An important aspect of developing new potentially ‘curative’ treatments for Parkinson’s is our ability to accurately test and evaluate them. Our current methods of assessing Parkinson’s are basic at best (UPDRS and brain imaging), and if we do not improve our ability to measure Parkinson’s, many of those novel treatments will fail the clinical trial process and forever remain just “potentially” curative.
Blood pressure issues are a common feature of Parkinson’s that does not get a lot of attention, but new technology could provide us with new insight.
In today’s post, we look at new technology (under development) which could be applied to Parkinson’s, for the measuring and assessment of blood pressure, and we will look at how it could be used in certain clinical trials.
Apple watch 4 (not an endorsement). Source: NewScientist
Late last year, the tech giant Apple released yet more new versions of their phones and watches (with much fanfare). And before we continue: this is not an advertisement or endorsement (unless Apple wants to talk to me???… ).
Of interest was the new version of their watch, which has a handy feature of being able to tell you when you have fallen over (a warning that one was about to fall would surely be more useful, no?).
Useful feature, but those buttons are rather close for anyone with a tremor. Source: ATT
And much was made about the ability of the watch to monitor heart rate, which is a very clever trick, particularly for people with atrial fibrillation (periods of abnormal activity in the atrials of the heart) – although there appear to a few issues to be ironed out (Click here to read more about this).
Many of these smart watches and wrist band monitoring gadgets can now detect heart rate, but monitoring of blood pressure would actually be more useful for the Parkinson’s community.
What does blood pressure have to do with Parkinson’s?
Recent analysis of blood samples collected during the Phase II clinical trial of Exenatide in Parkinson’s has uncovered a very interesting finding that could have major implications for not only Parkinson’s, but for many different neurological conditions.
Exenatide is a treatment that helps to control glucose levels in people with diabetes. More recently, however, it has been suggested that this drug may also have beneficial effects in Parkinson’s. A collection of clinical trials in Parkinson’s are currently unway to test this idea.
The researchers who conducted a Phase II clinical trial of Exenatide in Parkinson’s have analysed ‘exosomes‘ collected from the blood of participants, and they found something rather remarkable.
In today’s post we will discuss what exosomes are, what the researchers found, and why their discovery could have major implications for all of neurological research.
This week, however, researchers involved in the study reported yet another really interesting finding from the trial. And this one could have profound consequences for how we study not only Parkinson’s, but many other neurological conditions.
What did they find?
Last week this report was published:
Title: Utility of Neuronal-Derived Exosomes to Examine Molecular Mechanisms That Affect Motor Function in Patients With Parkinson Disease: A Secondary Analysis of the Exenatide-PD Trial.
Authors: Athauda D, Gulyani S, Karnati H, Li Y, Tweedie D, Mustapic M, Chawla S, Chowdhury K, Skene SS, Greig NH, Kapogiannis D, Foltynie T.
Journal: JAMA Neurol. 2019 Jan 14. doi: 10.1001/jamaneurol.2018.4304. [Epub ahead of print]
In the Exenatide Phase II clinical trial, 60 people with moderate Parkinson’s were randomly assigned to receive either 2mg of Exenatide or placebo once weekly for 48 weeks followed by a 12-week washout (no treatment) period. The results suggested a stablisation of motor features over the 48 weeks of the study in the treated group (while the condition in the placebo group continued to progress).
During the study (which was conducted between June 2014 – June 2016), blood samples were collected at each assessement.
From those blood samples, serum was collected and analysed.
Remind me again, what is serum?
Numerous readers have asked about a curious new clinical trial being conducted by a biotech firm called ‘Alkahest’. The company has recently initiated a large (90 participants) Phase II study of their Parkinson’s-focused treatment called GRF6021.
This is an experimental, intravenously-administered treatment, which is derived from a components of blood.
In today’s post, we will discuss some of the research behind GRF6021, what this new clinical trial involves, and have a look at some other interesting Parkinson’s-related activities that Alkahest has ongoing.
The Society of Neuroscience meeting is the largest annual research conference on brain relelated research, bringing approximately 40,000 neuroscientists together in October. At the Society of Neuroscience meeting in San Diego this year, however, there was considerable interest focused on several presentations dealing with blood.
The first presentation was from a group of researchers at the University of California, San Francisco.
The research team – led by group leader Dr Saul Villeda – were presenting new data suggesting that circulating immune cells were most likely responsible for the age-related reduction in neurogenesis (formation of new neurons) that occurs in certain areas of the brain (Click here to read the abstract for this presentation). They reported that the aged hematopoietic (blood) system led to impaired neurogenesis. Their take-home-message: the older the blood system, the less new cells being produced by the brain.
Sounds interesting right?
Well, at the same time in another part of the conference a second group of researchers were presenting equally impressive data: They have zeroed in of a small fraction of normal, young blood that they believe has interesting properties, particularly in reversing the cognitive deficits associated with aging mice (Click here to read the abstract of this presentation).
Their research has even narrowed down to a specific protein, called C-C chemokine receptor type 3 (or CCR3), which when inhibited was found to improve cognitive function and decreased neuroinflammation in aged mice (Click here to read the abstract of the presentation).
The humble lab mouse. Source: Pinterest
But specifically for our interests here at the SoPD, these same researchers displayed data which demonstrated that treatment with a novel fraction of human plasma resulted in significant improvements in motor function, cell survival and neuroinflammation three weeks after treatment in multiple mouse models of Parkinson’s (Click here to read the abstract of the poster).
(PLEASE NOTE: The author of this blog was not present at the SFN meeting and is working solely with the abstracts provided)
This second group of scientists were from a company called Alkahest, and they have recently started a clinical trial for people with Parkinson’s based on these results. That trial has garnered quite a bit of interest in the Parkinson’s community.What do Alkahest do?
Recently new research has been published that raises the question (again) as to whether there is something wrong with the immune system in Parkinson’s
Researchers from Germany and San Diego (USA) have published data suggesting that a particular type of blood cell may be acting up in Parkinson’s, getting involved with the neurodegenerative process that characterises the condition.
In their report they also found a clinically available treatment – called Secukinumab – that could reduce the effect.
In today’s post, we will look at what lymphocytes are, how they may be playing a role in Parkinson’s, and explain how secukinumab could potentially aid us in the treatment of PD.
Ouch! Source: CT
My 5 year old recently cut her leg, and there was a bit of blood. We patched her up with a plaster, but also took advantage of the moment to learn a little something about how the body works.
Me: Do you know what that red stuff is?
Little monster: It is blood?
Me: That’s right.
Little monster: Papa, where does blood come from?
That was when I got all excited, and pulled out my black board.
This was the answer I gave her:
An Advanced Glycation Endproduct (or AGE) is a protein or lipid that has become glycated.
Glycation is a haphazard process that impairs the normal functioning of molecules. It occurs as a result of exposure to high amounts of sugar. These AGEs are present at above average levels in people with diabetes and various ageing-related disorders, including neurodegenerative conditions. AGEs have been shown to trigger signalling pathways within cells that are associated with both oxidative stress and inflammation, but also cell death.
RAGE (or receptor of AGEs) is a molecule in a cell membrane that becomes activated when it interacts with various AGEs. And this interaction mediates AGE-associated toxicity issues. Recently researchers found that that neurons carrying the Parkinson’s associated LRRK2 G2019S genetic variant are more sensitive to AGEs than neurons without the genetic variant.
In today’s post we will look at what AGE and RAGE are, review the new LRRK2 research, and discuss how blocking RAGE could represent a future therapeutic approach for treating Parkinson’s.
The wonder of ageing. Source: Club-cleo
NOTE: Be warned, the reading of this post may get a bit confusing. We are going to be discussing ageing (as in the body getting old) as well as AGEing (the haphazard process processing of glycation). For better clarification, lower caps ‘age’ will refer to getting old, while capitalised ‘AGE’ will deal with that glycation process. I hope this helps.
Ageing means different things to different people.
For some people ageing means more years to add to your life and less activity. For others it means more medication and less hair. More wrinkles and less independence; more arthritis and less dignity; More candles, and less respect from that unruly younger generation; More… what’s that word I’m thinking of? (forgetfulness)… and what were we actually talking about?
Wisdom is supposed to come with age, but as the comedian/entertainer George Carlin once said “Age is a hell of a price to pay for wisdom”. I have to say though, that if I had ever met Mr Carlin, I would have suggested to him that I’m feeling rather ripped off!
George Carlin. Source: Thethornycroftdiatribe
Whether we like it or not, from the moment you are born, ageing is an inevitable part of our life. But this has not stopped some adventurous scientific souls from trying to understand the process, and even try to alter it in an attempt to help humans live longer.
Regardless of whether you agree with the idea of humans living longer than their specified use-by-date, some of this ageing-related research could have tremendous benefits for neurodegenerative conditions, like Parkinson’s.
What do we know about the biology of ageing?
Here’s a good riddle for you:
Many epidemiological studies have suggested that coffee/caffeine consumption reduces one’s risk of developing Parkinson’s. Study after study has suggested that drinking coffee is beneficial.
Recently, however, Japanese researchers have discovered something really curious: people with Parkinson’s have reduced levels of caffeine in their blood compared to healthy controls… even when they have consumed the same amount of coffee. (???)
In today’s post we will look at what coffee is, review the results of this study, and try to understand what is going on.
Kaldi the goat herder. Source: CoffeeCrossroads
Legend has it that in 800AD, a young Ethiopian goat herder named Kaldi noticed that his animals were “dancing”.
They had been eating some berries from a tree that Kaldi did not recognise, but being a plucky young fellow – and being fascinated by the merry behaviour of his four-legged friends – Kaldi naturally decided to eat some of the berries for himself.
The result: He became “the happiest herder in happy Arabia” (Source).
This amusing encounter was apparently how humans discovered coffee. It is most likely a fiction as the earliest credible accounts of coffee-consumption emerge from the 15th century in the Sufi shrines of Yemen, but since then coffee has gone on to become one of the most popular drinks in the world.
Silly question, but what exactly is coffee?
Gene therapy involves treating medical conditions at the level of DNA – that is, altering or enhancing the genetic code inside cells to provide therapeutic benefits rather than simply administering drugs. Usually this approach utilises specially engineered viruses to deliver the new DNA to particular cells in the body.
For Parkinson’s, gene therapy techniques have all involved direct injections of these engineered viruses into the brain – a procedure that requires brain surgery. This year, however, we have seen the EXTREMELY rapid development of a non-invasive approach to gene therapy for neurological condition, which could ultimately see viruses being injected in the arm and then travelling up to the brain where they will infect just the desired population of cells.
Last week, however, this approach hit a rather significant obstacle.
In today’s post, we will have a look at this gene therapy technology and review the new research that may slow down efforts to use this approach to help to cure Parkinson’s.
Gene therapy. Source: rdmag
When you get sick, the usual solution is to visit your doctor.
They will prescribe a medication for you to take, and then all things going well (fingers crossed/knock on wood) you will start to feel better. It is a rather simple and straight forward process, and it has largely worked well for most of us for quite some time.
As the overall population has started to live longer, however, we have begun to see more and more chronic conditions which require long-term treatment regimes. The “long-term” aspect of this means that some people are regularly taking medication as part of their daily lives. In many cases, these medications are taken multiple times per day.
A good example of this is Levodopa (also known as Sinemet or Madopar) which is the most common treatment for the chronic condition of Parkinson’s disease.
When you swallow your Levodopa pill, it is broken down in the gut, absorbed through the wall of the intestines, transported to the brain via our blood system, where it is converted into the chemical dopamine – the chemical that is lost in Parkinson’s disease. This conversion of Levodopa increases the levels of dopamine in your brain, which helps to alleviate the motor issues associated with Parkinson’s disease.
Levodopa. Source: Drugs
This pill form of treating a disease is only a temporary solution though. People with Parkinson’s – like other chronic conditions – need to take multiple tablets of Levodopa every day to keep their motor features under control. And long term this approach can result in other complications, such as Levodopa-induced dyskinesias in the case of Parkinson’s.
Yeah, but is there a better approach?
In this post we discuss several recently published research reports suggesting that Parkinson’s disease may be an autoimmune condition. “Autoimmunity” occurs when the defence system of the body starts attacks the body itself.
This new research does not explain what causes of Parkinson’s disease, but it could explain why certain brain cells are being lost in some people with Parkinson’s disease. And such information could point us towards novel therapeutic strategies.
The first issue of Nature. Source: SimpleWikipedia
The journal Nature was first published on 4th November 1869, by Alexander MacMillan. It hoped to “provide cultivated readers with an accessible forum for reading about advances in scientific knowledge.” It has subsequently become one of the most prestigious scientific journals in the world, with an online readership of approximately 3 million unique readers per month (almost as much as we have here at the SoPD).
Each Wednesday afternoon, researchers around the world await the weekly outpouring of new research from Nature. And this week a research report was published in Nature that could be big for the world of Parkinson’s disease. Really big!
On the 21st June, this report was published:
Title: T cells from patients with Parkinson’s disease recognize α-synuclein peptides
Authors: Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A
Journal: Nature. 2017 Jun 21. doi: 10.1038/nature22815.
In their study, the investigators collected blood samples from 67 people with Parkinson’s disease and from 36 healthy patients (which were used as control samples). They then exposed the blood samples to fragments of proteins found in brain cells, including fragments of alpha synuclein – this is the protein that is so closely associated with Parkinson’s disease (it makes regular appearances on this blog).
What happened next was rather startling: the blood from the Parkinson’s patients had a strong reaction to two specific fragments of alpha synuclein, while the blood from the control subjects hardly reacted at all to these fragments.
In the image below, you will see the fragments listed along the bottom of the graph (protein fragments are labelled with combinations of alphabetical letters). The grey band on the plot indicates the two fragments that elicited a strong reaction from the blood cells – note the number of black dots (indicating PD samples) within the band, compared to the number of white dots (control samples). The numbers on the left side of the graph indicate the number of reacting cells per 100,000 blood cells.
The investigators concluded from this experiment that these alpha synuclein fragments may be acting as antigenic epitopes, which would drive immune responses in people with Parkinson’s disease and they decided to investigate this further.
Today there was a lot of Parkinson’s related activity in the news… well, more than usual at least.
Overnight there was the publication of a blood test for Parkinson’s disease, which looks very sensitive. And this afternoon, Acorda Therapeutics announced positive data for their phase three trial.
In this post, we’ll look at what it all means.
Blood cells. Source: Reference.com
Today we found out about an interesting new study from scientists at Lund University (Sweden), where they are developing a test that can differentiate between different types of Parkinsonisms (See our last post about this) using a simple blood test.
We have previously reported about an Australian research group working on a blood test for Parkinson’s disease, but they had not determined whether their test could differentiate between different kinds of neurodegenerative conditions (such as Alzheimer’s disease). And this is where the Swedish study has gone one step further…
Title: Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder
Authors: Hansson O, Janelidze S, Hall S, Magdalinou N, Lees AJ, Andreasson U, Norgren N, Linder J, Forsgren L, Constantinescu R, Zetterberg H, Blennow K, & For the Swedish BioFINDER study
Journal: Neurology, Published online before print February 8, 2017
PMID: N/A (This article is OPEN ACCESS if you would like to read it)
The research group in Lund had previously demonstrated that they could differentiate between people with Parkinson’s disease and other types of Parkinsonism to an accuracy of 93% (Click here to read more on this). That is a pretty impressive success rate – equal to basic clinical diagnostic success rates (click here for more on this).
The difference was demonstrated in the levels of a particular protein, neurofilament light chain (or Nfl). NfL is a scaffolding protein, important to the cytoskeleton of neurons. Thus when cells die and break up, Nfl could be released. This would explain the rise in Nfl following injury to the brain. Other groups (in Germany and Switzerland) have also recently published data suggesting that Nfl could be a good biomarker of disease progression (Click here to read more on this).
There was just one problem: that success rate we were talking about above, it required cerebrospinal fluid. That’s the liquid surrounding your brain and spinal cord, which can only be accessed via a lumbar puncture – a painful and difficult to perform procedure.
Lumbar puncture. Source: Lymphomas Assoc.
Not a popular idea.
This led the Swedish researchers to test a more user friendly approach: blood.
In the current study, the researchers took blood samples from three sets of subjects:
- A Lund set (278 people, including 171 people with Parkinson’s disease (PD), 30 people with Multiple system atrophy (MSA), 19 people with Progressive Supranuclear Palsy (PSP), 5 people with corticobasal syndrome (CBS), and 53 people who were neurologically healthy (controls).
- A London set (117 people, including 20 people with PD, 30 people with MSA, 29 people with PSP, 12 people with CBS, and 26 neurologically healthy controls
- An early disease set (109 people, including 53 people with PD, 28 people with MSA, 22 people with PSP, 6 people with CBS). All of the early disease set had a disease duration less than 3 years.
When the researchers looked at the levels of NfL in blood, they found that they could distinguish between people with PD and people with PSP, MSA, and CBS with an accuracy of 80-90% – again a very impressive number!
One curious aspect of this finding, however, is that the levels of Nfl in people with PD are very similar to controls. So while this protein could be used to differentiate between PD and other Parkinsonisms, it may not be a great diagnostic aid for determining PD verses non-PD/healthy control.
In addition, what could the difference in levels of Nfl between PD and other Parkinsonisms tell us about the diseases themselves? Does PD have less cell death, or a more controlled and orderly cell death (such as apoptosis) than the other Parkinsonisms? These are questions that can be examined in follow up work.
Like we said at the top, it’s been a busy day for Parkinson’s disease: Good news today for Acorda Therapeutics, Inc.
They announced positive Phase 3 clinical trial results for their inhalable L-dopa treatment, called CVT-301, which demonstrated a statistically significant improvement in motor function in people with Parkinson’s disease experiencing OFF periods.
We have previously discussed the technology and the idea behind this approach to treating Parkinson’s disease (Click here for that post).
The ARCUS inhalation technology. Source: ParkinsonsLife
Basically, the inhaler contains capsules of L-dopa, which are designed to break open so that the powder can escape. By sucking on the inhaler (see image below), the open capsule starts spinning, releasing the levodopa into the air and subsequently into the lungs. The lungs allow for quicker access to the blood system and thus, the L-dopa can get to the brain faster. This approach will be particularly useful for people with Parkinson’s disease who have trouble swallowing pills/tablets – a common issue.
The Phase 3, double-blind, placebo-controlled clinical trial evaluated the efficacy and safety of CVT-301 when compared with a placebo in people with Parkinson’s disease who experience motor fluctuations (OFF periods). There were a total of 339 study participants, who were randomised and received either CVT-301 or placebo. Participants self-administered the treatment (up to five times daily) for 12 weeks.
The results were determined by assessment of motor score, as measured by the unified Parkinson’s disease rating scale III (UPDRS III) which measures Parkinson’s motor impairment. The primary endpoint of the study was the amount of change in UPDRS motor score at Week 12 at 30 minutes post-treatment. The change in score for CVT-301 was -9.83 compared to -5.91 for placebo (p=0.009). A negative score indicates an improvement in overall motor ability, suggesting that CVT-301 significantly improved motor score.
The company will next release 12-month data from these studies in the next few months, and then plans to file a New Drug Application (NDA) with the Food and Drug Administration (FDA) in the United States by the middle of the year and file a Marketing Authorization Application (MAA) in Europe by the end of 2017. This timeline will depend on some long-term safety studies – the amount of L-dopa used in these inhalers is very high and the company needs to be sure that this is not having any adverse effects.
All going well we will see the L-dopa inhaler reaching the clinic soon.
The banner for today’s post was sourced from the Huffington Post
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