‘Prana’ is a Hindu Sanskrit word meaning “life force”.
An Australian biotech company has chosen this word for their name.
Recently Prana Biotechnology Ltd announced some exciting results from their Parkinson’s disease research programme.
In today’s post we will look at what the company is doing, the science underlying the business plan, and review the results they have so far.
At the end of March, over 3000 researchers in the field of neurodegeneration gathered in the Austrian capital of Vienna for the 13th International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders (also known as ADPD2017).
The Vienna city hall. Source: EUtourists
A lot of interesting new research in the field of Parkinson’s disease was presented at the conference (we will look at some other presentation in future posts), but one was of particular interest to us here at SoPD HQ.
The poster entitled: ‘Abstract: 104 – PBT434 prevents neuronal loss, motor function and cognitive impairment in preclinical models of movement disorders by modulation of intracellular iron’, was presented by Associate Professor David Finkelstein, of the Florey Institute of Neuroscience and Mental Health (Melbourne, Australia).
Unfortunately the ADPD2017 conference’s scientific programme search engine does not allow for individual abstracts to be linked to on the web so if you would like to read the abstract, you will need to click here for the search engine page and search for ‘PBT434’ or ‘Finkelstein’ in the appropriate boxes.
Prof Finkelstein was presenting preclinical research that had been conducted by an Australian biotech company called Prana Biotechnology Ltd.
Source: Prana Biotechnology Ltd
What does the company do?
Prana Biotechnology Ltd has a large portfolio of over 1000 small chemical agents that they have termed ‘MPACs’ (or Metal Protein Attenuating Compounds). These compounds are designed to interrupt the interactions between particular metals and target proteins in the brain. The goal of this interruption is to prevent deterioration of brain cells in neurodegenerative conditions.
For Parkinson’s disease, the company is proposing a particular iron chelator they have called PBT434.
What is an iron chelator?
Iron chelator therapy involves the removal of excess iron from the body with special drugs. Chelate is from the Greek word ‘chela’ meaning “claw”.
Chelator therapy. Source: Stanford
Iron overload in the body is a common medical problem, sometimes arising from disorders of increased iron absorption such as hereditary haemochromatosis. Iron chelator therapy represents one method of reducing the levels of iron in the body.
But why is iron overload a problem?
Iron. Source: GlobalSpec
Good question. It involves the basic properties of iron.
Iron is a chemical element (symbol Fe). It has the atomic number 26 and by mass it is the most common element on Earth (it makes up much of Earth’s outer and inner core). It is absolutely essential for cellular life on this planet as it is involved with the interactions between proteins and enzymes, critical in the transport of oxygen, and required for the regulation of cell growth and differentiation.
So why then – as Rosalind asked in Shakespeare’s As You Like It – “can one desire too much of a good thing?”
Well, if you think back to high school chemistry class you may recall that there are these things called electrons. And if you have a really good memory, you will recall that the chemical hydrogen has one electron, while iron has 26 (hence the atomic number 26).
The electrons of iron and hydrogen. Source: Hypertonicblog
Iron has a really interesting property: it has the ability to either donate or take electrons. And this ability to mediate electron transfer is one of the reasons why iron is so important in the body.
Iron’s ability to donate and accept electrons means that when there is a lot of iron present it can inadvertently cause the production of free radicals. We have previously discussed free radicals (Click here for that post), but basically a free radical is an unstable molecule – unstable because they are missing electrons.
How free radicals and antioxidants work. Source: h2miraclewater
In an unstable format, free radicals bounce all over the place, reacting quickly with other molecules, trying to capture the much needed electron to re-gain stability. Free radicals will literally attack the nearest stable molecule, to steal an electron. This leads to the “attacked” molecule becoming a free radical itself, and thus a chain reaction is started. Inside a living cell this can cause terrible damage, ultimately killing the cell.
Antioxidants can help try and restore the balance, but in the case of iron overload iron doctors will prescribe chelator treatment to deal with the situation more efficiently. By soaking up excess iron, we can limit the amount of damage caused by the surplus of iron.
So what research has been done regarding iron content and the Parkinsonian brain?
Actually, quite a lot.
In 1968, Dr Kenneth Earle used an X-ray based technique to examine the amount of iron in the substantia nigra of people with Parkinson’s disease (Source). The substantial nigra is one of the regions in the brain most badly damaged by the condition – it is where most of the brain’s dopamine neurones resided.
The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp
Earle examined 11 samples and compared them to unknown number of control samples and his results were a little startling:
The concentration of iron in Parkinsonian samples was two times higher than that of the control samples.
Since that first study, approximately 30 investigations have been made into levels of iron in the Parkinsonian brain. Eleven of those studies have replicated the Earle study by looking at postmortem tissue. They have used different techniques and the results have varied somewhat:
- Sofic et al. (1988) 1.8x increase in iron levels
- Dexter et al. (1989) 1.3x increase in iron levels
- Uitti et al. (1989) 1.1x increase in iron levels
- Riederer et al 1989 1.3x increase in iron levels
- Griffiths and Crossman (1993) 2.0x increase in iron levels
- Mann et al. (1994) 1.6x increase in iron levels
- Loeffler et al. (1995) 0.9 (lower)
- Galazka-Friedman et al., 1996 1.0 (no difference)
- Wypijewska et al. (2010) 1.0 (no difference)
- Visanji et al, 2013 1.7x increase in iron levels
Overall, however, there does appear to be a trend in the direction of higher levels of iron in the Parkinsonian brains. A recent meta-analysis of all this data confirmed this assessment as well as noting an increase in the caudate putamen (the region of the brain where the dopamine neuron branches release their dopamine – Click here for that study).
Brain imaging of iron (using transcranial sonography and magnetic resonance imaging (MRI)) has also demonstrated a strong correlation between iron levels in the substantia nigra region and Parkinson’s disease severity/duration (Click here and here to read more on this).
Thus, there appears to be an increase of iron in the regions most affected by Parkinson’s disease and this finding has lead researchers to ask whether reducing this increase in iron may help in the treatment of Parkinson’s disease.
How could iron overload be bad in Parkinson’s disease?
Well in addition to causing the production of free radicals, there are many possible ways in which iron accumulation could be aggravating cell loss in Parkinson’s disease.
Possible causes and consequences of iron overload in Parkinson’s disease. Source: Hindawi
High levels of iron can cause the oxidation of dopamine, which results in the production of hydrogen peroxide (H2O2 – a reactive oxygen species – the stuff that is used to bleach hair and is also used as a propellant in rocketry!). This reaction can cause further oxidative stress that can then lead to a range of consequences including protein misfolding, lipid peroxidation (which can cause the accumulation of the Parkinson’s associated protein alpha synuclein), mitochondrial dysfunction, and activation of immune cells in the brain.
And this is just a taster of the consequences.
Ok, so iron overload is bad, but what was the research presented in Austria?
Title: PBT434 prevents neuronal loss, motor function and cognitive impairment in preclinical models of movement disorders by modulation of intracellular iron
Authors: D. Finkelstein, P. Adlard, E. Gautier, J. Parsons, P. Huggins, K. Barnham, R. Cherny
Location: C01.a Posters – Theme C – Alpha-Synucleinopathies
The researchers at Prana Biotechnology Ltd assessed the potential of one of their candidate drugs, PBT434, in both cell culture and animal models of Parkinson’s disease. The PBT434 drug was selected for further investigation based on its performance in cell culture assays designed to test the inhibition of oxidative stress and iron-mediated aggregation of Parkinson’s associated proteins like alpha synuclein.
PBT434 significantly reduced the accumulation of alpha synuclein and markers of oxidative stress, and prevented neuronal loss.
The investigators also demonstrated that orally administered PBT434 readily crossed the blood brain barrier and entered the brain. In addition the drug was well-tolerated in the experimental animals and improved motor function in toxin-induced (MPTP and 6-hydroxydopamine) and transgenic mouse models of Parkinson’s disease (alpha synuclein -A53T and tau – rTg4510).
Interestingly, PBT434 also demonstrated neuroprotective properties in animal models of multiple systems atrophy (or MSA). Suggesting that perhaps iron chelation could be a broad neuroprotective approach.
The researchers concluded that this preclinical data demonstrates the efficacy of PBT434 as a clinical candidate for Parkinson’s disease. PBT434 shows a strong toxicology profile and favourable therapeutic activity. Prana is preparing its pre-clinical development package for PBT434 to initiate human clinical trials.
Does Prana have any other drugs in clinical trials?
Yes, they do.
Prana Biotechnology has another product called PBT2.
The Alzheimer’s study was called the IMAGINE Trial, but (there is always a ‘but’) recently PBT2 failed to meet its primary endpoint (significantly reducing levels of beta-amyloid – the perceived bad guy in Alzheimer’s disease) in a phase III trial of mild Alzheimer’s disease. PBT2 was, however, shown to be safe and very well tolerated over the 52 week trial, with no difference in the occurrence of adverse events between the placebo and treated groups.
In addition, there was less atrophy (shrinkage) in the brains of those patients treated with PBT2 when compared to control brains, 2.6% and 4.0%, respectively (based on brain imaging). The company is tracking measures of brain volume and cognition in a 12 month extension study. It could be interesting to continue that follow up long term to evaluate the consequences of long term use of this drug on Alzheimer’s disease – even if the effect is minimal, any drug that can slow the disease down is useful and could be used in conjunction with other neuroprotective medications.
For Huntington’s disease, the company is also using the PBT2 drug and this study has had a bit more success. The study, called Reach2HD, was a six month phase II clinical trial in 109 patients with early to mid-stage Huntington’s disease, across 20 sites in the US and Australia. The company was aiming to assess the safety profile of this drug in this particular condition, as well as determining the motor and behavioural benefits.
In the ReachHD study, PBT2 showed signs of improving some aspects of cognitive function in the study, which potentially represents a major event for a disease for which there is very little in the way of medical treatments.
For a full description of the PBT2 trials, see this wikipedia page on the topic.
Is Prana the only research group working on iron chelators technology for Parkinson’s disease?
There is a large EU-based consortium called FAIR PARK II, which is running a five year trial (2015 – 2020) of the iron chelator deferiprone (also known as Ferriprox). The study is a multi-centre, placebo-controlled, randomised clinical trial involving 338 people with recently diagnosed Parkinson’s disease.
The population will be divided into two group (169 subjects each). They will then be assigned either deferiprone (15 mg/kg twice a day) or a placebo. Each subject will be given 9-months of treatment followed by a 1-month post-treatment monitoring period, in order to assess the disease-modifying effect of deferiprone (versus placebo).
Deferiprone. Source: SGPharma
As far as we are aware, this FAIR PARK II clinical trial is still recruiting participants – please click here to read more about this – thus it will most likely be some time before we hear the results of this study.
Are there natural sources of chelators?
Yes there are. In fact, many natural antioxidants exert some chelating activities.
Prominent among the natural sources of chelators: Green tea has components of plant extracts, such as epigallocatechin gallate (EGCG – which we have previously discussed in regards to Parkinson’s disease, click here to read that post) which possess structures which infer metal chelating properties.
As we have said before people, drink more green tea!
Anyone fancy a cuppa? Source: Expertrain
So what does it all mean?
Summing up: We do not know what causes Parkinson’s disease. Most of our experimental treatments are focused on the biological events that occur in the brain around and after the time of diagnosis. These include an apparent accumulation of iron in affected brain regions.
Research groups are currently experimenting with drugs that reduce the levels of iron in the brain as a potential treatment for Parkinson’s disease. Preclinical data certainly look positive. We will now have to wait and see if those results translate into the human.
Previous clinical trials of metal chelators in neurodegeneration have had mixed success in demonstrating positive benefits. It may well be, however, that this treatment approach should be used in conjunction with other neuroprotective approaches – as a supplement. It will be interesting to see how Prana Biotechnology’s drug PBT434 fares in human clinical trials for Parkinson’s disease.
Stay tuned for more on this.
UPDATE – 3rd May 2017
Today the results of a double-blind, phase II clinical trial of iron chelator deferiprone in Parkinson’s disease were published. The results of the study indicate a mildly positive effect (though not statistically significant) after 6 months of daily treatment.
Title: Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease
Authors: Martin-Bastida A, Ward RJ, Newbould R, Piccini P, Sharp D, Kabba C, Patel MC, Spino M, Connelly J, Tricta F, Crichton RR & Dexter DT
Journal: Scientific Reports (2017), 7, 1398.
PMID: 28469157 (This article is OPEN ACCESS if you would like to read it)
In this Phase 2 randomised, double-blinded, placebo controlled clinical trial, the researchers recruited 22 people with early stage Parkinson’s disease (disease duration of less than 5 years; 12 males and 10 females; aged 50–75 years). They were randomly assigned to either a placebo group (8 participants), or one of two deferiprone treated groups: 20 mg/kg per day (7 participants) or 30 mg/kg per day (7 participants). The treatment was two daily oral doses (taken morning and evening), and administered for 6 months with neurological examinations, brain imaging and blood sample collections being conducted at 0, 3 and 6 months.
Deferiprone therapy was well tolerated and brain imaging indicated clearance of iron from various parts of the brain in the treatment group compared to the placebo group. Interestingly, the 30 mg/kg deferiprone treated group demonstrated a trend for improvement in motor-UPDRS scores and quality of life (although this was not statistically significance). The researchers concluded that “more extensive clinical trials into the potential benefits of iron chelation in PD”.
Given the size of the groups (7 people) and the length of the treatment period (only 6 months) in this study it is not really a surprise that the researchers did not see a major effect. That said, it is very intriguing that they did see a trend towards motor score benefits in the 30 mg/kg deferiprone group – remembering that this is a double blind study (so even the investigators were blind as to which group the subjects were in).
We will now wait to see what the FAIR PARK II clinical trial finds.
UPDATE: 28th June 2017
Today, the research that Prana biotechnology Ltd was presenting in Vienna earlier this year was published:
Title: The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease.
Authors: Finkelstein DI, Billings JL, Adlard PA, Ayton S, Sedjahtera A, Masters CL, Wilkins S, Shackleford DM, Charman SA, Bal W, Zawisza IA, Kurowska E, Gundlach AL, Ma S, Bush AI, Hare DJ, Doble PA, Crawford S, Gautier EC, Parsons J, Huggins P, Barnham KJ, Cherny RA.
Journal: Acta Neuropathol Commun. 2017 Jun 28;5(1):53.
PMID: 28659169 (This article is OPEN ACCESS if you would like to read it)
The results suggest that PBT434 is far less potent than deferiprone or deferoxamine at lowering cellular iron levels, but this weakness is compensated by the reduced levels of alpha synuclein accumulation in models of Parkinson’s disease. PBT434 certainly appears to be neuroprotective demonstrating improvements in motor function, neuropathology and biochemical markers of disease state in three different animal models of Parkinson’s disease.
The researchers provide little information as to when the company will be exploring clinical trials for this drug, but in the press release associated with the publication, Dr David Stamler (Prana’s Chief Medical Officer and Senior Vice President, Clinical Development) was quoted saying that they “are eager to begin clinical testing of PBT434”. We’ll keep an eye to the ground for any further news.
FULL DISCLOSURE: Prana Biotechnology Ltd is an Australasian biotechnology company that is publicly listed on the ASX. The information presented here is for educational purposes. Under no circumstances should investment decisions be made based on the information provided here. The SoPD website has no financial or beneficial connection to either company. We have not been approached/contacted by the company to produce this post, nor have we alerted them to its production. We are simply presenting this information here as we thought the science of what the company is doing might be of interest to other readers.
In addition, under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. Metal chelators are clinically available medications, but it is not without side effects (for more on this, see this website). We urge caution and professional consultation before altering a treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.
The banner for today’s post was sourced from Prana
Recently the results of a small clinical study looking at Resveratrol in Alzheimer’s disease were published. Resveratrol has long been touted as a miracle ingredient in red wine, and has shown potential in animal models of Parkinson’s disease, but it has never been clinically tested.
Is it time for a clinical trial?
In today’s post we will review the new clinical results and discuss what they could mean for Parkinson’s disease.
From chemical to wine – Resveratrol. Source: Youtube
In 2006, there was a research article published in the prestigious journal Nature about a chemical called resveratrol that improved the health and survival of mice on a high-calorie diet (Click here for the press release).
Title: Resveratrol improves health and survival of mice on a high-calorie diet.
Authors: Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA.
Journal: Nature. 2006 Nov 16;444(7117):337-42.
PMID: 17086191 (This article is OPEN ACCESS if you would like to read it)
In this study, the investigators placed middle-aged (one-year-old) mice on either a standard diet or a high-calorie diet (with 60% of calories coming from fat). The mice were maintained on this diet for the remainder of their lives. Some of the high-calorie diet mice were also placed on resveratrol (20mg/kg per day).
After 6 months of this treatment, the researchers found that resveratrol increased survival of the mice and insulin sensitivity. Resveratrol treatment also improved mitochondria activity and motor performance in the mice. They saw a clear trend towards increased survival and insulin sensitivity.
The report caused a quite a bit of excitement – suddenly there was the possibility that we could eat anything we wanted and this amazing chemical would safe us from any negative consequences.
That report was proceeded by numerous studies demonstrating that resveratrol could extend the life-span of various micro-organisms, and it was achieving this by activating a family of genes called sirtuins (specifically Sir1 and Sir2) (Click here, here and here for more on this).
Subsequent to these reports, there have been numerous scientific publications suggesting that resveratrol is capable of all manner of biological miracles.
Wow! So what is resveratrol?
Do you prefer your wine in pill form? Source: Patagonia
Resveratrol is a chemical that belongs to a group of compounds called polyphenols. They are believed to act like antioxidants. Numerous plants produce polyphenols in response to injury or when the plant is under attack by pathogens (microbial infections).
Fruit are a particularly good source of resveratrol, particularly the skins of grapes, blueberries, raspberries, mulberries and lingonberries. One issue with fruit as a source of resveratrol, however, is that tests in rodents have shown that less than 5% of the oral dose was observed as free resveratrol in blood plasma (Source). This has lead to the extremely popular idea of taking resveratrol in the form of wine, in the hope that it could have higher bioavailability compared to resveratrol in pill form. Red wines have the highest levels of Resveratrol in their skins (particularly Mabec, Petite Sirah, St. Laurent, and pinot noir). This is because red wine is fermented with grape skins longer than is white wine, thus red wine contains more resveratrol.
EDITOR’S NOTE: Sorry to rain on the parade, but it is important to note here that red wine actually contains only small amounts of resveratrol – less than 3-6 mg per bottle of red wine (750ml). Thus, one would need to drink a great deal of red wine per day to get enough resveratrol (the beneficial effects observed in the mouse study described above required 20mg/kg of resveratrol per day. For a person weighting 80kg, this would equate to 1.6g per day or approximately 250 750ml bottles).
We would like to suggest that consuming red wine would NOT be the most efficient way of absorbing resveratrol. And obviously we DO NOT recommend any readers attempt to drink 250 bottles per day (if that is even possible).
The recommended daily dose of resveratrol should not exceed 250 mg per day over the long term (Source). Resveratrol might increase the risk of bleeding in people with bleeding disorders. And we recommend discussing any change in treatment regimes with your doctor before starting.
So what did they find in the Alzheimer’s clinical study?
Well, the report we will look at today is actually a follow-on to published results from a phase 2/safety clinical trial that were reported in 2015:
Title: A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease.
Authors: Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, Brewer JB, Rissman RA, Raman R, Aisen PS; Alzheimer’s Disease Cooperative Study.
Title: Neurology. 2015 Oct 20;85(16):1383-91.
PMID: 26362286 (This article is OPEN ACCESS if you would like to read it)
The researchers behind the study are associated with the Georgetown research group that conducted the initial Nilotinib clinical study in Parkinson’s disease (Click here for our post on this).
The investigators conducted a randomized, placebo-controlled, double-blind, multi-center phase 2 trial of resveratrol in individuals with mild to moderate Alzheimer disease. The study lasted 52 weeks and involved 119 individuals who were randomly assigned to either placebo or resveratrol 500 mg orally daily treatment.
EDITOR’S NOTE: We appreciate that is daily dose exceeds the recommended daily dose mentioned above, but it is important to remember that the participants involved in this study were being closely monitored by the study investigators.
Brain imaging and samples of cerebrospinal fluid (the liquid within which the brain sits) were collected at the start of the study and after completion of treatment.
The most important result of the study was that resveratrol was safe and well-tolerated. The most common side effect was feeling nausea and diarrhea in approximately 42% of individuals taking resveratrol (curiously 33% of the participants blindly taking the placebo reported the same thing). There was also a weight loss effect between the groups, with the placebo group gaining 0.5kg on average, while the resveratrol treated group lost 1kg on average.
The second important take home message is that resveratrol crossed the blood–brain barrier in humans. The blood brain barrier prevents many compounds from having any effect in the brain, but it does not stop resveratrol.
The investigators initially found no effects of resveratrol treatment in various Alzheimer’s markers in the cerebrospinal fluid. Not did they see any effect in brain scans, cognitive testing, or glucose/insulin metabolism. The authors were cautious about their conclusions based on these results, however, as the study was statistically underpowered (that is to say, there were not enough participants in the various groups) to detect clinical benefits. They recommended a larger study to determine whether resveratrol is actually beneficial.
While exploring the idea of a larger study, the researchers have re-analysed some of the data, and that brings us to the report we want to review today:
Title: Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease.
Authors: Moussa C, Hebron M, Huang X, Ahn J, Rissman RA, Aisen PS, Turner RS.
Journal: J Neuroinflammation. 2017 Jan 3;14(1):1. doi: 10.1186/s12974-016-0779-0.
PMID: 28086917 (This article is OPEN ACCESS if you would like to read it)
In this report, the investigators conducted a retrospective study re-examining the cerebrospinal fluid and blood plasma samples from a subset of subjects involved in the clinical study described above. In this study, they only looked at the subjects who started with very low levels in the cerebrospinal fluid of a protein called Aβ42.
Amyloid beta (or Aβ) is the bad boy/trouble maker of Alzheimer’s disease; considered to be critically involved in the disease. A fragment of this protein (called Aβ42) begin clustering in the brains of people with Alzheimer’s disease and as a result, low levels of Aβ42 in cerebrospinal fluid have been associated with increased risk of Alzheimer’s disease and considered a possible biomarker of the condition (Click here to read more on this).
The resveratrol study investigators collected all of the data from subjects with cerebrospinal fluid levels of Aβ42 less than 600 ng/ml at the start of the study. This selection criteria gave them 19 resveratrol-treated and 19 placebo-treated subjects.
In this subset re-analysis study, resveratrol treatment appears to have slowed the decline in cognitive test scores (the mini-mental status examination), as well as benefiting activities of daily living scores and cerebrospinal fluid levels of Aβ42.
One of the most striking results from this study is the significant decrease observed in the cerebrospinal fluid levels of a protein called Matrix metallopeptidase 9 (or MMP9) after resveratrol treatment. MMP9 is slowly emerged as an important player in several neurodegenerative conditions, including Parkinson’s disease (Click here to read more on this). Thus the decline observed is very interesting.
This re-analysis indicates beneficial effects in some cases of Alzheimer’s as a result of taking resveratrol over 52 weeks. The researchers concluded that the findings of this re-analysis support the idea of a larger follow-up study of resveratrol in people with Alzheimer’s disease.
Ok, but what research has been done on resveratrol in Parkinson’s disease?
Yes, good question.
One of the earliest studies looking at resveratrol in Parkinson’s disease was this one:
Title: Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson’s disease in rats.
Authors: Jin F, Wu Q, Lu YF, Gong QH, Shi JS.
Journal: Eur J Pharmacol. 2008 Dec 14;600(1-3):78-82.
In this study, the researchers used a classical rodent model of Parkinson’s disease (using the neurotoxin 6-OHDA). One week after inducing Parkinson’s disease, the investigators gave the animals either a placebo or resveratrol (at doses of 10, 20 or 40 mg/kg). This treatment regime was given daily for 10 weeks and the animals were examined behaviourally during that time.
The researchers found that resveratrol improved motor performance in the treated animals, with them demonstrating significant results as early as 2 weeks after starting treatment. Resveratrol also reduced signs of cell death in the brain. The investigators concluded that resveratrol exerts a neuroprotective effect in this model of Parkinson’s disease.
Subsequent studies have also looked at what effect resveratrol could be having on the Parkinson’s disease associated protein alpha synuclein, such as this report:
Title: Effect of resveratrol on mitochondrial function: implications in parkin-associated familiarParkinson’s disease.
Authors: Ferretta A, Gaballo A, Tanzarella P, Piccoli C, Capitanio N, Nico B, Annese T, Di Paola M, Dell’aquila C, De Mari M, Ferranini E, Bonifati V, Pacelli C, Cocco T.
Journal: Biochim Biophys Acta. 2014 Jul;1842(7):902-15.
PMID: 24582596 (This article is OPEN ACCESS if you would like to read it)
In this study, the investigators collected skin cells from people with PARK2 associated Parkinson’s disease.
What is PARK2 associated Parkinson’s disease?
There are about 20 genes that have been associated with Parkinson’s disease, and they are referred to as the PARK genes. Approximately 10-20% of people with Parkinson’s disease have a genetic variation in one or more of these PARK genes (we have discussed these before – click here to read that post).
PARK2 is a gene called Parkin. Mutations in Parkin can result in an early-onset form of Parkinson’s disease. The Parkin gene produces a protein which plays an important role in removing old or sick mitochondria.
Hang on a second. Remind me again: what are mitochondria?
We have previously written about mitochondria (click here to read that post). Mitochondria are the power house of each cell. They keep the lights on. Without them, the lights go out and the cell dies.
Mitochondria and their location in the cell. Source: NCBI
You may remember from high school biology class that mitochondria are bean-shaped objects within the cell. They convert energy from food into Adenosine Triphosphate (or ATP). ATP is the fuel which cells run on. Given their critical role in energy supply, mitochondria are plentiful and highly organised within the cell, being moved around to wherever they are needed.
Another Parkinson’s associated protein, Pink1 (which we have discussed before – click here to read that post), binds to dysfunctional mitochondria and then grabs Parkin protein which signals for the mitochondria to be disposed of. This process is an essential part of the cell’s garbage disposal system.
Park2 mutations associated with early onset Parkinson disease cause the old/sick mitochondria are not disposed of correctly and they simply pile up making the cell sick. The researchers that collected the skin cells from people with PARK2 associated Parkinson’s disease found that resveratrol treatment partially rescued the mitochondrial defects in the cells. The results obtained from these skin cells derived from people with early-onset Parkinson’s disease suggest that resveratrol may have potential clinical application.
Thus it would be interesting (and perhaps time) to design a clinical study to test resveratrol in people with PARK2 associated Parkinson’s disease.
So why don’t we have a clinical trial?
Resveratrol is a chemical that falls into the basket of un-patentable drugs. This means that big drug companies are not interested in testing it in an expensive series of clinical trials because they can not guarantee that they will make any money on their investment.
There was, however, a company set up in 2004 by the researchers behind the original resveratrol Nature journal report (discussed at the top of this post). That company was called “Sirtris Pharmaceuticals”.
Sirtris identified compounds that could activate the sirtuins family of genes, and they began testing them. They eventually found a compound called SRT501 which they proposed was more stable and 4 times more potent than resveratrol. The company went public in 2007, and was subsequently bought by the pharmaceutical company GlaxoSmithKline in 2008 for $720 million.
From there, however, the story for SRT501… goes a little off track.
In 2010, GlaxoSmithKline stopped any further development of SRT501, and it is believed that this decision was due to renal problems. Earlier that year the company had suspended a Phase 2 trial of SRT501 in a type of cancer (multiple myeloma) because some participants in the trial developed kidney failure (Click here to read more).
Then in 2013, GlaxoSmithKline shut down Sirtris Pharmaceuticals completely, but indicated that they would be following up on many of Sirtris’s other sirtuins-activating compounds (Click here to read more on this).
Whether any of those compounds are going to be tested on Parkinson’s disease is yet to be determined.
We’ll let you know when we hear of anything.
So what does it all mean?
Summing up: Resveratrol is a chemical found in the skin of grapes and berries, which has been shown to display positive properties in models of neurodegeneration. A recent double blind phase II efficacy trial suggests that resveratrol may be having positive benefits in Alzheimer’s disease.
Preclinical research suggests that resveratrol treatment could also have beneficial effects in Parkinson’s disease. It would be interesting to see what effect resveratrol would have on Parkinson’s disease in a clinical study.
Perhaps we should have a chat to the good folks at ‘CliniCrowd‘ who are investigating Mannitol for Parkinson’s disease (Click here to read more about this). Maybe they would be interested in resveratrol for Parkinson’s disease.
ONE LAST EDITOR’S NOTE: Under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. SoPD can not be held responsible for actions taken based on the information provided here.
The banner for today’s post was sourced from VisitCalifornia
Donating blood helps to save lives. And an awful lot of blood is needed on a daily basis: In the England alone, over 6,000 blood donations are required every day to treat patients.
There has been concerns over the years about what can be transmitted via blood donation (from donor to recipient). The good news is that we now know that Parkinson’s disease is not.
Today’s post looks at recent research investigating this issue and discusses the implications of the findings.
Blood transfusions save lifes. Source: New York Times
The average adult human carries approx. 10 pints (about 6 litres) of blood in his body. So much blood, that we actually have an excess – we can survive with a little less. And this allows us to donate blood to blood banks on a regular basis (approx. every 8 weeks). Roughly 1 pint can be given during each blood donation and our bodies will have no trouble replacing it all.
These donations can be used in blood transfusions, replacing blood that has been lost via accident or during surgical procedures. It may surprise you that blood transfusion (from human to human) has been practised for some time. The very first blood transfusion was performed by an obstetrician named Dr. James Blundell in the late 1820’s.
Dr. James Blundell. Source: Wikpedia
The exact date of that first procedure is the subject of debate, but Blundell wrote up his experience in the journal Lancet in 1829:
Blundell’s article in the journal Lancet. Source: Wikipedia
Since that time, blood transfusions have gradually become an everyday occurrence at hospitals all over the world. And as we suggested above a lot of blood is used on a daily basis, keeping people alive. Determining whether each donation of blood is safe to use is obviously a critical step in this process, and all donated blood is tested for HIV, hepatitis B and C, syphilis and other infectious diseases before it is released to hospitals. But for a long time there has been a lingering concern that not everything is being detected and filtered out.
In fact there has been a serious concern that some neurodegenerative conditions like Alzheimer’s and Parkinson’s disease may be transmissible. If these diseases are being caused by ‘prion-like behaviour’ from the particular proteins involved with these conditions (eg. beta amyloid and alpha synuclein, respectively), then there is a very real possibility that such rogue proteins could be transferred via blood transfusions.
This was a concern (note the past tense) until July of this year when this research report was published (with a rather mis-leading title):
Title: Transmission of neurodegenerative disorders through blood transfusion. A cohort study
Authors: Edgren G, Hjalgrim H, Rostgaard K, Lambert P, Wikman A, Norda R, Titlestad KE, Erikstrup C, Ullum H, Melbye M, Busch MP, Nyrén O.
Journal: Ann Intern Med. 2016 Sep 6;165(5):316-24.
The researchers in this study took all of the data from the enormous nationwide registers of blood transfusions in Sweden and Denmark – collectively almost 1.5 million people have received transfusions in these two countries between 1968 and 2012 – and compared the medical records of the recipients to those of the donors (you have to love the Scandinavians for the medical databases!). Approximately 3% of the recipients received a blood transfusion from a donor who was diagnosed with one of the neurodegenerative diseases included in this study (Alzheimer’s, Parkinson’s and Motor neurone disease (or Amyotrophic lateral sclerosis – ALS). There was absolutely no evidence of transmission of any of these diseases.
For the statistic lovers amongst you, the hazard ratio for dementia in recipients of blood from donors with dementia versus recipients of blood from healthy donors was 1.04 (95% CI, 0.99 to 1.09). Estimates for individual diseases, Alzheimer disease and Parkinson disease were 0.99 (CI, 0.85 to 1.15) and 0.94 (CI, 0.78 to 1.14), respectively.
These statistics mean that if Parkinson’s disease is being transmitted via a blood transfusion, it is an extremely rare event.
So what does this mean for our understanding of Parkinson’s disease?
Well, we already know that you can’t catch Parkinson’s disease from your spouse (Click here to read more on this) and there is a lot of other evidence to suggest that Parkinson’s disease is not contagious (Click here to read more on this). So this is one less thing for carers, family members and friends to worry about.
But if Parkinson’s disease is not caused by some contagious agent, this knowledge has major implications for our understanding of the disease. Previous lab-based research has pointed toward a ‘Prion’-like nature to alpha synuclein (the protein most associated with Parkinson’s disease. Prions being small infectious agents made up entirely of protein material, that can lead to disease that is similar to viral infection. And researchers actually found that if you inject specific types of alpha synuclein into the muscles of mice, those animals would start to develop cell loss in the brain (Click here to read more about this).
If Parkinson’s disease is a ‘prion’ condition, then we have to ask one important question: why isn’t it being transmitted via blood transfusion? Alpha synuclein is certainly found in the blood of people with Parkinson’s disease.
It could be that an infectious agent initiated the condition many years ago and it has very slowly been developing (similar to chronic infections resulting from Hepatitis – click here to read more on this).
Research like we have reviewed today may result in a serious re-think of our theory of Parkinson’s disease.
The banner for today’s post was sourced from CampusCluj
Exciting results published this week regarding a small phase 1b clinical trial of a new treatment for Alzheimer’s disease. In this post, we shall review the findings of the study and consider what they may mean for Parkinson’s disease.
An Alzheimer’s brain scans on the left, compared to a normal brain (right). Source: MedicalExpress
Alzheimer’s disease is the most common neurodegenerative disease, accounting for 60% to 70% of all cases of dementia. It is a progressive neurodegenerative condition, like Parkinson’s disease, affecting approximately 30 million people around the world.
Inside the brain, in addition to cellular loss, Alzheimer’s is characterised by the increasing presence of two features:
- Neurofibrillary tangles
- Amyloid plaques
A schematic demonstrating the difference between healthy and Alzheimer’s affected brains. Source: MmcNeuro
The tangles are aggregations of a protein called ‘Tau’ (we’ll comeback to Tau in a future post). These tangles reside within neurons initially, but as the disease progresses the tangles can be found in the space between cells – believed to be the last remains of a dying cell.
Amyloid plaques are clusters of proteins that outside the cells. A key component of the plaque is beta amyloid. Beta-amyloid is a piece of a larger protein that sits in the outer wall of nerve cells where it has certain functions. In certain circumstances, specific enzymes can cut it off and it floats away.
The releasing of Beta-Amyloid. Source: Wikimedia
Beta-amyloid is a very “sticky” protein and it has been believed that free floating beta-amyloid proteins begin sticking together, gradually building up into the large amyloid plaques. And these large plaques were considered to be involved in the neurodegenerative process of Alzheimer’s disease. Thus, for a long time scientists have attempted to reduce the amount of free-floating beta-amyloid in the brain. One of the main ways they do this is with antibodies.
What are antibodies?
An antibody is the foundation of our immune system. It is a Y-shaped structure, that is used to alert the body when a foreign or unhealthy agent is present.
An artist’s impression of a Y-shaped antibody. Source: Medimmune
Two arms off the Y-shaped antibody have what is called ‘Antigen binding sites‘. An antigen is a molecule that is capable of inducing a response from the immune system (usually a foreign agent, but it can be a sick/dying cell).
A schematic representation of an antibody. Source: Wikipedia
There are currently billions of antibodies in your body -each with specific sets of antigen binding sites – awaiting the presence of their antigen. Antibodies are present in two forms: secreted, free floating antibodies, and membrane-bound antibodies. Secreted antibodies are produced by B-cells, which are part of the immune system. And it’s this secreted form of antibody that modern science has used to produce new medicines.
Really? How does that work?
Scientists can make antibodies in the lab that target specific proteins and then inject those antibodies into a patient’s body and trick the immune system into removing that particular protein. This can be very tricky, and one has to be absolutely sure of the design of the antibody because you do not want any ‘off-target’ effects – the immune system removing a protein that looks very similar to the one you are actually targeting.
These manufactured antibodies are used in many different areas of medicine, particularly cancer (over 40 antibody preparations have been approved by the U.S. Food and Drug Administration for use in humans against cancers). Recently, large pharmaceutical companies (like Biogen) have been attempting to use these manufactured antibodies against other conditions, like Alzheimer’s disease.
Which brings us to the study published this week:
Title: The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease.
Authors: Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O’Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A.
Journal: Nature. 2016 Aug 31;537(7618):50-6.
In this study, the researcher conducted a 12-month, double-blind, placebo-controlled trial of the antibody Aducanumab. This antibody specifically binds to potentially harmful beta-amyloid aggregates (both small and large). At the very start of the trial, each participants was given a brain scan which allowed the researchers to determine the baseline level of beta-amyloid in the brains of the subjects.
All together the study involved 165 people, randomly divided into five different groups: 4 groups received the 4 different concentrations of the drug (1, 3, 6 or 10 mg per kg) and 1 group which received a placebo treatment. Of these, 125 people completed the study which was 12 months long. Each month they received an injection of the respective treatment (remember these are manufactured antibodies, the body can’t make this particular antibody so it has to be repeated injected).
After 12 months of treatment, the subjects in the 3, 6 and 10 mg per kg groups exhibited a significant reduction in the levels of beta-amyloid protein in the brain (according to brain scan images), indicating that Aducanumab – the injected antibody – was doing it’s job. Individuals who received the highest doses of Aducanumab had the biggest reductions in beta-amyloid in the brain. Interestingly, this reduction in beta-amyloid in the brain was accompanied by a slowing of the clinical decline as measured by tests of dementia. Individuals treated with the placebo saw neither any reduction in their brain levels of beta amyloid nor their clinical decline.
The authors considered this study strong justification for larger phase III trials. Two of them are now in progress, with completion dates expected around 2020.
So this is a good thing right?
Yes, this is a very exciting result for the Alzheimer’s community. But the results must be taken with a grain of salt. We have discussed beta-amyloid in a previous post (Click here for that post). While it has long been considered the bad boy of the Alzheimer’s world, the function of beta-amyloid remains the subject of debate. Some researchers worry about the medical removal of it from the brain, especially if it has positive functions like anti-microbial (or disease fighting) properties.
Given that the treatment is given monthly and can thus be controlled, we can sleep easy knowing that disaster won’t befall the patients receiving the antibody. And if they continue to demonstrate a slowing/halting of the disease, it would represent a MASSIVE step forward in the neurodegenerative field. I guess what I am saying is that it is too soon to say. It will be interesting, however, to see what happens as these patients are followed up over time. And the two phase 3 clinical trials currently ongoing, which involve hundreds of participants, will provide a more definitive idea of how well the treatment is working.
So what does this have to do with Parkinson’s disease?
Yeah, so let’s get back to our area of interest: Parkinson’s disease. Biogen is the pharmaceutical company that makes the Alzheimer’s antibody (Aducanumab) discussed above. Biogen is also currently conducting a phase 1 safety trial (on normal healthy adults) of an antibody that targets the Parkinson’s disease associated protein, alpha synuclein. We are currently waiting to hear the results of that trial.
Several other companies have antibody-based approaches for Parkinson’s disease (all of them targeting the protein alpha synuclein). These companies include:
- Prothena – which completed phase 1 safety trials in March 2015 (Click here for more)
- Neuropore – which also completed phase 1 safety trials in March 2015 (Click here for more)
There are some worries regarding this approach, however. For example, alpha synuclein is highly expressed in red blood cells, and some researchers worry about what affects the antibodies may have on their function. In addition, alpha synuclein has been suspected of having anti-viral properties – reducing viruses ability to infect a cell and replicate (click here to read more on this). Thus, removal of alpha synuclein by injecting antibodies may not necessarily be a good thing for the brain’s defense system.
Unlike beta-amyloid, however, most of alpha synuclein’s activities seem to be conducted within the walls of brain cells, where antibodies can’t touch it. Thus the hope is that the only alpha synuclein being affected by the antibody treatment is the variety that is free floating around the brain.
The results of the Alzheimer’s study are a tremendous boost to the antibody approach to treating neurodegenerative diseases and it will be very interesting to watch how this plays out for Parkinson’s disease in the near future.
Watch this space!
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A new study has found traumatic brain injury with loss of consciousness is associated with the risk of Parkinson’s disease, but (interestingly) not Alzheimer’s disease. In this post we will review the study and its findings, before considering the implications of the results.
Image sourced from GQ
There has been a lot of talk on the interweb and various media outlets recently about the long term consequences of head injuries associated with physical sports like boxing, rugby, ice hockey and American football (click here for more on this).
Of particular concern is when individuals lose consciousness at the time of the head injury, which has been associated with worse outcomes than simply suffering a bang on the head.
A group of American researchers recently decided to assess whether there was any association between traumatic head injury with loss of consciousness and the increased risk for Alzheimer’s disease.
What they found may have profound implications for Parkinson’s disease.
Title: Association of Traumatic Brain Injury With Late-Life Neurodegenerative Conditions and Neuropathologic Findings.
Authors: Crane PK, Gibbons LE, Dams-O’Connor K, Trittschuh E, Leverenz JB, Keene CD, Sonnen J, Montine TJ, Bennett DA, Leurgans S, Schneider JA, Larson EB.
Journal: JAMA Neurol. 2016 Jul 11. doi: 10.1001/jamaneurol.2016.1948.
PMID: 27400367 (This study is OPEN ACCESS if you would like to read it)
The researchers collected the results of 3 large studies, collectively involving 7130 participants who had head injury data (2879 men and 4251 women; average age of 79.9 years). Of these 845 had suffered traumatic brain injuries with loss of consciousness for at least 1 hour. Interestingly, the researchers found no statistically significant association between traumatic brain injuries with loss of consciousness and risk of Alzheimer’s disease.
Next they looked at Parkinson’s disease and found that people who suffered traumatic brain injuries with loss of consciousness of more than 1 hour had a statistically significant increase in developing Parkinson’s disease (2-3 times more than normal controls).
Of the 7130 participants in the study, postmortem autopsy analysis reports were available for 1589 of the subjects. The researchers looked for the neuropathological hallmarks of Parkinson’s disease, called Lewy bodies, and they found no correlation between people who suffered traumatic brain injuries with loss of consciousness of less than 1 hour and the presence of Lewy bodies. When they looked in the brains of people who suffered traumatic brain injuries with loss of consciousness of more than 1 hour, they did find a correlation. And importantly these neuropathological events were not associated with genetic mutations.
So what does it all mean?
The results indicate that traumatic brain injuries with loss of consciousness of more than 1 hour could significantly increase a person’s risk of Parkinson’s disease. The crucial detail in the results is the ‘loss of consciousness of more than 1 hour’. Traumatic head injury can often result in disruption to the blood-brain-barrier (the protective film surrounding the brain), which may result in certain pathogens entering the brain. So the more severe the injury, perhaps the longer the barrier is disrupted. Why this event may relate solely to Parkinson’s disease and not Alzheimer’s disease, however, remains to be determined.
It would be interesting to assess how this finding relates to the greater Parkinson’s community. That is to say, determine how many of the people with Parkinson’s disease have a head injury with loss of consciousness in their past medical records?
Reading this study, one cannot help thinking of the recent passing of Boxing great Muhammad Ali. Ali died this year having spent the last third of his life living with Parkinson’s disease. Many boxing careers have probably involved one or two severe head injuries with loss of consciousness, so why are there not more cases of Parkinson’s disease in the boxing community? Many retired boxers suffer from what is called Dementia pugilistica – a neurodegenerative condition with Alzheimer’s-like dementia. Some estimates suggest that 15-20% of boxers may be affected, with symptoms usually starting 12-16 years after the start of a career in boxing. Some very famous boxers have been diagnosed with this condition, including world champions Floyd Patterson, Joe Louis, Sugar Ray Robinson and boxer/coach Freddie Roach.
The difference between the results of today’s study and dementia pugilistica may lie in the repeated nature of the injuries in boxers and the length of time individuals were unconscious. It will be interesting to see what becomes of this research.
The banner for today’s post was sourced from the Huffington Post
This week an interesting new study dealing with the biology of Alzheimer’s was published in the journal Science Translational Medicine. It has drawn a lot of attention as it may be turning our understanding of Alzheimer’s disease on it’s head. If the results are independently replicated and verified, it could potentially have major implications for Parkinson’s disease.
For the last 30 years, a protein called beta-amyloid has been considered one of the bad boys of the most common neurodegenerative condition, Alzheimer’s disease.
What is Alzheimer’s disease?
Alzheimer’s disease is a progressive neurodegenerative condition that can occur in middle or old age. It involves a generalized degeneration of the brain, not localised to specific regions like Parkinson’s disease.
What happens in the Alzheimer’s brain?
In the brain, in addition to cellular loss, Alzheimer’s is characterised by the presence of two features:
- Neurofibrillary tangles
- Amyloid plaques
The tangles are aggregations of a protein called ‘Tau’ (we’ll comeback to Tau in a future post). These tangles reside within neurons initially, but as the disease progresses the tangles can be found in the space between cells – believed to be the last remains of a dying cell.
A normal brain vs an Alzheimer’s affected brain. Source: MMCNeuro
Amyloid plaques are clusters of proteins that sit between cells. A key component of the plaque is beta amyloid. Beta-amyloid is a piece of a larger protein that sits in the outer wall of nerve cells where it has certain functions. In certain circumstances, specific enzymes can cut it off and it floats away.
Beta-Amyloid. Source: Wikimedia
Beta-amyloid is a very “sticky” protein and for a long time it has been believed that free floating beta-amyloid proteins begin sticking together, gradually building up into the large amyloid plaques. And these large plaques were considered to be involved in the neurodegenerative process of Alzheimer’s disease.
So what was discovered this week?
This week a study was published that suggests a new (and positive) function for beta amyloid:
Title: Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease.
Authors: Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE, Moir RD.
Journal: Sci Transl Med. 2016 May 25;8(340):340ra72.
The researchers took three types of mice:
- genetically normal mice
- mice with no beta amyloid
- mice producing a lot of beta amyloid
They infected all of the mice with the microbe that causes meningitis, and they found that the mice producing a lot of beta amyloid lived significantly longer than other groups of mice. They then repeated the experiment in a species of microscopic worm – called C.elegans – and found similar results. These findings suggested that beta amyloid was having a positive effect in the brain.
But then they noticed something strange.
The mice producing a lot of beta amyloid usually do not develop a lot of protein aggregation until old age, but when the researchers looked in the brains of the mice they infected with meningitis, they found significant levels of aggregation in the mice producing a lot of beta amyloid but at a young age..
This led the researchers to conduct some cell culture experiments in which they watched what was happening to the bacteria and beta amyloid. They found that the beta amyloid was sticking to the bacteria and this was leading to the formation of protein aggregates.
The results of these experiments suggested to the researchers an intriguing possibility that beta amyloid may be playing a protective in the brain – acting as an immune system for the brain – against infection.
Thus the aggregations we see in the brains of people with Alzheimer’s may not be the cause of the cell death associated with the disease, but rather evidence of the ‘brain’s immune system’ trying to fight back against unknown infectious agents. The researcher’s of the study were quick to point out that this antimicrobial action of beta amyloid is simply a new function of the protein, and it may have nothing to do with the disease itself. But it will be interesting to see where this research goes next.
What has this got to do with Parkinson’s disease?
Parkinson’s disease is only definitive diagnosed at the postmortem stage. This is done by microscopic examination of the brain. In the brains of people with Parkinson’s disease, there are protein aggregates calls Lewy bodies. These are densely packed clusters of a protein called ‘alpha synuclein‘.
The brown spot is a Lewy body inside of a brain cell. Source: Cure Dementia
If the results of the study presented above are correct and beta amyloid is a protective protein in the brain against infection, could it not be that alpha synuclein may be playing a similar role? It is a fascinating idea that it will be interesting to test.
What are the implications of the study?
Currently, there are numerous clinical trials for Alzheimer’s disease, involving treatments that act against beta amyloid. If the study presented above is correct, and beta amyloid has a role in protecting the brain, these new treatments in clinical trial may actually be weakening the brain’s ability to fight infection.
Similarly, if alpha synuclein is found to exhibit ‘protective’ properties like beta amyloid, then the alpha synuclein vaccine clinical trials currently underway (in which the body’s immune system is primed to remove free floating alpha synuclein, in an attempt to stop the disease from spreading) may need to be reconsidered. At a minimum, investigations into whether alpha synuclein has antimicrobial properties need to be conducted.
Today’s banner was sourced from PBS.
If I were to tell you that there exists a miraculous elixir derived from the saliva of a monster and it may aid us in the treatment of Parkinson’s disease, would you think me mad?
In 1974, a small study was published in the Journal of Chronic Diseases that presented a rather startling set of results:
In the study, Lipman and colleagues conducted some routine glucose tolerance tests on a group of 56 people with Parkinson’s Disease (7 additional subjects with Parkinson’s were excluded because they had been previously diagnosed with diabetes).
After being asked to fast overnight, the subjects were then given 100g of glucose and blood samples were collected from them every hour for 3 hours. When the glucose levels in the blood were measured and compared with the results of 5 previous studies conducted on normal healthy adults of the same age (one of those studies involved 7000 participants), it was found that the people with Parkinson’s disease in the Lipman study had a much higher average level of glucose in their blood than all of the other 5 studies looking at healthy individuals.
Shockingly, almost half (46.4%) of the participants in the Lipman study actually fulfilled the criteria for a diagnosis of diabetes.
More recent survey data has revealed that diabetes is established in between 8–30% of people with Parkinson’s disease (click here for more on this) – obviously this is in excess of the approximately 6% prevalence rate in the general public (Source: DiabetesUK).
What is diabetes?
‘Diabetes mellitus’ is what we commonly refer to as diabetes. It is basically a group of metabolic diseases that share a common feature: high blood sugar (glucose) levels for a prolonged period.
There are three types of diabetes:
- Type 1, which involves the pancreas being unable to generate enough insulin. This is usually an early onset condition (during childhood) and is controlled with daily injections of insulin.
- Type 2, which begins with cells failing to respond to insulin. This is a late/adult onset version of diabetes that is caused by excess weight and lack of exercise.
- Type 3, occurs during 2-10% of all pregnancies, and is transient except in 5-10% of cases.
What is this stuff called insulin?
Insulin is a hormone – that our body makes – which allows us to use sugar (glucose) from the food that you eat. Glucose is a great source of energy. After eating, our body is releases insulin which then attaches to cells and signals to those cells to absorb the sugar from our bloodstream. Without insulin, our cells have a hard time absorbing glucose. Think of insulin as a “key” which unlocks cells to allow sugar to enter the cell.
Ok, so how is it all connected to Parkinson’s disease?
The short answer is ‘we currently don’t know’.
There have, however, been numerous studies now that suggest an association between diabetes and Parkinson’s disease. The first of these studies was:
Title: Prospective cohort study of type 2 diabetes and the risk of Parkinson’s disease.
Authors: Driver JA, Smith A, Buring JE, Gaziano JM, Kurth T, Logroscino G.
Journal: Diabetes Care. 2008 Oct;31(10):2003-5.
In this study, 21,841 male doctors (participants in the Physicians’ Health Study) were followed over 23 years. The researchers found that people with diabetes had an increased risk of developing Parkinson’s disease risk. Interestingly they reported that the highest Parkinson’s disease risk was seen in individuals with short-duration, older-onset diabetes.
In another study:
Title: Diabetes and risk of Parkinson’s disease.
Authors: Xu Q, Park Y, Huang X, Hollenbeck A, Blair A, Schatzkin A, Chen H.
Journal: Diabetes Care. 2011 Apr;34(4):910-5. doi: 10.2337/dc10-1922. Epub 2011 Mar 4.
This study came from another long term study, which was following 288,662 participants of the National Institutes of Health-AARP Diet and Health Study. The researchers found that the risk of Parkinson’s disease was approximately 40% higher among diabetic patients than among participants without diabetes. In this study, however, the analysis showed that the risk was largely limited to individuals who had diabetes for more than 10 years.
A third study:
Title: Diabetes and the risk of developing Parkinson’s disease in Denmark.
Authors: Schernhammer E, Hansen J, Rugbjerg K, Wermuth L, Ritz B.
Title: Diabetes Care. 2011 May;34(5):1102-8.
Using data from the nationwide Danish Hospital Register hospital records, the researchers found that having diabetes was associated with a 36% increased risk of developing Parkinson’s disease. Interestingly, they reported that the risk was stronger in women and patients with early-onset Parkinson’s disease (eg. diagnosed before the age of 60 years).
EDITORIAL NOTE HERE: It is important to understand that these studies do not suggest that having diabetes will naturally lead to Parkinson’s disease. They are simply pointing out that diabetics have an increased risk of developing the condition. We present this data here for informative purposes and to make people aware.
It is of interest to note that there is also an association between diabetes and Alzheimer’s disease (click here and here for more on this). Thus Parkinson’s disease is not the only neurodegenerative condition associated with diabetes.
Is the association between Parkinson’s disease and diabetes genetic?
At present, the answer is no.
The connection between diabetes and Parkinson’s disease does not appear to be genetic, as genome wide sequencing studies have found no common mutations or associations between the two conditions (click here for more on this).
So what are we doing with this knowledge?
This is the Gila monster (Source: Californiaherps).
Named after the Gila River Basin of New Mexico and Arizona, where these lizards are found found, the saliva of the Gila monster was found to have some rather amazing properties with regards to the management of type 2 diabetes. This was due largely to a protein extracted from the saliva, called exendin-4. Scientists have made a synthetic version of exendin-4 which they have called Exenatide.
When tested in a three year clinical trial, Exenatide was found to return people with type 2 diabetes to healthy sustained glucose levels and progressive weight loss.
Exenatide is a glucagon-like peptide-1 (GLP-1) agonist. These types of drugs work by mimicking the functions of the natural hormones in your body that help to lower blood sugar levels after meals. They do this by aiding the release of insulin from the pancreas, blocking a hormone that causes the liver to release its stored sugar into the bloodstream, and slowing glucose absorption into the bloodstream.
Great, but what has this got to do with Parkinson’s disease?!?
Exenatide has also been found to have impressive results in both animal models of Parkinson’s disease and in an open-label clinical trial.
The first study to report a positive effect of Exenatide in a Parkinson’s disease model was:
Title: Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease.
Authors: Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, Kortesmaa J, Mercer A, Nielsen E, Rönnholm H, Wikström L.
Journal: J Neurosci Res. 2008 Feb 1;86(2):326-38.
In this study, the scientists found that exendin-4 (aka Exenatide) improved both behavioural motor ability and protected dopamine neurons in a rodent model of Parkinson’s disease (and the drug was given 5 weeks after the animals developed the motor features). How these results were achieved – the biology behind the results – is unclear, but the effect was interesting enough to encourage other groups to also test Exenatide and they found similar results:
Title: Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson’s disease.
Authors: Harkavyi A, Abuirmeileh A, Lever R, Kingsbury AE, Biggs CS, Whitton PS.
Journal: J Neuroinflammation. 2008 May 21;5:19. doi: 10.1186/1742-2094-5-19.
PMID: 18492290 (This study is OPEN ACCESS if you would like to read it)
The scientists in this study tested exendin-4 (aka Exenatide) on two different rodent models of Parkinson’s disease and they found similar results to the previous study. The drug was given 1 week after the animals developed the motor features, but still positive effects were observed.
These (and other) initial results led to the initiation of a clinical trial. Given that Exenatide is already approved for use with diabetes, testing the drug in Parkinson’s disease was a relatively straightforward process (funded by the Cure Parkinson’s Trust).
Title: Exenatide and the treatment of patients with Parkinson’s disease.
Authors: Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, Whitton P, Wyse R, Isaacs T, Lees A, Limousin P, Foltynie T.
Journal: J Clin Invest. 2013 Jun;123(6):2730-6.
PMID: 23728174 (This study is OPEN ACCESS if you would like to read it)
The researchers running the clinical study gave Exenatide to a group of 21 patients with moderate Parkinson’s disease and evaluated their progress over a 14 month period (comparing them to 24 control subjects with Parkinson’s disease). Exenatide was well tolerated by the participants, although there was some weight loss reported amongst many of the subjects (one subject could not complete the study due to weight loss). Importantly, Exenatide-treated patients demonstrated improvements in their clinician assessed PD ratings, while the control patients continued to decline.
Importantly, in a two year follow up study – this was 12 months after the patients stopped receiving Exenatide – the researchers found that patients previously exposed to Exenatide demonstrated a significant improvement (based on a blind assessment) in their motor features when compared to the control subjects involved in the study.
The results of this initial clinical study are intriguing and exciting, but it is important to remember that the study was open-label: the subjects knew that they were receiving the drug. This means that we can not discount the placebo effect causing some of the beneficial effects reported.
We look forward to reading the results of that trial.
And Exenatide is not the only diabetes drug being tested
Pioglitazone is another licensed diabetes drug that is now being tested in Parkinson’s disease. It reduces insulin resistance by increasing the sensitivity of cells to insulin. Pioglitazone has been shown to offer protection in animal models of Parkinson’s disease (click here and here for more on this). And the drug is currently being tested in a clinical trial.
We look forward to reading these results as well.
As with melanoma and red hair, there appears to be a curious connection between diabetes and Parkinson’s disease. Large longitudinal studies point to people with diabetes as having a higher risk of Parkinson’s disease than non-diabetic individuals. Why this is remains unclear, but some of the drugs used for treating diabetes may provide novel therapeutic options in the treatment of Parkinson’s disease. We will continue to follow this research and report results as they come to hand.
And you didn’t believe me about the monster saliva!
There was an interesting new study published yesterday:
Title: Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns.
Author: Sanchez-Mut JV, Heyn H, Vidal E, Moran S, Sayols S, Delgado-Morales R, Schultz MD, Ansoleaga B, Garcia-Esparcia P, Pons-Espinal M, de Lagran MM, Dopazo J, Rabano A, Avila J, Dierssen M, Lott I, Ferrer I, Ecker JR, Esteller M.
Journal: Transl Psychiatry. 2016 Jan 19;6:e718. doi: 10.1038/tp.2015.214.
PMID: 26784972 – this article is OPEN ACCESS if you would like to read it.
The researchers were curious to look for common genetic markers between the major neurodegenerative disease. It is often forgotten that the different neurodegenerative conditions, such as Alzheimer’s disease and Parkinson’s disease, share some common pathological features (the characteristic signs of the diseases in the brain).
For example, when you look at the brains of people with Alzheimer’s disease, approximately 50% of them will also have the alpha-synuclein-containing ‘Lewy bodies’ in their brains, which are more commonly associated with Parkinson’s disease. Likewise, Beta-amyloid plaques and neurotangles, which are characteristic features of Alzheimer’s disease are commonly found in Parkinson’s disease brains (click here and click here for more on this topic).
To find these shared genetic markers, the researcher extracted DNA from the prefrontal cortex (Brodmann area 9) of the brains of people with Alzheimer’s disease, dementia with Lewy bodies, Parkinson’s disease and Alzheimer-like neurodegenerative profile associated with Down’s syndrome samples (more than 75 percent of people with Down Syndrome aged 65 and older develop Alzheimer’s disease – click here for more on this).
Importantly, the researchers were looking at DNA methylation, which is a commonly used tool that allows a cell to fix genes in the “off” position. That is to say, the gene can not be activated. Thus the researchers were looking for regions of DNA that have to closed down.
They found that a very defined set of genes are turned off in these neurodegenerative disorders, suggesting that these condition might have similar underlying mechanisms or processes that subsequently develop into different clinical entities. These newly identified regions of DNA methylation will be further investigated with the goal that one day they may be used as biomarkers in diagnosis and also as potential new targets for the regenerative therapies.
It all began with a 51 year old woman named Auguste Deter.
Auguste Deter. Source: Wikipedia
She was admitted by her husband to the Institution for the Mentally Ill and for Epileptics in Frankfurt, Germany on the 25th November, 1901. Her husband complained that she suffering memory loss and having delusions.
The attending doctor was Dr Alois Alzheimer.
Over the next year, Alois continued to examine Auguste – and what he began calling the “Disease of Forgetfulness” – until he left the institute to take up a position in Munich. He made regular visits back to Frankfurt, however, to follow up on Auguste.
Auguste dies on the 8th April, 1906. She had become completely demented and had existed in a vegatative state. When he examined the brain, Alois found the hall marks of what we today call ‘Alzheimer’s disease’ (namely neurofibrillary tangles and plaques).
Now, almost 110 years later, Alzheimer’s disease is the most common neurodegenerative condition – Parkinson’s disease is the second most common. Alzheimer’s affects 850,000 people in the UK alone (Source: Alzheimer’s Society). Huge efforts have been made in researching this condition and last week some interesting new data was published about the disease that may also have implications for Parkinson’s disease.
Title: Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy.
Authors: Jaunmuktane Z, Mead S, Ellis M, Wadsworth JD, Nicoll AJ, Kenny J, Launchbury F, Linehan J, Richard-Loendt A, Walker AS, Rudge P, Collinge J, Brandner S.
Journal: Nature. 2015 Sep 10;525(7568):247-50.
Published in the prestigious science journal, Nature, the article found signs of Alzheimer’s disease in the autopsied brains of people who had died from Creutzfeldt-Jakob disease (CJD) – the prion induced neurodegenerative condition.
What’s a prion?
Good question! A prion is a small infectious particle – usually composed of an abnormally-folded version of a normal bodily protein – that causes progressive neurodegenerative conditions. The first prion discovered in mammals was Prion protein (PRP): this is the prion that causes CJD.
PrP is considered the only known prion in mammals, but recently other proteins have exhibited prion-like behaviour. One such protein is Amyloid-β protein – the protein that is found clustered in clumps in the brains of people with Alzheimer’s disease.
The brains that were analysed in the study from the journal Nature were collected at death from people who had received human growth-hormone earlier in their lives. The growth-hormone had been extracted from human cadavers and it was injected into people with growth problems (this was a common practise during the 1950s to mid 1980s). Unfortunately, some of the growth-hormone appears to have been contaminated with PrP (possibly one of the cadavers used had undiagnosed CJD) and numerous people were injected with it (65 cases in Britain alone). Many of these individuals have been followed and we have learned a great deal from them regarding CJD. Some of these individuals have also donated their brains to science and it was some of these brains that were analysed in the study being discussed here.
What the authors of the study were expecting to see when they analysed these brains was lots of clusters of PrP. What the authors were not expecting to see was the clustering of Amyloid-β protein in these brains.
Amyloid-β protein (brown) in a section of brain tissue. Source: Nature
Of the eight brains (from people who received PrP infected growth-hormone) the authors analysed, six of them had clustering of Amyloid-β protein present in the brain (in four of those cases it was wide-spread). These brains came from people aged between aged 36–51 years – in such cases it is very rare to see large accumulations of Amyloid-β protein. The researchers also analysed the DNA of the individuals involved in the study and found that none of them were genetically susceptible to Alzheimer’s disease.
The researchers then compared these six brain with the brains of people who died from CJD caused by other means – 119 brains in total and none of them had Amyloid-β protein present in the brain. From these and other experiments, the authors suggested that this was the first human evidence of transmission of Alzheimer’s related pathology.
It is very important to note several details in the study:
1. None of the people whose brains were used in the study exhibited the clinical signs of Alzheimer’s.
2. None of the brains with Amyloid-β pathology had what is called ‘hyperphosphorylated tau neurofibrillary tangles’ – SImilar clumps of Amyloid-β protein, tau neurofibrillary tangles are another characteristic feature of Alzheimer’s disease brains. Their absence is curious.
3. The authors can not dismiss the possibility that the Amyloid-β was not present in the growth-hormone solution. In this case, the Amyloid-β accumulation in the brains could have been caused by some other unknown agent that was present in the injected solution.
A rare editorial note here: The Science of PD is disappointed with the way that this study has been handled by the wider media. While the results are interesting and the authors can be congratulated on their work, a correct interpretation of the results requires further study. This study has simply demonstrated was that Amyloid-β protein may be transmissible in a similar fashion to PrP.
So why are we discussing this Alzheimer’s research here at the Science of Parkinson’s Disease?
Well, for a long time now Parkinson’s researchers have suspected that similar mechanisms may underlying what is happening in PD. That is to say, a prion-like protein may be transmitted between cells in the body (possibly from the gut to the brain – see previous posts) allowing the disease to progress. One protein in particular, Alpha Synuclein, which is present in Lewy bodies – the neurological features associated with Parkinson’s disease, has been implicated in this regards. Recent evidence from lab-based studies suggest that this is possible in cell cultures and in rodents, but whether it is possible in humans is yet to be determined.
NOTE: Since publishing this post, we contacted the authors of the study regarding the presence of Alpha Synuclein and they told us that they were currently conducted a large study investigating what other proteins are also present. Thus far they have not seen any Alpha Synuclein accumulation. Interesting….