Homocysteine, CoQ10, and Parkinson's Disease

Gorgone G, Currò M, Ferlazzo N, et al. Coenzyme Q10, hyperhomocysteinemia and MTHFR C677T polymorphism in levodopa-treated Parkinson's disease patients. Neuromolecular Med. 2012 Feb 22. [Epub ahead of print]

 

Prospective case/control study

 

60 patients with an established diagnosis of Parkinson’s disease (PD) and 82 healthy, age- and gender-matched control subjects

 

Circulating levels of homocysteine, vitamin B12, folate, and the ratio of oxidized coenzyme Q10 (CoQ10) to total CoQ10 (expressed as %CoQ) were measured in both groups. The presence or absence of C677T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism was also assessed. 

 

Patients with PD were significantly more likely to have the TT677 MTHFR polymorphism than controls (P=0.01). Patients carrying this genotype had the highest levels of homocysteine as well as oxidized CoQ10 (%CoQ10; P<0.0001). Even after adjusting for age, gender, B12, and folate status, there was an association with higher homocysteine levels and %CoQ10 in the patients with PD vs controls (P<0.0001). Independently, the presence of the TT677 genotype as well as the daily dose of levodopa were directly correlated with homocysteine levels (P<0.0001 and P=0.03 respectively). Lastly, homocysteine had a significant correlation with circulating %CoQ10 in PD subjects (P<0.0001).

 

Homocysteine (Hcy) is a known neurotoxin,¹ with presumed toxicity due to oxidative damage to neurons, including the dopaminergic neurons of the substantia nigra. The association between homocysteine levels and circulating oxidized CoQ10 (%CoQ10) has not been looked at previous to this study. Given the strong correlation between homocysteine levels and %CoQ10, the authors suggest that the percentage of oxidized CoQ10 in circulation can act as an assessable marker of intracellular toxic effects of Hcy. 

 

While the association of %CoQ10 is interesting as a research tool, testing of homocysteine is much more practical in a clinical setting. Testing for polymorphisms in the MFTHR genotype may be useful in PD patients with high homocysteine levels; however, as a genotype test, it is of less value than testing its phenotypic implications, such as homocysteine levels themselves. So, from a clinical perspective, testing homocysteine itself is the most appropriate means of assessing its potential contribution to progressive neuronal degeneration in our PD patients. 

 

As a clinician, one cannot help but wonder: If high homocysteine is corrected early in life, can we stall or even prevent the onset of PD altogether in susceptible patients? One would hope that such an extrapolation would hold true. Indeed, such presumptions are made routinely throughout preventative medicine. It is one of the privileges of practicing within a framework of nontoxic interventions. So, for our patients who are at higher risk of PD, such as Vietnam veterans, those exposed to high amounts of pesticides, and those with immediate family members with PD, the above study should affect how aggressively we pursue testing and normalization of homocysteine levels. 

 

But what about the role of CoQ10? This study showed that patients with PD have higher levels of oxidized CoQ10 in systemic circulation. The oxidative process and mitochondrial defects are intertwined and strongly implicated in the pathogenesis of PD.² As I discussed in a review for this journal in November 2010, several small studies have shown that CoQ10 may be a promising nutritional supplement for PD patients when used at high doses (>1,200 mg/d).³ Unfortunately, what was to be a landmark study on supplemental high-dose CoQ10 in PD was recently halted due to lack of statistically significant benefit of CoQ10 at interim analysis of the data. 

 

The study, called “Effects of coenzyme Q10 (CoQ) in Parkinson disease (QE3),” began recruiting at 68 centers across the United States and Canada in 2008.⁴ This large phase III trial was to recruit 600 participants into 1 of 3 arms and assess symptoms intermittently over a 16-month period:

There are many possible reasons for the lack of benefit from CoQ10 in the QE3 trial, but the above study offers one more possibility. What if the use of supplemental CoQ10 in high doses does not adequately attenuate the neurotoxic effects of high levels of homocysteine? In other words, perhaps the continuous generation of oxidative toxicity within the cells by homocysteine is one means of keeping the oxidation rate high regardless of how much reduced CoQ10 is given. To my knowledge, none of the clinical studies using oral CoQ10 in PD has ever included measuring or normalizing homocysteine levels as part of its design, including the large QE3 study.

 

 

The pathogenesis of PD is multifactorial, and ample evidence shows oxidative stressors are derived from more than just homocysteine. However, the clear correlation of homocysteine and intracellular oxidation in PD patients begs for further research. One means of determining if homocysteine’s oxidative potential overwhelmed the possible benefits of oral CoQ10 in the QE3 study is to test participants’ blood samples retrospectively for the presence or absence of polymorphisms in the MTHFR gene. Such an analysis would at least answer the question of whether high homocysteine was a confounding factor in the study. While we leave such re-analysis to researchers, the least we can do as clinicians is prioritize normalization of homocysteine levels over the more costly use of high dose CoQ10 in our patients with PD.