There is a lot of clinical and biological similarities between the neurodegenerative conditions of Parkinson’s and multiple systems atrophy (or MSA).
Recently, however, researchers have published a report suggesting that these two conditions may be differentiated from each other using a technique analysing protein in the cerebrospinal fluid – the liquid surrounding the brain, that can be accessed via a lumbar puncture.
Specifically, the method differentiates between different forms of a protein called alpha synuclein, which is associated with both conditions.
In today’s post, we will look at what multiple systems atrophy (MSA) is, discuss how this differentiating technique works, and explore what it could mean for people with either of these conditions.
Getting a diagnosis of Parkinson’s can be a tricky thing.
For many members of the affected community, it is a long and protracted process.
Firstly, there will be multiple visits with doctors and neurologists (and perhaps some brain imaging) until one is finally given a diagnosis of PD. There are a number of conditions that look very similar to Parkinson’s, which must be ruled out before a definitive diagnosis can be proposed.
But even after being diagnosed, there are a group of conditions that look almost identical to Parkinson’s. And many people will be given a diagnosis of Parkinson’s before they are then given a corrected diagnosis of one of these other conditions.
Can you give me an example of one of these other conditions?
Sure. A good example is multiple systems atrophy.
What is Multiple System Atrophy?
Dense spherical clusters of a protein – called Lewy bodies – are one of the classical hallmarks of the Parkinsonian brain. They are a common pathological feature, but curiously they are not present in all cases of Parkinson’s.
For example, some individuals with certain forms of Parkinson’s associated with specific genetic mutations do not exhibit any Lewy bodies. Variations in a region of DNA called LRRK2 will increase one’s risk of developing Parkinson’s, but many of those who go on to develop LRRK2-associated Parkinson’s will have a complete absence of Lewy bodies in their brains. These cases have represented an enigma for the Parkinson’s research community and have been difficult to reconcile.
Recently, however, researchers from the University of Pennsylvania have reported a different kind of protein clustering in these LRRK2-associated cases with “no Lewy bodies”. The accumulating protein is called Tau.
In today’s post, we will look at what Tau is, review what the new research report found, and discuss what this discovery could potentially mean for the future treatment of Parkinson’s.
Neuropathologists conducting a gross examination of a brain. Source: NBC
At present, a definitive diagnosis of Parkinson’s can only be made at the postmortem stage with an examination of the brain.
Until that moment, all cases of Parkinson’s are ‘suspected’. When a neuropathologist makes an examination of the brain of a person who passed away with the clinical features of Parkinson’s, there are two characteristic hallmarks that they will be looking for in order to provide a final diagnosis of the condition:
1. The loss of specific populations of cells in the brain, such as the dopamine producing neurons in a region called the substantia nigra, which lies in an area called the midbrain (at the base of the brain/top of the brain stem). As the name suggests, the substantia nigra region is visible due to the production of a ‘substance dark’ molecule called neuromelanin in the dopamine neurons. And as you can see in the image below, the Parkinsonian brain has less dark pigmented cells in the substantia nigra region of the midbrain.
The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinsonian brain (right). Source:Memorangapp
2. Dense, circular clusters (or aggregates) of protein within cells, which are called Lewy bodies.
A cartoon of a neuron, with the Lewy body indicated within the cell body. Source: Alzheimer’s news
A Lewy body is referred to as a cellular inclusion, as they are almost always found inside the cell body. They generally measure between 5–25 microns in diameter (5 microns is 0.005 mm) and thus they are tiny. But when compared to the neuron within which they reside they are rather large (neurons usually measures 40-100 microns in diameter).
A photo of a Lewy body inside of a neuron. Source: Neuropathology-web
Do all Parkinson’s brains have Lewy bodies?
Funnily enough, no.
And this is where the wheels fall off the wagon in our understanding (and ‘definitive’ definition) of Parkinson’s.
What do you mean?
Novel methods for treating neurodegenerative conditions are being proposed on a weekly (sometimes daily) basis.
Recently researchers from the University of Cambridge have presented an intriguing new method of removing proteins from inside of cells which involves small proteins called antibodies.
Antibodies are an important part of the immune systems response to infection. But their function usually only applies to objects floating around outside of cells.
In today’s post, we will look at what antibodies are, explain how this new system works, and discuss some of the issues we face with taking this new technique forward.
A brain cell from a person with Alzheimer’s. The red tangles in the yellow cell body are toxic misfolded “TAU” proteins next to the cell’s green nucleus. Source: NPR
Here at the SoPD, we often talk about the clustering (or aggregation) of proteins.
Densely packed aggregates of a protein are a common feature of many neurodegenerative conditions, including Parkinson’s.
In fact, the aggregation of a protein called alpha synuclein are one of the cardinal features of the Parkinsonian brain.
Aggregated alpha synuclein protein in the Parkinsonian brain (stained in brown). Source: Wikimedia
Researchers have long been devising new ways of trying to reduce the amount of alpha synuclein collecting in the brain cells of people with Parkinson’s.
In most cases, their efforts have focused on utilising the cell’s own waste disposal systems.
How do cells dispose of waste?
There are two major pathways by which the cells in your body degrade and remove rubbish:
At the end of each year, it is a useful practise to review the triumphs (and failures) of the past 12 months. It is an exercise of putting everything into perspective.
2017 has been an incredible year for Parkinson’s research.
And while I appreciate that statements like that will not bring much comfort to those living with the condition, it is still important to consider and appreciate what has been achieved over the last 12 months.
In this post, we will try to provide a summary of the Parkinson’s-related research that has taken place in 2017 (Be warned: this is a VERY long post!)
The number of research reports and clinical trial studies per year since 1817
As everyone in the Parkinson’s community is aware, in 2017 we were observing the 200th anniversary of the first description of the condition by James Parkinson (1817). But what a lot of people fail to appreciate is how little research was actually done on the condition during the first 180 years of that period.
The graphs above highlight the number of Parkinson’s-related research reports published (top graph) and the number of clinical study reports published (bottom graph) during each of the last 200 years (according to the online research search engine Pubmed – as determined by searching for the term “Parkinson’s“).
PLEASE NOTE, however, that of the approximately 97,000 “Parkinson’s“-related research reports published during the last 200 years, just under 74,000 of them have been published in the last 20 years.
That means that 3/4 of all the published research on Parkinson’s has been conducted in just the last 2 decades.
And a huge chunk of that (almost 10% – 7321 publications) has been done in 2017 only.
So what happened in 2017? Continue reading
Here at the SoPD, we regularly talk about the ‘bad boy’ of Parkinson’s disease – a protein called Alpha Synuclein.
Twenty years ago this year, genetic variations were identified in the alpha synuclein gene that increase one’s risk of developing Parkinson’s. In addition, alpha synuclein protein was found to be present in the Lewy bodies that are found in the brains of people with Parkinson’s. Subsequently, alpha synuclein has been widely considered to be the villain in this neurodegenerative condition and it has received a lot of attention from the Parkinson’s research community.
But it is not the only protein that may be playing a role in Parkinson’s.
Today’s post is all about TAU.
I recently informed my wife that I was thinking of converting to Taoism.
She met this declaration with more of a smile than a look of shock. And I was expecting the latter, as shifting from apatheism to any form of religious belief is a bit of a leap you will appreciate.
When asked to explain myself, I suggested to her that I wanted to explore the mindfulness of what was being proposed by Lao Tzu (the supposed author of the Tao Te Ching – the founding document of Taoism).
This answer also drew a smile from her (no doubt she was thinking that Simon has done a bit of homework to make himself sound like he knows what he was talking about).
But I am genuinely curious about Taoism.
Most religions teach a philosophy and dogma which in effect defines a person. Taoism – which dates from the 4th century BCE – flips this concept on its head. It starts by teaching a single idea: The Tao (or “the way”) is indefinable. And then it follows up by suggesting that each person should discover the Tao on their own terms. Given that most people would prefer more concrete definitions in their own lives, I can appreciate that a lot of folks won’t go in for this approach.
Personally speaking, I quite like the idea that the Tao is the only principle and everything else is a just manifestation of it.
According to Taoism, salvation comes from just one source: Following the Tao.
Oh and don’t worry, I’m not going to force any more philosophical mumbo jumbo on you – Taoism is just an idea I am exploring as part of a terribly clichéd middle-life crisis I’m working my way through (my wife’s actual response to all of this was “why can’t you just be normal and go buy a motor bike or something?”).
My reason for sharing this, however, is that this introduction provides a convenient segway to what we are actually going to talk about in this post.
You see, some Parkinson’s researchers are thinking that salvation from neurodegenerative conditions like Parkinson’s will come from just one source: Following the TAU.
What is TAU?
In Silicon valley (California), everyone is always looking for the “next killer app” – the piece of software (or application) that is going to change the world. The revolutionary next step that will solve all of our problems.
The title of today’s post is a play on the words ‘killer app’, but the ‘app’ part doesn’t refer to the word application. Rather it relates to the Alzheimer’s disease-related protein Amyloid Precursor Protein (or APP). Recently new research has been published suggesting that APP is interacting with a Parkinson’s disease-related protein called Leucine-rich repeat kinase 2 (or LRRK2).
The outcome of that interaction can have negative consequences though.
In today’s post we will discuss what is known about both proteins, what the new research suggests and what it could mean for Parkinson’s disease.
Seattle. Source: Thousandwonders
In the mid 1980’s James Leverenz and Mark Sumi of the University of Washington School of Medicine (Seattle) made a curious observation.
After noting the high number of people with Alzheimer’s disease that often displayed some of the clinical features of Parkinson’s disease, they decided to examined the postmortem brains of 40 people who had passed away with pathologically confirmed Alzheimer’s disease – that is, an analysis of their brains confirmed that they had Alzheimer’s.
What the two researchers found shocked them:
Title: Parkinson’s disease in patients with Alzheimer’s disease.
Authors: Leverenz J, Sumi SM.
Journal: Arch Neurol. 1986 Jul;43(7):662-4.
Of the 40 Alzheimer’s disease brains that they looked at nearly half of them (18 cases) had either dopamine cell loss or Lewy bodies – the characteristic features of Parkinsonian brain – in a region called the substantia nigra (where the dopamine neurons are located). They next went back and reviewed the clinical records of these cases and found that rigidity, with or without tremor, had been reported in 13 of those patients. According to their analysis 11 of those patients had the pathologic changes that warranted a diagnosis of Parkinson’s disease.
And the most surprising aspect of this research report: Almost all of the follow up studies, conducted by independent investigators found exactly the same thing!
It is now generally agreed by neuropathologists (the folks who analyse sections of brain for a living) that 20% to 50% of cases of Alzheimer’s disease have the characteristic round, cellular inclusions that we call Lewy bodies which are typically associated with Parkinson disease. In fact, in one analysis of 145 Alzheimer’s brains, 88 (that is 60%!) had chemically verified Lewy bodies (Click here to read more about that study).
A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia
Oh, and if you are wondering whether this is just a one way street, the answer is “No sir, this phenomenon works both ways”: the features of the Alzheimer’s brain (such as the clustering of a protein called beta-amyloid) are also found in many cases of pathologically confirmed Parkinson’s disease (Click here and here to read more about this).
So what are you saying? Alzheimer’s and Parkinson’s disease are the same thing???
This week an interesting new study dealing with the biology of Alzheimer’s was published in the journal Science Translational Medicine. It has drawn a lot of attention as it may be turning our understanding of Alzheimer’s disease on it’s head. If the results are independently replicated and verified, it could potentially have major implications for Parkinson’s disease.
For the last 30 years, a protein called beta-amyloid has been considered one of the bad boys of the most common neurodegenerative condition, Alzheimer’s disease.
What is Alzheimer’s disease?
Alzheimer’s disease is a progressive neurodegenerative condition that can occur in middle or old age. It involves a generalized degeneration of the brain, not localised to specific regions like Parkinson’s disease.
What happens in the Alzheimer’s brain?
In the brain, in addition to cellular loss, Alzheimer’s is characterised by the presence of two features:
- Neurofibrillary tangles
- Amyloid plaques
The tangles are aggregations of a protein called ‘Tau’ (we’ll comeback to Tau in a future post). These tangles reside within neurons initially, but as the disease progresses the tangles can be found in the space between cells – believed to be the last remains of a dying cell.
A normal brain vs an Alzheimer’s affected brain. Source: MMCNeuro
Amyloid plaques are clusters of proteins that sit between cells. A key component of the plaque is beta amyloid. Beta-amyloid is a piece of a larger protein that sits in the outer wall of nerve cells where it has certain functions. In certain circumstances, specific enzymes can cut it off and it floats away.
Beta-Amyloid. Source: Wikimedia
Beta-amyloid is a very “sticky” protein and for a long time it has been believed that free floating beta-amyloid proteins begin sticking together, gradually building up into the large amyloid plaques. And these large plaques were considered to be involved in the neurodegenerative process of Alzheimer’s disease.
So what was discovered this week?
This week a study was published that suggests a new (and positive) function for beta amyloid:
Title: Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease.
Authors: Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE, Moir RD.
Journal: Sci Transl Med. 2016 May 25;8(340):340ra72.
The researchers took three types of mice:
- genetically normal mice
- mice with no beta amyloid
- mice producing a lot of beta amyloid
They infected all of the mice with the microbe that causes meningitis, and they found that the mice producing a lot of beta amyloid lived significantly longer than other groups of mice. They then repeated the experiment in a species of microscopic worm – called C.elegans – and found similar results. These findings suggested that beta amyloid was having a positive effect in the brain.
But then they noticed something strange.
The mice producing a lot of beta amyloid usually do not develop a lot of protein aggregation until old age, but when the researchers looked in the brains of the mice they infected with meningitis, they found significant levels of aggregation in the mice producing a lot of beta amyloid but at a young age..
This led the researchers to conduct some cell culture experiments in which they watched what was happening to the bacteria and beta amyloid. They found that the beta amyloid was sticking to the bacteria and this was leading to the formation of protein aggregates.
The results of these experiments suggested to the researchers an intriguing possibility that beta amyloid may be playing a protective in the brain – acting as an immune system for the brain – against infection.
Thus the aggregations we see in the brains of people with Alzheimer’s may not be the cause of the cell death associated with the disease, but rather evidence of the ‘brain’s immune system’ trying to fight back against unknown infectious agents. The researcher’s of the study were quick to point out that this antimicrobial action of beta amyloid is simply a new function of the protein, and it may have nothing to do with the disease itself. But it will be interesting to see where this research goes next.
What has this got to do with Parkinson’s disease?
Parkinson’s disease is only definitive diagnosed at the postmortem stage. This is done by microscopic examination of the brain. In the brains of people with Parkinson’s disease, there are protein aggregates calls Lewy bodies. These are densely packed clusters of a protein called ‘alpha synuclein‘.
The brown spot is a Lewy body inside of a brain cell. Source: Cure Dementia
If the results of the study presented above are correct and beta amyloid is a protective protein in the brain against infection, could it not be that alpha synuclein may be playing a similar role? It is a fascinating idea that it will be interesting to test.
What are the implications of the study?
Currently, there are numerous clinical trials for Alzheimer’s disease, involving treatments that act against beta amyloid. If the study presented above is correct, and beta amyloid has a role in protecting the brain, these new treatments in clinical trial may actually be weakening the brain’s ability to fight infection.
Similarly, if alpha synuclein is found to exhibit ‘protective’ properties like beta amyloid, then the alpha synuclein vaccine clinical trials currently underway (in which the body’s immune system is primed to remove free floating alpha synuclein, in an attempt to stop the disease from spreading) may need to be reconsidered. At a minimum, investigations into whether alpha synuclein has antimicrobial properties need to be conducted.
Today’s banner was sourced from PBS.