Blood levels of caffeine and its metabolites may be promising diagnostic biomarkers for early Parkinson’s disease, Japanese researchers reported.
Unrelated to total caffeine consumption or disease severity, serum levels of caffeine and nine of its downstream metabolites were significantly lower in patients with early Parkinson’s, Shinji Saiki, MD, PhD, of Juntendo University School of Medicine in Tokyo, and colleagues reported online in Neurology.
There were no significant genetic variations in the enzymes metabolizing caffeine between patients and controls.
Caffeine concentrations also were significantly decreased in Parkinson’s patients with motor fluctuations than in those without motor complications. However, patients in more severe disease stages did not have lower levels of caffeine, “suggesting that the decrease in caffeine metabolites occurs from the earliest stages of Parkinson’s,” David G. Munoz, MD, of the University of Toronto, and Shinsuke Fujioka, MD, of Fukuoka University in Japan, wrote in an accompanying editorial.
Some previous reports have suggested an inverse association between daily caffeine consumption and reduced risk of developing Parkinson’s, although a recent randomized controlled trial found no benefit to caffeine intake for Parkinson’s symptoms.
Mechanistically, caffeine could improve motor symptoms by antagonizing adenosine 2A receptors (A2A-Rs), but changes in the entire caffeine metabolic pathway in Parkinson’s patients are unclear.
In this study, researchers examined blood samples of 108 patients with idiopathic Parkinson’s disease and 31 age-matched healthy controls, separating caffeine and 11 downstream metabolites by high-performance liquid chromatography. All Parkinson’s patients had been treated at Juntendo University Hospital; on average, they had mild to moderate disease severity. Age, sex, and total caffeine intake were similar for both groups.
The researchers also recruited an additional 51 healthy controls and 67 Parkinson’s patients for gene analysis, screening for mutations in caffeine-associated genes by direct sequencing.
Blood levels of caffeine and nine of its 11 metabolites were lower in Parkinson’s patients than in controls (P<0.0001). The difference could be used to separate patients from controls reliably, with an area under the receiver operating characteristic curve of 0.98.
Analyses of caffeine-related genes showed no significant differences between patients and controls. The researchers saw no significant genetic variations in CYP1A2 or CYP2E1, the encoding cytochrome P450 enzymes primarily involved in metabolizing caffeine, between the groups. They found no associations between disease severity and single nucleotide variants of the ADORA2A gene, which encodes A2A-R.
They also detected no correlations between levodopa equivalent doses and absolute concentrations of caffeine and its metabolites.
One reason why early Parkinson’s patients had decreased caffeine levels may be related to intestinal absorption, the authors suggested. Gastrointestinal problems like constipation can affect up to 80% of Parkinson’s patients, sometimes preceding symptom onset by years, and a recent analysis showed that fecal microbial flora is altered in patients with Parkinson’s.
Another explanation might be anti-parkinsonian agents.
“There is an elephant in the room: almost all patients with Parkinson’s were receiving treatment,” wrote Munoz and Fujioka. “The authors address this issue by finding no association between levels of caffeine metabolites and levodopa equivalent doses, but it is obvious that the validity of the study hangs on this point.”
“If a future study were to demonstrate similar decreases in caffeine in untreated patients with Parkinson’s, or persons with prodromal signs of Parkinson’s including REM behavior disorder, many of whom would be expected to develop Parkinson’s, the implications of the current study would take enormous importance,” they continued. This could lead to an easy test for early diagnosis or point to a basic mechanism of Parkinson’s pathogenesis.
One limitation of this study is that it did not include severe Parkinson’s cases; its reduced power may have limited the researchers’ ability to detect an association between disease severity and caffeine levels. Despite the lack of correlation between levodopa equivalent doses and caffeine concentration, Parkinson’s medications still might have affected metabolism, the authors added.
“Similar to a recent study showing progressive decreases in caffeine metabolites with disease exacerbation, de novo Parkinson’s studies including larger study populations and studies on differential diagnostic values among patients with Parkinson’s and other parkinsonian patients should be performed,” they wrote.