Caffeine as symptomatic treatment for Parkinson disease (Café-PD)

Postuma, Ronald B.; Anang, Julius; Pelletier, Amélie; Joseph, Lawrence; Moscovich, Mariana; Grimes, David A.; Furtado, Sarah; Munhoz, Renato P.; Appel‐Cresswell, Silke; Moro, Adriana; Borys, Andrew; Hobson, Douglas E.; Lang, Anthony E.

doi:10.1212/wnl.0000000000004568

Cited by 112 publications

(96 citation statements)

References 28 publications

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“…Previous studies have shown the relationships between altered purine metabolism and PD pathology. A panel of metabolites, that is, adenosine, inosine, guanosine, hypoxanthine, and uric acid, has been reported to be altered in PD brains compared to controls (Tufi et al ; Garcia‐Esparcia et al ; Burnstock ; Postuma et al ). Our results indicated that neuroinflammation induced a significant decrement in adenosine and high levels of catabolic intermediates such as inosine, hypoxanthine, and xanthine.…”

Section: Discussionmentioning

confidence: 99%

Metabolomics‐driven identification of adenosine deaminase as therapeutic target in a mouse model of Parkinson's disease

Huang

Zhang

et al. 2019

Journal of Neurochemistry

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Neuroinflammation is one of the driving forces of progressive neurodegeneration in Parkinson’s disease (PD). The metabolomics approach has been proved highly useful in identifying potential therapeutic targets. Here, to identify inflammation‐relevant treatment targets for PD, mass spectrometry‐based untargeted metabolomics was applied to characterize metabolic changes in the striatum of mice with double‐hit PD induced by lipopolysaccharide plus 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). Seven days after the final MPTP administration, metabolites from the purine metabolism pathway, including adenosine, 1‐methyladenosine, adenine, inosine, hypoxanthine, xanthine, xanthosine, and guanosine, were found to be significantly dysregulated. The metabolite–protein interaction network and changes in the concentration ratio of these metabolites indicated that adenosine and adenosine deaminase (ADA; EC 3.5.4.4) were the most promising therapeutic targets and adenosine augmentation might be a rational approach to slow PD progression. These findings were then verified in a subacute MPTP‐induced PD mouse model treated with ADA inhibition alone or in conjunction with antagonism of adenosine A2A receptors (A2AR). Behavioral, biochemical, and immunohistochemical analysis demonstrated that ADA inhibition significantly ameliorated the MPTP‐mediated motor disabilities, dopamine depletion, and dopaminergic cell death. Significantly enhanced neuroprotective effects were further observed when the ADA inhibitor was utilized in conjunction with an A2AR antagonist. Together, our study indicated for the first time that ADA inhibitors protected against neurodegeneration induced by the neurotoxin MPTP, and ADA inhibitors in combination with A2AR antagonists showed additive antiparkinsonian effects.

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Section: Discussionmentioning

confidence: 99%

Metabolomics‐driven identification of adenosine deaminase as therapeutic target in a mouse model of Parkinson's disease

Huang

Zhang

et al. 2019

Journal of Neurochemistry

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“…This result was largely unexpected because the observational study associations between caffeine-containing drinks (both coffee and tea) have almost always suggested a negative association between caffeine and PD 4,24 . This has meant that caffeine has been explored as a potentially therapeutic option for PD 25 . It is not clear what would account for observing consistently negative observational associations between caffeine and PD, and a potentially detrimental effects of caffeine on PD in MR analyses, but the effect for coffee drinking in this analysis was also not in favour of a true protective effect.…”

Section: Discussionmentioning

confidence: 99%

The Parkinson’s Disease Mendelian Randomization Research Portal

Noyce

Ciga

Kim

et al. 2019

Preprint

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Word count: 4391Abstract word count: 253 ABSTRACT BackgroundMendelian randomization (MR) is a method for exploring observational associations to find evidence of causality. ObjectiveTo apply MR between multiple risk factors/phenotypic traits (exposures) and Parkinson's disease (PD) in a large, unbiased manner, and to create a public resource for research. MethodsWe used two-sample MR in which the summary statistics relating to SNPs from genome wide association studies (GWASes) of 5,839 exposures curated on MR Base were used to assess causal relationships with PD. We selected the highest quality exposure GWASes for this report (n=401). For the disease outcome, summary statistics from the largest published PD GWAS were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted (IVW) method, followed by a range of sensitivity analyses. We used a false discovery rate (FDR) corrected p-value of <0.05 from the IVW analysis to prioritize traits of interest. ResultsWe observed evidence for causal associations between twelve exposures and risk of PD. Of these, nine were causal effects related to increasing adiposity and decreasing risk of PD.The remaining top exposures that affected PD risk were tea drinking, time spent watching television and forced vital capacity, but the latter two appeared to be biased by violations of underlying MR assumptions. DiscussionWe present a new platform which offers MR analyses for a total of 5,839 GWASes versus the largest PD GWASes available (https://pdgenetics.shinyapps.io/pdgenetics/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD.

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“…Other available therapies that might be “repurposed” for disease modification based on either epidemiological or basic science studies include caffeine and antidepressants including tricyclics, fluoxetine, and trazodone. The latter has the novel effect of potentially supressing the overactive unfolded protein response by inhibition of Phospho‐Eukaryotic Initiation Factor 2a (eIF2α‐P) activity .…”

Section: Targets For Disease Modificationmentioning

confidence: 99%

Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations

2018

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The greatest unmet therapeutic need in Parkinson's disease is the development of treatment that slows the relentless progression of the neurodegenerative process. The concept of "disease modification" encompasses intervention types ranging from those designed to slow the underlying degeneration to treatments directed at regenerating or replacing lost neurons. To date all attempts to develop effective disease-modifying therapy have failed. Many reasons have been proposed for these failures including our rudimentary understanding of disease pathogenesis and the assumption that each targeted mechanisms of disease apply to most patients with the same clinical diagnosis. Here we review all aspects of this broad field including general concepts and past challenges followed by a discussion of treatment approaches under the following 4 categories: (1) α-synuclein, (2) pathogenic mechanisms distinct from α-synuclein (most also potentially triggered by α-synuclein toxicity), (3) non-SNCA genetic subtypes of "PD," and (4) possible disease-modifying interventions not directly influencing the underlying PD pathobiology. We emphasize treatments that are currently under active clinical development and highlight a wide range of important outstanding questions and concerns that will need to be considered to advance the field of disease modification in PD. Critically, it is unknown whether the dysfunctional molecular pathways/organelles amenable to modification occur in a sequential fashion across most clinically affected individuals or manifest differentially in independent molecular subtypes of PD. It is possible that there is no "order of disruption" applicable to most patients but, rather, "type of disruption" applicable to subtypes dependent on unknown factors, including genetic variability and other causes for heterogeneity in PD. Knowing when (early vs late), which (eg, synaptic transmission, endosomal sorting and maturation, lysosomal degradation, mitochondrial biogenesis), and in whom (PD subtype) specific disrupted cell pathways are truly pathogenic versus compensatory or even protective, will be important in considering the use of single or combined ("cocktails") putative disease-modifying therapies to selectively target these processes. Beyond the current phase 2 or 3 studies underway evaluating treatments directed at oxidative stress (inosine), cytosolic Ca (isradipine), iron (deferiprone), and extracellular α-synuclein (passive immunization), and upcoming trials of interventions affecting c-Abl, glucagon-like peptide-1, and glucocerebrosidase, it might be argued that further trials in populations not enriched for the targeted pathogenic process are doomed to repeat the failures of the past. © 2018 International Parkinson and Movement Disorder Society.

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Caffeine as symptomatic treatment for Parkinson disease (Café-PD)

Abstract: This study provides Class I evidence that for patients with PD, caffeine does not significantly improve motor manifestations.

Cited by 112 publications

References 28 publications

Metabolomics‐driven identification of adenosine deaminase as therapeutic target in a mouse model of Parkinson's disease

Metabolomics‐driven identification of adenosine deaminase as therapeutic target in a mouse model of Parkinson's disease

The Parkinson’s Disease Mendelian Randomization Research Portal

Disease Modification in Parkinson's Disease: Current Approaches, Challenges, and Future Considerations

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