Preventive Neurology Unit Showcase

Yesterday alongside the launch of the second phase of PREDICT-PD (a new drive to recruit 10'000 participants to the study!) was the showcase of the Preventive Neurology Unit. The Preventive Neurology Unit is a new and exciting unit that is part of the Wolfson Institute at Queen Mary University London. The Wolfson Institute of Preventive Medicine has a proud history of leading the way in terms of cancer prevention and epidemiology with many high impact publications. Now, thanks to Barts Charity, we are trying to replicate some of the successful preventive techniques used in cancer and apply them to neurological diseases.

The showcase yesterday gave the three senior clinical lecturers the opportunity to explain some of their work and objectives as well as hearing from Professor Jack Cuzick and Professor Gavin Giovannoni about their hopes for this new unit.

The showcase began by Dr Charles Marshall explaining his work regarding the benefits and difficulties of diagnosing Alzheimer's disease as early as possible. Current research suggests that amyloid deposits can begin accumulating in patient's brains up to 20 years before they have any symptoms of dementia. This period before symptoms begin would be the ideal time to intervene with medications to prevent the onset of dementia but unfortunately there is no way to easily identify these people. Dr Marshall explained how the use of 'Brain Stress tests' could help to identify patients before they develop any symptoms of dementia and how his work will use these tests to see if people who will go onto develop Alzheimer's dementia can be identified earlier and therefore start treatments sooner.

Next up was Dr Alastair Noyce who explained the PREDICT-PD project which I am sure most readers of this blog are familiar with. Dr Noyce explained how the project evolved from a keyboard tapping test called the BRAIN test and now has 1000 participants who have been taking part over 5 years and will soon have 10'000 participants! The benefits of this research could be huge if we can begin to identify patients who are highly likely to develop Parkinson's before they suffer from any symptoms then we can begin to start trying to prevent Parkinson's in the first place. Dr Noyce also explained some fascinating results about Exenatide (a diabetes medication) which has recently been shown to potentially have some neuroprotective effect in Parkinson's and could be the first disease modifying medication for Parkinson's disease. Medications such as this would be ideal to use in further studies if PREDICT-PD can successfully identify those at high risk of Parkinson's.

The final talk about preventive approaches to Multiple Sclerosis was delivered by Dr Ruth Dobson. The complex links between EBV, childhood obesity and vitamin D levels were examined. Dr Dobson explained some of the intriguing results regarding EBV infection and Multiple Sclerosis and some of the difficulties of interpreting this relationship. The audience was also fascinated to hear about the links between foetal and neonatal vitamin D levels and MS. The main point that Dr Dobson emphasised is that a preventive approach to MS has to happen much earlier than the couple of years prior to diagnosis; the most important potential modifiable risk factors are all in early childhood or potentially in-utero!

Overall the showcase was very successful and the audience provided lots of insightful questions and interesting discussion. It is an exciting time to be working on preventive approaches to neurological disease and yesterday definitely highlighted that.

Treatable causes of memory problems in Parkinson's?

Following on from Alastair's post about links between metabolic syndrome and risk of Parkinson's disease, I've been reading this study which looks at a concept related to the metabolic syndrome - vascular risk. Here the authors are interested in how risk factors such as high blood pressure, diabetes and body mass affect people in the early stages of Parkinson's and particularly how they relate to the subtle problems with thinking and memory.

They studied 140 people with early-stage Parkinsons and around 60 healthy people of the same age, who were assessed for vascular risk factors and performance on tests of thinking and memory and followed up for 4 years. These patients and healthy subjects all had MRI scans to look for subtle signs of damage to the brain due to problems with blood vessels.

They looked at links between factors such as diabetes and blood pressure, scores on cognitive tests and the number of areas of abnormalities on MRI. Their first important finding was no difference between areas of abnormality on MRI scan between Parkinson's patients and healthy participants. However, in Parkinson's disease but not healthy people, MRI abnormalities were associated with poor performance on memory tests. Furthermore, the risk score was associated with a deterioration in an overall test of mental processes over time.

There are some issues with this study - in traditional statistics, we set a standard of certainty, which allows for a small amount of error. The more experiments you do, the more chance you will make an error and find a positive result by chance. This study looks at many associations, increasing the risk that some results may not be true.

However, it's particularly important to study these associations due to the fact that factors such as blood pressure and diabetes are treatable with current medications. If these factors play any significant role in memory problems in Parkinson's, we will need to look for them and aggressively treat them from early in the disease. We need to build up an evidence basis for this, looking in more detail for example at the level of blood pressure over which treatment will improve outcomes. In the meantime, it's a good reminder for physicians and patients of the multiple additional potential benefits of managing blood pressure, diabetes and weight.

- anna

https://www.ncbi.nlm.nih.gov/pubmed/30169897?log$=activity

Eur J Neurol. 2018 Aug 31. doi: 10.1111/ene.13797. [Epub ahead of print]

Modifiable Vascular Risk Factors, White Matter Disease, and Cognition in Early Parkinson's Disease

Chahine LM, Dos Santos C, Fullard M, Scordia S, Weintraub D, Erus G, Rosenthal L, Davatzikos C, McMillan CT.

Dementia in Parkinson's Disease (PD) is common and disabling. Identification of modifiable risk factors for it is essential. Vascular risk factors may be associated with cognitive decline in early PD. Biomarkers that serve as surrogates of the long-term effect of vascular risk factors on PD are needed. To that end, we aimed to quantitate white matter hyperintensities in early PD, measure associations with vascular risk factors, and examine relationships between white matter hyperintensities and longitudinal cognition.
Participants in the Parkinson Progression Markers Initiative study (141 PD patients, 63 healthy controls) with adequate baseline structural brain MRIs were included. Hypertension and diabetes history, and body mass index, were combined to create a vascular risk score. White matter hyperintensities were quantitated via automated methods. Cognition was assessed annually with a comprehensive test battery.
Vascular risk score was associated with white matter hyperintensities for total brain (β=0.210;p=0.021), total white matter (β=0.214;p=0.013), frontal (β=0.220;p=0.002) and temporal (β=0.212;p=0.002) regions. Annual rate of change in global cognition was greater in those with higher vascular risk score (β=-0.040;p=0.008) and greater white matter hyperintensities (β=-0.029;p=0.049). Higher temporal white matter hyperintensity burden was associated with great decline over time in verbal memory (β=-0.034;p=0.031).
In early PD, modifiable vascular risk factors are associated with white matter hyperintensities on brain MRI. Temporal white matter hyperintensity burden predicts decline in verbal memory. White matter hyperintensities may serve as a surrogate marker for the effect of vascular risk factors on cognitive abilities in PD. This article is protected by copyright. All rights reserved.

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 - Type 2 diabetes linked to higher rate of Parkinson’s

Some of you may have already seen in the newspapers details of our recent study on the link between Type 2 Diabetes and Parkinson's disease... 

In our study, we used the Hospital Episode Statistics database and looked at a very large number of people (2,017,115) with a type 2 diabetes diagnosis during a hospital admission from 1999-2011, excluding people who already had a Parkinson’s diagnosis. We compared them to a group of over 6 million people from the same database without type 2 diabetes. Among the people with diabetes, 14,252 had a diagnosis of Parkinson’s during a later hospital admission, compared with 20,878 in the comparison group. After excluding people with some similar conditions, and controlling for age, sex and region of residence, we found that people with type 2 diabetes were 32 per cent more likely to have a subsequent diagnosis of Parkinson’s. The link was strongest among younger people (aged 25-44), and people with more complications from their diabetes.

Over the years, this link has proved less of a challenge to study and more of a challenge to interpret. For example, whilst most studies done on this subject suggest some sort of link between diabetes and risk of Parkinson's, the curious fact is that some suggest an increased risk of Parkinson's in those with diabetes, and some studies suggest a decreased risk. The difference may be accounted for by the design of the individual studies and requires further exploration. Our study adds to the literature and increases confidence that the association is such that type 2 diabetes increases risk, but whether this is due to common underlying mechanisms of disease or a true causal link between the two remains to be seen.

What is true, is that diabetes drugs may help treat Parkinson's, and we have already seen a great example of this in the last year. Exenetide appears to have a benefit on the symptoms of Parkinson's and furthermore may alter the underlying disease process. But before we can say that definitively, we need further studies.

- Alastair Noyce

Neurology
Eduardo De Pablo-Fernandez, Raph Goldacre, Julia Pakpoor, Alastair J. Noyce, Thomas T. Warner First published June 13, 2018, DOI: https://doi.org/10.1212/WNL.0000000000005771

http://n.neurology.org/content/early/2018/06/13/WNL.0000000000005771

Objective
To investigate the association between type 2 diabetes mellitus (T2DM) and subsequent Parkinson disease (PD). 

Methods
Linked English national Hospital Episode Statistics and mortality data (1999–2011) were used to conduct a retrospective cohort study. A cohort of individuals admitted for hospital care with a coded diagnosis of T2DM was constructed, and compared to a reference cohort. Subsequent PD risk was estimated using Cox regression models. Individuals with a coded diagnosis of cerebrovascular disease, vascular parkinsonism, drug-induced parkinsonism, and normal pressure hydrocephalus were excluded from the analysis.

Results
A total of 2,017,115 individuals entered the T2DM cohort and 6,173,208 entered the reference cohort. There were significantly elevated rates of PD following T2DM (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.29–1.35; p < 0.001). The relative increase was greater in those with complicated T2DM (HR 1.49, 95% CI 1.42–1.56) and when comparing younger individuals (HR 3.81, 95% CI 2.84–5.11 in age group 25–44 years).

Conclusions
We report an increased rate of subsequent PD following T2DM in this large cohort study. These findings may reflect shared genetic predisposition and/or disrupted shared pathogenic pathways with potential clinical and therapeutic implications.