Low Levels of Caffeine, Metabolites May Identify Early Parkinson's Disease

Deborah Brauser

January 05, 2018

More research suggests that caffeine may be neuroprotective against Parkinson's disease (PD) — and that low caffeine levels in blood samples could act as an early biomarker of PD.

The study of 139 participants showed that those with PD had significantly lower levels of caffeine and nine of its metabolites than levels in those without PD.

Interestingly, this finding did not depend on total caffeine intake. Although both groups averaged about 2 cups of coffee per day, those with PD had a total caffeine level of 24 pmol/10 µL, compared with 79 pmol/10 µL for the healthy volunteers.

In addition, there were a 77% sensitivity rate and a 74% specificity rate for caffeine in serum samples as a diagnostic biomarker for PD.

Dr Nobutaka Hattori

Corresponding author Nobutaka Hattori, MD, PhD, Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan, told Medscape Medical News that past epidemiological studies have suggested that heavy consumption of coffee could be protective against PD.

However, the new findings also show that "malabsorption for caffeine" could be a PD risk factor, he said.

"Probably, people with a risk for PD may have malabsorption of caffeine in the small intestine. Thus, modifying the delivery system, such as the transdermal system, may increase concentration of caffeine,” added Dr Hattori. Alternatively, high caffeine intake “may halt the progression of the disease."   

The study findings were published online January 3 in Neurology.

Entire Metabolic Pathway

In a previous mouse study, a neuroprotective effect from caffeine was shown against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), while another study showed neuroprotection against MPTP from the caffeine metabolites paraxanthine and theophylline, note the investigators.

"However, changes in the entire caffeine metabolic pathway in patients with PD remain unclear," they write. In addition, "the development of blood-based biomarkers for PD is of high priority because of the easy sample collection procedure."

The researchers enrolled 108 patients with mild to moderate PD but without dementia (54% men; mean age, 67.1 years) at one hospital in Japan between December 2013 and February 2014. The age-matched comparator group comprised 31 healthy adults (43% men; mean age, 63.3 years).

Liquid chromatography-mass spectrometry was used to measure levels of caffeine and all 11 of its metabolites from all participants' blood serum samples.

Results showed that overall caffeine levels were significantly lower in the patients with PD than in those without PD (P < .0001).

Nine of the 11 caffeine metabolites were also significantly lower for the PD group, including the "big 3" of theophylline (P < .0001), theobromine (P = .0004), and paraxanthine (P < .0001).

There was no significant between-group difference in levels of 1-methyluric acid (P = .135), and 1,3,7-trimethyluric acid levels were actually higher in patients with PD (P = .002).

However, both of these metabolites "were under the limit of detection in 32% and 63% of participants, respectively," write the researchers.

Reliable Biomarker?

For the patients with PD, those with motor complications (47%) had lower levels of caffeine and of 1,7-dimethyluric acid than did those without these symptoms (P = .01 and P < .0001, respectively).

Additional gene analysis included the original participants plus 67 more patients with PD (49% men) and 51 more healthy volunteers (49% men).

Direct sequencing showed no significant between-group differences in genetic variations in the enzymes primarily involved in caffeine metabolism (CYP1A2 and CYP2E1).

The study also detected no links "between disease severity and single nucleotide variants of the ADORA2A gene encoding adenosine 2A receptor…implying a dissociation of receptor sensitivity changes and phenotype," report the investigators.

Finally, receiver-operating characteristic (ROC) curve analyses showed that caffeine at a cutoff of 33.04 pmol/10 µL had an area under the curve (AUC) of 0.78 as a PD biomarker. The AUC jumped to 0.87 with the addition of caffeine's "big 3" metabolites — and to 0.98 with the addition of all the metabolites.

The investigators note that because no associations were found between caffeine/its metabolites and disease severity, sex, and gene variants, yet the association was significant in patients with motor complications, the study "further indicates the neuroprotective effects of caffeine."

In addition, "caffeine metabolite profiles may be reliable diagnostic biomarkers for early PD," they write.

"I think that caffeine may have multipotential activities against not only PD but also Alzheimer's disease and cancer," added Dr Hattori. The study findings are "very surprising and important for clinicians."

Possible Breakthrough

David G. Munoz, MD, University of Toronto, Ontario, Canada, and Shinsuke Fujioka, MD, Fukuoka University, Japan, write in an accompanying editorial that the study showcases a "possible diagnostic and pathogenic breakthrough."

They note that the ROC curve of 0.98 "is remarkably good for a diagnostic test" but question what the mechanism is for decreased levels of caffeine in these patients.

"Other than the suggestion that intestinal absorption of caffeine may be impaired, the study provides no clues, but there is an elephant in the room: almost all the patients with PD were receiving treatment," write Dr Munoz and Dr 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."

The editorialists note that future research should assess caffeine metabolism in untreated patients with PD or those with prodromal signs of PD. If similar decreases are found there, "the implications of the current study would take enormous importance," they write.

Dr Munoz noted in a press release that PD has been notoriously difficult to diagnose in patients, especially those in the early stages of the disease.

"If these results can be confirmed, they would point to an easy test for early diagnosis of Parkinson's, possibly even before symptoms are appearing," he said.

The study was funded by the Japan Agency for Medical Research and Development-CREST; the Japanese Ministry of Education, Culture, Sports, Science, and Technology; and the Japan Society for the Promotion of Science (JSPS). Dr Hattori has received personal fees from Hisamitsu Pharmaceutical, Dai-Nippon Sumitomo Pharma, Otsuka Pharmaceutical, Novartis, GlaxoSmithKline, Nippon Boehringer Ingelheim, FP Pharmaceutical, Eisai, Kissei Pharmaceutical, Janssen Pharmaceutical, Nihon Medi-Physics, and Kyowa Hakko-Kirin. He has also received research grants from the Japan Agency for Medical Research and Development-CREST and from the JSPS. A full list of disclosures for the other study authors appears in the original article. Dr Munoz receives research funding from the Michael J. Fox Foundation for Parkinson's Disease, the Physicians' Services Foundation, the Radiological Society of North America, and the Brain Tumor Foundation of Canada. Dr Fujioka has served on the editorial board of Parkinsonism and Related Disorders and has received research support from a JSPS KAKENHI grant.   

Neurology. Published online January 3, 2018. Full article, Editorial

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