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.

RNR

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.

Food for thought

The race is on, and waiting for the start gun is a loser’s strategy!

At least this is true in the race to beat neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s. Many studies to stop or slow these conditions have failed when they recruit people with established disease. By this point the disease-causing proteins (β-amyloid and tau in the case of Alzheimer’s and α-synuclein in the case of Parkinson’s) are too widespread for benefit to be noticeable. The best metaphor I’ve heard is that it is easier to blow out a match than put out a forest fire.

This week sees the open access publication of a nutritional supplement for prodromal Alzheimer’s disease. Participants were recruited if they fulfilled one of the internationally agreed definitions of Prodromal Alzheimers. To do this they needed some memory impairment that wasn’t severe enough to impact on their daily life, and some other evidence of underlying Alzheimer’s. This could be MRI, amyloid-specific PET scans or spinal fluid findings supportive of Alzheimer’s. Participants either drank a nutritional supplement, that has been designed to give large doses of micronutrients that theoretically counteract some of the damage caused by Alzheimers, or a similar tasting placebo drink. They had neuropsychological assessments at 6 months, 1 year and 2 years from the start.

Unfortunately, this study didn’t reach its primary endpoint of improved composite scores of the neuropsychological testing. However, it also had several secondary outcomes, and they did find that the people taking the supplement had a relative preservation of the hippocampal volume on MRI scans after 2 years compared to those taking placebo. The hippocampus is a brain structure that is central to memory, and is usually found to be shrunken in brain scans of people with Alzheimer’s.

So is this study the death knell for the supplement, especially after studies of its effects in people with established disease also failed to meet their primary target? Well, not necessarily. This study used ‘surrogate outcome measures’. The real question in disease preventing trials is: did the intervention prevent the disease? When dealing with a ‘prodromal’ or ‘prediagnostic’ condition, this might take many years. Clinical trials are incredibily expensive and labour intensive to run and so often use surrogate measures to shorten the duration of the study. This is akin to saying “I can run a mile in 5 minutes, therefore I can run a marathon in 2 hours 10 minutes.” This is misleading, as the two are not necessarily compatible enough to know that performance in one test is indicative of the other. Secondly, the fact that there was less shrinking of a key, and relevant, brain structure suggests that there might be some benefit. There are extension studies that are ongoing and data will be published when those are complete. We eagerly await their results.

As a final thought, this study lends strong support to our endeavours at PREDICT-PD, and those of others around the world. There is a strong desire to get a robust method of diagnosing Parkinson’s. This is not just an abstract academic exercise, but is of key concern to the public and pre-diagnostic states are being carefully examined by industry too. It is essential to bring together all three groups of stakeholders if we are to succeed in our fight against these neurodegenerative diseases.

RNR

http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(17)30332-0/fulltext

Soininen H, Solomon A, Visser PJ, Hendrix SB, Blennow K, Kivipelto M, et al. 24-month intervention with a specific multinutrient in people with prodromal Alzheimer's disease (LipiDiDiet): a randomised, double-blind, controlled trial. The Lancet Neurology. 2017 Dec;16(12):965–75. 

BACKGROUND:Nutrition is an important modifiable risk factor in Alzheimer's disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimer's disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease. Here, we report the 24-month results of the trial.

METHODS:LipiDiDiet was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands, and Sweden), with optional 12-month double-blind extensions. The trial enrolled individuals with prodromal Alzheimer's disease, defined according to the International Working Group (IWG)-1 criteria. Participants were randomly assigned (1:1) to active product (125 mL once-a-day drink containing Fortasyn Connect) or control product. Randomisation was computer-generated centrally in blocks of four, stratified by site. All study personnel and participants were masked to treatment assignment. The primary endpoint was change in a neuropsychological test battery (NTB) score. Analysis was by modified intention to treat. Safety analyses included all participants who consumed at least one study product dose. This trial is registered with the Dutch Trial Register, number NTR1705.

FINDINGS:Between April 20, 2009, and July 3, 2013, 311 of 382 participants screened were randomly assigned to the active group (n=153) or control group (n=158). Mean change in NTB primary endpoint was -0·028 (SD 0·453) in the active group and -0·108 (0·528) in the control group; estimated mean treatment difference was 0·098 (95% CI -0·041 to 0·237; p=0·166). The decline in the control group was less than the prestudy estimate of -0·4 during 24 months. 66 (21%) participants dropped out of the study. Serious adverse events occurred in 34 (22%) participants in the active group and 30 (19%) in control group (p=0·487), none of which were regarded as related to the study intervention.

INTERPRETATION:The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimer's disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed.

FUNDING:European Commission 7th Framework Programme.