Coffee and Parkinson’s disease

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Background

Parkinson’s Disease (PD) is a debilitating neurodegenerative disorder. In Europe, almost 1.2 million people are estimated to have PD, with about 75,000 new cases diagnosed every year48. The age of onset of PD is usually over 60, but it is estimated that one in ten people are diagnosed before the age of 50, with slightly more men than women affected49.

The cardinal features of Parkinson’s disease are the slowing down of motor function, resting tremor, muscular rigidity, gait disturbances, and postural reflex impairment. The underlying pathological lesion is the progressive destruction of dopaminergic neurons in the midbrain. There is currently no available treatment to either prevent or slow down this neuronal loss and the resulting dopamine decrease in the midbrain.

Experimental and epidemiological research has focused on lifestyle, dietary and environmental risk factors, including coffee consumption.

Coffee, caffeine and risk of Parkinson’s disease

A large number of epidemiological studies report an inverse, dose-responsive relationship between coffee/caffeine consumption and the risk of developing PD. Coffee consumption appears to reduce or delay the development of PD and caffeine is most likely the causal factor. In women, however, the interaction between caffeine and hormonal therapy still needs further clarification.

As early as 1968, a study reported a higher percentage of non-coffee consumers in the control compared to the affected group50.

Subsequent studies performed in Spain51, Sweden52 and Germany53 found an inverse relationship between coffee consumption and PD, and a lower coffee consumption before disease onset.

The first prospective study on 8,004 Japanese American men living in Hawaii (the Honolulu Heart Program), carried out over a median duration of 27 years, reported an inverse association between PD incidence with a five-fold reduced risk for those drinking more than four cups of coffee per day when compared to non-consumers. The same inverse relationship was shown for caffeine from non-coffee sources54.

However, a case control study published in 2014 suggested only a weak inverse association between coffee intake and the risk of PD55.

Two meta-analyses, including 20 and 26 studies respectively, reported that the global risk of developing PD decreased by 31% (relative risk 0.69)56 and 25% (relative risk 0.75) in coffee drinkers compared to non-coffee drinkers57. Some of the individual studies found very strong risk reductions, up to 80% with the consumption of over 4 cups of coffee per day. The second meta-analysis found that the overall risk of developing PD fell by 24-32% per 300 mg increase in caffeine intake (i.e. with every 3 cups of coffee, approximately). These data confirm an inverse association between caffeine intake and the risk of PD which can hardly by explained by bias or uncontrolled confounding56,57.

In an additional 2013 dose, response meta-analysis showed a linear relationship between risk reduction of PD with tea and caffeine consumption, however, the association with coffee intake reached a maximum at approximately 3 cups of coffee a day58.

In women, the data are more equivocal. One study found a U-shaped relation, with moderate consumption of coffee/caffeine being the most protective59.

A further study performed on 77,713 women, followed up for 18 years, reported that in those not taking postmenopausal hormones, coffee was as protective against PD as in men. In women taking estrogens, the risk for PD was similar to men in case of low coffee consumption, but significantly increased four-fold in women drinking 6 or more cups of coffee a day when compared to non-coffee drinkers60.

A case-control study, part of the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), did not find convincing evidence that variations in the genes coding for caffeine metabolism (CYP1A2 and NAT2) or estrogen receptors (ESR1 and ESR2) could predict the risk of PD linked to hormone replacement therapy use61.

A randomised control trial published in 2012 evaluated the effects of caffeine intake on the symptoms of PD, including daytime somnolence, motor severity and other non-motor features.  The results showed improved objective motor measures, but only equivocal effects of caffeine on somnolence in PD; further evidence is required62.

A review of 304,980 participants in the National Institutes of Health-AARP Diet and Health Study suggested that higher caffeine intake was associated with subsequent lower PD risk in both men and women. The authors conducted a meta-analysis of prospective studies and confirmed that caffeine intake was inversely associated with PD risk in both men and women and suggested that there was no gender difference in the relation between caffeine and PD63.

Additionally, a prospective study published in 2012 confirmed previous findings showing a protective effect of caffeine on PD risk, with an attenuating influence of HRT in women. Consumption of decaffeinated coffee was not associated with a reduced risk of PD64.

Mechanism of action

Experimental studies have identified a mechanism of action for caffeine’s preventative role in the development of PD.

Low doses of caffeine antagonize mainly adenosine A2A receptors, which are located with D2 dopaminergic receptors in the striatum, i.e. the cerebral region involved in the control of locomotion and movement and in which dopaminergic neurontransmission is dramatically impaired in patients with PD. In the striatum, the blockade of A2A receptors increases motor activity and improves motor deficits in models of PD, via the stimulation of D2 receptors65, 66.

In animals, caffeine counteracts the symptoms of PD induced in rats and mice and enhances the effects of the classical treatment of PD, the precursor of dopamine, L-DOPA67,68.

Data obtained from several preclinical studies point to the beneficial effects of chronic A2A receptor antagonists (such as caffeine) on PD motor disability and on motor complications produced by long-term L-DOPA treatment, suggesting that they will be effective in the symptomatic treatment of PD58.

Moreover, the A2A antagonists, including caffeine and D2 agonists, have neuroprotective properties and can attenuate the degeneration of dopaminergic cells in various animal models57, 69.

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