Wednesday, 30 May 2018

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.


Thursday, 24 May 2018

Public Engagement

I had the great honour and privilege to be asked to speak to the Parkinson’s UK Barnet and Brent Branch last night. This was the second time I have had this opportunity to meet and engage with a wonderful group of people.

At PREDICT-PD we are working tirelessly to understand more of the ‘prodromal’, ‘premotor’ or ‘prediagnostic’ stage of Parkinson’s [these are all largely interchangeable terms for the period where Parkinson’s is present in the brain and causing mild, often non-motor symptoms]. However, there is little public or academic conversation about the public ‘appetite’ for moving the point of diagnosis from where it currently sits.

After a brief introduction to the topic, I sat back down, and picked up my notebook and invited the group to engage in a conversation and share some of their thoughts and experiences. I was humbled by the honesty and candour shown by many people with Parkinson’s and their family members.

Some clear themes came out of our conversation:


  • ·     Receiving a diagnosis of Parkinson’s is a pivotal moment in a person’s life. As clinicians, the way we offer the diagnosis has a deep and lasting impact that will be remembered, not only by the individual, but by their family for decades. I heard some wonderful stories of good practice, where clinicians had taken their time, been thorough and provided a supportive and accurate diagnosis. Others unfortunately had not been so lucky, and had the diagnosis changed many times or left totally unsupported after a brusque diagnosis. I could only apologise for these experiences. I did also reiterate that Parkinson’s is a clinical diagnosis, with no perfect test in life, and the evidence suggests that even the best experts get the diagnosis wrong 15% of the time.
  • ·     So many people last night spoke of the power that comes with acknowledging Parkinson’s, not only to themselves, but to others around them. Telling the ‘tutter’ behind you in the queue at the supermarket that you can’t ‘hurry up’ because you have Parkinson’s changes the shopping trip from being an ordeal to a much more pleasant affair. 
  • ·     Family members (and individuals with Parkinson’s) are often relieved by the diagnosis – at last an explanation for all those symptoms, and “at least it wasn’t something else”
  • ·     When we discussed the benefits and problems with moving the diagnosis earlier in the disease process, there were not many good things to hear. Too many people suffer at workwith changes to their jobs, reduced hours or even face unemployment as a result of the diagnosis. Others struggle to come to terms with the diagnosis for some time and suffer psychologically, which could be worse if there were fewer symptoms to make it ‘real’.
  • ·     However, many saw a positive aspect to learning the diagnosis earlier. This would offer an opportunity start engaging with exercise which has been shown robustly in research and very definitely in the community last night to have a profoundly positive impact on mood, thinking, movement and quality of life. It would also help people make appropriate life decisions, especially regarding work, pension, travel: living the life you want to live regardless of the Parkinson’s.
  • ·     When I asked similar questions but in the context of available treatments that change the course of the condition, the group was unanimous: tell us as early as possible!

We left the meeting on a really positive note. There is much excitement in the academic community about how close we are to having truly disease modifying options in Parkinson’s. The road is long, and we still have much work to do: but we’re getting there. I’m delighted that the group last night shared my optimism and excitement.

I was also delighted to share with them (and you, dear reader) this link to Parkinson's TV - an English language version of the amazing Dutch videos created by Prof Bas Bloem's Parkinson'sNET in the Netherlands. Another example of real partnership between people with Parkinson's, researchers and clinicians - answering the questions you have, as well as some that you didn't know you wanted to have!


RNR

Sunday, 20 May 2018

Plain English - BDNF variant is associated with milder motor symptom severity in early-stage Parkinson's disease

Single nucleotide polymorphisms (also known as SNPs) describe common genetic variation and can be used to tag regions across the human genome. When SNPs tag regions near to known genes they can help give clues as to how that gene might affect a given disease.   

It is interesting that variation at this SNP (called rs6265) is associated with slower progression in Parkinson's disease because it is near to the BDNF gene whose protein product influences the growth of nerve cells. The very same SNP (rs6265) is also associated with an number of the protective factors for Parkinson's such as smoking, body mass index and coffee consumption...

Coincidence... probably not...

- Alastair Noyce

Parkinsonism Relat Disord. 2018 May 9. pii: S1353-8020(18)30232-3. doi: 10.1016/j.parkreldis.2018.05.003. [Epub ahead of print]

Fischer DL, Auinger P, Goudreau JL, Paumier KL, Cole-Strauss A, Kemp CJ, Lipton JW, Sortwell CE.

INTRODUCTION: Parkinson's disease (PD) progression is heterogeneous. Variants in PD-related genes may alter disease progression or severity. We examined if the single nucleotide variant rs6265 in the gene BDNF alters clinical phenotype in early-stage, unmedicated PD.

METHODS: A retrospective analysis was conducted using data collected in the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) study. DNA samples (n = 217) were genotyped for the BDNF rs6265 variant, and the primary endpoint was time to initiate levodopa. The Parkinson's Progression Markers Initiative (PPMI) was used for validation (n = 383).

RESULTS: The primary endpoint of time to initiate levodopa was associated with a delay in subjects with two copies of the rs6265 minor (Met66) allele (HR: 4.9; 95% CI: 1.3-18.8). Secondary endpoints were not different among genotypes. PPMI subjects with two Met66 alleles demonstrated significantly lower total and part III Movement Disorder Society - United Parkinson's Disease Rating Scale (MDS-UPDRS) scores at baseline, as well as more tremor-related symptoms, but not a delay in initiation of maintenance pharmacotherapy.

CONCLUSIONS: Data from two distinct, unmedicated, early-stage PD cohorts suggest that carrying two copies of the rs6265 Met66 allele (∼4% of the population) is associated with less severity in motor symptoms and potentially a slower rate of progression.

Wednesday, 9 May 2018

Plain English - Diabetes mellitus and Parkinson disease

This is the first of our new 'Plain English' blogs on Parkinson's research. We are responding to feedback from people who said that they sometimes find it hard to know who the target audience is for our blogs. Some posts are more understandable than others! So from on the Plain English posts will aim to be just that - understandable.

Below there is an abstract from an an article recently published in Neurology journal, in which the authors explore the relationship between diabetes and Parkinson's. Some previous studies have suggested that people with diabetes are at higher risk of being diagnosed with Parkinson's in the future. But the relationship does not end there... diabetes drugs have recently been shown to be effective in reducing the symptoms of Parkinson's and may even slow down the disease. 

In this article the authors show that people with a diagnosis of diabetes have some similarities to people with Parkinson's. The brain scans of people with diabetes looked similar to people with Parkinson's, and so did the levels of certain proteins in their spinal fluid. Furthermore they show that people with both Parkinson's and diabetes, the movement and memory problems tend to progress faster than in those with just Parkinson's on its own.

Interest in the link between Parkinson's and diabetes in increasing, so these types of study are important in helping us to better understand one affects the other.

- Alastair Noyce

Gennaro Pagano, Sotirios Polychronis, Heather Wilson, Beniamino Giordano, Nicola Ferrara, Flavia Niccolini and Marios Politis
Neurology
First published April 6, 2018
DOI: https://doi.org/10.1212/WNL.0000000000005475

http://n.neurology.org/content/90/19/e1654

Objective
To investigate whether diabetes mellitus is associated with Parkinson-like pathology in people without Parkinson disease and to evaluate the effect of diabetes mellitus on markers of Parkinson pathology and clinical progression in drug-naive patients with early-stage Parkinson disease.

Methods
We compared 25 patients with Parkinson disease and diabetes mellitus to 25 without diabetes mellitus, and 14 patients with diabetes mellitus and no Parkinson disease to 14 healthy controls (people with no diabetes mellitus or Parkinson disease). The clinical diagnosis of diabetes mellitus was confirmed by 2 consecutive fasting measurements of serum glucose levels >126 mL/dL. Over a 36-month follow-up period, we then investigated in the population with Parkinson disease whether the presence of diabetes mellitus was associated with faster motor progression or cognitive decline. 

Results
The presence of diabetes mellitus was associated with higher motor scores (p < 0.01), lower striatal dopamine transporter binding (p < 0.05), and higher tau CSF levels (p < 0.05) in patients with Parkinson disease. In patients with diabetes but without Parkinson disease, the presence of diabetes mellitus was associated with lower striatal dopamine transporter binding (p < 0.05) and higher tau (p < 0.05) and α-synuclein (p < 0.05) CSF levels compared to healthy controls. At the Cox survival analysis in the population of patients with Parkinson disease, the presence of diabetes mellitus was associated with faster motor progression (hazard ratio = 4.521, 95% confidence interval = 1.468–13.926; p < 0.01) and cognitive decline (hazard ratio = 9.314, 95% confidence interval = 1.164–74.519; p < 0.05).

Conclusions
Diabetes mellitus may predispose toward a Parkinson-like pathology, and when present in patients with Parkinson disease, can induce a more aggressive phenotype.




Picture from the Shake It Up Australia Foundation 
https://shakeitup.org.au/diabetes-drug-trial-parkinsons/

Thursday, 26 April 2018

Anti–Tumor Necrosis Factor Therapy and Incidence of Parkinson Disease Among Patients With Inflammatory Bowel Disease

This is a really interesting study. It looks at the relationship between inflammatory bowel disease and Parkinson's disease, which is something I have been wanting to do for sometime. There is lots of seemingly circumstantial evidence linking IBD and PD, including gastrointestinal inflammation, unusual relationships with smoking (for ulcerative colitis) and an association with the LRRK2 gene (for Crohn's disease). Here the authors show an association between PD and all IBD, and between PD and Crohn's disease and ulcerative colitis separately. People with IBD appeared to be at increased risk of PD during follow-up...

Perhaps more intriguing is that fact that they show a reduction in that increased risk if people were treated with drugs targeted against the mechanisms of IBD. Whether this represents a reduction in risk because the IBD is better treated or because the same drugs target a pathway that is important to PD remains to be seen....

Inga Peter, PhD; Marla Dubinsky, MD; Susan Bressman, MD; Andrew Park, PhD, MPH; Changyue Lu, MS; Naijun Chen, MS; Anthony Wang, PhD, MPH

JAMA Neurology 23rd April 2018

https://jamanetwork.com/journals/jamaneurology/fullarticle/2679038

Importance
Despite established genetic and pathophysiologic links between inflammatory bowel disease (IBD) and Parkinson disease (PD), clinical data supporting this association remain scarce. Although systemic inflammation is considered a potential biological mechanism shared between the 2 diseases, the role of reduced systemic inflammation through IBD-directed anti–tumor necrosis factor (anti-TNF) therapy in PD risk is largely unknown.

Objective
To compare the incidence of PD among individuals with or without IBD and to assess whether PD risk among patients with IBD is altered by anti-TNF therapy.

Design, Setting, and Participants 
This is a retrospective cohort study analyzing information in the Truven Health MarketScan administrative claims database and the Medicare Supplemental Database between January 1, 2000, and March 31, 2016. Individuals were selected who had at least 2 claims for IBD diagnoses, at least 6 months of follow-up, and no prior diagnosis of PD on or before the IBD index date. Exposure to Anti-TNF therapy was measured from the anti-TNF index date to the last date of anti-TNF coverage or the end of enrollment or PD index date, whichever was earliest. Incidence rates per 1000 person-years were calculated, and crude and adjusted incidence rate ratios were estimated by Poisson regression models and presented with 95% CIs.

Main Outcomes and Measures 
Incidence of PD among patients with IBD with or without exposure to anti-TNF therapy.

Results
In total, 144 018 individuals with IBD were matched on age, sex, and year of index date with 720 090 unaffected controls. Of them, 1796 individuals had at least 2 PD diagnoses and at least 1 filled PD-related prescription. The mean (SD) age of individuals with IBD was 51 (17) years, and 44% were men. The incidence of PD among patients with IBD was 28% higher than that among unaffected matched controls (adjusted incidence rate ratio, 1.28; 95% CI, 1.14-1.44; P < .001). A 78% reduction in the incidence rate of PD was detected among patients with IBD who were exposed to anti-TNF therapy compared with those who were not exposed (adjusted incidence rate ratio, 0.22; 95% CI, 0.05-0.88; P = .03).

Conclusions and Relevance 
A higher incidence of PD was observed among patients with IBD than among individuals without IBD. Early exposure to antiinflammatory anti-TNF therapy was associated with substantially reduced PD incidence. These findings support a role of systemic inflammation in the pathogenesis of both diseases. Further studies are required to determine whether anti-TNF treatment administered to high-risk individuals may mitigate PD risk.

Tuesday, 17 April 2018

Changing Tack

In a very wide ranging and well written review, two leaders of the Parkinson’s field lay down set the terms of engagement and (to mix my combative metaphors), lay down the gauntlet in the quest to find disease modifying treatments.

After defining three kinds of ‘disease modification’ (neuroprotection: preventing the progression of PD; neurorescue: repairing damaged brain cells; neurorestoration: replacing what has been lost), they provide a brief but comprehensive overview of why every attempt so far has failed, from both a mechanistic perspective as well as a methodological perspective.

The key messages to take from this article are thus:
1.     We really need to stop thinking of Parkinson’s as a single condition. As well as many different ways that people experience their Parkinson’s (the different phenotypes), there are also many different molecular and cellular processes. Each person will likely have a different milieu of process that results in their particular phenotype.
2.     Once we can do this, we can start approaching disease modification in a more personalised way. This means recruiting the people with the right kind of Parkinson’s, at the right time, to the right study. We need to become much more sophisticated in the way we study new treatments, probably recruiting very specific groups of participants, for example people with particular genetic changes related to their Parkinson’s, and testing cocktails of treatments, rather than our current blunderbuss approach.
3.     Given that Parkinson’s is a complex, and slowly progressive condition, we must have better progression markers on which to design our studies.
This is going to require a lot of work, with the Parkinson’s population, scientists, clinicians, and industry. In order to get the highly effective treatments that our oncologists have avaiable to them, we need to change the terms of warfare.

What can we all do in the mean time? Pay attention to these three battles. Not necessarily throw the baby out with the bathwater if a particular study doesn’t prove miraculous (which it almost certainly won’t). And if you have Parkinson’s: exercise more!

At PREDICT-PD towers, we strongly believe that identifying the disease earlier, in the prodromal phase, will bring us closer to many of these objectives. Earlier disease is more likely to be simpler disease; it may be possible to identify early phenotypes that map onto particular pathological pathways; we have an opportunity to identify biomarkers that predict the development of established Parkinson’s, thus giving an ideal method of proving efficacy of new treatments.

RNR

Disease modification in Parkinson's Disease: Current approaches, challenges, and future considerations.

Anthony E Lang and Alberto J Espay.

Mov Disord, 2018 vol. 386 p. 896.

http://doi.wiley.com/10.1002/mds.27360


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 Ca2+ (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.



Friday, 6 April 2018

Costing the earth

We know that Parkinson’s exacts a heavy price. The individual has a raft of motor and non-motor symptoms that significantly reduce their quality of life. Their loved ones share that burden, and research has shown that their quality of life of suffers greatly, too.

To use they hackneyed phrase, “in these times of austerity”, it is vital to legitamise and acount for every penny spent. In order to pursuade people (more explicitly, funders) of the need to provide a service, talking about loss of quality of life is not enough. It all comes down to the ‘bottom line’.

We heartily welcome the comprehensive and up to date analysis of the cost of Parkinson’s in the UK. The authors (including Professor Anette Schrag, one of the leading investigators of the PREDICT-PD study) report the results of a review of UK national GP and health records from 1993 – 2013. They compared the health service use of everyone 30 years or older who were given a new diagnosis of Parkinson’s during this 20-year period, with people of the same age, gender and location (attend the same GP surgery).

Their results are both astounding and unsuprising. GP and hospital care costs £5000 per year on average for people with Parkinson’s, compared to only £2000 per year for the controls. Furthermore, as the condition became more advanced, so did the costs associated with it. These costs were due to GP visits, outpatient hospital visits, inpatient care, A&E attendances and medications.

What this study brings is an up to date assessment of the cost of Parkinson’s. When considering the number of people with the condition is likely to increase, this represents an invaluable method of identifying how crucial it is to provide better, more efficient services to the Parkinson’s community. It also underscores just how important it is to be able to provide a disease modifying treatment, that will reduce the rate of progression to the more advance, more expensive stages of the disease.

What this study was unable to account for is the non-NHS based costs. These have recently been estimated at around £16,500 per person per year: through lost earnings, time off work, and other out-of-pocket expenses (see figure – from Parkinson’s UK). Including all of these brings the average cost of PD for British society to about £25,000 per person per year!


Financial cost of living with Parkinson's including out of pocket expenses

RNR

https://onlinelibrary.wiley.com/doi/pdf/10.1002/mds.

Short- and long-term cost and utilization of health care resources in Parkinson's disease in the UK.

Mov Disord. 2018 Mar 30;12(12):956.

BACKGROUND:There is currently no robust long-term data on costs of treating patients with Parkinson's disease. The objective of this study was to report levels of health care utilization and associated costs in the 10 years after diagnosis among PD patients in the United Kingdom.

METHODS:We undertook a retrospective population-based cohort study using linked data from the UK Clinical Practice Research Datalink and Hospital Episode Statistics databases. Total health care costs of PD patients were compared with those of a control group of patients without PD selected using 1:1 propensity score matching based on age, sex, and comorbidity.

RESULTS:Between 1994 and 2013, 7271 PD patients who met study inclusion criteria were identified in linked Clinical Practice Research Datalink-Hospital Episode Statistics; 7060 were matched with controls. The mean annual health care cost difference (at 2013 costs) between PD patients and controls was £2471 (US$3716) per patient in the first year postdiagnosis (P < 0.001), increasing to £4004 (US$6021) per patient (P < 0.001) 10 years following diagnosis because of higher levels of use across all categories of health care utilization. Costs in patients with markers of advanced PD (ie, presence of levodopa-equivalent daily dose > 1100 mg, dyskinesias, falls, dementia, psychosis, hospital admission primarily due to PD, or nursing home placement) were on average higher by £1069 (US$1608) per patient than those with PD without these markers.


CONCLUSIONS:This study provides comprehensive estimates of health care costs in PD patients based on routinely collected data. Health care costs attributable to PD increase in the year following diagnosis and are higher for patients with indicators of advanced disease. © 2018 International Parkinson and Movement Disorder Society.

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...