PLAIN ENGLISH: Metabolic syndrome and risk of Parkinson disease: A nationwide cohort study

This is a really nice study which looks at the link between the 'metabolic syndrome' and Parkinson's. As the authors describe, the metabolic syndrome is a combination of things that increase the risk of heart disease (among other things) and earlier death... things like higher blood pressure and cholesterol, diabetes, and central obesity. 

The study shows a clear link between each of these things and risk of a future diagnosis of Parkinson's... this is interesting because it might mean that controlling blood pressure and diabetes etc in mid-life might lower risk of Parkinson's in the future.

The big advantages are the size of the study (more than 17 million people), which in turn is a large proportion of the entire population over the age of 40 in South Korea. Another big advantage is that there were relatively few exclusions from the study where data were missing for participants. Both of these facts guard against incorrect results.

However the disadvantages of the study centre on the fact that it does not adequately take account of reverse causation, that is, undiagnosed Parkinson's causing changes in blood pressure, and the risk of high cholesterol, diabetes and obesity. You have to remember that Parkinson's is 'clinical diagnosis' which means that it is made by an expert on the basis of the clinical examination findings. The doctors assessing these patients in routine healthcare settings were not looking for signs of Parkinson's specifically and therefore subtle signs could have easily been missed.

Parkinson's changes in the brain are likely to be happening 5, 10, 15 or more years before that diagnosis is eventually made. This means that event though the authors of this study excluded new case of Parkinson's within 4 years of finding of high blood pressure, high cholesterol, diabetes and obesity, that is probably not a sufficient amount of time. Increasingly sedentary lifestyle in the early and undiagnosed phase of Parkinson's could have resulted in an increased likelihood of some of these factors. 

It is also likely that people with increasing features of the 'metabolic syndrome' are at higher risk of death before they get diagnosed with Parkinson's, which in itself could have resulted in biased results. However, the authors took account of this in one of their analyses and even mentioned that they did this following a comment from someone who reviewed their paper. As a footnote, I have never seen this mentioned in a paper before (that a reviewer asked for something and the authors included it) even though it frequently happens. I think it is great! The peer review process for scientific papers often improves them (sometimes it doesn't !) and we should feel able to acknowledge improvements at every stage before publication...

- Alastair Noyce

Ga Eun Nam, Seon Mee Kim , Kyungdo Han, Nan Hee Kim, Hye Soo Chung, Jin Wook Kim, Byoungduck Han, Sung Jung Cho, Ji Hee Yu, Yong Gyu Park, Kyung Mook Choi  

PLOS Medicine

Published: August 21, 2018

https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002640

Background

The association of metabolic syndrome (MetS) with the development of Parkinson disease (PD) is currently unclear. We sought to determine whether MetS and its components are associated with the risk of incident PD using large-scale cohort data for the whole South Korean population.

Methods and findings

Health checkup data of 17,163,560 individuals aged ≥40 years provided by the National Health Insurance Service (NHIS) of South Korea between January 1, 2009, and December 31, 2012, were included, and participants were followed up until December 31, 2015. The mean follow-up duration was 5.3 years. The hazard ratio (HR) and 95% confidence interval (CI) of PD were estimated using a Cox proportional hazards model adjusted for potential confounders. We identified 44,205 incident PD cases during follow-up. Individuals with MetS (n = 5,848,508) showed an increased risk of PD development compared with individuals without MetS (n = 11,315,052), even after adjusting for potential confounders including age, sex, smoking, alcohol consumption, physical activity, income, body mass index, estimated glomerular filtration rate, and history of stroke (model 3; HR, 95% CI: 1.24, 1.21–1.27). Each MetS component was positively associated with PD risk (HR, 95% CI: 1.13, 1.10–1.16 for abdominal obesity; 1.13, 1.10–1.15 for hypertriglyceridemia; 1.23, 1.20–1.25 for low high-density lipoprotein cholesterol; 1.05, 1.03–1.08 for high blood pressure; 1.21, 1.18–1.23 for hyperglycemia). PD incidence positively correlated with the number of MetS components (log-rank p < 0.001), and we observed a gradual increase in the HR for incident PD with increasing number of components (p < 0.001). A significant interaction between age and MetS on the risk of incident PD was observed (p for interaction < 0.001), and people aged ≥65 years old with MetS showed the highest HR of incident PD of all subgroups compared to those <65 years old without MetS (reference subgroup). Limitations of this study include the possibilities of misdiagnosis of PD and reverse causality.

Conclusions

Our population-based large-scale cohort study suggests that MetS and its components may be risk factors of PD development.

Kaplan–Meier curves of incidence probability of Parkinson disease (PD) for up to 7 years according to the number of metabolic syndrome (MetS) components.

Having an increased number of MetS components was associated with increased risk of PD development during the follow-up period compared to having no components (log-rank p < 0.001).

The Importance of being Picky

This week the UCL Institute of Neurology who ran the randomised trial of the diabetes drug, Exenatide as a disease modifying treatment for Parkinson’s, have published a paper looking at particular groups who may benefit more from the treatment. 

The tenet of clinical trials is that you specify who can enter the trial, and you give one group the intervention (in this case drug) of interest, and you give another group something else (in this case placebo), and see which does better against a pre-specified list of measures. This implies a ‘winner-takes-all’ outcome that is beyond reproach. Either the new drug did better than no drug, or it didn’t – end of discussion. 

This approach is important. New drugs are met with excitement, clinicians want it to work, scientists have often spent years suggesting that it will, and patients are desperate for it to work. Therefore rigid and robust tests with a categorical ‘winner’ help to provide an unbiased outcome.

However, the disadvantage is that the baby can get thrown out with the bathwater. The randomised clinical trial, when done well is a robust and unbiased tool for making a judgement. However, it is not ‘perfect’. No matter how good the design of the study, there will be flaws and biases that are both explicit and hidden, and there is always the issue of ‘generalisability’ – how well the recruited volunteers represent the patient in clinic.

The UCL team have continued to look at the data. For a future trial, are there some people that are likely to do better from this treatment, and are the some people that will never respond. This is key and at the heart of this endeavour is the understanding that a ‘One-size-fits-all’ approach in Parkinson’s will never work.

As Exenatide, and other compounds, are proven to be safe for people with Parkinson’s, great care will need to be taken to ensure that the right people are chosen for trials of effectiveness. This will entail careful analysis and subgroup analyses of early studies.

In this analysis, it seems that people with a shorter duration of disease and less impact of disease (in other words, milder disease) may get more benefit from Exenatide. This fits closely with the hypothesis that lies at the heart of PREDICT-PD: very early identification of Parkinson’s will allow effective disease modification that may be enough to proactively prevent the onset of motor symptoms.

RNR

onlinelibrary.wiley.com/doi/pdf/10.1111/ejn.14096

Athauda D, Maclagan K, Budnik N, Zampedri L, Hibbert S, Aviles-Olmos I, et al. Post hoc analysis of the Exenatide-PD trial - factors that predict response. Eur J Neurosci. 2018 Aug 2.

Exenatide, a glucagon-like peptide-1 agonist and a licensed treatment for Type 2 diabetes significantly reduced deterioration in motor symptoms in patients with Parkinson's disease in a randomised, placebo-controlled trial. Additionally, there were trends favouring the exenatide group in assessments of non-motor symptoms, cognition and quality of life. The aim of this exploratory post-hoc analysis was to generate new hypotheses regarding (1) whether candidate baseline factors might predict the magnitude of response to exenatide and (2) whether the beneficial effects of exenatide reported for the overall population are consistent in various subgroups of patients. Univariate and multivariate analyses were conducted to determine possible predictors of motor response to exenatide in this cohort. Potential treatment by subgroup interactions for changes in; motor severity, non-motor symptoms, cognition and quality of life after 48-weeks treatment with exenatide were evaluated among post-hoc subgroups defined by age, motor phenotype, disease duration, disease severity, BMI and insulin resistance. In the subgroup analyses, exenatide once-weekly was associated with broadly improved outcome measures assessing motor severity, non-motor symptoms, cognition and quality of life across all subgroups, however tremor-dominant phenotype and lower MDS-UPDRS Part-2 scores predicted greatest motor response to exenatide and there was an indication that patients with older age of onset and disease duration over 10 years responded less well. While patients with a range of demographic and clinical factors can potentially benefit from exenatide once-weekly, these data support an emphasis towards recruiting patients at earlier disease in future planned clinical trials of GLP-1 receptor agonists in PD. This article is protected by copyright. All rights reserved.

Plain English - Low body mass index and life prognosis in Parkinson's disease

Over the last few years we have seen research that suggests being underweight has a negative or detrimental effect on survival with diseases like Parkinson's. The same has been shown for motor neurone disease and Alzheimer's. Whether this reflects a more aggressive form of the disease, which in itself also affects weight, or whether being a bit heavier makes you a bit more 'robust' to these diseases remains to be seen. 

In this study the authors show something similar. When they looked backwards in time in a large number of patients with Parkinson's, they saw that those that were underweight had survived for a shorter time than those that were normal weight or over weight. We must be cautious in how we interpret the results because they don't necessarily suggest that being heavier is better and indeed obesity causes an increase in heart and vascular disease, diabetes, and cancer. However it does suggest that being underweight and having Parkinson's is not a good idea either. Aiming for a recommended normal weight and BMI (body mass index) appears to offer the best option considering all outcomes. 

The reason I am particularly interested in this study is because last year we published research showing that higher BMI appears to protect you against Parkinson's. The special thing about the analysis that we did was that it assessed the effect that BMI has on Parkinson's (BMI -> Parkinson's) without being affected by the effect that Parkinson's has on BMI (Parkinson's -> BMI). The method we used was called Mendelian randomisation and it is increasingly used to assess whether risk factors cause a disease as opposed to simply being associated.

The relationship between weight and BMI and Parkinson's disease is complicated and is an important area for further study.

- Alastair Noyce

Parkinsonism Relat Disord. 2018 May 15. pii: S1353-8020(18)30241-4. doi: 10.1016/j.parkreldis.2018.05.011. [Epub ahead of print]
Park K, Oeda T, Kohsaka M, Tomita S, Umemura A, Sawada H.

https://www.prd-journal.com/article/S1353-8020(18)30241-4/fulltext

INTRODUCTION: Patients with Parkinson's disease (PD) frequently lose weight, even in the early stages of the disease. Our objective was to clarify the association between low body mass index (BMI) and life prognosis in PD.

METHODS: We conducted a retrospective cohort study of 651 PD patients (380 females), with a primary endpoint of survival. Because of sex differences in BMI, male and female data were separated. We compared survival times between underweight (BMI < 18.5) and non-underweight (BMI ≥ 18.5) patients and calculated hazard ratios (HRs) adjusted for other relevant factors. To investigate the semi-quantitative relationship between relative risk of death and BMI, we divided patients into lower, middle, and upper thirds of BMI and calculated the HRs of the lower and upper thirds, with reference to the middle third.

RESULTS: Seventy-nine patients (41 females) died over a mean (standard deviation) observation period of 39 (26) months. Underweight patients had poorer life prognosis than non-underweight patients and the difference was larger in males than in females (adjusted HR 3.8 (95% confidence interval 1.9-7.9) in males and 1.8 (0.9-3.5) in females). In males, the relationship between survival and BMI was much poorer in the bottom third and slightly poorer in the top third compared with the middle third. In females, the higher the BMI, the better the survival prognosis; however, the difference was not statistically significant.

CONCLUSION: Low BMI had a significant impact on the life prognosis of PD patients, especially males.