Total cholesterol and the risk of Parkinson disease
LucaMascitelli, MD, Comando Brigata alpina Julia, 8 Via S. Agostino, Udine 33100 Italylumasci@libero.it
Francesca Pezzetta, MD (Tolmezzo, Italy), Mark R. Goldstein, MD,FACP (Bonita Springs, FL)
Submitted June 04, 2008
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.
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.