"State of the Union - a 200 year overview of PD research"

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Written by Bruce Davies   B.A., B.D.,  M.B.A.

August 25, 2015

 

So, 198 years have passed since Dr. James Parkinson (in 1817) published his essay reporting 6 cases of ‘paralysis agitans’. He called it “An Essay on the Shaking Palsy” and it described the characteristic resting tremor, abnormal posture and gait, paralysis and diminished muscle strength, and the way that the disease progresses over time.

For his efforts, we named the disease after him.

 

Parkinson’s disease (PD) has been around forever and some ancient texts describing its characteristic symptoms even date back to 1,200 BC.

 

Question: What progress have we made in preventing, or halting, or curing PD?

Answer: None, we cannot do any of these three things right now.

 

Question: What progress have we made in treating the symptoms of PD patients?

Answer: Quite a lot, and improving steadily all the time, but eventually the disease overpowers all of them.

 

Arresting PD, the second most prolific, progressive, neurological disease (Alzheimer’s is #1) would be highly desirable. Curing it would be even better. Preventing it would be ideal. Treating its symptoms is where the big money is for the medical and pharmaceutical industries. An outright PD cure would entail reassigning all these professionals to new employment.

 

We will not be evaluating symptom treatments in this review except where they impinge on strategic clues as to how to align our research. We will rather focus on our progress in research which may guide us to halting disease progression, or developing a cure. Hopefully, if we can achieve either of these goals our understanding will be sufficient to define a ‘preventative strategy’.

 

 

PD is a highly complex problem to solve, and each research study has the potential to help provide clues as to how to proceed. Some clues are more important than others, but the difficulty is deciding where to put that emphasis.

 

Let us consider some of these clues and see if you have any new ideas as to what you think we should pursue in future research. We desperately need ideas from people who think ‘outside the box’ and work in different thought environments. Here are some clues to provoke your thoughts and suggestions ….

 

(1)  PD occurs mostly in older people – average is 63 years. It very rarely affects infants or persons under 30, and “young onset” (prior to 50) like Michael J. Fox (diagnosed at 29) is somewhat a-typical. So the decline of the efficiency of bodily systems due to ageing clearly has some kind of facilitating role.  

(2)  PD is the second most common neurological degenerative disease after Alzheimer’s (progressive memory loss/obliteration). Patient population in USA for PD is around 1 million, whilst Alzheimers is about 10 times that number. Globally, PD is probably at least in the 8-10 million range.

(3)  On the whole, globally, men are more likely to develop PD than women by a factor of 2 - 1, but there are serious differences by country. In Japan, Russia and the Netherlands women are more often affected than men. The extremes of the ranges are Nigeria (men 3.3 to 1 woman) and Japan (men 0.67 to 1 women).  This suggests that differing hormones (testosterone vs progesterone + estrogen) play a role, but other factor(s) temper hormone differences by location / culture / life-style.

(4)  Genetics play a role in PD, but that role is surprisingly small based on current proven research. Whilst we can implicate mutations in more than 25 (of our approximately 2,500 genes), all of them together currently only explain about 10% of all PD cases. About 85% of cases are termed “sporadic PD”, which in medical language means they are of unknown origin. Of the 10% of cases we can currently tie to genetics, the most common aberration is on the LLRK2 gene, but this only accounts for less than 2% of all PD cases. (Most recently, mutations on the GBA gene, especially common in the Ashkenazi Jewish population, have been attracting attention with some researchers speculating that 6% may be affected … or 3-4% of the general PD population.)

(5)  PD involves a shortage of a neuro-transmitting chemical called dopamine which the brain uses to send instructions to muscles in order to control and co-ordinate bodily movements. This dopamine shortage, due to the death of dopamine producing neurons in the brain stem (substantia nigra), impacts both muscle systems under conscious control (for example: walking, balance, tennis, weight-training) as well as the systems which are “automatic” (like breathing, swallowing, intestinal motions that move food through the digestive system).

(6)  We can use DaTscans to look at a part of the central brain called the substantia nigra where we can see that most of the dopamine producing neurons have died off and are missing in PD patients. (The substantia nigra is a bit like the gearbox on your car which transfers the engine’s motion to the wheels, so when it malfunctions the brain message to the body / muscles is defective or non-existent.) It is estimated that 80% of these dopamine neurons are gone by the time the patient first reports movement disorder symptoms.

(7)  There are certain things which are protective and / or correlate negatively with your chances of developing PD over your lifespan. These include (inter-alia): dying young; regular cardio-vascular exercise; using nicotine and / or amphetamines and / or coffee (caffeine). In the USA, incidence of PD is lowest in the Black population, followed by Asian, then White, then Hispanic. Best of all is being a black Nigerian female.

(8)  In 2014 Finish researchers  (Scheperjans et al) discovered that PD patients have different gut bacteria profiles from healthy persons. (This appears to also true of Autism and Diabetes, inter alia). Trillions of different bacteria live in the human digestive system, probably weighing about 5 pounds per person. PD patients have a shortage (-78%) of one ‘family’ of bacteria called Prevotellaceae. The researchers also found that levels of another family of bacteria called Enterobacteriaceae appear to be linked to severity of Parkinson's symptoms. They observed patients who had more difficulty with balance and walking tended to have higher levels of these bacteria. Recent research shows gut bacteria interact with parts of the nervous system via various pathways, including the enteric nervous system - the so-called "brain in the gut" - and the vagus nerve. (This confirms Braak’s model – see below).

(9)  The substantially advantageous advances in western medicine for treating PD over the last 200 years have been few and far between. For me there are only 3 developments of profound significance, but this in no way detracts from the cumulative value of 1,000s of other valuable research studies.

(10)                   

(a) The most impactful discovery dates from 1961 and involves the ingestion of L-dopa, a precursor of dopamine, (and major ingredient of “Sinemet”) which can be absorbed in the first 15-17cm of the colon. A small percentage thereof passes through the highly protective “blood-brain barrier” where it is converted into the missing neuro-chemical “dopamine” in the brain. This replenishment temporarily restores some of the patient’s movement abilities. (You may remember the Robert De Niro and Robin Williams movie “Awakenings”.)  Outside of traditional western medicine, the same result appears to have been achieved in places like India generations before this via the ingestion of velvet bean seed (Mucuna Pruriens) which also contains L-dopa (a.k.a. Levidopa), and is now sold over-the-counter in health food stores.

 

(b)  The second major break comes in 1997 when mutations on the SCNA gene in an Italian family are tied to their massive incidence of PD. This gene is responsible for the production of a protein (alpha-synuclein) which is abundant in the brain, heart, muscles, colon and other tissues. This brings alpha-synuclein firmly under the spotlight as a key player in PD when it starts to form clumps due to some malfunction which causes it to stick (miss-fold). These aggregations are found in all PD brains when dissected after death. The larger clumps are referred to as ‘Lewy bodies’. The SNCA gene mutations prove to only account for an extremely small number of PD cases but they provided the clue that PD’s common thread lay in the pathological accumulations of “sticky” alpha-synuclein in the brain which appears to be toxic to dopamine producing neurons.

(c)  The third major break involves the work of a German anatomist, Professor Heiko Braak et al, around 2003, who conducted post-mortems on PD patients and proposed a model which showed the origin of alpha-synuclein aggregations gradually working their way from the gut and nose into the mid-brain. According to Braak’s model an unknown pathogen, akin to a slow-virus, may enter the nervous system through both the nasal and intestinal mucosae, eventually resulting in a cascade of neuro-degenerative events in the brain. In 2015, this idea of a pathogen being transferred from the gut to the brain, perhaps over 20 years in some cases, was supported by the findings of Danish researchers (Svensson et al) that linked surgical removal (vagotomy) of the vagus nerve (the gut-brain nerve connection),  to a 50% reduction in the incidence of PD.

 

(11)                  Environmental triggers for PD have been suspected by most researchers for the longest time, and Braak’s theory is consistent with this in that the nose and gut are our primary interface with the environment around us. In addition, UCLA researchers (Jeff Bronstein et al 2014) have produced data linking exposure to certain catagories of chemicals (pesticides), and certain genetic mutations, with PD onset. This study finds that pesticides that inhibit aldehyde dehydrogenase (ALDH) activity can raise PD risk by up to 6-fold and that having a particular genetic predisposition also raises that risk.

(12)        There are a variety of controlled animal studies which make claims of significantly improving or curing PD symptoms with certain treatments. The studies generally involve the chemical creation of PD in a variety of animals (mice, fruit flies, zebra fish etc.) followed by rectification via doses of things like mannitol, or Ceylon cinnamon (Cinnamonum verum), or custom designed “tweezer molecules” to dismantle alpha-synuclein aggregation. Whilst some of these studies are extremely well conducted, they do not yet extend to PD trials in humans.

(13)                  There are however a couple of PD vaccines which have successfully completed FDA phase 1 trials in Austria and Ireland which are designed to combat alpha-synuclein aggregation. This might be possible at different stages of the toxic process, which appears to spread from neuron to neuron, much like a bacterial infection moves from cell to cell. To quote Dr. Robert Hauser: “Therapies might be developed to (a) reduce α-synuclein concentrations, α-synuclein misfolding or aggregation; or (b) propagation from cell to cell; (c) upregulation of systems responsible for clearance of toxic aggregates or even (d) inhibition of the toxic pathway(s) induced by aggregates might be possible. However, key questions remain: one of the most important of these is the question of which synuclein species are toxic and which might be protective.”

(14)                  “Anyhow, there is now abundant evidence that the synuclein clumping with templating and propagation from neuron to neuron is the key event leading to neurodegeneration in many (probably most) forms of Parkinson’s disease. Note that genetic mutations in the synuclein gene (SNCA) cause PD (as a sole cause) AND duplications and triplications of the gene (ie extra copies, leading to higher than normal levels of normal synuclein) increase risk for PD. More recently discovered is the fact that you can implant synuclein clumps into the brain or gut of an animal and the process spreads, including neuronal degeneration. Most believe it is the relatively small clumps that cause propagation and neuronal degeneration. Big clumps (Lewy bodies) may be protective or just non-active. Now that said, it is unclear in most cases of PD what sets off (initiates) this process. Since the process may be able to start in the gut or olfactory nerve there is definitely interest in the possibility that some environmental exposure initiates the process, but how this might occur is a mystery” says Robert Hauser (June 2015)

(15)                  Solving this ‘mystery’ is obviously the subject of multiple in-progress studies. For example, Dennis Selkoe et al (from Brighams and Womans Hospital, Boston – June 2015) demonstrated that alpha-synuclein, although its true function is not clearly known, travels about the body in groups of one (a ‘monomer’) OR in groups of four (‘tetramers’) AND that any of the 5 known mutations on the alpha-synuclein gene (SNLA) resulted in an under-representation of the number of “four-somes”. So, it appears that we may be dealing with regular, healthy alpha-synuclein in most people but we also could have version(s) of abnormal alpha-synuclein (compliments of any of the SNCA gene mutations). The study showed a relationship between the presence of abnormal alpha-synuclein and reduced levels (> 20%) of the tetramer form (a shortage of “4-somes”). They also found a relationship between mutations and alpha-synuclein protein clumping together as well as having a toxic effect on the neurons. The problem is than the SNCA gene is only one of many (25+) genes that have been implicated by PD research, and alone it only accounts for an extremely small number of PD cases.

 

 

So, we are ready for the fourth and next big break-through.

Any ideas ?

If so, please jot them down and email them to info@ClubPD.com and we will disseminate them to the research community.

 

Finally, let’s note some of the most promising research efforts and opportunities which are underway or pending:

 

(a)  The Michael J Fox Foundation is doing an awesome job on a variety of fronts, in part bolstered by financial assistance from Sergey Brin (Google co-founder). The launch of Fox Insight is a brilliant addition to the research arsenal. Hopefully MJFF will expand the scope of Fox Insight more in line with the database I proposed in 2012 (seehttp://www.clubpd.com/content/how-we-can-collectively-expand-our-assault-parkinsons-disease).

(b)  23andMe.com has strategically accumulated a substantial volume of genetic data derived from selective DNA testing, which can be further analyzed. In January 2015, 23andMe and Genentech (Roche) announced that they will work together to generate whole genome sequencing data for about 3,000 people with PD, in order to identify new therapeutic targets for “treating the degenerative neurological condition”. 23andMe was co-founded and is managed by Anne Wojcicki, the now ex-wife of Google co-founder Sergey Brin. Under the agreement between the two companies, after the multi-year deal ends, 23andMe can conduct additional research on the data and make it available to other Parkinson's researchers. The data will be de-identified and contributed only by individuals who provide explicit permission to 23andMe.

(c)  The certainty that PD is some kind of alpha-synuclein story continues to increase, so the research is probably “on track” (see R. Hauser analysis at http://www.clubpd.com/content/paths-cure-pd)

(d)  Google’s recent reorganization combined with Sergey Brin’s genetic mutation on the LRRK2 gene (PD marker) bodes well for future aggressive and innovative PD research. (Google refers to these scientific forays as “moon shots”.) Now Google Genomics, the company’s cloud-computing platform for life science research, just added a tool called the Genome Analysis Toolkit (or GATK), which was developed by the Broad Institute of MIT and Harvard. This amazing piece of software will help scientists quickly analyze genome-sequencing data. Before, this information was sectioned off in academic labs across the country. But as a service, it’s now online for academic researchers to use free of charge. The main advantage however isn’t the accessibility, so much as all the possibilities that partnering with Google will offer. The Genome Analysis Toolkit will now run on Google’s very powerful cloud-computing infrastructure, giving it the horsepower it needs to rapidly crunch the massive data sets of human genomic data. Sequencing human DNA generates colossal amounts of data. It requires around 100 gigabytes per person. So for researchers, this is big news!

(e)  In August 2015 biotech company, Neuropore Therapies (San Diego CA) announced the start of its Phase I trial of NPT200-11, a compound that binds to the protein alpha-synuclein to reduce its toxicity. Separately another company, Biogen, recently began a Phase I trial of its antibody against alpha-synuclein.

(f)    Austrian biotech Affiris, and Irish biotech Progena have both completed FDA Phase I trials with their vaccines targeting alpha-synuclein. Both are proceeding to Phase II.

(g)  The possibility of finding ways to bring together PD patient data from various databases, and / or finding ways to make all that patient information anonymously available to PD researchers, holds considerable promise. Examples of such databases would be 23andMe, Fox Insight, Parkinson’s Disease Foundation, PatientsLikeMe.com, UPDRS reports from various sources and studies, Biogen, Sage Therapeutics, University of Rochester, etc.. The barrier in some cases is “the search for commercial advantage”, which unfortunately overrides “the search for a cure”.