Why aren't you developing a treatment for Parkinson's Disease???

I gave a presentation to my neurology department on PREDICT-PD this week and, in preparation, my unsuspecting partner was put to use as a test audience. His first comment was - "You keep talking about identifying people for future Parkinson's Disease treatments, why aren't you developing a treatment???"

It's a good question, and this recent article, published in Drug Discovery Today, illuminates the issues around drug-development well. It calls for adopting a more human approach to developing treatments, focussing on human cells, tissues and subjects. Levodopa therapy for Parkinson's, which treats the symptoms but not the process that leads to cell damage, was introduced around 50 years ago. It was the result of investigations into the human brain and observations on the side effects of anti-dopaminergic substances. Since then, there has been very little progress in developing treatments which actually prevent the death of brain cells.

This article suggests that a focus on imperfect animal models has delayed progress - for example animal models often don't show the same side effects that humans do. No animal model has exactly the combination of brain damage and progressive symptoms we see with Parkinson's in humans and so promising results in animals have often not translated into humans. They discuss different therapeutic approaches - for example surgical approaches to repairing cells or DNA including stem cell treatments, gene therapy and peptide therapy, suggesting the need to observe results in human cells and tissues. They go on to discuss the use of computer-based techniques to model the potential interactions between new molecules and human systems as well as the detrimental effects of toxic molecules. Finally, they mention the importance of imaging techniques to monitor disease progression before symptoms develop.

The key to the success of all of these techniques is defining the right group of people to give treatments to, before they develop disease. Whilst the PREDICT-PD study may offer new insights into risk factors that could potentially suggest new therapies, it's main role will be in the selection of this group, in whom the benefits of treatment outweigh the risks. So, in a sense we are developing treatments, by playing a role in the bigger picture.

-Anna

https://www.sciencedirect.com/science/article/pii/S1359644618301442#bib1115

Drug Discov Today. 2018 Sep 18. pii: S1359-6446(18)30144-2. doi: 10.1016/j.drudis.2018.09.010. [Epub ahead of print]

Parkinson's disease research: adopting a more human perspective to accelerate advances.
Marshall LJ, Willett C

Parkinson's disease (PD) affects 1% of the population over 60 years old and, with global increases in the aging population, presents huge economic and societal burdens. The etiology of PD remains unknown; most cases are idiopathic, presumed to result from genetic and environmental risk factors. Despite 200 years since the first description of PD, the mechanisms behind initiation and progression of the characteristic neurodegenerative processes are not known. Here, we review progress and limitations of the multiple PD animal models available and identify advances that could be implemented to better understand pathological processes, improve disease outcome, and reduce dependence on animal models. Lessons learned from reducing animal use in PD research could serve as guideposts for wider biomedical research.

Participant article

Today I have the great pleasure in posting an article written by one of our amazing participants. This gentleman has been with us since the beginning of PREDICT-PD. He's come down to London (from the North-East of England) three times for in person and imaging assessments. His involvement has been incredible and a ready reminder to the whole study team how selfless and generous with their time all our participants are.
He has now written an article for the local Parkinson's UK support group newsletter about his experiences with Predict-PD, and the most precious gift he can give in the fight against Parkinson's: his brain.

Here are his own words:

I joined Parkinson’s UK many years ago after my sister, Pat Berry, founder and long-time president of the Scarborough branch, was diagnosed as a sufferer. I was co-opted onto the committee as press and publicity officer, a post I held till after a year after she had to give up the presidency because of failing health.

Around eight years ago I received an email from Predict PD, a research group funded by the Parkinson’s UK. They were seeking people without Parkinsons to sign up for the research project. One of the areas on the research list was for unaffected siblings of people who had Parkinsons. Intrigued I put my name forward and was one of 1,000 people put onto the research list.

Initially it was on-line questionnaires and keyboard tapping tests to check for speed of hand movement.

This was followed up by smell tests, as loss of smell ability is a common feature of Parkinsons. This was conducted by a booklet which I had to scratch and sniff to identify one of the listed items. This was later updated by the sniff booklet but giving the answers on-line.

I was visited here in Scarborough by Dr Alastair Noyce, who headed up the research team, where he conducted tests on memory, movement (including walking and turning while he recorded the result on camera), and nerve reactions.

Subsequently I was asked to go to the University College Hospital, department of nuclear medicine, in London to undergo a DATScan. This meant having a radioisotope injection, and then undergoing a 20 minute head scan by a specialist brain scanner. The isotope lights up the nerve endings under the skull, and the subsequent computer readings show up areas where the nerves have died. This is a useful indicator of confirming whether patients have Parkinson’s or some other brain condition.

This year I was again asked to go to London to the Department of Neurology for further tests. This was an ultrasound scan, performed by Dr Richard Rees, who has now joined the research team. A gel was rubbed on to my left and then right temples and the hand held scanner was then applied to my temples, and the subsequent pictures taken were then downloaded to the computer. At one stage I was able to watch the computer screen and could see my brain and the arteries feeding the blood supply. 

This means that I have now seen my brain in operation and my heart beating when I had two stents fitted in 2005. I feel very privileged to have seeing how my body works.

I then had an MRI scan on a new machine, which has a magnetic strength 60,000 times more than the gravitational pull of the Earth. I was inside this scanner for 50 minutes while the images were taken of my entire brain, again extremely useful in diagnosing Parkinson’s, Alzheimers, dementia, or brain injuries from accidents.

So I then came to a momentous decision. Predict PD now have around two hours of computer images which they can examine and compare to brain scans of Parkinson’s sufferers.

Brain scans and questionnaires are incredibly useful for researchers. However, having the real thing to look at is the only way to unlock the real secrets of the brain, and to allow specialists and tomorrow’s specialists to advance their work in helping patients.

So, though this can be a very private thing which most people would probably not be prepared to talk about, I have signed up that when I die my brain will be donated to the Queen Square Brain Bank for use by the research team. This is a basic pathology procedure that leaves the body with minimal visual damage. The eyes are not removed, and the body can be viewed without anyone knowing that the procedure has taken place.

As I have left instructions that I am to be cremated and my ashes buried in the family plot along with my sister and parents, I decided to make this donation rather than destroy something that could be useful to the research team.

Although at 79 years old, I do not apparently have any detrimental brain conditions, my brain is then useful as a control model which can be used to compare the damaged areas of Parkinson’s sufferers who are under treatment.

I feel an overwhelming aura of peace that part of me will live on after my death and I can continue to be of use to society.

My reason for writing this article is to, hopefully, encourage anyone in the Scarborough Group who is affected by Parkinson’s, to follow me and sign up to Brain donation. After all, it is only by ongoing research that any chance of early detection and prevention of the condition can make effective progress.

Even if only one person joins me in this it will make my decision to go down this route worthwhile.

The Predict PD team is embarking on a further research programme and are currently seeking to recruit 10,000 people without Parkinson’s to extend the research and help find ways of identifying Parkinson’s at the very earliest stages. If you would like to sign up for this the contact is support@predictpd.com

For any member wishing to join me in the Brain Bank donation the contact email for the information details and application form is :  l.haddon@ucl.ac.ukor telephone 02078378370 and ask for Lynn Haddon.

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).

News from the Land of Milk and Honey

I had the good fortune to attend a conference on Precision Medicine and Ageing today. This brought some of the leading scientists from the UK and Israel together, as part of the British Council’s Britain Israel Science and Innovation Network. The day included speakers talking about the latest breakthroughs in genomics, neuroscience, cellular biology and many other fields of scientific endeavour and how they relate to the biology of ageing (in health as well as disease) and how these breakthroughs are bringing us closer to the ‘promised land’ of Personalised, or Precision medicine.

The talk that I found the most interesting came from Dr Maya Leventer-Roberts, from the Clalit Research Institute. This is not a university department, but the in-house research arm of the largest of Israels four health providers. They have an unparallelled treasure-trove of health data. She explained that all Israeli citizens belong to one of these four organisations who provide all aspects of care: GP, pharmacy, testing laboratories, hospitals – you name it. What’s more, very few people change providers, so they have a well-coded database of people’s wellness, illness and health behaviour at all stages of life.

I have since found a paper from last year which uses some of their data to examine a relatively neglected aspect of Parkinson’s – depression. Unfortunatley a huge proportion of people with Parkinson’s struggle with depression. We also know that late onset depression is a risk factor for Parkinson’s. 

In this study, they looked at mortality rates in Parkinson’s and the association with how adherent people were with antidepressents. They analysed the data of 10,000 people with a diagnosis of Parkinson’s as well as at least one prescription of an antidepressant. They then categorised people into how frequently they tookthe antidepressants by comparing their prescriptions from the doctor with the number of purchases of antidepressants from the pharmacies. Finally they looked at death by any cause over the 4 year study period.

They found that the people who had Parkinson’s and depression who took their antidepressants the least were 43% more likely to die within the 4 year period, compared to those who took it the most regularly. The increased mortality was exacerbated by having an increasing number of other medical problems.

I must stress the old adage: association does not equal causation. This kind of retrospective observational study cannot provethat one thing causes another. However, it is an important reminder that depression is an important aspect of Parkinson’s, and that poorly managed depression is associated with increased mortality. It also reminds me that older people, with Parkinson’s, depression and perhaps four or five other medical conditions may be on 15-20 or more tablets a day. What can I do as a clinician to help them remember what each is for, and why each is important to take? What can we do as a society to help people with depression with both drug and non-drug treatment options? How can we better prepare ourselves, individually and societally, for ageing and the only true inevitability of life?

RNR

Shoval G, Stubbs B, Balicer RD, Feldman B, Hoshen M, Zalsman G, et al. 

Low adherence to antidepressants is associated with increased mortality in Parkinson disease patients. 

Parkinsonism Relat Disord. 2017 Oct;43:92–6.

INTRODUCTION:The purpose of this study was to evaluate the relationship between adherence to antidepressants (AD) and all-cause mortality in a population-based cohort of patients with Parkinson's Disease (PD).

METHODS:From a database of more than 4 million people, 8553 patients with PD who purchased an AD at least once between the years 2008-2011 were retrospectively followed for all-cause mortality over 4-years. Adherence was measured as a ratio between dispensed and prescribed durations and was modeled as: non-adherence (<20%, n = 1566), poor (20%-50%, n = 1184), moderate (50%-80%, n = 1584), and good (>80%, n = 4219) adherence. Multivariable survival analyses adjusted for demographic and clinical variables including physical comorbidities known to influence mortality were conducted, however there was no adjustment for other psychiatric disorders and medications.

RESULTS:Unadjusted mortality rates were 20.4%, 25.1%, 23.4% and 25.6% in those classified as non-adherent, poor, moderate and good adherence respectively (χ2 = 18.45, p < 0.0001). The non-adherent and poor adherence groups had significantly increased adjusted mortality hazard ratios (HR) of 1.43 (CI: 1.26-1.62) and 1.26 (CI: 1.1-1.44) respectively compared to the good adherence group. Using the same model, the adjusted HR for death among males was 1.49 [95% CI: 1.36-1.62] compared to females. People with PD and Charslon's Comorbidity Index score of 3-4 (HR 1.3, P < 0.001) and 5+ (HR 1.78, P < 0.001) were more likely to die than those with 0-2 comorbidities.

CONCLUSIONS:Our findings suggest that poor adherence to AD is associated with increased all-cause mortality in people with PD. Given the high prevalence of depression and AD effectiveness, efforts to promote adherence should be prioritized in clinical practice.