Association of caffeine and related analytes with resistance to Parkinson disease among LRRK2 mutation carriers: A metabolomic study
Crotty GF, Maciuca R, Macklin EA, Wang J, Montalban M, Davis SS, Alkabsh JI, Bakshi R, Chen X, Ascherio A, Astarita G, Huntwork-Rodriguez S, Schwarzschild MA
Neurology · 51 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- Cohort study (indexed by PubMed)
- Studied in
- People
- Main outcome
- Clinical events such as disease or death
Who paid for it
- Funding
- Independent funding
- Nonprofit
- Michael J. Fox Foundation for Parkinson's Research
- Nonprofit
- Farmer Family Foundation
- Government
- National Institutes of Health
- Government
- National Institute of Neurological Disorders and Stroke
- Government
- NINDS NIH HHS
- Authors
- At least one author declares a financial tie to industry
- Grants
- National Institute of Neurological Disorders and Stroke (R01NS102735); National Institute of Neurological Disorders and Stroke (R21 NS090246); National Institute of Neurological Disorders and Stroke (R01NS110879); National Institutes of Health (R01NS110879)
Based on 5 listed funder(s) and full-text disclosure statement.
Publication
- Published
- 2020-10-01 · Neurology · vol. 95 · issue 24 · pp. e3428–e3437
- Publisher
- Lippincott Williams & Wilkins
- Cited
- 58 citations · more than 93% of similar papers · 2.8× the field average
- Impact
- Top 10% most cited in its field
- References
- 37 works
- Access
- Open access (hybrid journal) · CC-BY-NC-ND
- Research areas
- Parkinson's Disease Mechanisms and Treatments · Ginkgo biloba and Cashew Applications · Biochemical Analysis and Sensing Techniques
- Keywords
- LRRK2, Internal medicine, Medicine, Cohort, Caffeine, Paraxanthine, Gastroenterology, Parkinson's disease, Chemistry, Disease
- MeSH
- humans, parkinson disease, alkaloids, xanthines, caffeine, theophylline, neuroprotective agents, chromatography, liquid, cohort studies, heterozygote, aged, middle aged, female, male, mass spectrometry, metabolomics, leucine-rich repeat serine-threonine protein kinase-2
13 authors
From US
- Grace F. CrottyHarvard University; Massachusetts General Hospital; Denali Therapeutics (United States)
- Romeo D. MaciucaHarvard University; Massachusetts General Hospital; Denali Therapeutics (United States)
- Eric A. MacklinHarvard University; Massachusetts General Hospital; Denali Therapeutics (United States)
- Junhua WangHarvard University; Massachusetts General Hospital; Denali Therapeutics (United States)
- Manuel MontalbanHarvard University; Massachusetts General Hospital; Denali Therapeutics (United States)
- Sonnet S. DavisHarvard University; Massachusetts General Hospital; Denali Therapeutics (United States)
Abstract
Objective
To identify markers of resistance to developing Parkinson disease (PD) among LRRK2 mutation carriers (LRRK2+), we carried out metabolomic profiling in individuals with PD and unaffected controls (UC), with and without the LRRK2 mutation.
Methods
Plasma from 368 patients with PD and UC in the LRRK2 Cohort Consortium (LCC), comprising 118 LRRK2+/PD+, 115 LRRK2+/UC, 70 LRRK2-/PD+, and 65 LRRK2-/UC, and CSF available from 68 of them, were analyzed by liquid chromatography with mass spectrometry. For 282 analytes quantified in plasma and CSF, we assessed differences among the 4 groups and interactions between LRRK2 and PD status, using analysis of covariance models adjusted by age, study site cohort, and sex, with p value corrections for multiple comparisons.
Results
Plasma caffeine concentration was lower in patients with PD vs UC (p LRRK2+ carriers (by 76%) than among LRRK2- participants (by 31%), with significant interaction between LRRK2 and PD status (p = 0.005). Similar results were found for caffeine metabolites (paraxanthine, theophylline, 1-methylxanthine) and a nonxanthine marker of coffee consumption (trigonelline) in plasma, and in the subset of corresponding CSF samples. Dietary caffeine was also lower in LRRK2+/PD+ compared to LRRK2+/UC with significant interaction effect with the LRRK2+ mutation (p < 0.001).
Conclusions
Metabolomic analyses of the LCC samples identified caffeine, its demethylation metabolites, and trigonelline as prominent markers of resistance to PD linked to pathogenic LRRK2 mutations, more so than to idiopathic PD. Because these analytes are known both as correlates of coffee consumption and as neuroprotectants in animal PD models, the findings may reflect their avoidance by those predisposed to develop PD or their protective effects among LRRK2 mutation carriers.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY-NC-ND).
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