Vanguard Neurologist

i have been researching the association between statins, esp the lipophilic ones, and parkinson’s disease for >2yrs. there are several possible mechanisms by which statins may induce
neurodegenerative diseases(not just Parkinson’s, but ALS and Alzheimer’s, also). The first is the lowering of cholesterol itself–Ben A. Barres and Stephen J Smith. Science, November, 2001, Vol 294, pp1296-7:
“The smooth operation of the nervous system depends on rapid commmunication between nerve cells at meeting areas called syapses. Although synapses were first identified 100 years ago, their fomation, a process called synaptogenesis, has remained something of a mystery….two intriguing but unanticipated conclusions about synaptogenesis have been reached. The first is that neurons by themselves form few synapses unless they have help from other nerve cells called glial cells(1-3). The second reported by Mauch, et. al…, is that the synapse-promoting signal released by glial cells is CHOLESTEROL(emphasis mine)…

…Neurons in culture form few synapses unless glial cells called astrocytes are present. Astrocytes increase synapse number by secreting cholesterol bound to large lipoprotein particles containing apolipoprotein E (apoE).

These particles are internalized by neurons, leading to increased cholesterol within neuronal membranes . It is possible that apoE also activates yet to be identified signaling pathways within the neurons . These changes stimulate an increase in the number and efficacy of synapses.” (the target of statin use in alzheimer’s is apoE!)

Refs noted in above quote:
1. FW Pfrieger. BS Barres, Science 277. 1684 (1997)
2. EM Ullian., S Sapperstein, et al Science 291, 65 (2001)
3. K. Nagler, D. Mauch, j Physiol533. 665 (2001)
4. DH Mauch, et al Science 294. 1354 (2001)
It may or may not be important that the lipid that constitutes the largest percentage of all fats found in the SUBSTANTIA NIGRA is “dolichol” and dolichol production is directly dependent upon the mavelonate pathway–the same pathway that is totally blocked by all statins. does this fact have clinical relevance–who knows–no one has asked the question. it is just assumed that it must be okay..or hoped that it is in fact not an issue. or by not addressing it, it is in fact a non issue….
statins interrupt isoprentylation of many substances one of which results in a depression in selenoprotein expression. the functions of selenium are carried out by selenoproteins. several selenoproteins are expressed in the brain. glutathione peroxidase is one of these, serving an important role as protection from reactive oxygen species-induced cell damage as well as the re-cycling of glutathione. selenium concentrations in the CSF and serum of patients with PD are lower compared to normal subjects. [meseguer et al 1999, aguilar et al 1998])and the lowest density of glutathione peroxidase positive glial cells is found in the substantia nigra–leaving this dopaminergic cell group with less protection from oxidative stress and vulnerable to PD (Damier et al 1996) (i feel the interruption of isoprentylation of Sec tRNA will prove to be the major contributor of statins effect and the development of parkinson’s)

and of course statins interrupt the pathway to coenzyme q10 production.that has been discussed many times–and the importance of
coq10 to the mitochondrial electron transport chain–esp complexes 1, 2
and 4 (theory that PD is the result of mt dysfunction, specifically dysfunction of complex 1 of
the ETC) and for coq10′s function as a major anti-oxidant , esp in the
brain….
in the
study by A. Lieberman:Statins, cholesterol, Co-enzyme Q10, and Parkinson’s disease.
Lieberman A, Lyons K, Levine J, Myerburg R.
which concluded that there did not “seem” to be a difference btn his 2 groups–one taking stains and one not taking a statin. the most IMPORTANT part (my opinion)in this study was the notation that 5 patients who were originally in the non-statin group were started on a statin during the trial.
ALL FIVE OF THE SUBJECTS DEVELOPED WORSENING OF THEIR SYMPTOMS AFTER STARTING THE STATIN.

the statins were stopped for a “washing out” period–and after 2or 4 (cannot remember the time interval) weeks when the symptoms did not revert to pre-statin levels the investigators decided that these effects were not caused by the statin and the drugs were reordered……
There are many individuals with either ALS or Parkinson’s who are questioning the role of statins in the development of their respective diseases. The study to be undertaken by the UNC group will have to run for >2 yrs–actually given that the half life of brain cholesterol is thought to be 4 1/2- 5 yrs. the study would have to run for much more than 2 yrs for brain cholesterol to reach “critical levels” if low cholesterol is the initiating factor in these diseases. I wonder why statistics from the Framingham study or the study in Scotland are not used as epidemiological studies to at least give stronger evidence that statins are involved in neurodegenerative diseases? are those studies so difficult to do? to obtain funding? no one wants to alienate the pharmaceutical industry?

Let me first comment on posting by M M Levy above. I am so pleased about the calibre of responses and interaction we are getting on this site. This is exactly what we had hoped for. For thise of you with less scientific backgrounds, what the post focuses on is the important antioxidant systems which are affected negatively by statin medications – well beyond the interuption of the pathway for synthesis of coenzyme Q10 ( which even of itself is a major issue). Further, cholesterol plays so many important roles in human physiology and especially brain physiology, that we really must be more circumspect when deciding to aggressively lower it as exemplified by the citation referenced above  by Mauch CNS Synaptogenesis Promoted by Glia-Derived Cholesterol — Mauch et al. 294 (5545): 1354 — Science in which the fundamental role of cholesterol in the formation of synapses (connections allowing communication between brain cells) is described.

Finally, to Bill Worth I would say that there is precious little science to support the use of statins in the actual treatment of M.S.

In response to MM Levy above, the answer is that it would not be difficult at all. In fact there are plenty of other ongoing epidemiological studies from which this data could be extracted and correlations made. As you might expect however, most funding for this type of research is allocated to determine the positive effects of drug interventions.

[...] People generally assume that if they have high cholesterol, taking a statin drug to lower it makes good sense as it will reduce the risk of coronary artery disease. However, careful analysis of the data shows that this is a false assumption. In the January 30, 2007 edition of the journal, The Lancet, Dr. J. Abramson of Harvard University Medical School reviewed the data supporting the use of cholesterol lowering statin drugs for primary prevention of coronary artery disease. That is, is there truly any benefit associated with the use of statin drugs just to lower cholesterol in people without proven coronary artery disease. His conclusion, “ Our analysis suggests that lipid-lowering statins should not be prescribed for true primary prevention in women of any age or for men older than 69 years.” These conclusions were reached after evaluating all eight of the studies designed to evaluate the usefulness of statin drugs in terms of preventing coronary artery disease. As we are now seeing an increasing body of evidence that there may be some significant risks associated with these drugs  Parkinson’s Linked to Statin Drugs it’s time to start asking meaningful questions – now with important scientific support, as to why so many physicians seem so compelled to prescribe statin drugs in situations where there is no evidence of need. [...]

My 77 year-old Mother has dementia and has had minor tremor in her hands for a few years. She has been on Lipitor for a year. A geriatric psychiatrist diagnosed her with Parkinson’s after her tremors suddenly became much worse two weeks ago. Should I request she be taken off Lipitor? Her total cholesterol was 225 before starting Lipitor.