substrate for RBD has not been identified in humans.

Critical revision of the manuscript for important intellectual content: Rocca and Ahlskog. 2010. Balgaard.16 Rapid eye movement sleep behavior disorder precedes typical PD by more than 12 years in many patients. et al. however. Study supervision: Rocca and Ahlskog.com at . Anemia may have a similar long preclinical time line. underwent autopsy 15 to 20 years later.31 and muscle32 is consistently impaired in patients with PD compared with control individuals. and ES010751). the association was significant only for the first 4 years of follow-up.36. Ahlskog JE. requiring additional causative factors to advance to the next level. Therefore. Thus. Division of Epidemiology. Financial Disclosure: None reported. 16. multifactorial and multistage causes). 200 First St SW. 3. REFERENCES 1. and anemia may be a risk factor for PD rather than an early manifestation. Rocca. In fact.13. Dr Rocca is funded by the National Institutes of Health (grants AR030582. 2. Brain. given the relative proportions of asymptomatic (incidental) Lewy body pathology vs PD in the general population.edu). the lag time from the appearance of these manifestations to the onset of motor manifestations of PD has not been studied adequately.37. Ageing and Parkinson’s disease: substantia nigra regional selectivity.14 Finally.COM Downloaded from www. be overly simplistic to assume there is a continuous evolution from the inception to the full development of PD. without development of PD.archneurol. The greatest association was with anemia starting 20 to 29 years before PD16. it was only documented in 1 population-based. Arch Neurol. However. analyses restricted to anemia that occurred more than 30 years before the onset of PD still revealed a significant association (Table). Incidental Lewy body disease is found in approximately 10% to 17% of people older than 60 years. Author Contributions: Drs Savica and Rocca had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.36 available indicate a relatively shorter lag time compared with the manifestations listed in the Table. Beating a dead horse: dopamine and Parkinson disease.34 OTHER EARLY MANIFESTATIONS WITH SHORTER TIMELINES Olfactory impairment and depression are 2 other nonmotor manifestations that have been repeatedly described in the preclinical phase of PD. Rocca. Peterson BJ.12 isolated RBD was found to evolve into PD in 38% of patients. Lees AJ. In the Honolulu-Asia Aging Study.ARCHNEUROL. the epidemiologic search for the causes of PD must encompass early and later factors (ie.11. and material support: Savica. 2011 ©2010 American Medical Association.114(pt 5):2283-2301. Rochester. on June 4. Study concept and design: Savica. For example. in some individuals. Survival study of Parkinson disease in Olmsted County. 1991. Drafting of the manuscript: Savica and Ahlskog. AG006786. 3 patients with long-standing isolated RBD presented with newly diagnosed parkinsonism and abnormal dopamine brain imaging within 14. Mayo Clinic.44 Lewy body neurodegenerative processes may occur in a stepwise fashion. . Thus. Analysis and interpretation of data: Savica and Ahlskog. MPH. Correspondence: Walter A. JULY 2010 800 WWW.33. However. each was found to harbor Lewy body pathology. (REPRINTED) ARCH NEUROL / VOL 67 (NO.30 lymphocytes.15 In summary. Funding/Support: This study did not receive any specific funding.42 5 years.11 CONCLUSIONS The Table summarizes several studies suggesting a relatively long premotor phase of PD. there is a paucity of studies investigating this or other systemic abnormalities in the preclinical phase of PD. some initial causative factor or factors must already be present at that time. Additional Contributions: Barbara J. respectively.36 Other investigators noted that olfactory dysfunction was significantly associated with subsequent development of PD within the ensuing 2 to 5 years among first-degree relatives of patients with PD.60(1):91-96. the pathogenetic process may not advance to the full clinical syndrome without a second (or more) causative factor(s). MD. however. 20 years). typed the manuscript. RBD may precede PD by 12 years or more (Table). but only when it was documented long before PD (median.35.7 years.69(17):1701-1711. Elbaz A.16 Anemia has also been associated with a higher risk of Alzheimer disease. MN 55905 (rocca@mayo. Neurology. In a population-based. studies assessing the interval from the documentation of depression to the onset of motor manifestations of PD suggested that the association becomes insignificant for depression occurring earlier than 2 years. However. ANEMIA Parkinson disease may have systemic correlates outside the central or peripheral nervous systems. A conservative view would place the earliest evidence of Lewy body PD at least 20 years before the onset of typical motor manifestations. However. Accepted for Publication: January 19. and Ahlskog.35 olfactory dysfunction was associated with an increased risk of PD. In addition.46 which is 5 to 10 times the frequency of PD. such a noncontinuous evolution seems plausible. 7). The limited studies10. Constipation and anxiety disorders appear to be present in some patients more than 20 years before PD motor symptoms. peripheral mitochondrial function in platelets. with a mean interval of 12. BS. however. this finding requires replication. case-control study.10 or 10 years. the Mayo Clinic Cohort Study of Personality and Aging failed to reveal an association of high score on the depression scale of the Minnesota Multiphasic Personality Inventory with the long-term risk of PD. technical. 2003. Two patients with isolated RBD. Bower JH. All rights reserved. olfactory dysfunction predicted postmortem Lewy body pathology among individuals who died free of parkinsonism. Fearnley JM.38 A number of studies39-41 suggest that depression may predate PD motor manifestations.In a prospective study. case-control study. Administrative. Department of Health Sciences Research. 2007. Minnesota. and 38 years. anemia was a significant risk factor for later PD.45. It may.43 In addition.

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