Skip Navigation


American Journal of Epidemiology Advance Access originally published online on August 11, 2006
American Journal of Epidemiology 2006 164(10):998-1002; doi:10.1093/aje/kwj283
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
164/10/998    most recent
kwj283v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (11)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by de Lau, L. M. L.
Right arrow Articles by Breteler, M. M. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by de Lau, L. M. L.
Right arrow Articles by Breteler, M. M. B.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

American Journal of Epidemiology Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

Original Contribution

Serum Cholesterol Levels and the Risk of Parkinson's Disease

Lonneke M. L. de Lau1,2, Peter J. Koudstaal2, Albert Hofman1 and Monique M. B. Breteler1

1 Department of Epidemiology and Biostatistics, Erasmus Medical Center, Rotterdam, the Netherlands
2 Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands

Correspondence to Dr. M. M. B. Breteler, Department of Epidemiology and Biostatistics, Erasmus Medical Center, P.O. Box 1738, 3000 DR Rotterdam, the Netherlands (e-mail: m.breteler{at}erasmusmc.nl).

Received for publication February 13, 2006. Accepted for publication April 13, 2006.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Several recent findings suggest a role of lipid and cholesterol metabolism in the pathogenesis of Parkinson's disease. Therefore, the authors examined the association between serum levels of cholesterol and the risk of Parkinson's disease in the prospective, population-based Rotterdam Study among 6,465 subjects aged 55 or more years with repeated in-person examination and on average 9.4 years of follow-up (1990–2004). Higher serum levels of total cholesterol were associated with a significantly decreased risk of Parkinson's disease (age- and sex-adjusted hazard ratio per mmol/liter increase in cholesterol = 0.77, 95% confidence interval: 0.64, 0.94), with evidence for a dose-effect relation. The association was restricted to women and remained unchanged after adjustment for multiple potential confounders. These findings may indicate a role of lipids in the pathogenesis of Parkinson's disease. Alternatively, they could reflect the strong correlation—especially in women—between levels of serum cholesterol and the antioxidant coenzyme Q10. If confirmed, this would provide further support for an important role of oxidative stress in the pathogenesis of Parkinson's disease.

cholesterol; cohort studies; lipid metabolism; neurodegenerative diseases; Parkinson disease; prospective studies; risk factors; serum


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The exact mechanism that underlies the selective dopaminergic cell death in Parkinson's disease is as yet unknown, but mitochondrial dysfunction and oxidative stress are thought to play a major role. Several recent findings also suggest a role of lipid and cholesterol metabolism in Parkinson's disease pathogenesis. Cholesterol is a major component of neuronal cell membranes and synapses and essential for maintaining their structure and function (1Go). Results of in vitro studies suggest an association between lipids and the localization and structure of the alpha-synuclein protein, the major component of the pathologic Lewy bodies found in brains of patients with Parkinson's disease (2Go–4Go). Lower serum levels of total cholesterol have been described in patients with Parkinson's disease compared with controls (5Go, 6Go). Moreover, serum cholesterol is the most important determinant of serum levels of coenzyme Q10, a powerful antioxidant and mitochondrial electron acceptor, that has shown beneficial effects in animal studies and initial trials on Parkinson's disease (7Go–9Go). To evaluate a potential role of cholesterol in Parkinson's disease, we examined the relation between serum levels of total and high density lipoprotein cholesterol and the risk of Parkinson's disease prospectively among 6,465 participants of the population-based Rotterdam Study.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
The Rotterdam Study is a prospective, population-based, cohort study among 7,983 persons aged 55 or more years in a district of Rotterdam, the Netherlands. The study was approved by the Medical Ethics Committee of the Erasmus Medical Center (Rotterdam), and written informed consent was obtained from all participants. At both baseline (1990–1993) and three follow-up rounds (1993–1994, 1997–1999, and 2002–2004), all participants were interviewed and underwent extensive physical examination and venipuncture. We used a two-phase design to identify subjects with Parkinson's disease (10Go). Participants were screened for parkinsonian signs (resting tremor, rigidity, bradykinesia, or impaired postural reflexes) in a standardized way. Individuals who screened positive received a structural diagnostic workup comprising the Unified Parkinson's Disease Rating Scale and neurologic examination. In addition, the cohort was continuously monitored through computerized linkage to general practitioners' medical files. Parkinson's disease was diagnosed if two or more parkinsonian signs were present in a person not taking antiparkinsonian drugs or if at least one sign had improved after medication was started, and when all causes of secondary parkinsonism (dementia, use of neuroleptics, cerebrovascular disease, multiple system atrophy, or progressive supranuclear palsy) could be excluded.

Total cholesterol and high density lipoprotein cholesterol concentrations in serum were determined within 2 weeks by an automated enzymatic procedure in nonfasting blood samples drawn at baseline. Apolipoprotein E (APOE) genotyping was performed on coded genomic DNA samples. Smoking status (classified as current, former, or never smoking), medication use, dietary intake of vitamin E (in milligrams/day), and coffee consumption (cups/day) were assessed during the baseline interview, and height and weight were measured to calculate body mass index (weight (kg)/height (m)2).

Baseline neurologic screening was performed in 6,969 participants. We excluded participants diagnosed with parkinsonism (n = 130) or dementia (n = 273) at baseline, resulting in a cohort at risk to develop Parkinson's disease during follow-up of 6,566 persons. In 6,465 of those, serum total and high density lipoprotein cholesterol were measured.

Statistical methods included Cox's proportional hazards regression analysis to evaluate the association of baseline serum total cholesterol and high density lipoprotein cholesterol with the risk of incident Parkinson's disease. Cholesterol levels were analyzed as both continuous variables (per mmol/liter increase for total cholesterol and per 0.1 mmol/liter increase for high density lipoprotein cholesterol) and in quartiles of the distribution. Analyses were initially adjusted for age and sex. Additional adjustments were made for smoking habits, vitamin E intake, and coffee consumption, because all of these factors have been related to a decreased risk of Parkinson's disease (11Go, 12Go) and probably are associated with concentrations of total and high density lipoprotein cholesterol (13Go). Analyses were further adjusted for body mass index, baseline use of cholesterol-lowering medication, and APOE genotype (categorized into {varepsilon}3{varepsilon}3, {varepsilon}4+, and {varepsilon}2+ ({varepsilon}2{varepsilon}4 excluded)), because APOE is an important determinant of plasma cholesterol (14Go), and the {varepsilon}2 allele is associated with an increased risk of Parkinson's disease (15Go). All analyses were repeated after exclusion of participants who reported use of lipid-lowering medication at baseline. We performed separate analyses for men and women, as the mean baseline serum levels for men and women were significantly different. Analyses were furthermore stratified on smoking status, coffee consumption, APOE genotype, high or low vitamin E intake, and use of lipid-lowering medication.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Follow-up information was available on 99 percent of the participants, through either complete in-person reexamination or the continuous monitoring system. During a total of 60,709 person-years of follow-up (mean follow-up time: 9.4 years), 87 new cases of Parkinson's disease were detected. Baseline characteristics of the study population are shown in table 1. Table 2 shows hazard ratios with 95 percent confidence intervals for Parkinson's disease according to serum total cholesterol, overall and for men and women separately.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Baseline characteristics of participants from the Rotterdam Study, Rotterdam, the Netherlands, 1990–1993

 

View this table:
[in this window]
[in a new window]

  		TABLE 2. Serum total cholesterol levels and risk of Parkinson's disease, the Rotterdam Study, Rotterdam, the Netherlands, 1990–2004*

 
Overall, higher levels of serum total cholesterol were associated with a significantly decreased risk of Parkinson's disease, with analyses in quartiles showing a clear linear relation. Stratified analyses showed a strong association in women but no association in men. None of the other stratified analyses showed different results across strata. Results for high density lipoprotein cholesterol levels are shown in table 3. No obvious association was seen in men. In women, there was a slight positive association but without clear evidence for linearity. Additional adjustments for smoking, dietary vitamin E, coffee consumption, body mass index, APOE genotype, and baseline use of lipid-lowering drugs did not change any of the results, and neither did exclusion of participants who used lipid-lowering medication at baseline.


View this table:
[in this window]
[in a new window]

  		TABLE 3. Serum high density lipoprotein cholesterol levels and the risk of Parkinson's disease, the Rotterdam Study, Rotterdam, the Netherlands, 1990–2004*

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this prospective, population-based, cohort study with a large number of person-years of follow-up, we found that serum total cholesterol was inversely related to the risk of Parkinson's disease. This association was restricted to women. As serum cholesterol levels were measured before the clinical onset of Parkinson's disease, the observed associations are unlikely to have resulted from consequences of the disease itself. Other kinds of bias are also unlikely to explain our findings, given our extensive case-finding procedures and nearly complete follow-up. Besides, the results show evidence for a dose-effect relation and remained virtually unchanged after adjustment for several potential confounders.

Evidence is accumulating that alterations in fat metabolism are involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease (1Go, 5Go). Results from a recent meta-analysis showed an increased risk of Parkinson's disease in carriers of the APOE {varepsilon}2 allele (15Go), which is associated with lower plasma levels of total cholesterol (14Go). In contrast, the {varepsilon}2 allele is considered protective against Alzheimer's disease, and a positive association has been reported between total cholesterol and Alzheimer's disease risk (14Go).

Decreased cholesterol synthesis was observed in skin fibroblasts from patients with Parkinson's disease (16Go), and lower levels of total cholesterol have been described in Parkinson's disease patients compared with controls (5Go, 6Go). In vitro studies have shown that alpha-synuclein is closely associated with cholesterol-enriched lipid rafts in the cell membrane (2Go) and that alpha-synuclein aggregation might be regulated by fatty acids (3Go, 4Go). In a study on nutritional factors, we previously found a significant inverse association between dietary intake of total fat and unsaturated fatty acids and the risk of Parkinson's disease (17Go). A decreased risk of Parkinson's disease with higher intake of polyunsaturated fatty acids was observed in another prospective cohort study as well (18Go). Our results also suggested an inverse association between dietary cholesterol intake and Parkinson's disease risk, although they did not reach statistical significance (17Go). However, these findings were based on 31,501 person-years of follow-up (mean follow-up time: 6.0 years) and 51 incident cases. For analyses on dietary intake, we now have 51,483 person-years of follow-up (mean follow-up time: 9.7 years) and 72 incident cases. When we redid our earlier analyses on dietary fat intake and risk of Parkinson's disease, we found a significant inverse association between dietary intake of cholesterol and the risk of Parkinson's disease. Again, stratified analyses revealed that this association was restricted to women (per standard deviation increase in energy-adjusted dietary intake of cholesterol: hazard ratio = 0.65, 95 percent confidence interval: 0.44, 0.96 in women; hazard ratio = 0.86, 95 percent confidence interval: 0.61, 1.21 in men).

We do not know exactly which mechanism underlies our findings or how the difference in findings between men and women might be explained. As the intact blood-brain barrier is impermeable to cholesterol-transporting lipoproteins and most brain cholesterol is synthesized in situ (1Go), it is even unclear whether serum cholesterol levels reflect changes in cholesterol metabolism in the central nervous system. An alternative hypothetical explanation for our findings is provided by the fact that serum cholesterol is the most important determinant of the serum concentration of coenzyme Q10, a molecule that acts as both an essential electron acceptor for complexes I and II in the mitochondrial respiratory chain and a powerful endogenous antioxidant. Cholesterol and coenzyme Q10 derive from the same biosynthetic pathway, and virtually all coenzyme Q10 in plasma is incorporated in lipoproteins, primarily low density lipoprotein (19Go, 20Go). Interest is increasing in the use of coenzyme Q10 as a potential treatment for Parkinson's disease, given the supposed role of oxidative stress and mitochondrial complex I dysfunction in Parkinson's disease pathogenesis (7Go, 9Go). Beneficial effects of oral coenzyme Q10 administration have been found in animal models for Parkinson's disease (7Go, 8Go) and in a multicenter, placebo-controlled, randomized phase II trial (9Go).

The lack of an association between cholesterol levels and Parkinson's disease risk in men in the present study might be due to a weaker correlation between cholesterol and coenzyme Q10 levels in men. It has been reported that a larger proportion of the variation in coenzyme Q10 is explained by total cholesterol in women as compared with men (19Go). On the other hand, lipid-modifying effects of estrogens have been reported that might account for the observed differences between men and women (21Go, 22Go). Our results call for further research on the relation among cholesterol, coenzyme Q10, and the risk of Parkinson's disease.


   ACKNOWLEDGMENTS
 
Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

  1. Reiss AB, Siller KA, Rahman MM, et al. Cholesterol in neurologic disorders of the elderly: stroke and Alzheimer's disease. Neurobiol Aging 2004;25:977–89.[CrossRef][ISI][Medline]
  2. Fortin DL, Troyer MD, Nakamura K, et al. Lipid rafts mediate the synaptic localization of alpha-synuclein. J Neurosci 2004;24:6715–23.[Abstract/Free Full Text]
  3. Welch K, Yuan J. Alpha-synuclein oligomerization: a role for lipids? Trends Neurosci 2003;26:517–19.[CrossRef][ISI][Medline]
  4. Sharon R, Goldberg MS, Bar-Josef I, et al. alpha-Synuclein occurs in lipid-rich high molecular weight complexes, binds fatty acids, and shows homology to the fatty acid-binding proteins. Proc Natl Acad Sci U S A 2001;98:9110–15.[Abstract/Free Full Text]
  5. Teunissen CE, Lutjohann D, von Bergmann K, et al. Combination of serum markers related to several mechanisms in Alzheimer's disease. Neurobiol Aging 2003;24:893–902.[CrossRef][ISI][Medline]
  6. Sohmiya M, Tanaka M, Tak NW, et al. Redox status of plasma coenzyme Q10 indicates elevated systemic oxidative stress in Parkinson's disease. J Neurol Sci 2004;223:161–6.[CrossRef][ISI][Medline]
  7. Matthews RT, Yang L, Browne S, et al. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci U S A 1998;95:8892–7.[Abstract/Free Full Text]
  8. Beal MF, Matthews RT, Tieleman A, et al. Coenzyme Q10 attenuates the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced loss of striatal dopamine and dopaminergic axons in aged mice. Brain Res 1998;783:109–14.[CrossRef][ISI][Medline]
  9. Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 2002;59:1541–50.[Abstract/Free Full Text]
  10. de Lau LM, Giesbergen PC, de Rijk MC, et al. Incidence of parkinsonism and Parkinson disease in a general population: the Rotterdam Study. Neurology 2004;63:1240–4.[Abstract/Free Full Text]
  11. Hernan MA, Takkouche B, Caamano-Isorna F, et al. A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson's disease. Ann Neurol 2002;52:276–84.[CrossRef][ISI][Medline]
  12. Zhang SM, Hernan MA, Chen H, et al. Intakes of vitamins E and C, carotenoids, vitamin supplements, and PD risk. Neurology 2002;59:1161–9.[Abstract/Free Full Text]
  13. Jee SH, He J, Appel LJ, et al. Coffee consumption and serum lipids: a meta-analysis of randomized controlled clinical trials. Am J Epidemiol 2001;153:353–62.[Abstract/Free Full Text]
  14. Michikawa M. Cholesterol paradox: is high total or low HDL cholesterol level a risk for Alzheimer's disease? J Neurosci Res 2003;72:141–6.[CrossRef][ISI][Medline]
  15. Huang X, Chen PC, Poole C. APOE-{varepsilon}2 allele associated with higher prevalence of sporadic Parkinson disease. Neurology 2004;62:2198–202.[Abstract/Free Full Text]
  16. Musanti R, Parati E, Lamperti E, et al. Decreased cholesterol biosynthesis in fibroblasts from patients with Parkinson disease. Biochem Med Metab Biol 1993;49:133–42.[CrossRef][ISI][Medline]
  17. de Lau LM, Bornebroek M, Witteman JC, et al. Dietary fatty acids and the risk of Parkinson disease: the Rotterdam Study. Neurology 2005;64:2040–5.[Abstract/Free Full Text]
  18. Abbott RD, Ross GW, White LR, et al. Environmental, life-style, and physical precursors of clinical Parkinson's disease: recent findings from the Honolulu-Asia Aging Study. J Neurol 2003;250(suppl 3):III30–9.
  19. Kaikkonen J, Nyyssonen K, Tuomainen TP, et al. Determinants of plasma coenzyme Q10 in humans. FEBS Lett 1999;443:163–6.[CrossRef][ISI][Medline]
  20. Miles MV, Horn PS, Morrison JA, et al. Plasma coenzyme Q10 reference intervals, but not redox status, are affected by gender and race in self-reported healthy adults. Clin Chim Acta 2003;332:123–32.[CrossRef][ISI][Medline]
  21. Shulman LP. Effects of progestins in different hormone replacement therapy formulations on estrogen-induced lipid changes in postmenopausal women. Am J Cardiol 2002;89:47E–54E; discussion 54E–55E.[CrossRef][ISI][Medline]
  22. Mudali S, Dobs AS, Ding J, et al. Endogenous postmenopausal hormones and serum lipids: the Atherosclerosis Risk in Communities Study. J Clin Endocrinol Metab 2005;90:1202–9.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 NeurologyHome page
G. Hu, R. Antikainen, P. Jousilahti, M. Kivipelto, and J. Tuomilehto
Total cholesterol and the risk of Parkinson disease
Neurology, May 20, 2008; 70(21): 1972 - 1979.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
A. D. Wahner, J. M. Bronstein, Y. M. Bordelon, and B. Ritz
Statin use and the risk of Parkinson disease
Neurology, April 15, 2008; 70(16_Part_2): 1418 - 1422.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
C. Becker, S. S. Jick, and C. R. Meier
Use of antihypertensives and the risk of Parkinson disease
Neurology, April 15, 2008; 70(16_Part_2): 1438 - 1444.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
A. Alonso, L. A. G. Rodriguez, G. Logroscino, and M. A. Hernan
Gout and risk of Parkinson disease: A prospective study
Neurology, October 23, 2007; 69(17): 1696 - 1700.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
K. C. Simon, H. Chen, M. Schwarzschild, and A. Ascherio
Hypertension, hypercholesterolemia, diabetes, and risk of Parkinson disease
Neurology, October 23, 2007; 69(17): 1688 - 1695.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
164/10/998    most recent
kwj283v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (11)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by de Lau, L. M. L.
Right arrow Articles by Breteler, M. M. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by de Lau, L. M. L.
Right arrow Articles by Breteler, M. M. B.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?