At the end of each year, it is a useful practise to review the triumphs (and failures) of the past 12 months. It is an exercise of putting everything into perspective.
2017 has been an incredible year for Parkinson’s research.
And while I appreciate that statements like that will not bring much comfort to those living with the condition, it is still important to consider and appreciate what has been achieved over the last 12 months.
In this post, we will try to provide a summary of the Parkinson’s-related research that has taken place in 2017 (Be warned: this is a VERY long post!)
The number of research reports and clinical trial studies per year since 1817
As everyone in the Parkinson’s community is aware, in 2017 we were observing the 200th anniversary of the first description of the condition by James Parkinson (1817). But what a lot of people fail to appreciate is how little research was actually done on the condition during the first 180 years of that period.
The graphs above highlight the number of Parkinson’s-related research reports published (top graph) and the number of clinical study reports published (bottom graph) during each of the last 200 years (according to the online research search engine Pubmed – as determined by searching for the term “Parkinson’s“).
PLEASE NOTE, however, that of the approximately 97,000 “Parkinson’s“-related research reports published during the last 200 years, just under 74,000 of them have been published in the last 20 years.
That means that 3/4 of all the published research on Parkinson’s has been conducted in just the last 2 decades.
And a huge chunk of that (almost 10% – 7321 publications) has been done in 2017 only.
So what happened in 2017? Continue reading
‘Parkinsonisms’ refer to a group of neurological conditions that cause movement features similar to those observed in Parkinson’s disease. They include multiple system atrophy (MSA) and Progressive supranuclear palsy (PSP) and idiopathic Parkinson’s.
Newly published research now shines a light on a possible mechanism for differentiating between multiple system atrophy and idiopathic Parkinson’s.
In today’s post we will look at what multiple system atrophy is, review the new research report, and discuss what these results could mean for the Parkinson’s community.
Brain immaging of multiple system atrophy–related spatial covariance pattern (MSARP) and Parkinson disease–related spatial covariance pattern (PDRP). Source: Neurology
For a long time I have been looking to write a piece of Multiple system atrophy.
I have been contacted by several readers asking for more information about it, and the only thing really delaying me – other than the tsunami of Parkinson’s related research that I am currently trying to write posts for – was the lack of a really interesting piece of research to base the post around.
Guess what came into my inbox yesterday:
Title: Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication.
Authors: Woerman AL, Kazmi SA, Patel S, Aoyagi A, Oehler A, Widjaja K, Mordes DA, Olson SH, Prusiner SB.
Journal: Proc Natl Acad Sci U S A. 2017 Dec 26. pii: 201719369.
This is a really interesting piece of research, that continues a line of other really interesting research.
And if it is independently replicated and verified, it will have massive implications for the Parkinson’s community, particularly those affected by Multiple System Atrophy.
But before we deal with that, let’s start with the obvious question:
What is Multiple System Atrophy?
For the vast majority of the general population, science is consumed via mass media head lines and carefully edited summaries of the research.
The result of this simplified end product is an ignorance of the process that researchers need to deal with in order to get their research in the public domain.
As part of our efforts to educate the general public about the scientific research of Parkinson’s disease, it is necessary to also make them aware of that process, the issues associated with it, and how it is changing over time.
In todays post, we will look at how new research reports are being made available to the public domain before they are published.
Getting research into the public domain. Source: STAT
Every morning here at the SoPD, we look at what new research has entered the public domain over night and try to highlight some of the Parkinson’s disease relevant bits on our Twitter account (@ScienceofPD).
To the frustration of many of our followers, however, much of that research sits behind the pay-to-view walls of big publishing houses. One is allowed to read the abstract of the research report in most cases, but not the full report.
Given that charity money and tax payer dollars are paying for much of the research being conducted, and for the publication fee (approx. $1500 per report on average) to get the report into the journal, there is little debate as to the lack of public good in such a system. To make matter worse, many of the scientists doing the research can not access the published research reports, because their universities and research institutes can not afford the hefty access fees for all of the journals.
To be fair, the large publishing houses have recognised that this is not a sustainable business model, and they have put forward the development of open-access web-based science journals, such as Nature communications, Scientific reports, and Cell reports. But the fees for publishing in these journals can in some cases be higher than the closed access publications.
This is crazy. What can we do about it?
Well, there have been efforts for some time to improve the situation.
Projects like the Public Library of Science (or PLOS) have been very popular and are now becoming a real force on the scientific publishing landscape (they recently celebrated their 10 year anniversary and during that time they have published more than 165,000 research articles). But they too have costs associated with maintaining their service and publications fees can still be significant.
Is there an easier way of making this research available?
So this is Prof Paul Ginsparg.
Looks like the mad scientist type right? Don’t be fooled. He’s awesome! Prof Ginsparg is a professor of Physics and Computing & Information Science at Cornell University.
Back in 1991, he started a repository of pre-print publications in the field of physics. The repository was named arXiv.org, and it allowed physics researchers to share and comment on each others research reports before they were actually published.
The site slowly became an overnight sensation.
The number of manuscripts deposited at arXiv passed the half-million mark on October 3, 2008, the million manuscript mark by the end of 2014 (with a submission rate of more than 8,000 manuscripts per month). The site currently has 1,257,315 manuscripts that are freely available to access. A future nobel prize winning bit of research is probably in there!
Now, by their very nature, and in a very general sense, biomedical researchers are a jealous bunch.
For many years they looked on with envy at the hive of activity going on at arXiv and wished that they had something like it themselves. And now they do! In November 2013, Cold Spring Harbor Laboratory in New York launched BioRxiv.
And the website is very quickly becoming a popular destination: by April 21, 2017, >10,000 manuscript had been posted, at a current rate of over 800 manuscripts per month (Source).
Recently they got a huge nod of financial support from the Chan Zuckerberg Initiative – a foundation set up by Facebook founder Mark Zuckerberg and his wife Priscilla Chan to “advance human potential and promote equality in areas such as health, education, scientific research and energy” (Wikipedia).
So what is bioRxiv?
bioRxiv is a free OPEN ACCESS service that allows researchers to submit draft copies of scientific papers — called preprints — for their colleagues to read and comment on before they are actually published in peer-reviewed scientific journals.
Here are two videos explaining the idea:
Sounds great right?
To demonstrate how the bioRxiv process works, we have selected an interesting manuscript from the database that we would like to review here on the SoPD.
This is the article:
Title: In Vivo Phenotyping Of Parkinson-Specific Stem Cells Reveals Increased a-Synuclein Levels But No Spreading
Authors: Hemmer K, Smits LM, Bolognin S, Schwamborn JC
PMID: N/A (You can access the manuscript by clicking here)
In this study (which was posted on bioRxiv on the 19th May, 2017), the researchers have acquired skin cells from an 81 year old female with Parkinson’s disease who carries a mutation (G2019S) in the LRRK2 gene.
Mutations in the Leucine-rich repeat kinase 2 (or Lrrk2) gene are associated with an increased risk of developing Parkinson’s disease. The most common mutation of LRRK2 gene is G2019S, which is present in 5–6% of all familial cases of Parkinson’s disease, and is also present in 1–2% of all sporadic cases. We have previously discussed Lrrk2 (Click here to read that post).
The structure of Lrrk2 and where various mutations lie. Source: Intech
The skin cells were transformed using a bit of biological magic in induced pluripotent stem (or IPS) cells. We have previously discussed IPS cells and how they are created (Click here to read that post). By changing a subjects skin cell into a stem cell, researchers can grow the cell into any type of cell and then investigate a particular disease on a very individualised basis (the future of personalised medicine don’t you know).
IPS cell options available to Parkinson’s disease. Source: Nature
Using this IPS cell with a mutation in the LRRK2 gene, the researchers behind todays manuscript next grew the cells in culture and encouraged the cells to become dopamine producing cells (these are some of the most vulnerable cells in Parkinson’s disease). The investigators had previously shown that neurons grown in culture from cells with the G2019S mutation in the LRRK2 gene have elevated levels of of the Parkinson’s disease protein alpha Synuclein (Click here to read that OPEN ACCESS paper).
In this present study, the investigators wanted to know if these cells would also have elevated levels of alpha synuclein when transplanted into the brain. Their results indicate that the cells did. Next, the investigators wanted to use this transplantation model to see if the high levels of alpha synuclein in the transplanted cells would lead to the protein being passed to neighbouring cells.
Why did they want to do that?
One of the current theories regarding the mechanisms underlying the progressive spread of Parkinson’s disease is that the protein alpha synuclein is lead culprit. Under normal conditions, alpha synuclein usually floats around as an individual protein (or monomer), but sometime it starts to cluster (or aggregate) with other monomers of alpha synuclein and these form what we call oligomers. These oligomers are believed to be a toxic form of alpha synuclein that is being passed from cell to cell. And it ‘seeds’ the disease in each cell it is passed on to (Click here for a very good OPEN ACCESS review of this topic).
There have been postmortem analysis studies of the brains from people with Parkinson’s who have had cell transplantation therapy back in the 1990s. The analysis shows that some of the transplanted cells have evidence of toxic alpha synuclein in them – some of those cells have Lewy bodies in them, suggesting that the disease has been passed on to the healthy introduced cells from the diseased brain (Click here for the OPEN ACCESS research report about this).
In the current bioRxiv study, the investigators wanted to ask the reverse question:
Can unhealthy, toxic alpha synuclein producing cells cause the disease to spread into a healthy brain?
So after transplanted the Lrrk2 mutant cells into the brains of mice, they waited 11 weeks to see if the alpha synuclein would be passed on to the surrounding brain. According to their results, the unhealthy alpha synuclein did not transfer. They found no increase in levels of alpha synuclein in the cells surrounding the transplanted cells. The researchers concluded that within the parameters of their experiment, Parkinson’s disease-associated alpha synuclein spreading was not detected.
Interesting. When will this manuscript be published in a scientific journal?
We have no idea.
One sad truth of the old system of publication is: it may never be.
And this illustrates one of the beautiful features of bioRxiv.
This manuscript is probably going through the peer-review process at a particular scientific journal at the moment in order for it to be properly published. It is a process that will take several months. Independent reviewers will provide a critique of the work and either agree that it is ready for publication, suggest improvements that should be made before it can be published, or reject it outright due to possible flaws or general lack of impact (depending on the calibre of the journal – the big journals seem to only want sexy science). It is a brutal procedure and some manuscripts never actually survive it to get published, thus depriving the world of what should be freely available research results.
And this is where bioRxiv provides us with a useful forum to present scientific biological research that may never reach publication. Perhaps the researchers never actually intended to publish their findings, and just wanted to let the world know that someone had attempted the experiment and these are the results they got (there is a terrible bias in the world of research publishing to only publish positive results).
The point is: with bioRxiv we can have free access to the research before it is published and we do not have to wait for the slow peer-review process.
And there is definitely some public good in that.
EDITORS NOTE HERE: We are not suggesting for a second that the peer-review process should be done away with. The peer-review process is an essential and necessary aspect of scientific research, which helps to limit fraud and inaccuracies in the science being conducted.
What does it all mean?
This post may be boring for some of our regular readers, but it is important for everyone to understand that there are powerful forces at work in the background of scientific research that will determine the future of how information is disseminated to both the research community and general population. It is useful to be aware of these changes.
We hope that some of our readers will be bold/adventurous and have a look at some of what is on offer in the BioRxiv database. Maybe not now, but in the future. It will hopefully become a tremendous resource.
And we certainly encourage fellow researchers to use it (most of the big journals now accept preprint manuscripts being made available on sites like bioRxiv – click here to see a list of the journals that accept this practise) and some journals also allow authors to submit their manuscript directly to a journal’s submission system through bioRxiv via the bioRxiv to Journals (B2J) initiative (Click here for a list of the journals accepting this practise).
The times they are a changing…
The banner for today’s post was sourced from ScienceMag
Exciting news this week from the world of neurodegenerative research. Researchers have identified two clinically available drugs that display neuroprotective properties.
The drugs – Dibenzoylmethane and Trazodone – are currently used to treat cancer and depression, respectively.
In this post, we will review the research and discuss what it could mean for folks with Parkinson’s disease.
Old drugs – new tricks? Source: Repurposingdrugs101
As you may have heard from media reports (for examples, click here, here and here), researchers have identified two clinically available drugs that may help in the fight against neurodegenerative conditions, like Parkinson’s disease.
The re-purposing of clinically available drugs is the focus of much attention within the Parkinson’s community as it represents a means of bringing treatments to the clinic faster. The traditional lengthy clinical trial process that is required in the development of new medications means getting a new drug to market for neurodegeneration can take up to 15 years, as the trials run over several years each (and there are three phases to pass through).
Shortening the wait. Source: Austinpublishing
In an age of smart phones and instant gratification, who has that kind of patience? ( #Wewontwait ).
Thus, re-purposing of available drugs represents a more rapid means of bringing new treatments/therapies to the Parkinson’s community.
So what is the new research all about?
This is Professor Giovanna Mallucci.
Prof Giovanna Mallucci. Source: MRC
Her area of research interest is understanding mechanisms of neurodegeneration, with a particular focus on prion and Alzheimer’s disease.
A few years ago, her group published this report:
Title: Sustained translational repression by eIF2α-P mediates prion neurodegeneration.
Authors: Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, Bushell M, Mallucci GR.
Journal: Nature. 2012 May 6;485(7399):507-11.
PMID: 22622579 (This article is OPEN ACCESS if you would like to read it)
In this study, Prof Mallucci’s group were interested in the biological events that were occurring in the brain following infection of mice with prion disease – another neurodegenerative condition. They found that a sudden loss of protein associated with the connections between neurons (those connections being called synapses) occurred at 9 weeks post infection. This led them to investigate the production of protein and they found that an increase in the levels of phosphorylation of a protein called eIF2alpha was associated with the reduction in protein synthesis occurring at 9 weeks post infection.
What is Phosphorylation?
Phosphorylation of a protein is basically the process of turning it on or off – making it active or inactive – for a particular function.
Phosphorylation of a kinase protein. Source: Nature
And what is eIF2alpha?
Eukaryotic Translation Initiation Factor 2 Alpha is (as the label on the can suggests) a translation initiation factor. This means that this particular protein functions in the early steps of the production of protein. That is to say, eIF2alpha has important roles in the first steps – the initiation – of making other proteins.
eIF2alpha’s role in neurodegeneration. Source: Frontiers
The increased phosphorylation of eIF2alpha results in the inactivation of eIF2alpha and therefore the transient shutdown of protein production.
This shutdown in protein production can serve as an important ‘checkpoint’ when a cell is stressed. By blocking general protein production, a damaged or stressed cell can have the opportunity to either recuperate or be eliminated (if the damage is beyond repair).
The shutdown can also be caused by the unfolded protein response (or UPR). The unfolded protein response is a protective mechanism triggered by rising levels of misfolded proteins.
What are misfolded proteins?
When proteins are being produced, they need to be folded into the correct shape to do their job. Things can turn ugly very quickly for a cell if protein are being misfolded or only partially folded.
Two proteins. Guess which is the misfolded protein. Source: Biogeekery
In fact, misfolded proteins are suspected of being responsible for many of the neurodegenerative conditions we know of (including Parkinson’s, Alzheimer’s, etc). Thus the unfolded protein response gives a cell time to stop protein production, degrade & dispose of any misfolded proteins, and then re-activate proteins involved with increasing the production again.
And Prof Mallucci’s group found an increase in the phosphorylation of eIF2alpha?
Yes. At 9 weeks post infection with prions, there is a decrease in the proteins required for maintaining the connections between neurons and an increase in the phosphorylation of eIF2alpha.
The interesting thing is that the researchers found that levels of phosphorylated eIF2alpha increased throughout the course of study.
So, the researchers asked themselves if promoting a recovery in protein production in the cells in neuroprotective. To test this they used a protein called GADD34, which is a specific eIF2alpha phosphatase (a phosphatase is a protein that dephosphates a protein). By introducing a lot of GADD34 in the cells, the researchers were able to re-activate eIF2alpha, rescue the connectivity between neurons and protect the cells from dying.
A cool trick, huh?
This report established the importance of eIF2alpha in the early stages of neurodegeneration, and Prof Mallucci and her group next decided to conduct a massive screening study of currently available medications to see which could be used to target eIF2alpha levels.
And that research gave rise to the report that caused so much excitement this week. This report here:
Title: Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice
Authors: Halliday M, Radford H, Zents KAM, Molloy C, Moreno JA, Verity NC, Smith E, Ortori CA, Barrett DA, Bushell M, Mallucci GR.
Journal: Brain, 2017 Epub early online publication
PMID: N/A (This article is OPEN ACCESS if you would like to read it)
The investigators began by testing 1,040 compounds (that represent many of the clinically available drugs we have) on tiny microscopic worms (called C.elegans). These worms represent a useful experimental model for screening drugs as many aspects of biology can be examined. These worms were exposed to both a chemical (called tunicamycin, which induces the unfolded protein response we were talking about above) and one of the 1040 compounds.
Of the 1040 compounds tested, the investigators selected the 20 that provided the best protection to the worms. They next analysed those top 20 compounds for their ability to reduce levels of phosphorylated eIF2alpha in cells. Cells were engineered to produce a bioluminescent signal when eIF2alpha was phosphorylated. The researchers used a potent blocker of the unfolded protein response (called GSK2606414) and a drug called ISRIB (which is an experimental drug which reverses the effects of eIF2alpha phosphorylation) as controls for the experiment.
Their results were interesting:
The results of the top 20 drugs screened. Source: Brain
As you can see from the graph above, there were five compounds (highlighted with ***) that provided a similar level of reduction as the ISRIB (control) drug:
- Azadirachtin – which is the active ingredient in many pesticides.
- Dibenzoylmethane – a cancer treatment.
- Proguanil – a medication used to treat and prevent malaria.
- Trazodone – an antidepressant used to treat depression and anxiety disorders.
- Trifluoperazine – an antipsychotic of the phenothiazine chemical class.
The investigators decided not to further investigate Azadirachtin as it is a pesticide and displays a poor ability to penetrant the blood-brain-barrier – the protective layer surrounding the brain. They also rejected Proguanil because while it is safe to use in humans, it is toxic in mice. This detail limited the amount of preclinical testing for neurodegeneration that the researchers could do. And finally Trifluoperazine was eliminated as it should not be used in the elderly populations (apparently it ‘increases the risk of death’!), which obviously limited it’s further utility given that age is a major determinant of neurodegeneration.
This selection process left the researchers with Dibenzoylmethane and Trazodone.
The researchers found that both of these drugs can cross the blood-brain-barrier and were able to prevent neurodegeneration and rescue behavioural deficits in prion-infected mice. And they observed no toxic effects of these treatments in other organs (such as the pancreas). The drugs restore correct protein production and increased the survival of the prion-infected mice.
Taking the study one step further, Prof Mallucci and her group asked if the drugs could be effective in a model of another neurodegenerative condition, such as Alzheimer’s disease. To investigated this, they treated rTg4510 mice with both of the drugs. rTg4510 mice produce a lot of a human protein (called tau) that has a particular mutation (known as P301L), which results in the onset of Alzheimer’s like pathology at an early age. The rTg4510 mice received either trazodone or Dibenzoylmethane on a daily basis from 4 months of age and were examined at 8 months of age. The researchers found significantly less cell loss and shrinkage in the brains of the mice treated with one of the two drugs when compared to rTg4510 mice that received no treatment.
The researchers concluded that “these compounds therefore represent potential new disease-modifying treatments for dementia. Trazodone in particular, a licensed drug, should now be tested in clinical trials in patients”.
As Professor Mallucci suggested to the press: “We know that trazodone is safe to use in humans, so a clinical trial is now possible to test whether the protective effects of the drug we see on brain cells in mice with neurodegeneration also applies to people in the early stages of Alzheimer’s disease and other dementias. We could know in 2-3 years whether this approach can slow down disease progression, which would be a very exciting first step in treating these disorders. Interestingly, trazodone has been used to treat the symptoms of patients in later stages of dementia, so we know it is safe for this group. We now need to find out whether giving the drug to patients at an early stage could help arrest or slow down the disease through its effects on this pathway.”
This is great for Alzheimer’s disease, but what about Parkinson’s?
Well, the researchers did not test the drugs in models of Parkinson’s disease. But we can assume that several research groups are going to be testing this drug in the near future… if they aren’t already!
But have increased levels of eIF2alpha been seen in Parkinson’s disease?
Great question. And the answer is: Yes.
Title: Activation of the unfolded protein response in Parkinson’s disease.
Authors: Hoozemans JJ, van Haastert ES, Eikelenboom P, de Vos RA, Rozemuller JM, Scheper W.
Journal: Biochem Biophys Res Commun. 2007 Mar 16;354(3):707-11.
In this study the investigators analysed the levels of Unfolded Protein Response activation in the postmortem brains of people who passed away with or without Parkinson’s disease. Specifically, they focused their analysis on the substantia nigra (the region where the dopamine neurons reside and which is most severely affected in Parkinson’s).
The researchers found that both eIF2alpha and a protein called PERK (also known as protein kinase-like ER kinase – which phosphalates eIF2alpha) are present in the dopamine neurons in the substantia nigra of brains from people with Parkinson’s disease, but not in healthy control brains. And as the graph below shows, the investigators noted that there was a trend towards the levels of these proteins peaking within the first five years after diagnosis.
eIF2alpha & PERK levels in the brain. Source: ScienceDirect
Similar postmortem analysis studies have also highlighted the increased levels of Unfolded Protein Response activation in the Parkinsonian brain (Click here to read more on this).
The increase in Unfolded Protein Response activation could be a common feature across different neurodegenerative conditions, suggesting that trazodone and dibenzoylmethane could be used widely to slow the progress of various conditions.
Another connection to Parkinson’s disease is the finding that high levels of the Parkinson’s associated protein alpha synuclein can cause the Unfolded Protein Response:
Title: Induction of the unfolded protein response by α-synuclein in experimental models of Parkinson’s disease.
Authors: Bellucci A, Navarria L, Zaltieri M, Falarti E, Bodei S, Sigala S, Battistin L, Spillantini M, Missale C, Spano P.
Journal: J Neurochem. 2011 Feb;116(4):588-605.
PMID: 21166675 (This article is OPEN ACCESS if you would like to read it)
The researchers in this study found that introducing large amounts of alpha synuclein into cell cultures results in the initiation of the unfolded protein response. They also observed this phenomenon in genetically engineered mice that produce large amounts of alpha synuclein.
Thus, there is some evidence for eIF2alpha and unfolded protein response-related activities in Parkinson’s disease
So is there are evidence that Dibenzoylmethane might be neuroprotective for Parkinson’s disease?
Yes there is (sort of):
Title: A dibenzoylmethane derivative protects dopaminergic neurons against both oxidative stress and endoplasmic reticulum stress.
Authors: Takano K, Kitao Y, Tabata Y, Miura H, Sato K, Takuma K, Yamada K, Hibino S, Choshi T, Iinuma M, Suzuki H, Murakami R, Yamada M, Ogawa S, Hori O.
Journal: Am J Physiol Cell Physiol. 2007 Dec;293(6):C1884-94. Epub 2007 Oct 3.
PMID: 17913843 (This article is OPEN ACCESS if you would like to read it)
The investigators of this study found a derivative of dibenzoylmethane which they called 14-26 (chemical name 2,2′-dimethoxydibenzoylmethane) displayed neuroprotective functions both in cell culture and animal models of Parkinson’s disease. The researchers did not look at the unfolded protein response or eIF2alpha and PERK levels, nor did they determine if dibenzoylmethane itself exhibits neuroprotective properties.
This may now need to be re-addressed.
And is there any evidence trazodone having neuroprotective effects in other neurodegenerative conditions?
For a review of the neuroprotective effects of trazodone (and other anti-psychotic/anti-depressant drugs) in Huntington’s Disease – Click here.
This sounds very positive for Parkinson’s disease then, no?
Weeeeeell, there is a word of caution to be thrown in here:
There have been reports in the past of trazodone causing motor-related issues in the elderly. Such as this one:
Title: Can trazodone induce parkinsonism?
Authors: Albanese A, Rossi P, Altavista MC.
Journal: Clin Neuropharmacol. 1988 Apr;11(2):180-2.
This report was a single case study of a 74 year old lady who developed depression after losing her sister with whom she lived. She was prescribed trazodone, which was effective in improving her mood. Just several months later, however, she began presenting Parkinsonian symptoms.
Firstly the onset of a resting tremor in the left arm, then a slowing of movement and a masking of the face. The attending physician withdrew the trazodone treatment and within two months the symptoms began to disappear, with no symptoms apparent 12 months later.
And unfortunately this is not an isolated case – other periodic reports of trazodone-induced motor issues have been reported (Click here and here for examples). And this is really strange as Trazodone apparently has no dopaminergic activity that we are aware of. It is a serotonin antagonist and reuptake inhibitor (SARI); it should not affect the re-uptake of norepinephrine or dopamine within the brain.
Thus, we may need to proceed with caution with the use of Trazodone for Parkinson’s disease.
So what does it all mean?
The repurposing of old drugs to treat alternative conditions is a very good idea. It means that we can test treatments that we usually know a great deal about (with regards to human usage) on diseases that they were not initially designed for, in a rapid manner.
Recently, scientists have identified two clinically available drugs that have displayed neuroprotection in two different models of neurodegeneration. Without doubt there will now be follow up investigations, before rapid efforts are made to set up clinical trials to test the efficacy of these drugs in humans suffering from dementia.
Whether these two treatments are useful for Parkinson’s disease still needs to be determined. There is evidence supporting the idea that they may well be, but caution should always be taken in how we proceed. This does not mean that other clinically available drugs can not be tested for Parkinson’s disease, however, and there are numerous clinical trials currently underway testing several of them (Click here to read more on this).
We’ll let you know when we hear anything about these efforts.
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. While some of the drugs discussed on this website are clinically available, they may have serious side effects. We urge caution and professional consultation before altering any 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 Linkedin
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….