A sense of (and the science of) smell

Losing the sense of smell is a common feature associated with Parkinson’s disease. But this feature of the condition may help us to better understand the condition. Some autopsy studies have suggested that the olfactory system is one of the first structures in the brain to be affected by the disease.


Source: Guardian

How do we smell?


That’s both a pathetic attempt at humour and a serious answer. Compared with fellow members of the mammalian family, human beings have a pretty poor sense of smell.

The process of smelling stuff is conducted through structures called the olfactory bulbs. The human olfactory bulbs lie on the base of our brains, protruding forward towards our nose (and nasal cavity).


A view of the human brain from below (olfactory bulbs are in yellow). Source: StudyBlue


A view of the human brain from in front (olfactory bulbs are in yellow). Source: StudyBlue

Inside your nose there is an area of smell sensitive cells that lies on the roof of the nasal cavity (about 7 cm behind your nostrils). That area is called the olfactory epithelium, and it plays a critical role in our sense of smell.

The size of the human olfactory epithelium is rather small and reflects our poor sense of smell, especially when compared, for example, to a dog  (humans have about 10 cm2 (1.6 sq in) of olfactory epithelium, while some dogs have 170 cm2 (26 sq in)).


The human olfactory system. Source: Biology junction.com

When you inhale an odor (or odorant molecules) through your nose, there are tiny receptors (called olfactory receptors) on the  olfactory epithelium that are the first step in detecting the smell. Every single olfactory receptor cell presents just one (and only one) type type of odorant receptor. When they detect that odor, the olfactory receptor cell reacts by sending an electrical signal along its branch (called an axon) to the olfactory bulbs in the brain.

As the axon of olfactory receptor cell enters the olfactory bulb it forms clusters with other olfactory receptor cell axons, and these clusters are called glomeruli. Inside the glomerulus (singular), the axons make contact the branches of a type of brain cell called a mitral cell. Mitral cells send their axons to many different areas of the brain, including the anterior olfactory nucleus, piriform cortex, the amygdaloid complex, the entorhinal cortex, and the olfactory tubercle.


Source: YaleScientific

From here our understanding of olfactory processing is less well understood. The piriform cortex is considered the area most likely associated with identifying particular odor. The amygdala is involved in emotional and social functions (eg. mating and recognition), while the entorhinal cortex (and connected hippocampus) is associated with memory – this area is probably activated when a particular smell reminds us of something in our childhood.

What is known about our sense of smell in Parkinson’s disease?

In 1975, two researchers in Minnesota noticed that many of their people with Parkinson’s disease that they were assessing had reduced olfactory abilities. They decided to test this observation:


Title: Olfactory function in patients with Parkinson’s disease.
Authors: Ansari KA, Johnson A.
Journal: J Chronic Dis. 1975 Oct;28(9):493-7.
PMID: 1176578

The researchers took 22 people with Parkinson’s disease and 37 age/sex-matched controls and repeatedly tested them in a double blind study to determine their olfactory acuity. In each test, the subjects were given five test tubes. Two of the tubes in each set contained 0.5 ml of diluted amyl acetate (which has a distinct smell). The other three tubes contained just water. The subjects were asked to inhale through their nose and then identify which two tubes in each set contained the amyl acetate. The highest dilution (the weakest smelling solution) at which the subject could correctly identify the two amyl acetate containing tubes was designated as their olfactory threshold.

The researchers found that people with Parkinson’s disease had a significantly reduced olfactory acuity (a lower olfactory threshold than compared to control subjects). They also noted that subjects with more progressive forms of the disease exhibited a worse performance on the test. Numerous studies have now replicated this overall result, including a recent study that indicated that smoking may have a protective role on the olfactory ability (Click here and here for more on this).

EDITORIAL NOTE: Please understand that the loss of smell in Parkinson’s disease does not immediately mean that you will have a more progressive form of the condition. There is simply a trend in the data that suggests the loss of smell is a risk factor for having a more progressive version of the condition. 

We would also like to discourage any thoughts of taking up smoking in order to protect your sense of smell.

So what is actually happening in the Parkinson’s disease brain?

This is Prof Heiko Braak:


He’s a dude. We’ve mentioned him before in a previous post.

Many years ago, he and his colleagues were intrigued with the hyposmia (reduction in olfactory ability) in Parkinson’s disease. They conducted a series of autopsy studies, looking at 413 brains! Specifically, they were looking for deposits of the Parkinson’s disease-related protein, alpha synuclein, in the brains and where the protein was accumulating. The accumulation of alpha synuclein is believed to be associated with the loss of cells in the brain.

In total they found 30 brains that exhibited accumulation of alpha synuclein. Of interest, they found that 16 of those brains had accumulation of alpha synuclein in the olfactory bulb. And in one particular case, the olfactory bulb was the only affected part of the brain, except for a tiny region of the brain stem.

The researchers were curious about the possibility that the olfactory system could be a potential starting point for Parkinson’s disease, but they were quick to point out that only half the cases they analysed (16/30) had accumulation of alpha synuclein in the olfactory bulb. Thus, while the olfactory system may be involved, it seems unlikely that the nose is the sole induction site of Parkinson’s disease.

After this study was published, however, Braak and his colleagues went on to analyse the accumulation of alpha synuclein in the lining of the gut and their results suggested this as another possible site of induction (we have written about this in a previous post). They have subsequently proposed a model of disease spread based on entry to the brain via the nose and gut:


The Braak stages of Parkinson’s disease. Source: Nature Reviews Neurology.

It is interesting to observe that studies by other scientists have indicated that the nasal epithelium of people with Parkinson’s disease (both with and without the loss of olfactory abilities) is not damaged or presenting an accumulation of alpha synuclein (Click here for more on this).

So what happens to the olfactory bulbs in Parkinson’s disease?

A recent review of the previous studies investigating olfactory bulb volume in people with Parkinson’s disease was published in the Open Access journal PlosOne:


Title: Changes in Olfactory Bulb Volume in Parkinson’s Disease: A Systematic Review and Meta-Analysis.
Authors: Li J, Gu CZ, Su JB, Zhu LH, Zhou Y, Huang HY, Liu CF.
Journal: PLoS One. 2016 Feb 22;11(2):e0149286.
PMID: 26900958  (this report is OPEN ACCESS if you would like to read it)

The authors of the study conducted a systematic review (or meta-analysis) of all of the previous studies (six in total) that have measured the size of the olfactory bulb in the brains of people with Parkinson’s disease (using brain imaging techniques). They found that in all of the 6 studies (collectively 216 PD patients and 175 healthy controls) there was a significant reduction in the size of the olfactory bulbs of people with Parkinson’s disease. Strangely, they authors also found the right olfactory bulb was larger than the left in subjects with Parkinson’s disease across all of the studies, and this effect was not found in the healthy controls.

The motor features of Parkinson’s disease usually begin asymmetrically – by this we mean that the left arm is affected before the right, or the right leg has tremor before the left. This is different for each person, as the disease has no particular preference for either side of the body. So why on earth is the right olfactory bulb more affected than the left?

There is your homework question for tonight!

I’ll expect your answers tomorrow.


Diagnosed 2500 years ago? No problem.

Something different for you today – a history lesson…with some science.

The history of Parkinson’s disease dates back well before Dr James Parkinson made his observations about 6 patients 199 years ago (oh, big anniversary coming up! Who knew)

But it may surprise you to know that the history of Parkinson’s disease dates back before even Jesus turned up.

You actually have to go back a long back in order to get to the beginning…

If you were demonstrating the early features of Parkinson’s disease in the year 500 BCE, there was really only one place in the world that you wanted to be:


India. Source: blogs.umb.edu

Not only did India have a extremely sophisticated system of diagnosis for what we call Parkinson’s disease, but they also have a VERY effective treatment!

Don’t believe me? Read on.

The diagnosis

Around 5000 BCE, the wise and farsighted members of the Indian medical establishment began pooling their collective knowledge – firstly in an oral form, but then eventually in a written format. That written material became the text known as the Ayurveda (/aɪ.ərˈveɪdə/; Sanskrit for “the science of life” or “Life-knowledge”).

It can not be understated how sophisticated the Ayurveda was for its time. This was a period bridging the ‘new stone age’ and the ‘Bronze age’. People’s understanding of medical afflictions was basically limited to what the Gods and evil spirits were doing to them.

The earliest account of Parkinson’s disease features in the Ayurveda  was compiled by Susruta (the 600 BC author of “Susruta Samhita”). He described slowness (cestasanga in Sanskrit) and akinesia (cestahani) in certain individuals, and also (curiously) reported that certain poisons could cause rigidity and tremor.

To demonstrate to you just how sophisticated the Ayurveda was, consider this: when faced with a person exhibiting tremor a practitioner using the Ayurveda could chose between six different types of tremor:

  1. Vepathu (a generalised tremor)
  2. Prevepana (excessive shaking)
  3. Kampa vata (tremors due to vata)
  4. Sirakampa (head tremor)
  5. Spandin (quivering)
  6. Kampana (tremors)

Number 3 (Kampa vata) on that list is what we now refer to as Parkinson’s disease. Kampa basically means ‘tremor’, while Vata is more difficult to define – it is essentially the property/force that governs all movement in the mind and body (blood flow, breathing, etc – even the movement of thoughts).

The treatment

Since the 3rd century BCE, practitioner of the Ayurveda have been using the seeds of Mucuna pruriens in treating conditions of tremor. 


Mucuna Prurien seeds. Source: Kisalaya

Commonly known as the cowhage plant, Mucuna pruriens are a tropical legume. They are called atmagupta in Sanskrit. Powdered seeds of atmagupta mixed in milk was generally given to treat Kampa vata. And it worked very effectively!

How did it work?

In 1937, a pair of chemist discovered the secret ingredient that allowed Mucuna pruriens seeds to work their magic. 

Title: Isolation of l-3:4-dihydroxyphenylalanine from the seeds of Mucuna pruriens.
Authors: Damodaran M, Ramaswamy R.
Journal: Biochem J. 1937 Dec;31(12):2149-52. No abstract available.
PMID: 16746556   (this article is OPEN ACCESS and available to read if you would like)

They found that the seeds contained very high concentrations of a chemical that you and I are familiar with: L-dopa.
Remarkably, Mucuna Pruriens are approximately 4-6% L-dopa, making them mother nature’s natural treatment for Parkinson’s disease. And remember that for over 2000 years, this treatment (atmagupta) has been utilised in the treatment of Kampa vata  in India!

EDITORIAL NOTE: This will probably get me in trouble with the major drug companies, but it would be a worthwhile enterprise for an NGO to set up some Mucuna pruriens plantations in strategically located positions around the world, in order to supply the growing number of people with Parkinson’s disease in the 3rd world. Just a thought. 

How does atmagupta compare with modern L-dopa?

Interesting question.

One that has already been tested:


Title: Mucuna pruriens in Parkinson’s disease: a double blind clinical and pharmacological study.
Authors: Katzenschlager R, Evans A, Manson A, Patsalos PN, Ratnaraj N, Watt H, Timmermann L, Van der Giessen R, Lees AJ.
Journal: J Neurol Neurosurg Psychiatry. 2004 Dec;75(12):1672-7.
PMID: 15548480   (this report is OPEN ACCESS if you would like to read it)

In this double blind clinical study, the researchers gave 8 people with Parkinson’s disease with a short duration L-dopa response and dyskinesias single doses of 200/50 mg L-dopa or 15-30 g of mucuna preparation. They gave these treatments in a randomised fashion at weekly intervals. They found that mucuna seed powder formulation had a more rapid onset of action and a longer period without dyskinesias. The researchers concluded that ‘this natural source of L-dopa might possess advantages over conventional L-dopa preparations in the long term management of PD’. A grand conclusion, but they also note that a more long term assessment is required.

And that concludes your history lesson for today – hope you liked it!

Cleaning up with Ambroxol

Exciting news recently with the announcement of the Ambroxol study starting.

Exciting for two reasons:

  1. Ambroxol has the potential to make a major impact in the lives of some people with Parkinson’s disease.
  2. It illustrates how FAST things are moving in the world of Parkinson’s disease!


Inside each and every cell, there are millions of tiny actions taking place. Minute processes all working in a collective manner allowing the cell to function normally. There are lots of proteins helping to make other proteins, lots of proteins helping other proteins to get to where they need to be, and lots of proteins helping to break down other proteins after they have done their job.

All this activity generates a lot of waste. And a fundamental part of the activity in any cell is waste disposal. If that does not function properly, the cell is in serious trouble.

One of the most common genetic mutations associated with Parkinson’s disease – called GBA – results in cells having trouble getting rid of waste.


Adapted from a cartoon by Dr Jing Pu. Source: The Nichd connection

What is GBA?

Glucocerebrosidase (or GBA) is an enzyme that helps with the recycling of waste. It is active in inside ‘lysosomes‘.

What are Lysosomes?

Lysosomes are small structures inside cells that act like recycling centers. Waste gets put inside the lysosome where enzymes like GBA help to break it down into useful parts. Mutations in the GBA gene can result in an abnormally short, non-functioning version of the enzyme. And in those cases the breaking down of waste inside the lysosome because inhibited.

What is the connection between GBA and Parkinson’s disease?

GBA mutations are the most common genetic anomaly associated with Parkinson’s disease. People with a mutation in their GBA gene are at higher risk of developing Parkinson’s disease than the general population. And people with Parkinson’s are approximately five times more likely to carry a GBA mutation than healthy control subjects.

So what is Ambroxol?

Ambroxol is a commonly used treatment for respiratory diseases. It promotes mucus clearance and eases coughing. Ambroxol is also anti-inflammatory, reducing redness in a sore throat.

Ok, but why the excitement for Parkinson’s disease?

In May of 2014 – less than 2 years ago – this study was published:


Title: Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells.
Authors: McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A, Foltynie T, Cooper JM, Abramov AY, Gegg M, Schapira AH.
Journal: Brain. 2014 May;137(Pt 5):1481-95.
PMID: 24574503    (This report is OPEN ACCESS if you want to read it)

It was the first time that Ambroxol – a commercially available drug – had been tested in a Parkinson’s disease related context.

In this study the researchers collected skin cells (called fibroblasts) from eleven people with GBA mutations (some had been diagnosed with Parkinson’s disease). They measured the amount of glucocerebrosidase protein and enzyme activity in these cells, and they found that glucocerebrosidase enzyme activity was significantly reduced in fibroblasts from GBA mutations (on average just the enzyme was acting at just 5% of normal levels). They found that ambroxol increased glucosylceramidase activity in fibroblasts from people with GBA mutations AND in fibroblasts from healthy controls. Ambroxol treatment also reduced markers of oxidative stress in GBA mutant cells.

Given the increase in glucocerebrosidase activity after ambroxol treatment, the researchers wondered whether the drug would reduce alpha-synuclein levels in cells that were over-expressing this protein. Amazingly, after 5 days of ambroxol treatment, levels of alpha-synuclein had decreased significantly (15% on average 15%).

You can understand why the researchers were a little bit excited by these results. Here was a drug that re-activated the recycling unit in the cell and reduced levels of one of the main proteins associated with Parkinson’s disease. If the drug can reduce the levels of alpha synuclein in the brains of people with Parkinson’s disease, maybe the researchers will be able to slow down (or even halt) the disease!

Additional studies have now been reported which have confirmed the initial results.

And now the clinical trial?

Funded by the Cure Parkinson’s Trust and the Van Andel Research Institute (USA), it was announced this week that they had started recruiting subjects to be involved in a clinical trial at the Royal Free Hospital in London. The trial is a phase 1 study which will test the safety of Ambroxol in Parkinson’s disease. The researchers will also look to see if Ambroxol can increase levels of glucocerebrosidase and whether this has any beneficial effects in the subjects. The study will be conducted on 20 people with Parkinson’s disease who also have GBA mutations. They will be given the drug and followed over the next 24 months.

These are exciting times for the world of Parkinson’s disease as these drugs are no longer simply reducing the motor features of the condition, but actually attempting to slow/halt the disease.

And as we suggested at the start of the post the pace of these developments is becoming hard to keep up with.

Diabetes, Monster saliva, and Parkinson’s disease


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.

Diabetic patient doing glucose level blood test
Diabetic patient doing glucose level blood test using ultra mini glucometer and small drop of blood from finger and test strips isolated on a white background. Device shows 115 mg/dL which is normal

Source: Gigaom

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.
PMID: 18599528

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.
PMID: 21378214

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.
PMID: 21411503

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).

Cute huh?

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.
PMID: 17803225

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.

There is, however, a follow up double blind clinical study currently underway – funded by the Michael J Fox Foundation – which will be completed in June of this year (2016).

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.

Summing up

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!

Something lrrk-ing in the water…


Before you read any further, I feel it only fair to warn the squeamish amongst you that todays post is going to deal with the topic of urine. I myself have a little ‘three-nager’ who is potty training at the moment, so I am rather intimately familiar with the stuff. But consider yourselves fair warned.


Warning out of the way, let’s begin:

What is urine?

Urine is a liquid excression from our body, consisting of water, salts and a substance called urea. It is made in the kidneys, temporarily stored in the bladder, and eventually released through the urethra. Pretty simple right.

On a good day approximately 90-95%  of your urine will be water. Within the remaining 5%, however, there is a lot of solids that have been removed from the blood system by the kidneys. Those solids may be considered waste by our bodies, but they can tell us a lot about what is happening inside us.

Last week some researchers from the University of Alabama and Columbia University (NY) published a study that analysed some of those solids – looking at one enzyme in particular – being excreted in urine. They wanted to determine whether there were any differences between normal healthy individuals and people with Parkinson’s disease.

Their results are really interesting:



Title: Urinary LRRK2 phosphorylation predicts parkinsonian phenotypes in G2019S LRRK2 carriers.
Authors: Fraser KB, Moehle MS, Alcalay RN, West AB; LRRK2 Cohort Consortium.
Journal: Neurology. 2016 Feb 10.
PMID: 26865512

We have previously discussed Lrrk2 (and you can find that post here). It is a gene that is particularly interesting with regards to Parkinson’s disease because mutations in that gene are associated with susceptibility to the condition.

The Lrrk2 gene gives rise to an enzyme that has different functions in our cells. The researchers in the current study extracted the lrrk2 enzyme from the solid waste of urine and started analysing the “phosphorylation status of the enzyme”.

Ok, um,…what is Phosphorylation?

Phosphorylation is the process by which a phosphoryl group is added to a molecule.

And what is a phosphoryl group?!?

Oh, never you mind. Just remember that phosphorylation is basically the way in which many enzymes – like Lrrk2 – are turned on (and off when they are dephosphorylated). Through phosphorylation the function/activity of an enzyme is changed. They can go from dormant to active through this process. And this addition of the phosphoryl group to the molecule can occur at different places on that molecule, affecting the resulting activity in different ways.

So what did the researchers find?

The scientists found that people with Parkinson’s disease who also have a particular mutation in the Lrrk2 gene (that mutation is called p.G2019S) had almost 5 times more phosphorylation at a particular part of the Lrrk2 enzyme than normal healthy control subjects. Interestingly, those levels were also 4.5 times higher than those of people with PD, but who did not have the Lrrk2 mutation.

This means that the researchers have found a potential biomarker of the Lrrk2 mutation (independent of Parkinson’s disease itself). This finding could offers us a means of determining people with the Lrrk2 mutation – who may be susceptible to Parkinson’s disease – with a simple urine test.

But the researchers also noticed that among all of the study participants who have the Lrrk2 mutation,those who also had Parkinson’s disease had levels of phosphorylation twice as high as those who did not have Parkinson’s disease. Thus the overall results suggest that regardless of mutation status, higher levels of Lrrk2 phosphorylation are associated with a greater risk or the presence of Parkinson’s disease.


A diagram graph illustrating the findings of the Lrrk2 study. Source: Neurology

What does this mean?

Firstly, we need to point out that the study was conducted on a small population of men (two studies actually – the first had 14 subjects, and the second had 62 subjects). The results need to be independently replicated in larger groups (ideally also containing some female participants).

The results are very exciting, however, as they may point towards potential therapeutic pathways. It could also provide a means of monitoring clinical trials – a feature that the University of Alabama researchers are currently testing in another clinical trial. They are investigating if a LRRK2 inhibitor drug, called Sunitinib, results in lower leaves of phosphorylated Lrrk2 in the urine.

The research is also encouraging with regards to the search for biomarkers in Parkinson’s disease – a quest that has struggled somewhat until recently. Novel biomarkers provide useful tools in our fight against this terrible disease.

Brain (not Heart) warming research

The great Isaac Asimov once said:

“The most exciting phrase to hear in science, the one that heralds new discoveries, is not ‘Eureka!’ but ‘huh, that’s funny’…”

Here at the Science of Parkinson’s disease we suspect that this was the situation when some Italian scientists made a curious discovery in some early-onset Parkinson’s disease subjects.


An image of a brain scan. Source: DailyMail

Last week they published their observation in the journal Movement Disorders:


Title: Abnormal Brain Temperature in Early-Onset Parkinson’s Disease
Authors: Rango M, Piatti M, Di Fonzo A, Ardolino G, Airaghi L, Biondetti P, & Bresolin N.
Journal: Movement Disorders, 2016 Mar;31(3):425-6.
PMID: 26873586

The researchers were conducting brain scans of 5 people with early onset Parkinson’s disease (3 men and 2 women, with an average age of 41±6 years) and 10 control/normal subjects (6 men and 4 women with an average age of 43±7 years). The study was a follow on from a smaller previous study conducted by the same researchers. There was absolutely no difference in the average body temperature of all the subjects (36.7±0.48°C) and healthy subjects (36.5±0.84 °C).

But when the researchers began looking at different brains regions, they found there were substantial increases in temperature in the early-onset Parkinson’s patients when compared to the control subjects.

The areas of the brain where significant temperature differences were observed included:

  • the hypothalamus (38.50±0.20 vs. 37.01±0.60 °C; PD subjects vs controls)
  • the posterior cingulate gyrus (37.60±0.20 vs. 36.70±0.40 °C)
  • the centrum semiovale (38.00±0.60 vs. 36.60±0.60 °C)
  • the lenticulate nucleus (38.80±0.80 vs. 37.40±0.60 °C)

There was also a slight difference in the visual cortex in the patient group, but this was not statistically significant (37.20±0.20 vs. 36.80±0.40 °C).

Dysfunction in the hypothalamus is known to occur in Parkinson’s disease (click here for more information on this). Changes in the posterior cingulate gyrus (an area involved with emotion) have also been reported (click here for more information on this). But our knowledge of the role of the centrum semiovale and lenticulate nucleus in Parkinson’s disease requires further investigation.

Please remember that all things being equal, there should be no difference whatsoever in brain temperatures. The brain is an extremely sensitive organ and its temperature is rigidly controlled.

So why is there a difference?

Basically the researchers have no idea and, to their credit, they admit as much.

They also point out to the reader that any temperature change in the hypothalamus – an area of the brain that regulates temperature in the body – should result in a corrective response to restore proper temperature in the brain. But apparently in the early-onset Parkinsonian brain it doesn’t. They also note that dopamine-based Parkinson’s treatments (such as levodopa) should decrease overall brain temperature because they increase cerebral blood flow (a natural cooling system for the brain). But again, this doesn’t appear to be happening.

They speculate that maybe these temperature differences are the result of ongoing disease-related activities in the brain, and they offer some well considered ideas as to why this maybe. But there are many other areas of the brain that are affected by Parkinson’s disease – why is there no change in temperature in those regions?

The researchers also ask whether cooling the brain may be considered as a therapeutic option. An interesting idea but this still needs to be tested. And the results of the current study also need to be replicated – independently validated by other groups.

In those replication studies it would be interesting to conduct the same experiment on people with Parkinson’s disease at different stages of the disease to see the effect is consistent or changing over time.

A curious result. Opening up new areas of research. And further evidence that it’s the ‘huh, that’s funny’ results that ultimately lead to the  ‘Eureka!’ moments.

The science of focused ultrasound therapy

Novel therapeutic approaches for Parkinson’s disease are popping up all the time.

Recently there has been quite a bit of noise in the media regarding something called ‘focused ultrasound-based therapies‘ for Parkinson’s disease. We’re talking about reports such as this and this.

The initial results look very exciting and the Michael J Fox foundation has helped to fund a phase one clinical trial of the technology, but what exactly is focused ultrasound?

Let’s start at the beginning: Ultrasound

Ultrasound is defined as sounds at frequencies greater than 20 kHz. These are at high frequencies and short wavelengths.


Approximate frequency ranges corresponding to ultrasound. Source: Wikipedia

The human ear is not designed to register ultrasound, but it is still useful to us. Since ultrasound was first used by Paul Langevin to detect submarines in 1917, we have found many uses for it, most of them in the field of medicine (notably the imaging of unborn babies and breaking up kidney stones).

The use of ultrasound in procedures involving the brain has previously been very limited because of that natural protective helmet we call the skull. Normal ultrasound does not penetrate the skull very well. High intensity ultrasound, however, does.

So what is focused ultrasound?

High intensity focused ultrasound, also known as magnetic resonance guided focused ultrasound, is a procedure that uses very intense ultrasound generated from multiple points but focused on one specific area. The waves from those different points of emission are all in phase – that is to say their waves match. All that ultrasound concentrated in one location generates a lot of heat at that focal point. That heat allows for the destruction of diseased or damaged tissue at that particular point of focus.



A schematic demonstrating the focused ultrasound technique. Source: Ghanouni et al (2015)

The procedure is relatively quick, non-invasive (no surgery). The subject is placed on a bed and their head is covered by a cooling unit. Around the cooling unit is the ultrasound transducer array – multiple generators of the ultrasound pointing in toward the skull.


Images demonstrating the focused ultrasound technique: Source: Ghanouni et al (2015)

The subject, the cooling unit, and the transducer array are then placed inside an MRI brain scanning machine to allow for extremely accurate focusing of the ultrasound waves. Once everything is in place, the procedure will begin. According to the scientists conducting the research, the procedure – from start to finish – takes approximately 2 hours.

07_14_13632_03a_cmyk A brain scan image of the area being targeted (red cross). The skull is in green, and the cooled water unit is is red.  Source: Ghanouni et al (2015)

So what has been done research wise?

The research about using focused ultrasound in Parkinson’s disease is still very new. The first papers investigating the utility of the technology with regards to PD were only published a couple of years ago.

These papers include:


Title: First experience with MR-guided focused ultrasound in the treatment of Parkinson’s disease.
Authors: Magara A, Bühler R, Moser D, Kowalski M, Pourtehrani P, Jeanmonod D.
Journal: J Ther Ultrasound. 2014 May 31;2:11.
PMID: 25512869  (This article is OPEN SOURCE if you would like to read it)

This study was the first report of focused ultrasound being employed in humans with Parkinson’s disease. The researchers performed a pallidothalamic tractotomy (or destruction of the fibres connecting the basal ganglia to the thalamus – see our previous post about these structures). This removed the inhibitory signal being sent to the thalamus, allowing it to function more freely.

In this paper, the procedure was performed on 13 patients, demonstrating the safety and efficacy of the approach. The investigators reported a 60% improvement in Parkinson’s motor assessment (using the UPDRS) at 3 months post procedure.



Title: MRI Guided Focused Ultrasound Thalamotomy for Moderate-to-Severe Tremor in Parkinson’s Disease.
Authors: Schlesinger I, Eran A, Sinai A, Erikh I, Nassar M, Goldsher D, Zaaroor M.
Journal: Parkinsons Dis. 2015;2015:219149.
PMID: 26421209  (This article is also OPEN SOURCE if you would like to read it)

This study involved 7 subjects with Parkinson’s disease who received a thalamotomy (the destruction of part of the thalamus) using focused ultrasound. The subjects demonstrated a better than 50% improvement in their motors scores and the effects were sustained for at least 7 months post procedure.


Title: Unilateral magnetic resonance-guided focused ultrasound pallidotomy for Parkinson disease.
Authors: Na YC, Chang WS, Jung HH, Kweon EJ, Chang JW.
Journal: Neurology. 2015 Aug 11;85(6):549-51.
PMID: 26180137

In this case study report, the researchers conducted a pallidotomy (the destruction of the source of the fibres projecting to the thalamus) using focused ultrasound in a patient with Parkinson’s disease who had extremely severe dyskinesias (uncontrollable movements associated with long term use of PD medications). They reported 70-80% reductions in many of the motor assessments at 6 months post-procedure. The researchers noted many of the complications of deep brain stimulation that can be avoided with this technique (those complications include infection & hemorrhage due to surgery, and hardware-related complications with the expensive devices).

Importantly all of these study illustrated that the focused ultrasound technique was safe and had beneficial effects.

In Summary:

Focused ultrasound therapy is a new experimental treatment that is being tested in people with Parkinson’s disease. It is currently being oriented as a treatment option for people with Parkinson’s who have severe dyskinesias.

The pros of the focused ultrasound technology/approach:

  • No surgery – the procedure is non-invasive
  • No risk of infection
  • Little collateral damage (e.g. due to instruments passing through the cortex to get to the target region)
  • The effect is relatively immediate

The cons:

  • It does not cure the disease, merely  alleviates motor features (tremors, etc)
  • It is very important to note that the focused ultrasound procedure is irreversible.
  • Once performed, the effect is unadjustable – there is no ‘volume control’ on the resulting effect.
  • The technique is still experimental and the researchers do not know how long the effects will last.


We here at the Science of Parkinson’s have presented this post for information purposes. We are not affiliated with any of the groups/companies currently promoting this treatment. We have tried to remain unbiased in our explanations and assessment.

We would like to see some long-term data on the focused ultrasound approach before passing judgement on this treatment approach. Importantly, we need to know how long the effect can last – this will most likely vary from person to person. Given that the disease will still be progressing in individuals who have this treatment, it would be interesting to see the longer term consequences.

We would also like to see a comparative study between focused ultrasound and deep brain stimulation (the current best option for people with severe dyskinesias). Deep brain stimulation is an invasive, surgical procedure in which a ‘pacemaker’ like probe is inserted into the brain. Importantly deep brain stimulation is adjustable (the electrical signal being sent into the brain can be fine tuned) while focused ultrasound is not adjustable once the procedure is completed. Given this last detail, we believe that the focused ultrasound should remain a last choice option in any treatment approach to Parkinson’s disease (at least for the time being).

New Research – on how movement is controlled


A couple of very interesting studies were published a week ago that help us to better understand how we move. They are particularly important with respects to Parkinson’s disease.

The parts of the brain involved in movement

Movement is largely controlled by the activity in a specific collection of brain regions, collectively known as the ‘Basal ganglia‘.


The location of the basal ganglia structures (blue) in the human brain. Source: iKnowledge

The basal ganglia receives signals from the overlying cortex, processes that information before sending the signal on down the spinal cord to the muscles that are going to perform the movement.

There is also another important participant in the regulation of movement: the thalamus.


A brainscan illustrating the location of the thalamus in the human brain. Source: Wikipedia

The thalamus is a structure deep inside the brain that acts like the central control unit of the brain. Everything coming into the brain from the spinal cord, passes through the thalamus. And everything leaving the brain, passes through the thalamus. It is aware of most everything that is going on and it plays an important role in the regulation of movement.

The direct/indirect pathways

The processing of movement in the basal ganglia involves a direct pathway and an indirect pathway. In simple terms, the direct pathway encourages movement, while the indirect pathway does the opposite (inhibits it). The two pathways work together like a carefully choreographed symphony.

The motor features of Parkinson’s disease (slowness of movement and resting tremor) are associated with a breakdown in the processing of those two pathways, which results in a stronger signal coming from the indirect pathway – thus inhibiting/slowing movement.


Excitatory signals (green) and inhibitory signals (red) in the basal ganglia, in both a normal brain and one with Parkinson’s disease. Source: Animal Physiology 3rd Edition

Both the direct and indirect pathways finish in the thalamus, but their effects on the thalamus are very different. The direct pathway leaves the thalamus excited and active, while the indirect pathway causes the thalamus to be inhibited.

The thalamus will receive signals from the two pathways and then decide – based on those signals – whether to send an excitatory or inhibitory message to the cortex, telling it what to do (‘get excited and movement’ or ‘don’t get excited and don’t move’, respectively).

Where does dopamine come into the picture?

In Parkinson’s disease, the cells in the brain that produce the chemical dopamine are lost. These cells reside in a structure called the substantia nigra (or SNc in the figure above). What effect does this cell loss have on the direct and indirect pathways? Under normal circumstances the dopamine neurons excite the direct pathway and inhibit the indirect pathway.

In Parkinson’s disease the loss of dopamine neurons results in increased activity in the indirect pathway. As a result, the thalamus is kept inhibited. With the thalamus subdued, the overlying motor cortex has trouble getting excited, and thus the motor system is unable to work properly.

So what was published last week?

Two papers.

Both from the same lab (Well done!)

One in the prestigious scientific journal, Cell and the other in her sister journal, Neuron:


Title: Cell-Type-Specific Control of Brainstem Locomotor Circuits by Basal Ganglia.
Authors: Roseberry TK, Lee AM, Lalive AL, Wilbrecht L, Bonci A, Kreitzer AC.
Journal: Cell, 2016 Jan 28;164(3):526-537.
PMID: 26824660

The researchers in this study discovered signal sent from the basal ganglia that selectively activates a group of neurons an area of the brainstem called the ‘mesencephalic locomotor region’. Some of the neurons in this area release a chemical called glutamate. Glutamate is a neurotransmitter that excites the cells it comes into contact with. The researchers who conducted this study found that these glutamate-releasing cells in the mesencephalic locomotor region are responsible for initiating movement.


The researchers used a new technique called ‘optogenetics’ that allows light to activate or inhibit specific cells in the brain. By using this technique on the cells in the direct (dMSN in the figure above) or indirect pathways (iMSN) of the basal ganglia, the researchers were able to control the glutamate-releasing neurons in the mesencephalic locomotor region of mice -initiating or inhibiting their movement, respectively.

The researchers then took the study one step further and used the optogenetics approach directly on the glutamate-releasing neurons in the mesencephalic locomotor region, and they were able to control the initiation of movement in the mice irrespective of the signal being generated by the direct or indirect pathways. That is to say, when the glutamate-releasing neurons in the mesencephalic locomotor region were activated, the mouse would move even when the basal ganglia was sending an inhibitory signal.

So what does it all mean?

While some of the findings of the study were already known, the researchers here have elegantly linked the workings of the basal ganglia and the mesencephalic locomotor region, helping us to better understand the neurological functioning of movement. Deep brain stimulation of the mesencephalic locomotor region has already been attempted and it has demonstrated mixed results in people with Parkinson’s disease (it does appear to help with regards to reducing falls – click here and here for more on this).

It will be interesting to follow the research resulting from this current study.


Title: Pathway-specific remodeling of thalamostriatal synapses in Parkinsonian mice
Authors: Parker PRL, Lalive AL, Kreitzer AC.
Journal: Neuron, 2016
PMID: 26833136

In the second study, the researchers (the same folks who gave us the first paper!) found that the basal ganglia is biased towards the direct pathway. The signal coming from the neurons involved in the direct pathway are stronger than those in the indirect pathway. When dopamine is removed however (as in the case of Parkinson’s disease), the system swings in the opposite direction and becomes biased toward the indirect pathway – the neurons in the direct pathway begin to produce a weaker signal than their counters in the indirect pathway which increase the strength of their signal.

Given that both pathways influence the activity of the thalamus, the researchers next turned their attention to that structure. Again using the ‘optogenics‘ (light-activation) technique, the investigators reduced the inhibitory signal coming from the thalamus and were able to reversibly correct the motor impairs observed in the mice with Parkinson’s-like features.

What does this mean for Parkinson’s disease?
This study turns our attention away from what is happening in the basal ganglia and focuses it on the thalamus, which has not receive the same amount of attention with regards to Parkinson’s disease.

There is a lot already known about changes in the thalamus in Parkinson’s disease (click here for more on this), and deep brain stimulation of structures in neighbouring regions is a regular therapy for Parkinson’s disease (targeting the subthalamic nuclei). But this new paper further breaks down the circuitry of movement for us and offers novel directions for future therapeutic approaches for Parkinson’s disease.

We can be sure that a lot of Parkinson’s disease research is now going to focus on the thalamus.


Improving diagnosis

An inconvenient truth:

The diagnosis of Parkinson’s disease can only be definitively achieved at the postmortem stage.

There is currently no diagnostic test for this task and we are reliant on the training and skills of the neurologists making the diagnosis. Brain imaging techniques (such as DAT-scans) are great, but they can only aid physicians in their final decision.

And those decisions are not always right.

In 1992, a study looking at the brains of 100 subjects who had died with Parkinson’s disease, found that 24% of the cases did not fulfill the pathological requirements for the diagnosis of Parkinson’s disease. That study was:


Title: Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases.
Authors: Hughes AJ, Daniel SE, Kilford L, Lees AJ.
Journal: Journal of Neurol Neurosurg Psychiatry. 1992 Mar;55(3):181-4.
PMID: 1564476

Unfortunately, despite years of research, it would appear that there is still a large degree of error in the clinical diagnosis of Parkinson’s disease. A study published in 2014 in the journal Neurology that suggested that there is currently a 15% rate of misdiagnosis. That study was:



Title: Low clinical diagnostic accuracy of early vs advanced Parkinson disease: clinicopathologic study.
Authors: Adler CH, Beach TG, Hentz JG, Shill HA, Caviness JN, Driver-Dunckley E, Sabbagh MN, Sue LI, Jacobson SA, Belden CM, Dugger BN.
Journal: Neurology. 2014 Jul 29;83(5):406-12.
PMID: 24975862

It has to be said that clinicians face a very difficult task in diagnosing Parkinson’s disease. The variety of features (symptoms) that patients present with in the clinic, and the lack of diagnostic tools, leave neurologists making a judgement based largely on clinical observations.

But this degree of error ultimately has a huge impact on clinical studies and trials: if 10-20% of the participants are not Parkinsonian, are we really going to observe an accurate result?

Better diagnostic tests/tools are critically required.


In November last year, a study was published in the journal Immunology Letters which may help in this regard:

Title: Potential utility of autoantibodies as blood-based biomarkers for early detection and diagnosis of Parkinson’s disease.
Authors: DeMarshall CA, Han M, Nagele EP, Sarkar A, Acharya NK, Godsey G, Goldwaser EL, Kosciuk M, Thayasivam U, Belinka B, Nagele RG; Parkinson’s Study Group Investigators.
Journal: Immunol Letters, 168(1), 80-8.
PMID: 26386375  (this article is OPEN access if you would like to read it)

The researchers took 398 subjects, including 103 early-stage Parkinson’s disease subjects and they collected blood samples from them. They then screened the blood for 9,486 different autoantibodies that could be useful as biomarkers for Parkinson’s disease.

Antibodies are produced by our immune system to determine what is ‘self’ and not ‘self’. They are the foundation of our defenses against the big, bad germ/bacteria world. Autoantibodies are antibodies produced by our immune system that are directed against our own tissues. They target ‘self’.

And yeah, that is bad. Autoantibodies are associated with autoimmune diseases such as Lupus.

We are not sure why we produce autoantibodies. The causes of their production vary greatly and are not well understood. In Parkinson’s disease, however, autoantibodies may be produced as a result of the cell death in the brain. Some of the debris resulting from the dying cells will make its way into the bloodstream, to be removed from the body. Whilst in the blood, some of that debris could trigger the immune system, thus resulting in the production of autoantibodies.

De Marshall et al (the researchers who conducted this study) were hoping to take advantage of this autoantibody production and use them as biomarkers to not only differentiate between people with and without Parkinson’s disease, but also to differentiate between different stages of Parkinson’s disease (see the figure below).


Attempting to differentiate between different stages of Parkinson’s disease. Source: Immuno Letters

The researchers found that using the top 50 autoantibodies that they associated with Parkinson’s disease, they could successfully differentiate between people with and without Parkinson’s disease with 90% prediction accuracy in a blind analysis (they actually found that just the top 4 autoantibodies were enough).

Interestingly, the researchers then compared the early Parkinson’s group with a mild-moderate Parkinson’s group and they found that they could differentiate between the two groups with an overall accuracy of 97.5%!


These are very exciting results and we will be following this work with interest – not only from the standpoint of biomarkers, but also the role of autoantibodies in Parkinson’s disease.

New research – new targets of Lrrk2

This is Sergey Brin.


He’s a dude.

Having brought us ‘Google’, he is now turning his attention to other projects.

One of these other projects is close to our hearts: Parkinson’s disease.


In 1996, Sergey’s mother started experiencing numbness in her hands. Initially it was believed to be RSI, but then her left leg started to drag. In 1999, following a series of tests, Sergey’s mother was diagnosed with Parkinson’s disease. It was not the first time the family had been affected by the condition: Sergey’s late aunt had also had Parkinson’s disease.

Both Sergey and his mother have had their genome scanned for mutations that increase the risk of Parkinson’s disease. And both of them discovered that they were carrying a mutation on the 12th chromosome, in a gene called Leucine-rich repeat kinase 2 or Lrrk2.

Not everyone with this particular mutation will go on to develop Parkinson’s disease, but Sergey has decided that his chances are 50:50. Being one of the founders of a large company like Google, however, has left Sergey with resources at his disposal. And he has chosen to focus some of those resources on Lrrk2 research (call it an insurance  policy).

Today, the fruits of some of that research has been published and the results are really interesting:



Title: Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases
Authors: Martin Steger, Francesca Tonelli, Genta Ito, Paul Davies, Matthias Trost, Melanie Vetter, Stefanie Wachter, Esben Lorentzen, Graham Duddy, Stephen Wilson, Marco AS Baptista, Brian K Fiske, Matthew J Fell, John A Morrow, Alastair D Reith, Dario R Alessi, Matthias Mann
Journal: Elife 2016;10.7554/eLife.12813
PMID: 26824392  (This report is openly available for reading on the Elife website)

So what is Lrrk2?

Also known as dardarin (Basque for ‘trembling‘), Lrrk2 is a gene in our DNA that is responsible for making an enzyme. That Lrrk2 enzyme is involved in many different aspects of cell biology. From cellular remodeling and moving (‘trafficking’) various proteins around in the cell, to protein degradation and stabilization, Lrrk2 has numerous roles.

Discovered in 2004, Lrrk2 was quickly associated with Parkinson’s disease because mutations in this gene are amongst the most common in ‘familial Parkinson’s‘ (where an inherited genetic mutation is present in the sufferer; accounting for about 10-20% of all cases of 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.

Curiously, mutations in Lrrk2 are also associated with increased risk of Crohn’s disease and cancer.


The structure of Lrrk2 and where various mutations lie. Source: Intech

Given the association with Parkinson’s disease, there have been attempts to develop inhibitors of Lrrk2 as a means of treating the condition. These efforts, however, have been hampered by a poor agreement as to which proteins are interacting with Lrrk2.

The goal of the current study was to identify the key proteins that Lrrk2 acts upon.

What did they discover?

Using various techniques to accomplish their task, the scientists began with 30,000 possible targets and gradually whittled that number down to a small group of Lrrk2 targets.

Most importantly, they found that Lrrk2 is deactivating certain proteins that are called ‘Rabs’. The Rab family are heavily involved with trafficking (and that’s not the mafia drug variety!). Trafficking in cells in moving proteins around within the cell itself. And Lrrk2 was found to deactivate 4 Rab family members (3, 8, 10 and 12).

This is a very important result as not only does it provide us with novel Lrrk2 targets, but it also offers us an excellent tool with which we can determine if Lrrk2 inhibitors are actually working  – a functioning Lrrk2 inhibitor will lower the activity of Rab 3, 8 10 & 12 and this can be measured.

The results represent a major leap forward in our understanding of Lrrk2 and a significant return on investment for one Mr Sergey Brin.