Neurology -- Correspondence for Hu et al., 0 (2008) 10000312

Correspondence published:

Total cholesterol and the risk of Parkinson disease: Luca Mascitelli, MD, Francesca Pezzetta, MD (Tolmezzo, Italy), Mark R. Goldstein, MD,FACP (Bonita Springs, FL) (4 June 2008)

Reply from the authors: Gang Hu, MD, PhD, Riitta Antikainen, PhD (Oulu, Finland); Pekka Jousilahti, PhD; Miia. Kivipelto, PhD (Stockholm, Sweden); Jaakko Tuomilehto, PhD (Seinäjoki, Finland) (4 June 2008)

Total cholesterol and the risk of Parkinson disease 4 June 2008

Luca Mascitelli, MD,
Comando Brigata alpina Julia
8 Via S. Agostino, Udine 33100 Italy,
Francesca Pezzetta, MD (Tolmezzo, Italy), Mark R. Goldstein, MD,FACP (Bonita Springs, FL)
Send Correspondence to journal:
Re: Total cholesterol and the risk of Parkinson disease

lumasci{at}libero.it Luca Mascitelli, MD, et al.

In this large prospective study, Hu et al. found that high total cholesterol at baseline was associated with an increased risk of Parkinson disease (PD). [1] We are concerned that the take-home message of these results could be that lowering cholesterol with statins might reduce the incidence of PD.
Interestingly, the association between total cholesterol and the risk of PD was not significant in subjects aged 55 or older who have a much higher incidence of the disease. PD can be considered a neurodegenerative disorder of the central nervous system (CNS) whose major risk factor is age. Mounting evidence suggests that an autoimmune response against self-antigens residing in the site of insult can protect the body against CNS neurodegeneration.
Since autoimmunity is suppressed by naturally occurring regulatory CD4+CD25+T- cells (Tregs), in order to succeed in getting the desired autoimmune response for protection of the CNS neurons at risk of degeneration, the Treg-induced suppression must be alleviated. It has been shown that Treg depletion promotes survival of neurons after CNS insults. [2]
Furthermore, in a mouse model of neurodegenerative condition, it has been found that the systemic administration of dopamine or its D1-type agonist significantly enhanced protection against neuronal death after CNS mechanical and biochemical injury by alleviating the suppression imposed by Tregs. [3] Moreover, a recent study found that Treg frequency increases with age, and Tregs have a higher reactivity in the presence of neurodegeneration. [4]
On the other hand, a novel, in vivo, pleiotropic effect of statins is to induce the transcription factor forkhead box P3, resulting in a significant increase in the number of Tregs. [5] These statin-induced higher numbers of Tregs may suppress the beneficial immune effector mechanism in PD. Even though high serum total cholesterol levels at baseline may be associated with an increased risk of PD in younger individuals [1], it is unclear whether lowering cholesterol with statins will reduce the incidence of neurodegenerative disorders. Perhaps statin therapy should be contraindicated in patients with PD.
References
1. Hu G, Antikainen R, Jousilahti P, Kivipelto M, Tuomilehto J. Total cholesterol and the risk of Parkinson disease. Neurology 2008 Apr 9; [Epub ahead of print].
2. Kipnis J, Mizrahi T, Hauben E, Shaked I, Shevach E, Schwartz M. Neuroprotective autoimmunity: naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. Proc Natl Acad Sci USA 2002; 99:15620–15625.
3. Kipnis J, Cardon M, Avidan H, et al. Dopamine, through the extracellular signal-regulated kinase pathway, downregulates CD4+CD25+ regulatory T-cell activity: implications for neurodegeneration. J Neurosci 2004;24:6133-6143.
4. Rosenkranz D, Weyer S, Tolosa E, et al. Higher frequency of regulatory T cells in the elderly and increased suppressive activity in neurodegeneration. J Neuroimmunol 2007;188:117-127.
5. Mausner-Fainberg K, Luboshits G, Mor A, et al. The effect of HMG- CoA reductase inhibitors on naturally occurring CD4+CD25+ T cells. Atherosclerosis 2008;197:829-839.
Disclosures: The authors report no disclosures.

Reply from the authors 4 June 2008

Gang Hu, MD, PhD,
National Public Health Institute
Mannerheimintie 166, FIN-00300 Helsinki, Finland,
Riitta Antikainen, PhD (Oulu, Finland); Pekka Jousilahti, PhD; Miia. Kivipelto, PhD (Stockholm, Sweden); Jaakko Tuomilehto, PhD (Seinäjoki, Finland)
Send Correspondence to journal:
Re: Reply from the authors

hu.gang{at}ktl.fi Gang Hu, MD, PhD, et al.

We appreciate the comments from Mascitelli et al. on our findings. [1] They question whether lowering cholesterol with statins might increase the risk of incident PD and provide an interesting theory.
Autoimmune response against auto-antigens is beneficial while preventing the disease (PD). Tregs can suppress this beneficial response while promoting the disease. Tregs have been found to increase with age and statin use. Thus, statins may prevent the beneficial autoimmune response and increase the risk of PD.
Mascitelli et al. also consider that the association between high cholesterol and PD risk could be partially explained by the use of statins. Several epidemiologic studies have recently shown that high serum cholesterol is associated with an increased risk of dementia and AD. [6,7] One recent case-control study has also indicated that statin use may be associated with a lower PD occurrence, but the relatively small sample size (124 PD cases and 112 controls) may limit the statistical power. [8]
Information on the use of cholesterol-lowering agents in our study was obtained from the 1992 and 1997 surveys but not the earlier surveys of 1972-1987. To eliminate the possible effect of statin treatment on the incidence of PD, we performed a sensitivity analysis including the surveys from 1972 to 1992 (n=42,991) which were followed to the end of 1995. The use of statin therapy was minimal among Finns before 1996. After exclusion of participants who used cholesterol-lowering agents at baseline (n=103), sex- and multivariate-adjusted hazard ratios of PD at different levels of total cholesterol (<5, 5-5.9, 6-6.9, and ¡Ý7 mmol/l) were 1.00, 1.54 (95% CI, 0.94-2.52), 1.46 (95% CI, 0.90-2.37), and 1.98 (95% CI, 1.23-3.20) (P for trend=0.009).
No prospective studies or large clinical trials have assessed the association between use of statins and the risk of PD. Further studies are needed to test this hypothesis since we do not have data on the use of cholesterol-lowering agents during follow-up.
References
6. Notkola IL, Sulkava R, Pekkanen J, et al. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. Neuroepidemiology 1998;17:14-20.
7. Kivipelto M, Helkala EL, Laakso MP, et al. Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med 2002;137:149-155.
8. Huang X, Chen H, Miller WC, et al. Lower low-density lipoprotein cholesterol levels are associated with Parkinson's disease. Mov Disord 2007;22:377-381.
Disclosure: The authors report no disclosures.