Literature Review

Low Serum Caffeine Level Could Indicate Early Parkinson’s Disease

Data do not reveal an association between serum caffeine metabolite levels and levodopa equivalent doses.


Low serum caffeine and caffeine metabolite levels after an overnight fast may be a sensitive way to detect Parkinson’s disease, according to the results of a case–control study published online ahead of print January 3 in Neurology.

In the study, levels of caffeine and its metabolites were lower in patients with Parkinson’s disease and motor dysfunction, compared with those without motor dysfunction. The investigators detected no differences in serum levels of caffeine metabolites between patients with mild Parkinson’s disease and those with severe Parkinson’s disease, said Motoki Fujimaki, MD, of Juntendo University School of Medicine in Tokyo, and colleagues.

A Single-Center Study

Previous research had shown that people drinking four or more cups of coffee per day had a greater than fivefold reduction in the risk of developing Parkinson’s disease. Mouse models of Parkinson’s disease showed that caffeine and two of its metabolites have a neuroprotective effect. Those results suggested that serum caffeine might be useful as a blood marker for Parkinson’s disease.

To test that idea, Dr. Fujimaki and associates recruited 31 healthy controls (18 women) and 108 patients with Parkinson’s disease but no dementia (50 women). The control group’s mean caffeine intake of 115.81 mg/day was similar to that of patients with Parkinson’s disease (107.50 mg/day).

Serum caffeine levels measured after an overnight fast showed that a cutoff of 33.04 pmol/10 µL identified Parkinson’s disease with an area under the curve (AUC) of 0.78 (sensitivity, 76.9%; specificity, 74.2%). Inclusion of the primary caffeine metabolites theophylline, theobromine, and paraxanthine increased the AUC to 0.87. When the researchers included all 11 measurable metabolites, the AUC increased further to 0.98.

Genetic analyses revealed no significant differences in the frequencies of caffeine metabolism–associated genetic variants between patients and controls.

The study was limited by the fact that it was conducted at a single university hospital, and the patient population did not include many severe cases. The association should also be studied in other Parkinson’s disease patient populations, according to the authors.

Did Treatment Effects Influence the Findings?

A key question that the study raises is what caused the decrease in serum concentration found in patients with Parkinson’s disease, said David G. Munoz, MD, of the Department of Laboratory Medicine and Pathobiology at the University of Toronto, and Shinsuke Fujioka, MD, of the Department of Neurology at Fukuoka University in Japan, in an accompanying editorial. Almost all of the patients were receiving treatment, which could have affected serum levels, they added. The researchers looked for, but did not find, an association between serum caffeine metabolite levels and levodopa equivalent doses.

“The validity of the study depends on whether caffeine metabolism may be affected by treatment,” said Drs. Munoz and Fujioka. “To demonstrate the utility of caffeine metabolites unequivocally, a future study will have to reproduce these results in patients with untreated Parkinson’s disease or subjects at high risk of Parkinson’s disease, such as those with prodromal signs of Parkinson’s disease.”

—Jim Kling

Suggested Reading

Fujimaki M, Saiki S, Li Y, et al. Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease. Neurology. 2018 Jan 3 [Epub ahead of print].

Munoz DG, Fujioka S. Caffeine and Parkinson disease: A possible diagnostic and pathogenic breakthrough. Neurology. 2018 Jan 3 [Epub ahead of print].

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