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Table. 
Summary of Studies Suggesting a Long Premotor Phase of Parkinson Disease
Summary of Studies Suggesting a Long Premotor Phase of Parkinson Disease
1.
Elbaz  ABower  JHPeterson  BJ  et al.  Survival study of Parkinson disease in Olmsted County, Minnesota. Arch Neurol 2003;60 (1) 91- 96
PubMed
2.
Ahlskog  JE Beating a dead horse: dopamine and Parkinson disease. Neurology 2007;69 (17) 1701- 1711
PubMed
3.
Fearnley  JMLees  AJ Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 1991;114 (pt 5) 2283- 2301
PubMed
4.
Hilker  RSchweitzer  KCoburger  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
PubMed
5.
Morrish  PKSawle  GVBrooks  DJ An [18F]dopa-PET and clinical study of the rate of progression in Parkinson's disease. Brain 1996;119 (pt 2) 585- 591
PubMed
6.
Morrish  PKRakshi  JSBailey  DLSawle  GVBrooks  DJ Measuring the rate of progression and estimating the preclinical period of Parkinson's disease with [18F]dopa PET. J Neurol Neurosurg Psychiatry 1998;64 (3) 314- 319
PubMed
7.
Abbott  RDPetrovitch  HWhite  LR  et al.  Frequency of bowel movements and the future risk of Parkinson's disease. Neurology 2001;57 (3) 456- 462
PubMed
8.
Savica  RCarlin  JMGrossardt  BR  et al.  Medical records documentation of constipation preceding Parkinson disease: a case-control study. Neurology 2009;73 (21) 1752- 1758
PubMed
9.
Weisskopf  MGChen  HSchwarzschild  MAKawachi  IAscherio  A Prospective study of phobic anxiety and risk of Parkinson's disease. Mov Disord 2003;18 (6) 646- 651
PubMed
10.
Shiba  MBower  JHMaraganore  DM  et al.  Anxiety disorders and depressive disorders preceding Parkinson's disease: a case-control study. Mov Disord 2000;15 (4) 669- 677
PubMed
11.
Bower  JHGrossardt  BRMaraganore  DM  et al.  Anxious personality predicts an increased risk of Parkinson's disease. Mov Disord In press
12.
Schenck  CHBundlie  SRMahowald  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
PubMed
13.
Uchiyama  MIsse  KTanaka  K  et al.  Incidental Lewy body disease in a patient with REM sleep behavior disorder. Neurology 1995;45 (4) 709- 712
PubMed
14.
Boeve  BFDickson  DWOlson  EJ  et al.  Insights into REM sleep behavior disorder pathophysiology in brainstem-predominant Lewy body disease. Sleep Med 2007;8 (1) 60- 64
PubMed
15.
Stiasny-Kolster  KDoerr  YMöller  JC  et al.  Combination of “idiopathic” REM sleep behaviour disorder and olfactory dysfunction as possible indicator for α-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 2005;128 (pt 1) 126- 137
PubMed
16.
Savica  RGrossardt  BRCarlin  JM  et al.  Anemia or low hemoglobin levels preceding Parkinson disease: a case-control study. Neurology 2009;73 (17) 1381- 1387
PubMed
17.
Braak  HDel Tredici  KRüb  Ude Vos  RAIJansen Steur  ENHBraak  E Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24 (2) 197- 211
PubMed
18.
Braak  Hde Vos  RAIBohl  JDel Tredici  K Gastric α-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett 2006;396 (1) 67- 72
PubMed
19.
Braak  HSastre  MBohl  JREde Vos  RAIDel Tredici  K Parkinson's disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 2007;113 (4) 421- 429
PubMed
20.
Beach  TGAdler  CHLue  L  et al. Arizona Parkinson's 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
PubMed
21.
Edwards  LLQuigley  EMPfeiffer  RF Gastrointestinal dysfunction in Parkinson's disease: frequency and pathophysiology. Neurology 1992;42 (4) 726- 732
PubMed
22.
Ashraf  WPfeiffer  RFPark  FLof  JQuigley  EM Constipation in Parkinson's disease: objective assessment and response to psyllium. Mov Disord 1997;12 (6) 946- 951
PubMed
23.
Petrovitch  HAbbott  RDRoss  GW  et al.  Bowel movement frequency in late-life and substantia nigra neuron density at death. Mov Disord 2009;24 (3) 371- 376
PubMed
24.
Minguez-Castellanos  AChamorro  CEEscamilla-Sevilla  F  et al.  Do α-synuclein aggregates in autonomic plexuses predate Lewy body disorders? a cohort study. Neurology 2007;68 (23) 2012- 2018
PubMed
25.
Ahlskog  JE Parkinson's Disease Treatment Guide for Physicians.  New York, NY Oxford University Press2009;
26.
Olson  EJBoeve  BFSilber  MH Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain 2000;123 (pt 2) 331- 339
PubMed
27.
Boeve  BFSilber  MHFerman  TJLucas  JAParisi  JE Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy. Mov Disord 2001;16 (4) 622- 630
PubMed
28.
Boeve  BFSilber  MHSaper  CB  et al.  Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 2007;130 (pt 11) 2770- 2788
PubMed
29.
Eisensehr  ILinke  RTatsch  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, Parkinson's disease, and controls. Sleep 2003;26 (5) 507- 512
PubMed
30.
Parker  WD  JrBoyson  SJParks  JK Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol 1989;26 (6) 719- 723
PubMed
31.
Shinde  SPasupathy  K Respiratory-chain enzyme activities in isolated mitochondria of lymphocytes from patients with Parkinson's disease: preliminary study. Neurol India 2006;54 (4) 390- 393
PubMed
32.
Bindoff  LABirch-Machin  MACartlidge  NEParker  WD  JrTurnbull  DM Respiratory chain abnormalities in skeletal muscle from patients with Parkinson's disease. J Neurol Sci 1991;104 (2) 203- 208
PubMed
33.
Peters  RBurch  LWarner  JBeckett  NPoulter  RBulpitt  C Haemoglobin, anaemia, dementia and cognitive decline in the elderly, a systematic review. BMC Geriatr 2008;818
PubMed
34.
Atti  ARPalmer  KVolpato  SZuliani  GWinblad  BFratiglioni  L Anaemia increases the risk of dementia in cognitively intact elderly. Neurobiol Aging 2006;27 (2) 278- 284
PubMed
35.
Ross  GWPetrovitch  HAbbott  RD  et al.  Association of olfactory dysfunction with risk for future Parkinson's disease. Ann Neurol 2008;63 (2) 167- 173
PubMed
36.
Ross  GWAbbott  RDPetrovitch  H  et al.  Association of olfactory dysfunction with incidental Lewy bodies. Mov Disord 2006;21 (12) 2062- 2067
PubMed
37.
Ponsen  MMStoffers  DBooij  Jvan Eck-Smit  BLFWolters  ECBerendse  HW Idiopathic hyposmia as a preclinical sign of Parkinson's disease. Ann Neurol 2004;56 (2) 173- 181
PubMed
38.
Ponsen  MMStoffers  DTwisk  JWRWolters  ECBerendse  HW Hyposmia and executive dysfunction as predictors of future Parkinson's disease: a prospective study. Mov Disord 2009;24 (7) 1060- 1065
PubMed
39.
Nilsson  FMKessing  LVSørensen  TMAndersen  PKBolwig  TG Major depressive disorder in Parkinson's disease: a register-based study. Acta Psychiatr Scand 2002;106 (3) 202- 211
PubMed
40.
Schuurman  AGvan den Akker  MEnsinck  KTJL  et al.  Increased risk of Parkinson's disease after depression: a retrospective cohort study. Neurology 2002;58 (10) 1501- 1504
PubMed
41.
Leentjens  AFGVan den Akker  MMetsemakers  JFMLousberg  RVerhey  FRJ Higher incidence of depression preceding the onset of Parkinson's disease: a register study. Mov Disord 2003;18 (4) 414- 418
PubMed
42.
Alonso  AGarcía Rodriguez  LALogroscino  GHernán  MA Use of antidepressants and the risk of Parkinson's disease: a prospective study. J Neurol Neurosurg Psychiatry 2009;80 (6) 671- 674
PubMed
43.
Behari  MSrivastava  AKDas  RRPandey  RM Risk factors of Parkinson's disease in Indian patients. J Neurol Sci 2001;190 (1-2) 49- 55
PubMed
44.
Frigerio  RFujishiro  HAhn  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
PubMed10.1016/j.neurobiolaging.2009.05.019
45.
Klos  KJAhlskog  JEJosephs  KA  et al.  α-Synuclein pathology in the spinal cords of neurologically asymptomatic aged individuals. Neurology 2006;66 (7) 1100- 1102
PubMed
46.
Parkkinen  LPirttilä  TAlafuzoff  I Applicability of current staging/categorization of α-synuclein pathology and their clinical relevance. Acta Neuropathol 2008;115 (4) 399- 407
PubMed
Neurological Review
July 2010

When Does Parkinson Disease Start?

Arch Neurol. 2010;67(7):798-801. doi:10.1001/archneurol.2010.135
Abstract

There 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.

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.

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 studies46 estimated a 6-year preclinical phase.

However, the studies of Braak and colleagues1720 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.1720 Therefore, the previous estimates 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.

CLINICAL AND EPIDEMIOLOGIC DATA

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 case-control 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 analyses 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 α-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

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 studies3941 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).

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Article Information

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).

Accepted for Publication: January 19, 2010.

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  ABower  JHPeterson  BJ  et al.  Survival study of Parkinson disease in Olmsted County, Minnesota. Arch Neurol 2003;60 (1) 91- 96
PubMed
2.
Ahlskog  JE Beating a dead horse: dopamine and Parkinson disease. Neurology 2007;69 (17) 1701- 1711
PubMed
3.
Fearnley  JMLees  AJ Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 1991;114 (pt 5) 2283- 2301
PubMed
4.
Hilker  RSchweitzer  KCoburger  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
PubMed
5.
Morrish  PKSawle  GVBrooks  DJ An [18F]dopa-PET and clinical study of the rate of progression in Parkinson's disease. Brain 1996;119 (pt 2) 585- 591
PubMed
6.
Morrish  PKRakshi  JSBailey  DLSawle  GVBrooks  DJ Measuring the rate of progression and estimating the preclinical period of Parkinson's disease with [18F]dopa PET. J Neurol Neurosurg Psychiatry 1998;64 (3) 314- 319
PubMed
7.
Abbott  RDPetrovitch  HWhite  LR  et al.  Frequency of bowel movements and the future risk of Parkinson's disease. Neurology 2001;57 (3) 456- 462
PubMed
8.
Savica  RCarlin  JMGrossardt  BR  et al.  Medical records documentation of constipation preceding Parkinson disease: a case-control study. Neurology 2009;73 (21) 1752- 1758
PubMed
9.
Weisskopf  MGChen  HSchwarzschild  MAKawachi  IAscherio  A Prospective study of phobic anxiety and risk of Parkinson's disease. Mov Disord 2003;18 (6) 646- 651
PubMed
10.
Shiba  MBower  JHMaraganore  DM  et al.  Anxiety disorders and depressive disorders preceding Parkinson's disease: a case-control study. Mov Disord 2000;15 (4) 669- 677
PubMed
11.
Bower  JHGrossardt  BRMaraganore  DM  et al.  Anxious personality predicts an increased risk of Parkinson's disease. Mov Disord In press
12.
Schenck  CHBundlie  SRMahowald  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
PubMed
13.
Uchiyama  MIsse  KTanaka  K  et al.  Incidental Lewy body disease in a patient with REM sleep behavior disorder. Neurology 1995;45 (4) 709- 712
PubMed
14.
Boeve  BFDickson  DWOlson  EJ  et al.  Insights into REM sleep behavior disorder pathophysiology in brainstem-predominant Lewy body disease. Sleep Med 2007;8 (1) 60- 64
PubMed
15.
Stiasny-Kolster  KDoerr  YMöller  JC  et al.  Combination of “idiopathic” REM sleep behaviour disorder and olfactory dysfunction as possible indicator for α-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 2005;128 (pt 1) 126- 137
PubMed
16.
Savica  RGrossardt  BRCarlin  JM  et al.  Anemia or low hemoglobin levels preceding Parkinson disease: a case-control study. Neurology 2009;73 (17) 1381- 1387
PubMed
17.
Braak  HDel Tredici  KRüb  Ude Vos  RAIJansen Steur  ENHBraak  E Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24 (2) 197- 211
PubMed
18.
Braak  Hde Vos  RAIBohl  JDel Tredici  K Gastric α-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett 2006;396 (1) 67- 72
PubMed
19.
Braak  HSastre  MBohl  JREde Vos  RAIDel Tredici  K Parkinson's disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 2007;113 (4) 421- 429
PubMed
20.
Beach  TGAdler  CHLue  L  et al. Arizona Parkinson's 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
PubMed
21.
Edwards  LLQuigley  EMPfeiffer  RF Gastrointestinal dysfunction in Parkinson's disease: frequency and pathophysiology. Neurology 1992;42 (4) 726- 732
PubMed
22.
Ashraf  WPfeiffer  RFPark  FLof  JQuigley  EM Constipation in Parkinson's disease: objective assessment and response to psyllium. Mov Disord 1997;12 (6) 946- 951
PubMed
23.
Petrovitch  HAbbott  RDRoss  GW  et al.  Bowel movement frequency in late-life and substantia nigra neuron density at death. Mov Disord 2009;24 (3) 371- 376
PubMed
24.
Minguez-Castellanos  AChamorro  CEEscamilla-Sevilla  F  et al.  Do α-synuclein aggregates in autonomic plexuses predate Lewy body disorders? a cohort study. Neurology 2007;68 (23) 2012- 2018
PubMed
25.
Ahlskog  JE Parkinson's Disease Treatment Guide for Physicians.  New York, NY Oxford University Press2009;
26.
Olson  EJBoeve  BFSilber  MH Rapid eye movement sleep behaviour disorder: demographic, clinical and laboratory findings in 93 cases. Brain 2000;123 (pt 2) 331- 339
PubMed
27.
Boeve  BFSilber  MHFerman  TJLucas  JAParisi  JE Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy. Mov Disord 2001;16 (4) 622- 630
PubMed
28.
Boeve  BFSilber  MHSaper  CB  et al.  Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 2007;130 (pt 11) 2770- 2788
PubMed
29.
Eisensehr  ILinke  RTatsch  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, Parkinson's disease, and controls. Sleep 2003;26 (5) 507- 512
PubMed
30.
Parker  WD  JrBoyson  SJParks  JK Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol 1989;26 (6) 719- 723
PubMed
31.
Shinde  SPasupathy  K Respiratory-chain enzyme activities in isolated mitochondria of lymphocytes from patients with Parkinson's disease: preliminary study. Neurol India 2006;54 (4) 390- 393
PubMed
32.
Bindoff  LABirch-Machin  MACartlidge  NEParker  WD  JrTurnbull  DM Respiratory chain abnormalities in skeletal muscle from patients with Parkinson's disease. J Neurol Sci 1991;104 (2) 203- 208
PubMed
33.
Peters  RBurch  LWarner  JBeckett  NPoulter  RBulpitt  C Haemoglobin, anaemia, dementia and cognitive decline in the elderly, a systematic review. BMC Geriatr 2008;818
PubMed
34.
Atti  ARPalmer  KVolpato  SZuliani  GWinblad  BFratiglioni  L Anaemia increases the risk of dementia in cognitively intact elderly. Neurobiol Aging 2006;27 (2) 278- 284
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