Prevalence of Parkinson's disease across North America

This study looks at the current and projected prevalence of Parkinson's in the USA. Although the sources of data vary substantially, the authors do a good job of combining estimates and provide clear discussion for why estimates from some sources may lack precision. This kind of work is essential for planning health care resources, now and in the future. It also puts into sharp focus the increasing burden of disease and what neuroprotective therapies would mean in the fight against the rising tide....

Alastair Noyce

NPJ Parkinsons Dis. 2018 Jul 10;4:21. doi: 10.1038/s41531-018-0058-0. eCollection 2018.
Marras C, Beck JC, Bower JH, Roberts E, Ritz B, Ross GW, Abbott RD, Savica R, Van Den Eeden SK, Willis AW, Tanner CM; Parkinson’s Foundation P4 Group.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039505/

Estimates of the prevalence of Parkinson's disease in North America have varied widely and many estimates are based on small numbers of cases and from small regional subpopulations. We sought to estimate the prevalence of Parkinson's disease in North America by combining data from a multi-study sampling strategy in diverse geographic regions and/or data sources. Five separate cohort studies in California (2), Minnesota (1), Hawaii USA (1), and Ontario, Canada (1) estimated the prevalence of PD from health-care records (3), active ascertainment through facilities, large group, and neurology practices (1), and longitudinal follow-up of a population cohort (1). US Medicare program data provided complementary estimates for the corresponding regions. Using our age- and sex-specific meta-estimates from California, Minnesota, and Ontario and the US population structure from 2010, we estimate the overall prevalence of PD among those aged ≥45 years to be 572 per 100,000 (95% confidence interval 537-614) that there were 680,000 individuals in the US aged ≥45 years with PD in 2010 and that that number will rise to approximately 930,000 in 2020 and 1,238,000 in 2030 based on the US Census Bureau population projections. Regional variations in prevalence were also observed in both the project results and the Medicare-based calculations with which they were compared. The estimates generated by the Hawaiian study were lower across age categories. These estimates can guide health-care planning but should be considered minimum estimates. Some heterogeneity exists that remains to be understood.

Cerebrospinal fluid NFL in the differential diagnosis of parkinsonian disorders: A meta-analysis.

It is no secret that one of the major unmet needs for Parkinson's research is the development of biomarkers that allow us to measure change in the underlying disease process. As clinicians, we are frequently confronted with a patient that has some features of Parkinson's, but the diagnosis cannot be made definitively and they may in fact have a Parkinson's mimic. Neurofilament light chain (NFL) in spinal fluid has been studied in a variety of neurological diseases and when raised is a marker of nerve cell damage... in this meta-analysis NFL is shown to differentiate between Parkinson's and more aggressive Parkinson's mimics. It may aid accurate diagnosis of Parkinson's in the clinical setting. 

Of course we are interested in identifying who might be at risk of Parkinson's and predicting who might go on to get a diagnosis in years to come. NFL could yet be an important marker of nerve cell damage in such people and build confidence in the prediction process... 

Neurosci Lett. 2018 Jul 20;685:35-41. doi: 10.1016/j.neulet.2018.07.030. [Epub ahead of print]
Ge F, Ding J, Liu Y, Lin H, Chang T.

https://www.sciencedirect.com/science/article/abs/pii/S0304394018305032

Abstract

Neurofilament light chain (NFL) in cerebrospinal fluid (CSF) is a promising biomarker candidate which may discriminate atypical parkinsonian disorders (APD), mainly including multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), from Parkinson's disease (PD). We aim to evaluate the diagnostic accuracy of CSF NFL level as a differentiating biomarker between APD and PD. Databases of PubMed, OVID and Web of Science were searched for studies (published until May 31, 2017) that reported on CSF NFL as a diagnostic biomarker between APD and PD. Eight studies were pooled in this meta-analysis, including 341 PD and 396 APD patients and 388 healthy controls. The pooled sensitivity was 82% (95% CI, 68%-91%) and specificity was 85% (95% CI, 79%-89%) in differentiating APD from PD. The pooled positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) were 5.4 (95% CI, 3.6%-8.1%), 0.21 (95% CI, 0.11%-0.40%), and 25 (95% CI, 9%-69%) respectively; and the area under the curve (AUC) was 0.89 (95% CI, 0.86%-0.91%). Subgroup analysis revealed sensitivity and specificity were significantly influenced by study design. The APD subtypes, disease duration and severity were the main heterogeneity sources in specificity. The results of Deeks' test revealed a low risk of publication bias. The CSF NFL level may be used as a biomarker in discriminating APD from PD with high diagnostic accuracy at an early stage of disease. Large and longitudinal studies are still needed on individuals who are suspected to have APD.

Remedies from the natural world

An article caught my eye this week as several comments received on this blog and in clinic relate to ‘natural’ remedies for Parkinson’s. To provide some background, my therapeutic philosophy is a common one: I will only prescribe or endorse treatments that have gone through robust, unbiased, reproducible testing, and where the benefits outweight the risks. I also believe that there are undoubtedly treatments that have the power to radically alter diseases that are under our noses in the natural world, and once they are identified, purified and tested, will revolutionise medicine. Exenatide is a perfect example: originally derived from the saliva of the Gila monster, this is now a powerful drug against diabetes and may even have the ability to halt or slow Parkinson’s. 

This article looks at whether blackberry juice can reduce levodopa-induced dyskinesia. The first thing to point out was that they didn’t test it in humans with Parkinson’s disease, this experiment involved the MPTP mouse model of Parkinson’s. Mice were given the same amount of levodopa and then different groups were given increasing doses of blackberry juice. The good news is that there was some benefit on the extra movements associated with ‘dopamine overdose’. However, this was mainly seen in the 15mL/kg group. To put this into a human context (assuming that it works as well in humans with Parkinson’s as mice with MPTP induced parkinsonism, which is a very  big assumption, a human would have to drink over a litre of pure blackberry juice per day to have less dyskinesia. 

Science is a journey of increments. These positive results may yield a useful weapon for people with Parkinson’s, but plenty of work needs to be done. I highly recommend blackberries, especially ones forraged on a nice walk in the woods, but I wouldn’t suggest they’re going to make your Parkinson’s better just yet.

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Effects of blackberry (Morus nigra) fruit juice on levodopa-induced dyskinesia in a mice model of Parkinson's disease.

Fahimi Z¹, Jahromy MH¹.

J Exp Pharmacol. 2018 Jul 4;10:29-35. doi: 10.2147/JEP.S161782. eCollection 2018.

Abstract

BACKGROUND AND OBJECTIVE: 

Levodopa-induced dyskinesia (LID) is a movement disorder that occurs due to levodopa consumption for a long period to attenuate Parkinsonism. Plants have been the basis for medical treatments in human history and still widely practiced. Blackberry (Morus nigra) is one of the fruits rich in anthocyanin. The present study examined the effect of blackberry fruit juice on LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease in mice.

MATERIALS AND METHODS: 

In this study, 42 male mice were used, which were divided into six groups equally: one control group and five groups receiving MPTP injection. After confirmation of Parkinsonism in MPTP groups, one group was preserved without treatment and four other groups were treated with levodopa (50 mg/kg ip). After the onset of LID (2 weeks), one group was kept without additional treatment and three other groups were treated with three different doses of blackberry fruit juice (5, 10, and 15 mL/kg) with levodopa orally for 7 days. Abnormal involuntary movement scale (AIMS) and cylinder behavioral test were carried out according to the schedule. The collected data were analyzed using the SPSS software with the significant level of P<0.05.

RESULTS: 

Parkinson's disease was confirmed with AIMS test on the fourth day after MPTP injection. The onset of LID was observed after 2 weeks of levodopa treatment using both behavioral tests. The result of administration of M. nigra fruit juice for 1 week showed that this addition is useful in hindering LID. These effects were more pronounced at doses 10 and 15 mL/kg with nearly the same results on attenuating AIMS. Low dose of the fruit juice does not seem to affect LID significantly.

CONCLUSION: 

M. nigra fruit juice is effective to attenuate LID in an MPTP-induced Parkinson mice model.

An early diagnosis is not the same as a timely diagnosis of Parkinson’s disease

We do research to find answers to questions. These can be very practical or extremely esoteric. Both are vitally important – from studies that establish the best treatments for a disease to theoretical mathematics. Some research has immediate practical value, whereas some may not have any known economic benefit for years (for example the computer that I’m writing this on and you’re reading it on could not work without our understanding of quantum mechanics).

So if research can answer the ‘how’ questions, what about the ‘why’ – or even the ‘whether’ questions? These can be the ethical, social and philosophical challenges that cannot be easily answered with a randomised clinical trial, meta-analysis or other statistical constructs, yet must be addressed with almost all research outputs. Dolly the sheep was cloned in 1996 – we can clone a large mammal; but should we? The Manhattan project harnessed the power of the splitting of the atom in the 1940s, but such discoveries have only been used twice in wartime. We have discovered genes that hugely increase one’s risk of certain diseases, like breast or ovarian cancer, that are present from birth – but societies’ current rules exist to prevent testing children for many of these conditions.

We have just published a paper that tries to address some of the ethical and social challenges that affect our work. Parkinson’s remains a progressive disease with no cure, and yet we (and many others around the world) are working hard to make it easier to diagnose Parkinson’s at a much earlier stage. With infections and cancers, the axiom that earlier diagnosis is better for the individual holds as earlier detections leads to earlier treatment which is more likely to result in cure. However, that logical end point does not yet exist in Parkinson’s. Our position is that while research may well provide the tools for earlier diagnosis of Parkinson’s, the physician in clinic should not blindly use those tools, but engage in a dialogue with their decision-making partner – the patient. All medical interventions bring benefit and risk – and the art of medicine is in explaining both and finding the right balance. This is clear with major operations where both parties literally sign on the dotted line that they have discussed and accept the proposed benefits and risks. But the same is true even for making a diagnosis: benefits include knowledge of what is causing distress, discomfort and disease, access to potential treatments and support, planning for one’s future with understanding of how one’s life might change as a result of the condition; but there are risks too – social and personal stigma of disease, higher actuarial risk resulting in more expensive insurance products, fear of effects or side effects that may never happen and many more. Each patient brings their own history, agenda, hopes and fears to the clinic, and a one-size fits all approach cannot be used.

The paper is open access and we would love you to read, share and comment on our article. As Western societies have an increasingly older population, and some data suggesting that Parkinson’s is becoming more common, we all need to grapple with questions like these: who should be diagnosed, when should they be diagnosed, can we afford possible treatments – which risks will we accept and what benefits make those risks worthwhile?

The article can be found here– An early diagnosis is not the same as a timely diagnosis of Parkinson’s disease

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Plain English - LRRK2 G2019S Parkinson's disease with more benign phenotype than idiopathic

This research study compared patients with Parkinson's who carry the commonest gene mutation associated with the disease (called LRRK2), to patients with Parkinson's who do not carry this mutation. They found that on average patients with the mutation tended to have a milder form of Parkinson's (i.e. they had lower motor impairment scores and better scores on memory and other cognitive tests). 

Even though mutations in LRRK2 are the commonest genetic cause of Parkinson's, they are still pretty rare overall and affect about 1% of all patients with Parkinson's. This proportion is higher in North Africans (such as those in this study).

These findings in many ways match ones clinical impression as well. I would say on average patients with LRRK2 Parkinson's tend to have milder symptoms and a lower burden of non motor symptoms. These features may also be less prominent in the phase of the disease before diagnosis compared with Parkinson's that is not related to LRRK2. Of course, this is all 'on average'. On an individual basis it can be very tricky to choose between patients that do or don't have an underlying genetic cause, unless they are particular young when it starts or have a strong family history....

- Alastair Noyce

Acta Neurol Scand. 2018 Jul 10. doi: 10.1111/ane.12996. [Epub ahead of print]
Ben Romdhan S, Farhat N, Nasri A, Lesage S, Hdiji O, Ben Djebara M, Landoulsi Z, Stevanin G, Brice A, Damak M, Gouider R, Mhiri C.

https://onlinelibrary.wiley.com/doi/abs/10.1111/ane.12996

OBJECTIVES: The LRRK2-G2019S mutation is the most common cause of Parkinson's disease (PD) in North Africa. G2019S-PD has been described as similar to idiopathic with minor clinical differences. The aim of this study was to determine the G2019S-related phenotype and to investigate gender and gene dosage effects on clinical features of G2019S carriers.

PATIENTS AND METHODS: The G2019S mutation was screened in 250 Tunisian patients with PD. Twenty-four patients carrying mutations in other PD genes were excluded. Logistic regression models were used to compare clinical features between the studied groups.

RESULTS: G2019S carriers (107 cases) and non-carriers (119 cases) were similar in disease duration, levodopa doses, and gender and phenotype distributions. However, carriers had a younger age at examination, higher level of education, and were more likely to report family history of PD and to develop PD at earlier age (P = 0.017). Adjusted for age, sex, disease duration, levodopa-equivalent dose and educational level, MMSE scores remained significantly higher (adjust P = 0.019) and UPDRS-III scores were lower (adjust P = 0.012) in the G2019S carriers than non-carriers. Demographic characteristics of men and women with G2019S mutation were similar, but men had higher level of education, better cognition (adjust P-value for educational level = 0.042) and less tendency towards depression than females (adjust P = 0.046). Furthermore, PD phenotype did not differ between the homozygous and heterozygous G2019S carriers.

CONCLUSION: In this study, G2019S carriers had a more benign phenotype than non-carriers. Cognitive impairment and depression were less common in G2019S male carriers compared with females. In addition, we found that LRRK2 gene dosage does not influence the severity of PD.