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

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-

WWW.ARCHNEUROL.COM

Downloaded from www.archneurol.com at , on June 4, 2011

2010 American Medical Association. All rights reserved.

timates of the PD premotor phase that focused solely on

substantia nigra now appear to be gross underestimates.
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.

Table. Summary of Studies Suggesting a Long Premotor

Phase of Parkinson Disease
Approximate Length
of Premotor
Type of Study
Phase, y a

Source

CLINICAL AND EPIDEMIOLOGIC DATA

Neuropathology
Fearnley and Lees,3 1991
Neuroimaging
Hilker et al,4 2005
Morrish et al,5 1996
Morrish et al,6 1998
Constipation
Abbott et al,7 2001
Savica et al,8 2009
Anxiety disorders
Weisskopf et al,9 2003
Shiba et al,10 2000
Bower et al,11 in press
Rapid eye movement sleep
behavior disorder (RBD)
Schenck et al,12 1996
Uchiyama et al,13 1995
Boeve et al,14 2007
Stiasny-Kolster et al,15 2005
Anemia
Savica et al,16 2009

Epidemiologic studies have suggested that certain neurologic or psychiatric manifestations may precede the traditional motor manifestations of PD by long periods. In
addition, some epidemiologic studies have suggested the
occurrence of early manifestations of PD outside the central or peripheral nervous systems (Table).
CONSTIPATION
Symptoms of dysautonomia develop in most patients
during the course of PD, and constipation is probably
the most common manifestation. Constipation relates
to impaired colonic motility and is not simply attributable to medications.21 Previous authors22 have commented that constipation may sometimes precede the
initial motor manifestations of PD. This finding was
borne out in the Honolulu-Asia Aging Study,23 in which
men without PD or dementia were prospectively followed up after completing a bowel-movement questionnaire. Incidental Lewy body pathology was present
in nearly one-fourth of individuals with constipation
(1 bowel movement daily) compared with 6.5% of individuals without it. In an extension of that study, individuals with constipation who died without PD had significantly lower substantia nigra neuronal densities.23
Although these investigations focused on substantia nigra and locus caeruleus, other studies18,24 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, men with constipation had a significantly greater risk of subsequent development of PD, and
the mean interval from bowel-movement questionnaire
to PD symptoms was 10 years (12 years to diagnosis).7
These findings were extended to women by a casecontrol study in Olmsted County, Minnesota, that showed
an association between earlier-life constipation documented in medical records and subsequent risk of PD.
Importantly, the association remained significant when
restricted to constipation documented 20 or more years
before the onset of PD motor manifestations.8 In summary, constipation may precede the motor symptoms of
PD by at least 10 and perhaps more than 20 years (Table).
ANXIETY DISORDERS
Anxiety is common among patients with PD; it sometimes responds to dopamine replacement therapy.25 Several case-control or cohort studies suggested that anxiety may be 1 of the earliest manifestations of PD. First,
in a population-based, case-control study,10 anxiety diagnoses documented in historical medical records were
significantly associated with later PD, even when analy-

Case-control

5b

Clinical series
Clinical series
Clinical series

5.6 b
3.1 b
7b

Cohort
Case-control

10 b
20 c

Cohort
Case-control
Cohort

4 c
20 c
20 c

Cohort
Single case
Single case
Clinical series

12.7 b
15-20 c
15-20 c
14, 16, 38 d

Case-control

20 e

a Approximate length of premotor phase, as reported by the authors. For

some studies, the number corresponds to the observed mean or median length.
b Mean.
c Range.
d Number of years between RBD and the onset of Parkinson disease in each
of the 3 individuals described in the study.
e Median.

ses were restricted to 20 or more years before PD. Second, the Health Professionals Follow-up Study9 showed
that phobic anxiety was a significant risk factor for the
development of PD within 4 years. Finally, 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. 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, suggesting preexisting manifestations well beyond 20 years before PD.
In summary, anxiety and neuroticism may predate motor PD by more than 20 years (Table).
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.26 In fact, RBD has been associated with -synucleinopathies in general, including not only
PD but also dementia with Lewy bodies and multiple system atrophy.27 The precise neuroanatomical substrate for
RBD has not been identified in humans, but animal studies28 localize it to the region of the pontine subcaeruleus
nucleus; this region is at a brainstem level consistent with
early Braak stages.17 Patients with isolated RBD have reduced dopamine in the striatum, as shown by imaging.29

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

799

WWW.ARCHNEUROL.COM

Downloaded from www.archneurol.com at , on June 4, 2011

2010 American Medical Association. All rights reserved.

In a prospective study,12 isolated RBD was found to

evolve into PD in 38% of patients, with a mean interval
of 12.7 years. Two patients with isolated RBD, without
development of PD, underwent autopsy 15 to 20 years
later; each was found to harbor Lewy body pathology.13,14 Finally, 3 patients with long-standing isolated
RBD presented with newly diagnosed parkinsonism and
abnormal dopamine brain imaging within 14, 16, and 38
years, respectively.15 In summary, RBD may precede PD
by 12 years or more (Table).
ANEMIA
Parkinson disease may have systemic correlates outside
the central or peripheral nervous systems. For example,
peripheral mitochondrial function in platelets,30 lymphocytes,31 and muscle32 is consistently impaired in patients
with PD compared with control individuals. However, there
is a paucity of studies investigating this or other systemic
abnormalities in the preclinical phase of PD.
In a population-based, case-control study, anemia was
a significant risk factor for later PD, but only when it was
documented long before PD (median, 20 years). The greatest association was with anemia starting 20 to 29 years before PD16; analyses restricted to anemia that occurred more
than 30 years before the onset of PD still revealed a significant association (Table). However, this finding requires replication, and anemia may be a risk factor for PD
rather than an early manifestation.16 Anemia has also been
associated with a higher risk of Alzheimer disease.33,34
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. However, the lag
time from the appearance of these manifestations to the
onset of motor manifestations of PD has not been studied adequately. The limited studies10,11,35,36 available indicate a relatively shorter lag time compared with the
manifestations listed in the Table.
In the Honolulu-Asia Aging Study,35 olfactory dysfunction was associated with an increased risk of PD; however, the association was significant only for the first 4
years of follow-up. In addition, olfactory dysfunction predicted postmortem Lewy body pathology among individuals who died free of parkinsonism.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.37,38
A number of studies39-41 suggest that depression may
predate PD motor manifestations. However, 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,42 5 years,10 or
10 years.43 In addition, 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.11

CONCLUSIONS
The Table summarizes several studies suggesting a relatively long premotor phase of PD. Constipation and anxiety disorders appear to be present in some patients more
than 20 years before PD motor symptoms. Anemia may
have a similar long preclinical time line; however, it was
only documented in 1 population-based, case-control
study.16 Rapid eye movement sleep behavior disorder precedes typical PD by more than 12 years in many patients. A conservative view would place the earliest evidence of Lewy body PD at least 20 years before the onset
of typical motor manifestations. Thus, some initial causative factor or factors must already be present at that time.
It may, however, be overly simplistic to assume there
is a continuous evolution from the inception to the full
development of PD.44 Lewy body neurodegenerative processes may occur in a stepwise fashion, requiring additional causative factors to advance to the next level. In
fact, such a noncontinuous evolution seems plausible,
given the relative proportions of asymptomatic (incidental) Lewy body pathology vs PD in the general population. Incidental Lewy body disease is found in approximately 10% to 17% of people older than 60 years,36,45,46
which is 5 to 10 times the frequency of PD. Therefore,
in some individuals, the pathogenetic process may not
advance to the full clinical syndrome without a second
(or more) causative factor(s). Thus, the epidemiologic
search for the causes of PD must encompass early and
later factors (ie, multifactorial and multistage causes).
Accepted for Publication: January 19, 2010.
Correspondence: Walter A. Rocca, MD, MPH, Division
of Epidemiology, Department of Health Sciences Research, Mayo Clinic, 200 First St SW, Rochester, MN
55905 (rocca@mayo.edu).
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. Study concept and design: Savica, Rocca, and
Ahlskog. Analysis and interpretation of data: Savica and
Ahlskog. Drafting of the manuscript: Savica and Ahlskog.
Critical revision of the manuscript for important intellectual content: Rocca and Ahlskog. Administrative, technical, and material support: Savica. Study supervision: Rocca
and Ahlskog.
Financial Disclosure: None reported.
Funding/Support: This study did not receive any specific funding. Dr Rocca is funded by the National Institutes of Health (grants AR030582, AG006786, and
ES010751).
Additional Contributions: Barbara J. Balgaard, BS, typed
the manuscript.
REFERENCES
1. Elbaz A, Bower JH, Peterson BJ, et al. Survival study of Parkinson disease in
Olmsted County, Minnesota. Arch Neurol. 2003;60(1):91-96.
2. Ahlskog JE. Beating a dead horse: dopamine and Parkinson disease. Neurology.
2007;69(17):1701-1711.
3. Fearnley JM, Lees AJ. Ageing and Parkinsons disease: substantia nigra regional selectivity. Brain. 1991;114(pt 5):2283-2301.

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

800

WWW.ARCHNEUROL.COM

Downloaded from www.archneurol.com at , on June 4, 2011

2010 American Medical Association. All rights reserved.

4. Hilker R, Schweitzer K, Coburger S, et al. Nonlinear progression of Parkinson

disease as determined by serial positron emission tomographic imaging of striatal fluorodopa F 18 activity. Arch Neurol. 2005;62(3):378-382.
5. Morrish PK, Sawle GV, Brooks DJ. An [18F]dopa-PET and clinical study of the
rate of progression in Parkinsons disease. Brain. 1996;119(pt 2):585-591.
6. Morrish PK, Rakshi JS, Bailey DL, Sawle GV, Brooks DJ. Measuring the rate of
progression and estimating the preclinical period of Parkinsons disease with
[18F]dopa PET. J Neurol Neurosurg Psychiatry. 1998;64(3):314-319.
7. Abbott RD, Petrovitch H, White LR, et al. Frequency of bowel movements and
the future risk of Parkinsons disease. Neurology. 2001;57(3):456-462.
8. Savica R, Carlin JM, Grossardt BR, et al. Medical records documentation of constipation preceding Parkinson disease: a case-control study. Neurology. 2009;
73(21):1752-1758.
9. Weisskopf MG, Chen H, Schwarzschild MA, Kawachi I, Ascherio A. Prospective
study of phobic anxiety and risk of Parkinsons disease. Mov Disord. 2003;
18(6):646-651.
10. Shiba M, Bower JH, Maraganore DM, et al. Anxiety disorders and depressive disorders preceding Parkinsons disease: a case-control study. Mov Disord. 2000;
15(4):669-677.
11. Bower JH, Grossardt BR, Maraganore DM, et al. Anxious personality predicts an
increased risk of Parkinsons disease. Mov Disord. In press.
12. Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a parkinsonian
disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology. 1996;46(2):388-393.
13. Uchiyama M, Isse K, Tanaka K, et al. Incidental Lewy body disease in a patient
with REM sleep behavior disorder. Neurology. 1995;45(4):709-712.
14. Boeve BF, Dickson DW, Olson EJ, et al. Insights into REM sleep behavior disorder pathophysiology in brainstem-predominant Lewy body disease. Sleep Med.
2007;8(1):60-64.
15. Stiasny-Kolster K, Doerr Y, Mller JC, et al. Combination of idiopathic REM
sleep behaviour disorder and olfactory dysfunction as possible indicator for synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain.
2005;128(pt 1):126-137.
16. Savica R, Grossardt BR, Carlin JM, et al. Anemia or low hemoglobin levels preceding Parkinson disease: a case-control study. Neurology. 2009;73(17):13811387.
17. Braak H, Del Tredici K, Rb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging
of brain pathology related to sporadic Parkinsons disease. Neurobiol Aging. 2003;
24(2):197-211.
18. Braak H, de Vos RAI, Bohl J, Del Tredici K. Gastric -synuclein immunoreactive
inclusions in Meissners and Auerbachs plexuses in cases staged for Parkinsons disease-related brain pathology. Neurosci Lett. 2006;396(1):67-72.
19. Braak H, Sastre M, Bohl JRE, de Vos RAI, Del Tredici K. Parkinsons disease:
lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic
pre- and postganglionic neurons. Acta Neuropathol. 2007;113(4):421-429.
20. Beach TG, Adler CH, Lue L, et al; Arizona Parkinsons Disease Consortium.
Unified staging system for Lewy body disorders: correlation with nigrostriatal
degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol.
2009;117(6):613-634.
21. Edwards LL, Quigley EM, Pfeiffer RF. Gastrointestinal dysfunction in Parkinsons
disease: frequency and pathophysiology. Neurology. 1992;42(4):726-732.
22. Ashraf W, Pfeiffer RF, Park F, Lof J, Quigley EM. Constipation in Parkinsons disease: objective assessment and response to psyllium. Mov Disord. 1997;12
(6):946-951.
23. Petrovitch H, Abbott RD, Ross GW, et al. Bowel movement frequency in late-life
and substantia nigra neuron density at death. Mov Disord. 2009;24(3):371-376.
24. Minguez-Castellanos A, Chamorro CE, Escamilla-Sevilla F, et al. Do -synuclein
aggregates in autonomic plexuses predate Lewy body disorders? a cohort study.
Neurology. 2007;68(23):2012-2018.
25. Ahlskog JE. Parkinsons Disease Treatment Guide for Physicians. New York, NY:
Oxford University Press; 2009.
26. Olson EJ, Boeve BF, Silber MH. Rapid eye movement sleep behaviour disorder:

27.

28.

29.

30.
31.

32.

33.

34.

35.
36.
37.

38.

39.

40.

41.

42.

43.
44.

45.

46.

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

801

demographic, clinical and laboratory findings in 93 cases. Brain. 2000;123

(pt 2):331-339.
Boeve BF, Silber MH, Ferman TJ, Lucas JA, Parisi JE. Association of REM sleep
behavior disorder and neurodegenerative disease may reflect an underlying
synucleinopathy. Mov Disord. 2001;16(4):622-630.
Boeve BF, Silber MH, Saper CB, et al. Pathophysiology of REM sleep behaviour
disorder and relevance to neurodegenerative disease. Brain. 2007;130(pt 11):
2770-2788.
Eisensehr I, Linke R, Tatsch K, et al. Increased muscle activity during rapid eye
movement sleep correlates with decrease of striatal presynaptic dopamine transporters: IPT and IBZM SPECT imaging in subclinical and clinically manifest idiopathic REM sleep behavior disorder, Parkinsons disease, and controls. Sleep.
2003;26(5):507-512.
Parker WD Jr, Boyson SJ, Parks JK. Abnormalities of the electron transport chain
in idiopathic Parkinsons disease. Ann Neurol. 1989;26(6):719-723.
Shinde S, Pasupathy K. Respiratory-chain enzyme activities in isolated mitochondria of lymphocytes from patients with Parkinsons disease: preliminary study.
Neurol India. 2006;54(4):390-393.
Bindoff LA, Birch-Machin MA, Cartlidge NE, Parker WD Jr, Turnbull DM. Respiratory chain abnormalities in skeletal muscle from patients with Parkinsons disease.
J Neurol Sci. 1991;104(2):203-208.
Peters R, Burch L, Warner J, Beckett N, Poulter R, Bulpitt C. Haemoglobin, anaemia, dementia and cognitive decline in the elderly, a systematic review. BMC Geriatr.
2008;8:18.
Atti AR, Palmer K, Volpato S, Zuliani G, Winblad B, Fratiglioni L. Anaemia increases the risk of dementia in cognitively intact elderly. Neurobiol Aging. 2006;
27(2):278-284.
Ross GW, Petrovitch H, Abbott RD, et al. Association of olfactory dysfunction
with risk for future Parkinsons disease. Ann Neurol. 2008;63(2):167-173.
Ross GW, Abbott RD, Petrovitch H, et al. Association of olfactory dysfunction
with incidental Lewy bodies. Mov Disord. 2006;21(12):2062-2067.
Ponsen MM, Stoffers D, Booij J, van Eck-Smit BLF, Wolters EC, Berendse HW.
Idiopathic hyposmia as a preclinical sign of Parkinsons disease. Ann Neurol.
2004;56(2):173-181.
Ponsen MM, Stoffers D, Twisk JWR, Wolters EC, Berendse HW. Hyposmia and
executive dysfunction as predictors of future Parkinsons disease: a prospective
study. Mov Disord. 2009;24(7):1060-1065.
Nilsson FM, Kessing LV, Srensen TM, Andersen PK, Bolwig TG. Major depressive disorder in Parkinsons disease: a register-based study. Acta Psychiatr Scand.
2002;106(3):202-211.
Schuurman AG, van den Akker M, Ensinck KTJL, et al. Increased risk of Parkinsons disease after depression: a retrospective cohort study. Neurology. 2002;
58(10):1501-1504.
Leentjens AFG, Van den Akker M, Metsemakers JFM, Lousberg R, Verhey FRJ.
Higher incidence of depression preceding the onset of Parkinsons disease: a
register study. Mov Disord. 2003;18(4):414-418.
Alonso A, Garca Rodriguez LA, Logroscino G, Hernan MA. Use of antidepressants and the risk of Parkinsons disease: a prospective study. J Neurol Neurosurg Psychiatry. 2009;80(6):671-674.
Behari M, Srivastava AK, Das RR, Pandey RM. Risk factors of Parkinsons disease in Indian patients. J Neurol Sci. 2001;190(1-2):49-55.
Frigerio R, Fujishiro H, Ahn TB, et al. Incidental Lewy body disease: do some
cases represent a preclinical stage of dementia with Lewy bodies [published online June 26, 2009]? Neurobiol Aging. doi:10.1016/j.neurobiolaging.2009.05
.019.
Klos KJ, Ahlskog JE, Josephs KA, et al. -Synuclein pathology in the spinal cords
of neurologically asymptomatic aged individuals. Neurology. 2006;66(7):11001102.
Parkkinen L, Pirttil T, Alafuzoff I. Applicability of current staging/categorization
of -synuclein pathology and their clinical relevance. Acta Neuropathol. 2008;
115(4):399-407.

WWW.ARCHNEUROL.COM

Downloaded from www.archneurol.com at , on June 4, 2011

2010 American Medical Association. All rights reserved.