Improving diagnosis

February 2, 2016February 2, 2016 ~ Simon ~ 7 Comments

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:

Adler-title

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).

1-s2.0-S0165247815300341-gr3

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

February 2, 2016August 3, 2017 ~ Simon ~ 3 Comments

This is Sergey Brin.

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:

Elife

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.

New research – Urate and Parkinson’s

January 23, 2016January 23, 2016 ~ Simon ~ 4 Comments

New research this week lends further support to ongoing clinical trials focused on urate in Parkinson’s disease:

urate

Title: Prospective study of plasma urate and risk of Parkinson disease in men and women.
Authors: Gao X, O’Reilly ÉJ, Schwarzschild MA, Ascherio A.
Journal: Neurology. 2016 Jan 13.
PMID: 26764029

The researchers in this study looked at 90,214 participants who are involved in three ongoing US-based longitudinal studies (the Nurses’ Health Study (NHS), the Cancer Prevention Study II Nutrition (CPS-IIN), and the Health Professionals Follow-up Study (HPFS)). They identified 388 people in these cohorts who had developed Parkinson’s disease (202 men and 186 women) since their respective longitudinal studies began, and they matched them to 1,267 randomly selected control subjects.

Blood samples that had been taken from the Parkinson’s and control subjects were analysed, and the level of urate was measured. Normal levels of urate range from 3.5-7.2 milligrams per deciliter (mg/dL). The researchers found that there was no difference between in spectrum of urate levels in the women (with or without Parkinson’s).

In men, however, things were very different. The men with the lowest levels of urate had less than 4.9 mg/dL, while those with the highest levels had 6.3-9.0 mg/dL. Among the men with Parkinson’s disease, 45 had the highest level of urate and 58 had the lowest – if no difference existed, this number should be 50:50, but instead there is more than 30% difference. Men with high levels of urate had a lower chance of developing Parkinson’s disease.

The researchers then combined their results with the results from three previous studies on the same topic and found a very similar result. This led the researchers to conclude that men, but not women, with higher urate concentrations had a lower future risk of developing Parkinson’s, suggesting that urate could be protective against Parkinson’s risk or could slow disease progression during the preclinical stage of disease.

So, what is urate?

During the breaking down of dietary proteins, the liver produces large amounts of a chemical called ‘ammonia’. Ammonia is toxic for the body, so the liver breaks it down further, and one of the products of that process is urate. If the body does not get rid of it, urate can build up and form crystals within the joints. High blood concentrations of urate can lead to gout and is also associated with other medical conditions, such as diabetes and the formation of kidney stones.

Paradoxically, urate is also an ‘antioxidant’ – a chemical that prevents tissue from being damaged by the negative effects of oxygen (yes, we need oxygen but not too much). Other antioxidants include vitamin C, and vitamin E. It is this antioxidant function of urate that researchers believe has a positive effect in Parkinson’s disease.

What are the clinical trials we mentioned?

In September 2015, a Phase III trial of Inosine was initiated. The study will involve 270 people with early-stage Parkinson’s. Inosine is a chemical precursor to urate and Phase III is the ‘acid test’ – a double blind test of treatment efficacy. A Michael J Fox Foundation-funded Phase II study showed that Inosine is safe and tolerable, and it also raised levels of urate in people with early-stage Parkinson’s disease. Now it is time to see if this raising of urate levels has a positive outcome. Enrollment for this trial is currently underway and -given the results of the study published this week – it will be interesting to see if there is a stronger effect in men in this phase III trial.

IMPORTANT EDITOR’S NOTE HERE: Inosine is commercially available as a dietary supplement, but we must stress that patients should act with caution. Inosine has not yet been proven as a therapy for Parkinson’s disease, and, as we indicated above, it can cause serious conditions such as gout and kidney stones. Please do not initiate usage of this chemical without first discussing it with your physician.

Parkinson’s disease and the cancer drug

December 11, 2015September 2, 2017 ~ Simon ~ 7 Comments

In October, 40,000 neuroscientists from all over the world gathered in Chicago for the annual Society for Neuroscience conference. It is one of the premier events on the ‘brain science’ calendar each year and only a few cities in the USA have the facilities to handle such a huge event.

agu20141212-16

Science conference. Source: JPL

During the five day neuroscience marathon, hundreds of lecture presentations were made and thousands of research poster were exhibited. Many new and exciting findings were presented to the world for the first time, including the results of an interesting pilot study that has left everyone in the Parkinson’s research community very excited, but also scratching their heads.

The study (see the abstract here) was a small clinical trial (12 subjects; 6 month study) that was aiming to determine the safety and efficacy of a cancer drug, Nilotinib (Tasigna® by Novartis), in advanced Parkinson’s Disease and Lewy body dementia patients. In addition to checking the safety of the drug, the researchers also tested cognition, motor skills and non-motor function in these patients and found 10 of the 12 patients reported meaningful clinical improvements.

The study investigators reported that one individual who had been confined to a wheelchair was able to walk again; while three others who could not talk before the study began were able to hold conversations. They suggested that participants who were still in the early stages of the disease responded best, as did those who had been diagnosed with Lewy body dementia.

So what is Nilotinib?

Nilotinib (pronounced ‘nil-ot-in-ib’ and also known by its brand name Tasigna) is a small-molecule tyrosine kinase inhibitor, that has been approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML). That is to say, it is a drug that can be used to treat a type of leukemia when the other drugs have failed. It was approved for this treating cancer by the FDA in 2007.

The researchers behind the study suggest that Nilotinib works by turning on autophagy – the “garbage disposal machinery” inside each neuron. Autophagy is a process that clears waste and toxic proteins from inside cells, preventing them from accumulating and possibly causing the death of the cell.

The process of autophagy – Source: Wormbook

Waste material inside a cell is collected in membranes that form sacs (called vesicles). These vesicles then bind to another sac (called a lysosome) which contains enzymes that will breakdown and degrade the waste material.

Some details about the study:

The study was run at the Georgetown University Medical Center
The patients were given increasing doses of Nilotinib (150mg to 300mg/day) that were are significantly lower than the doses of Nilotinib used for CML treatment (800-1200mg/day).
The researchers took cerebrospinal fluid (CSF; the liquid surrounding the brain) and blood samples at the start of the study, 2 and 6 months into the study.
Nilotinib was detected in the CSF, indicating that it had no problem crossing the protective blood-brain-barrier – the membrane covering the brain that blocks many drugs from entering.
Participants exhibited positive changes in various cerebrospinal fluid biomarkers with statistically significant changes in an important protein called, Tau, which have been shown to increase with the onset of dementia.
The researchers found a significant reduction (>60%) in levels of α-Synuclein detected in the blood, but no change in CSF levels of α-Synuclein.
The investigators report that one individual confined to a wheelchair was able to walk again; three others who could not talk were able to hold conversations.

If the outcomes of this study are reproducible, then we here at the Science of Parkinson’s are assuming that Nilotinib is working by turning on the garbage disposal system of the remaining cells in the brain and allowing them to function better. This would suggest that there is a certain level of dysfunction in those remaining cells, which would be expected as this is a progressive disease. The study researchers reported that the small, daily dose of nilotinib turns on autophagy for about four to eight hours, and if that is enough to have such remarkable effects, then this treatment deserves more research.

The results of the study are intriguing and the participants of the study will continue to be treated and followed to see if the improvements continue.

BUT before we go getting too excited:

While these results sound extremely positive, there are several issues with this study that need to be considered before we celebrate the end of Parkinson’s disease.

Firstly, this study was an open-label trial – that means that everyone involved in the study (both researchers and subjects) knew what drug they were taking. There was also no control group or control treatment for comparative analysis in the study. Given these conditions there is always the possibility that what some of the subjects were experiencing was simply a placebo effect. Indeed the lead scientist on the project, Dr Fernando Pagan, pointed out that “It is critical to conduct larger and more comprehensive studies before determining the drug’s true impact.”

In addition, according to Novartis (the producer of the drug), the current cost of Nilotinib is about $10,360 (£6,900) per month for the daily 800mg dose used for cancer treatment. Even if the dose used in this study was only 150 to 300 mg/daily, it would still make this treatment extremely expensive.

Thirdly, Nilotinib has a number of adverse side-effects when used as an anti-cancer drug (at 800mg/day). These include headache, fatigue, nausea, vomiting, diarrhea, constipation, muscle/joint pain, skin issues, flu-like symptoms, and reduced blood cell count. It may not be the nicest of treatments to tolerate.

There are important reasons for optimism, however, with the results of this study:

In 2010, a group of researchers published a paper demonstrating the neuroprotective effects of another cancer drug very similar to Nilotinib. That drug was ‘Gleevec’

Title: Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin’s ubiquitination and protective function.
Authors: Ko HS, Lee Y, Shin JH, Karuppagounder SS, Gadad BS, Koleske AJ, Pletnikova O, Troncoso JC,Dawson VL, Dawson TM.
Journal: Proc Natl Acad Sci U S A. 2010 Sep 21;107(38):16691-6.
PMID: 20823226

And that Gleevec publication was followed up a couple of years ago with a second study demonstrating the neuroprotective effects of another Abl-inhibitor: Nilotinib!

Title: The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson’s disease.
Authors: Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM, Ko HS
Journal: Sci Rep. 2014 May 2;4:4874.
PMID: 24786396

These studies provided a strong rationale for testing brain permeable c-Abl inhibitors as potential therapeutic agents for the treatment of PD. The phase 2 trial at Georgetown will be starting in early 2016 and we will be watching this trial very closely.

“Red hair, sir, in my opinion, is dangerous”

December 6, 2015December 6, 2015 ~ Simon ~ 4 Comments

The quote entitling this post is from a PG Wodehouse book ‘Very Good, Jeeves!’.

We have previously discussed the curious connection between melanoma and Parkinson’s disease. There is also a well known connection between melanoma and red hair. And believe it or not, there is another really strange relationship between Parkinson’s disease and red hair.

Title: Genetic determinants of hair color and Parkinson’s disease risk.
Authors: Gao X, Simon KC, Han J, Schwarzschild MA, Ascherio A.
Journal: Ann Neurol. 2009 Jan;65(1):76-82.
PMID: 19194882

In 2009, researchers from Harvard University found a relationship between hair color and risk of Parkinson’s disease, when they examined the records of 131,821 US men and women who participated in the two large longitudinal studies, the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS).

The HPFS, which started in 1986, sends questionnaires to US health professionals (dentists, optometrists, etc) – aged 40-75. Every couple of years, members of the study receive questionnaires dealing with diseases and health-related issues (e.g. smoking, physical activity, etc). The questionnaire is supplemented by another questionnaires which is sent every four years, that deals with dietary information.

The NHS study – which was established in 1976 and then expanded in 1989 – has also collected questionnaire-based information from 238,000 registered nurses. Similar to the HPFS, every two years the study participants receive a questionnaire dealing with diseases and health-related topics.

In their study, the investigators found 264 of the male and 275 of the female responders to the HPFS and NHS questionnaires had been diagnosed with Parkinson’s disease. Of these individuals, 33 were black haired, 418 had brown hair, 62 were blond and 26 were redheads. Given that redheads make up just 1% of the general population but 5% of the people who were diagnosed with Parkinson’s disease in their study, the authors suggested that red haired people have a higher risk of developing Parkinson’s disease. Interestingly, they found a stronger association between hair color and Parkinson’s disease in younger-onset of PD (that is being diagnosed before 70 years of age) than those with age of onset greater than 70 years. When they took health and age related matters into account, the authors concluded that people with red hair are almost four times more likely to develop Parkinson’s disease than people with black hair.

NOTE: This result does not mean that people with red hair are definitely going to develop Parkinson’s disease, it simply suggests that they may be more vulnerable to the condition. And we should add that this result have never been replicated and we are not sure if anyone has ever attempted to reproduce it with a different database.

So how does (or could) this work?

The short answer is: we really don’t know.

The long answer involves explaining where there are no connections:

Red hair results from a genetic mutation. 80% of people with red hair have a mutation in a gene called MC1R – full name: melanocortin-1 receptor. Another gene associated with red hair is called HCL2 – ‘Hair colour 2’. We know that the connection between red hair and Parkinson’s disease is not genetic, as there is no association between MC1R mutations and Parkinson’s disease (for more on this, click here). We are not sure about HCL2, but this gene has never been associated with any disease.

What we do know is that redheads:

are more sensitive to cold (for more on this, click here)
are less responsive to subcutaneously (under the skin) administered anaesthetics (for more on this, click here)
suffer more from toothaches (for more on on this, click here)
are more sensitive to painkillers (for more on this, click here)
require more anesthetic for surgery (for more on this, click here)

Common myths associated with red hair include:

redheads bled more than others (this is not true – click here)…but they do bruise easier!
redheads are at greater risk of developing endometriosis (this is not true – click here)
redheads are more frequently left-handed (I can find no evidence for this, so I’ll put it in the myth basket until corrected).

There is also a strange link between red hair and multiple sclerosis, but it is too complicated to understand at the moment (women with red hair are more vulnerable to multiple sclerosis than men with red hair, for more on this, click here).

How any of these findings relates to Parkinson’s disease is unclear – we provide them here for those who are interested in following up this curious relationship.

One important caveat regarding this study is that incidence rates of Parkinson’s disease in countries with very high levels of red hair do not support the relationship (PD & red hair). In Scotland, approx. 10% of the population have red hair (source), and yet the England has a higher incidence of Parkinson’s disease (28.0/10,000 in England vs 23.9/10,000 in Scotland – source).

It may well be, however, that there is no direct connection between red hair and Parkinson’s disease. And until the results of the 2009 study mentioned above are replicated or supported by further findings, we here at the ‘Science of Parkinson’s disease’ shall consider this simply as a curious correlation.

The difference between men and women

November 28, 2015November 28, 2015 ~ Simon ~ 3 Comments

At the bottom of our previous post, we mentioned that Japan is the only country where women have a higher incidence of Parkinson’s disease than men.

We also suggested that we have no idea why this difference exists. Well, a study presented at the Cardiovascular, Renal and Metabolic Diseases conference in Annapolis City (Maryland) last week may now be able to explain why this is.

The prevalence of Alzheimer’s disease is significantly higher in women compared to men. One recent estimate suggested that almost two-thirds of individuals diagnosed with Alzheimer’s disease are women (More information here). One possible reason for this is that Alzheimer’s disease is a condition of the elderly and women live longer.

So why is it then is the exact opposite true in Parkinson’s disease???

Source: The Telegraph Newspaper

Men are approximately twice as likely to develop Parkinson’s disease as females (More information here)

In addition, women are on average diagnosed 2 years later than men (More information here)

This gender difference has long puzzled the Parkinson’s research community. But now a group from the University of North Texas Health Science Center think that they may have the answer.

The researchers – lead by Shaletha Holmes from Dr Rebecca Cunningham’s lab – observed that when they stressed dopamine neurons, adding the male hormone testosterone made the damage worse. Interestingly, they found that testosterone was doing this by acting on a protein called cyclooxygenase 2 (or COX2). When they blocked the actions of COX2 while stressing dopamine neurons, they found that they also blocked the damaging effect of testosterone. The researchers concluded that testosterone may exacerbate the damage (and death) in dopamine neurons that occurs in Parkinson’s disease, thus possibly explaining the sex differences described above.

Now, there are several interesting aspects to this finding:

Firstly, the use of Ibuprofen, the nonsteroidal anti-inflammatory drug used for relieving pain, has long been associated with reducing the risk of Parkinson’s disease (More information here).

Ibuprofen is a COX2 inhibitor.

But more importantly, several years ago it was shown that Japanese men have lower levels of testosterone than their Western equivalents. Here is the study:

Title: Evidence for geographical and racial variation in serum sex steroid levels in older men.
Authors: Orwoll ES, Nielson CM, Labrie F, Barrett-Connor E, Cauley JA, Cummings SR, Ensrud K, Karlsson M, Lau E, Leung PC, Lunggren O, Mellström D, Patrick AL, Stefanick ML, Nakamura K, Yoshimura N, Zmuda J, Vandenput L, Ohlsson C; Osteoporotic Fractures in Men (MrOS) Research Group.
Journal: Journal of Clinical Endocrinol. Metab. 2010 Oct;95(10):E151-60.
PMID: 20668046

The study suggested that total testosterone levels (while similar in men from Sweden, Tobago and the US) were 16 per cent higher in men from Hong Kong and Japan. BUT – and here’s the catch – Japanese men also had higher levels of a testosterone-binding hormone (Sex hormone-binding globulin or SHBG), so there is less of the testosterone floating around free to act. As a result, Japanese men had the lowest levels of active testosterone in the study.

Intriguingly, the researchers found that Japanese men who emigrated to the US had similar testosterone levels to men of European descent, suggesting that environmental influences may be having an effect of testosterone levels. Diet perhaps?

If testosterone is found to play a role in the gender difference found in Parkinson’s disease, the lower levels of free testosterone observed in Japanese men may explain why women in Japan have a higher risk of Parkinson’s disease than men.

EDITOR’S NOTE: WHILE WE HAVE NO DOUBTS REGARDING THE RESEARCH OF DR CUNNINGHAM AND HER GROUP, WE ARE TAKING A LEAP IN THIS POST BY APPLYING THE TESTOSTERONE RESULTS TO THE GENDER DIFFERENCE IN JAPAN. THIS IS PURE SPECULATION ON OUR PART. WE HAVE SIMPLY SAT DOWN AND TRIED TO NUT OUT POSSIBLE REASONS AS TO WHY THERE IS A REVERSED GENDER DIFFERENCE FOR PARKINSON’S DISEASE IN JAPAN. OUR THEORY IS YET TO BE TESTED, AND MAY BE COMPLETELY BONKERS. WE PRESENT IT HERE PURELY FOR DISCUSSION SAKE AND WELCOME YOUR THOUGHTS.

The Honolulu Heart Study

November 27, 2015November 4, 2024 ~ Simon ~ 16 Comments

In 1950, Dr Tavia Gordon noticed that while the overall mortality rates for men in the USA and Japan were very similar, the incidence of heart disease was significantly lower in Japan. This observation resulted in three longitudinal studies – one of which became known as the Honolulu Heart Study.

Dr Travis Gordon. Source: JSTOR

The original purpose of the study was to determine whether there was a difference in heart disease incidence between Japanese people living in Japan and individuals of Japanese ancestry living in Hawaii.

The subjects recruited for the study were “non-institutionalized men of Japanese ancestry, born 1900-1919, resident on the island of Oahu.” In all, 12,417 men were identified as meeting the criteria. Of those contacted, 1,269 questionnaires were ‘return to sender’, 2,962 men declined to participate in the study, and 180 died before the study commenced. That left 8,006 participants who would be studied and followed for the rest of their lives.

From October 1965 onwards, the participants were interviewed and given physical examinations every few years. The interview processed asked for:

Family and personal history of illness
Sociological history
Smoking status
Physical activity level

The physical examination was very thorough, looking at:

ECG (Electrocardiography – electrical activity of the heart)
Urine analysis
Measurements of weight, height, skinfold thickness, etc.
Blood pressure and serum cholesterol

As a result, the study built up a HUGE amount of epidemiological information regarding these 8,006 individuals.

So, what does this have to do with Parkinson’s disease????

Given the enormous number of individuals involved in the study and the length of time that they were followed, it was inevitable that a certain percentage of them would develop Parkinson’s disease as the study progressed. As a result, the Honolulu Heart Study represents one of the largest epidemiological study of Parkinson’s to date. In 1994, a group of research involved in the study, published some very interesting findings relating to Parkinson’s disease. That published article was:

Title: Epidemiologic observations on Parkinson’s disease: incidence and mortality in a prospective study of middle-aged men.
Authors: Morens DM, Davis JW, Grandinetti A, Ross GW, Popper JS, White LR.
Journal: Neurology, 1996 Apr;46(4):1044-50.
PMID: 8780088

In total, 92 of the 8006 individuals enrolled in the study developed Parkinson’s disease. The incidence of Parkinson’s cases was registered between 1965 and November 30th 1994. The majority of the cases were diagnosed between 55 and 79 years of age (n=80). Diagnosis after the age of 80 was very rare. It is interesting to note that when the researchers divided the group into those ‘born before 1910’ and those ‘born after 1910’, the older group (born before 1910) had a lower risk of Parkinson’s disease.

In another study, the same group of investigators noted

Title: Prospective study of cigarette smoking and the risk of developing idiopathic Parkinson’s disease.
Authors: Grandinetti A, Morens DM, Reed D, MacEachern D.
Journal: American Journal of Epidemiology 1994 Jun 15;139(12):1129-38.
PMID: 8209872

In this study the authors found that men who had smoked cigarettes at any time prior to their enrollment in the study in 1965, had a reduced risk of developing idiopathic Parkinson’s disease (relative risk = 0.39). That is to say, smoking reduced the chance of developing Parkinson’s disease. And a few years later the authors published a follow up paper which rejected the possibility that smoking was killing people before they could develop Parkinson’s disease (selective mortality representing a false positive). That follow up report can be found here.

EDITOR’S NOTE: THIS DOES NOT MEAN THAT EVERYONE SHOULD RUSH OUT AND START SMOKING. THERE DOES, HOWEVER, APPEAR TO BE SOME INGREDIENT IN CIGARETTES THAT REDUCES THE INCIDENCE OF PARKINSON’S DISEASE. A LOT OF RESEARCH IS CURRENTLY TRYING TO IDENTIFY THAT INGREDIENT.

This finding was made alongside other interesting correlations (Note: coffee and alcohol reduce the risk of Parkinson’s disease):

From Grandinetti et al (1994).

It should be noted that many of these associations (smoking in particular) had been reported before, but the Honolulu Heart Study was the first epidemiological study providing definitive proof. And it should be noted that subsequent epidemiological studies have found similar results.

INTERESTING FACTS ABOUT THE JAPANESE:

The Japanese as a population have a lower incidence of Parkinson’s disease (much like most of the Asian nations) than their western equivalents, despite living longer.
Japan is the only country in the world where females have a higher incidence of Parkinson’s disease than men (and we have no idea why!). Look here for more on this.

A gut feeling

September 9, 2015February 27, 2016 ~ Simon ~ 13 Comments

New Parkinson’s Research this week:

Title: Vagotomy and Subsequent Risk of Parkinson’s Disease.
Authors: Svensson E, Horváth-Puhó E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P, Sørensen HT.

Journal: Annals of Neurology, 2015, May 29. doi: 10.1002/ana.24448.
PMID: 26031848

What’s it all about?

This is Prof Heiko Braak:

Source – Memim.com

Many years ago, Prof Braak – a German neuroanatomist – sat down and examined hundreds of postmortem brains from people with Parkinson’s disease.

He had collected brains from people at different stages of Parkinson’s disease and was looking for any kind of pattern that might explain where and how the disease starts. His research led to what is referred to as the Braak stages of Parkinson’s disease – a six step explanation of how the disease spreads up from the brain stem and into the rest of the brain (see Braak et al, 2003).

The Braak stages of PD. Source: Doty RL (2012) Nature Reviews Neurology 8, 329-339.

Braak’s results also led him to propose that Parkinson’s disease may actually begin in the gut and then spread to the central nervous system (the brain). He based this on the observation that many brains that exhibited the very early stages of Parkinson’s disease had disease-related pathology in a population of neurons called the dorsal motor nucleus of the vagal nerve. This population of neurons connects to different organs in the body, such as the lungs, heart, kidneys and the gastrointestinal system (or the gut).

A diagram illustrating the vagal nerve connection with the enteric nervous system which lines the gastric system. Source: Braak et al (2006) Nature Reviews Neurology 8, 329-339

Braak and his colleagues went on to examine the nerves fibres around the gastrointestinal system and in those fibres he found large deposits of a Parkinson’s disease-related substance: a protein called alpha synuclein. These deposits were present even at very early stages of the disease, which supported his theory that maybe the disease was starting in the gut.

This ‘gut to brain’ theory was supported by the fact that people with Parkinson’s disease often complain of gastrointestinal problems (eg. constipation) and some of these issues may predate the onset of other Parkinson’s disease symptoms. In addition, a couple of years ago, a group of scientists in the USA found alpha-synuclein present in bowel biopsies taken from people years before they were actually diagnosed with Parkinson’s disease (that study can be found here).

The ‘gut to brain’ theory received a further boost recently with the publication of a paper by a Danish group, who retrospectively looked at all the people in Denmark that received a vagotomy between 1975 and 1995.

So what’s a vagotomy?

Good question.

A vagotomy is a surgical procedure in which the vagus nerve are cut. It is typically due to help treat stomach ulcers. A vagotomy can be ‘truncal‘ (in which the main nerve is cut) or ‘superselective’ (in which specific branches of the nerve are cut, which the main nerve is left in tact).

A schematic demonstrating the vagal nerve surrounding the stomach. Image A. indicates a ‘truncal’ vagotomy, where the main vagus nerves are cut above the stomach; while image B. illustrates the ‘superselective’ vagotomy, cutting specific branches of the vagus nerve connecting with the stomach. Source: Score

And what did the Danish scientists find?

The Danish researcher found that between 1975 and 1995, 5339 individuals had a truncal vagotomy and 5870 had superselective vagotomy. Using the Danish National registry (which which stores everyone’s medical information), they then looked for how many of these individuals went on to be diagnosed with Parkinson’s disease. They compared these vagotomy subjects with more than 60,000 randomly-selected, age-matched controls.

They found that subjects who had a superselective vagotomy had the same chance of developing Parkinson’s disease as anyone else in the general public (a hazard ratio (or HR) of 1 or very close to 1). But when they looked at the number of people in the truncal vagotomy group who were later diagnosed with Parkinson’s disease, the risk had dropped by 35%. Further, when they followed up the Truncal group 20 years later, checking to see who had been diagnosed with Parkinson’s in 2012, they found that they rate was half that of both the superselective group and the control group (see table below – HR=0.53). The authors concluded that a truncal vagotomy reduces the risk of developing Parkinson’s disease.

Source: Svensson et al (2015) Annals of Neurology – Table 2.

So what does it all mean?

The study is an extremely novel approach to investigating the ‘gut to brain’ theory of Parkinson’s disease and the authors can be congratulated on some excellent work. It adds further weight to the idea that something is happening in the gut very early in Parkinson’s disease. It suggests that by cutting one of the main nerves connecting to the stomach, the disease is slowed down if not avoided all together. It might also suggest that the disease is slower and strikes earlier than previously thought (given that some people with truncal vagotomies still developed Parkinson’s disease – maybe the condition started before the nerve was cut).

But there are a couple of important details that should be considered about the paper before everyone rushes out to get a vagotomy:

The number of people that received a truncal vagotomy (total = 5339) who went on develop Parkinson’s disease 20 years later was just 10 (compared with 29 in the superselective group). There may be some individuals who got lost in the system, but the number is still very low and caution should be used before we get too excited about a result based on a low number of subjects. It is important to determine whether this result can be replicated (in other countries).
The gut may not be the only avenue for the disease. There has also been theories regarding an environmental aspect to the cause of Parkinson’s disease, and there have been studies conducted looking at the nasal/olfactory system of people with Parkinson’s disease to determine if this is another point of entry for the disease (for a recent review on this, see this paper here).

In summary, very interesting study and fascinating result, but please don’t rush to your doctor and ask for your vagus nerve to be cut!

Beginnings

September 8, 2015September 8, 2015 ~ Simon ~ 2 Comments

Welcome to the Science of Parkinson’s Disease – a blog that has been set up by scientists to provide information and understanding about the neurodegenerative condition known as Parkinson’s disease.

Over the last 10 years, the advocacy for Parkinson’s disease has been tremendous and real awareness has been created by groups such as the Michael J Fox foundation, the Cure PD Trust, and Parkinson’s UK. They have generated enormous amounts of funding for scientific research and provided hope for disease halting therapies, while supporting and improving the general welfare of people suffering from this condition.

The media regularly announces new breakthroughs in the medical and scientific world, but there are few forums available for the general public to ask questions related to the science being conducted. The Science of Parkinson’s disease has been set up for this purpose.

The Science of Parkinson’s disease is run by research scientists working in the field, and it was begun with several goals in mind:

Try to answer any questions you may have about Parkinson’s disease.
Report each week on interesting/exciting research in the world of Parkinson’s disease.
Interview Parkinson’s disease researchers, providing a face to the people doing the work.
Help you to understand this disease better.

We look forward to hearing from you.

The Team