PLAIN ENGLISH: Gout and the risk of Parkinson's disease in older adults

First blog post of the year from me and, after feedback from literally everyone, I will be making a concerted effort to make them easy (easier) to understand. I can't get rid of the science I'm afraid... after all this is a research blog. But I (and we) can make bigger efforts to keep the focus on predicting Parkinson's, the PREDICT-PD study (predictpd.com) and related projects. 

The reason this blog was started was to help researchers, patients and the public understand how we use and weigh emerging research, which in turn informs our approach to our work on Parkinson's.

Take this study as an example... it looked at health insurance claims data from the USA over a 6 year period. The researchers looked at the link between claims for gout and subsequent claims for Parkinson's. They observed that, compared to people that made claims for other illnesses, people that claimed for gout were more likely to claim for Parkinson's in subsequent years. This in turn offers a weak suggestion that gout might be in some way linked with a higher risk of Parkinson's. However... we also know that this is only part of a much bigger story.

The biggest determinant of gout is the amount of a chemical in the blood known as uric acid. Generally speaking, people with higher levels of uric acid are more likely to have gout. It has also been noted on multiple occasions that people with Parkinson's tend to have lower levels of uric acid (both after diagnosis and in the years before)... which in turn has led to strategies to try and boost uric acid levels to treat Parkinson's (without introducing gout). 

So how does that make any sense at all?? High uric acid is associated with an increase in gout, gout is associated with an increase of Parkinson's, but Parkinson's is associated with low uric acid levels...?? We seem to be going in circles. 

But what if the explanation is simple... what if Parkinson's disease consumes uric acid and makes it look like low levels of uric acid are causing Parkinson's, when in fact it is the other way around? There have been similar examples in cancer where vitamin E was noted to be low in people that had prostate cancer, leading to the suggestion of supplementing vitamin E to reduce cancer. Instead the cancer rates appeared to increase... so it wasn't that low vitamin E was causing cancer... it was cancer consuming vitamin E and supplementing vitamin E only added more fuel to the fire.

If for some reason Parkinson's consumes uric acid, then gout may actually increase the risk of being diagnosed with Parkinson's and strategies to boost uric acid to treat or protect against Parkinson's may not lead to benefit and have the opposite effect...

Of course, this is speculation and certainly not the final say on the matter. Further research will likely reveal the truth over time...

- Alastair Noyce


BMC Neurol. 2019 Jan 5;19(1):4. doi: 10.1186/s12883-018-1234-x.
Singh JA, Cleveland JD.

BACKGROUND: In the presence of limited available data, our objective was to assess the association of gout with the risk of incident Parkinson's disease (PD) in adults 65 years or older.

METHODS: We used the 5% random sample of Medicare claims data from 2006 to 2012 to examine the association of gout with incident PD. The multivariable Cox regression model adjusted for demographics, comorbidity, and common cardiovascular disease and gout medications. We calculated hazard ratios (HR) and 95% confidence interval (CI). Sensitivity analyses adjusted for comorbidity categorically, or individually and for additional cardiovascular comorbidities.

RESULTS: In a cohort study, 1.72 million Medicare beneficiaries were eligible. The mean age was 75 years (standard deviation [SD], 7.6), 58% were female, 86% were White and 37% had Charlson-Romano comorbidity index score of ≥2. We found that 22,636 people developed incident PD, 1129 with gout and 21,507 without gout. The respective crude incidence rates of incident PD were 3.7 vs. 2.2 per 1000 person-years. We found that gout was associated with 1.14-times higher hazard ratio (95% CI, 1.07, 1.21) of PD in the main analysis; findings were confirmed in sensitivity analyses. We noted that the risk differed slightly by age; ages 65-75, 75-85 and > 85 had hazard ratios of incident PD with gout of 1.27 (95% CI, 1.16, 1.39), 1.07 (95% CI, 0.97, 1.16) and 0.97 (95% CI, 0.79, 1.20), respectively, but no gender or race differences were noted.

CONCLUSIONS: Gout was associated with a higher risk of incident PD in older adults, with the risk being significant in the age group 65-75 years. Future studies need to assess the mechanisms of this increased risk.

Gout again.. and is work affected by early Parkinson's?

After my positive blog-post on uric acid a while ago, we have another reminder that unfortunately in research things are often not so simple, especially when moving from observational findings to affecting real-world changes. We are ending the year with another negative trial in Parkinson's - it's recently been announced that the trial of urate-elevating drug Inosine is ending early as the investigators don't believe that the trial will achieve it's stated goal of slowing progression of Parkinson's. Alastair's paper on the causal relationship between urate levels and Parkinson's https://www.ncbi.nlm.nih.gov/pubmed/30014513 gave us a hint that uric acid, while associated with reduced risk, may not be directly causing this - so it's still important to understand more about these relationships and it will be instructive to read about the data that has been collected when this is published next year.

Talking of real-world impact, this interesting paper below explored the very real impact of early symptoms of Parkinson's disease on the workforce. At PREDICT-PD we are fascinated by what happens in the years before diagnosis of Parkinson's - a lot has been published on non-motor symptoms such as constipation, depression and sleep disorders - but not much on how this affects specific activities such as work. They looked at patients with Parkinson's who had to take sick leave and compared them to people who had taken sick leave for other reasons. Those with Parkinson's sick leave were more likely in the preceeding 5 years to have taken sick leave for reasons other than Parkinson's and more likely to have taken sick leave for musculoskeletal issues in particular. Given that the study was only able to look at sick-leave episodes exceeding 14 days, it illustrates the significant impact that these symptoms are having on patients in the early disease and even before diagnosis.

On a more positive note as we look towards the end of the year and Christmas, we are very pleased that recruitment is ramping up for the next stage of the PREDICT-PD project. We are working towards new publications of our own data in the coming months and we'd like to thank all for their ongoing support. If you or any family members are interested, please do have a look on www.predictpd.com.

Reduced workforce participation 5 years prior to first Parkinson’s disease sick-leave 

Jonathan Timpka, Örjan Dahlström, Armin Spreco, Maria H. Nilsson, Susanne Iwarsson, Toomas Timpka & Per Odin
https://www.nature.com/articles/s41531-018-0072-2 

Wishing you all the best over the festive season.

-anna 

  

Why gout might be surprisingly good for the brain

There has been quite a lot of interest in the role of uric acid in Parkinson's Disease. Uric acid is a by-product of normal cell function, and a normal part of urine. In medicine uric acid is well recognised for its role in gout, where high levels in the blood lead to joint swelling and pain.

However, in Parkinson's Disease, uric acid seems to have a protective value. The study I've looked at here took 200 Koreans who had newly been diagnosed with Parkinson's, testing their thought processes as well as smell and uric acid levels in the blood. They found that there was a significant link with uric acid - higher levels were associated with better scores on tests of cognitive function.

from nhsdirect.wales.nhs.uk 

from memorangapp.com

vs

Does this mean that uric acid is somehow neurologically protective? This study looks at one point in time, but in large groups where uric acid has been measured and the participants followed up for diagnosis of Parkinson's, those with higher levels are less likely to go on to develop the disease. Recent findings have suggested that uric acid is particularly associated with those who have cognitive problems, who tend to have more severe disease.

Other possibilities are that there are other factors related to both urate levels and risk of parkinson's - for example diet or smoking, or that lower urate levels could be caused by the disease itself.

However, this is a promising avenue and a good example of how potential treatments can result from studies looking at risk factors. A trial with a drug designed to increase urate levels, Inosine, has so far shown that it is effective and safe, although will require close monitoring for the known side effects of high urate.  I will be particularly interested to see how this drug affects thought processes as it is studied further.

-Anna

 https://www.researchgate.net/publication/328022951_Cognition_Olfaction_and_Uric_Acid_in_Early_de_novo_Parkinson's_Disease

Cognition, Olfaction and Uric Acid in Early de novo Parkinson's Disease.

Lee HR, Park JH, Han SW, Baik JS

OBJECTIVE: Cognitive impairment is one of the nonmotor symptoms in Parkinson's disease (PD), and olfactory dysfunction is used as a marker to detect premotor stages of PD. Serum uric acid (sUA) levels have been found to be a risk factor for PD. Our objective in this study was to examine whether sUA levels are associated with cognitive changes and olfactory dysfunction in early de novo PD patients.

METHODS: The study participants included 196 de novo PD patients. We assessed cognitive function by the Korean versions of the Mini-Mental State Examination and the Montreal Cognitive Assessment and assessed olfactory function by the Korean version of the Sniffin' Sticks test.

RESULTS: The mean sUA level was 4.7 mg/dL and was significantly lower in women than in men. Cognitive scores were lower in women, suggesting that sUA levels were related to cognitive function. The olfactory functions were not related to sUA level but were clearly associated with cognitive scores. Olfactory threshold, odor discrimination, and odor identification were all significantly related to cognitive scores.

CONCLUSION: We conclude that lower sUA levels were associated with cognitive impairment, not olfactory dysfunction, in de novo PD patients. This finding suggests that UA is neuroprotective as an antioxidant in the cognitive function of PD patients.