Increasing preclinical evidence is being presented that suggests the gastrointestinal system can play a role in models of Parkinson’s. In addition, there is mounting epidemiological data indicating that the gut can have some kind of influence in people with the condition.
Recently, a new paper was published which explores the involvement of the vagus nerve. This is the bundle of nerves connecting the gut to the brain.
Specifically, the researchers cut the vagus nerve in mice who had the Parkinson’s associated protein alpha synuclein introduced to their guts, and they found that these mice did not develop the characteristics of Parkinson’s, while those mice with intact vagus nerves did.
In today’s post, we will discuss this new report, review some of the additional preclinical and epidemiological data, and try to understand what it all means for our understanding of Parkinson’s.
Today’s post is about the origin of things. Specifically, Parkinson’s.
But we will begins with words: Consider for a moment the title of this post: Viva las vagus.
When most people read of the word ‘Viva‘, they think of it as a call to cheer or applaud somthing (for example: “Vive la France!” or “Viva las Vegas”), but the origin of the word has a slightly different meaning.
Viva is a shortening of the Latin term viva voce, meaning “live voice”. And in this context it refers to an oral examination – typically for an academic qualification. For example, a European PhD examination is referred to as “viva” and it is an oral denfense (sometimes public – eek!) of the thesis.
A PhD viva examination. Source: Guardian
‘Las’ is simply the Spanish word for ‘the’. And the word ‘vagus’ originates from the Latin, meaning ‘wandering, uncertain’.
Thus, the title of today’s post could – in effect – be “an examination of the uncertain”.
In anatomy and medicine the word, Vagus also refers to an important part of our nervous system.
The great American baseball legend, Yogi Berra, once said: “In theory, there is no difference between theory and practice. But in practice, there is.”
Silly as it reads, there is a great deal of truth to that statement.
In science, we very quickly chase after a particular theory as soon as a little bit of evidence is produced that supports it. Gradually, these theories become our basic understanding of a situation, until someone points out the holes in the theory and we have to revise it.
A new theory of Parkinson’s disease has recently been proposed. In today’s post we will review what the theory is suggesting and what evidence there is to support it.
“I still say it’s only a theory”. Source: NewYorker
In the age of ‘alternative facts’, it is always important to remember that we don’t know as much as we think we do. In fact, much of our modern world still relies on a kind of faith rather than actual ‘facts’. For example, we take a particular type of medicine, because it has worked for some people in the past, not because it will definitely make us better.
And the same applies to our understanding of neurodegenerative conditions, like Parkinson’s disease. Based on all the evidence we have collected thus far, we have theories of how Parkinson’s disease may be progressing. But there are always exceptions to the rule, and these force us to refine or reconsider our theories.
Recently a refinement to our theory of Parkinson’s disease has been suggested.
Who has suggested it?
This is Prof Ole Isacson.
He’s a dude.
And this is Dr Simone Engelender.
She’s awesome as well.
She is Associate Professor of Molecular Pharmacology at the Rappaport Family Institute for Research in the Medical Sciences in Haifa, Israel.
Together they have proposed a new theory of Parkinson’s disease that has the research community talking:
Title: The Threshold Theory for Parkinson’s Disease.
Authors: Engelender S, Isacson O.
Journal: Trends Neurosci. 2017 Jan;40(1):4-14.
The new theory proposes that Parkinson’s disease may actually be a ‘systemic condition’ (that is, affecting cells everywhere at the same time), but the clinical features – such as motor issues – only appear as certain thresholds are passed in the affected populations of neurons in the brain.
What does that mean?
Wait a minute. Let’s start at the beginning.
Before discussing what the new theory suggests, shall we first have a look at what the old theories proposed?
Ok, what did the old theory propose?
This is Prof Heiko Braak:
Source – Memim.com
He’s pretty cool too. Nice guy.
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 – from just after being diagnosed to having had the condition for decades – and he 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 (Click here to read more about this).
The Braak stages of PD. Source: Nature
Braak’s results also led him to propose that Parkinson’s disease may actually begin in the brain stem (which connects the brain to the spinal cord) and the disease slowly works it’s way up into the brain.
That is the ‘ascending’ theory of Parkinson’s disease.
This idea has been further adapted by Braak and others with the discovery of Parkinson’s disease features in the gut (we have discussed this in previous posts – Click here and here to read those posts).
But how does the disease actually spread?
The spread of the condition is believed to be due to the protein alpha synclein being passed between cells in some manner. This idea stemmed from the analysis of the brains of people with Parkinson’s disease who received cell transplantation therapy in the 1980-90’s. After those people passed away (due to natural causes), their brains were analysed and it was discovered that some of the cells in the transplants (1-5%) have Lewy bodies in them (Lewy bodies are one of the hallmarks of Parkinson’s disease, dense circular clusters of proteins including alpha synuclein). This suggests that the disease is passed on to the healthy transplanted cells in some way.
Photos of neurons from the post-mortem brains of people with Parkinson’s that received transplants. White arrows in the images above indicate lewy bodies inside transplanted cells. Source: The Lancet
So the research community has been working with the idea of an ‘ascending’ theory of Parkinson’s disease, and the spreading of the condition via the passing of alpha synuclein from cell to cell. And this theory has been fine,…
Why do I feel like there’s a ‘but’ coming?
Because there is a ‘but’ coming.
And it’s a big BUT.
But as Prof Isacson and Dr Engelender point out there are some holes in this theory.
Some big holes.
For example, in a 2008 study of 71 postmortem brains from people with Parkinson’s disease, 47% of the cases did not fit the predicted ‘Braak theory’ spread of alpha synuclein, and 7% of those cases did not have any cell loss in the dorsal motor nucleus (one of the first sites of damage in the Braak theory – Click here to read more).
Ok, so the theory is not perfect…what are Prof Isacson and Dr Engelender proposing instead?
They suggest that alpha synuclein accumulation starts at about the same time in nerve cells throughout the body, but the different groups of nerve cell differ in how much toxicity they can handle.
Some of these groups of cells can handle a lot (and more than half of the cells need to be lost before clinical features begin to appear), while others have a lower ‘threshold’ (only a few cells need to die before symptoms appear).
Prof Isacson and Dr Engelender argue that the nerve cells around the gut, for example, have a lower reserve (or total number), and, therefore, symptoms related to the gut become more obvious sooner as those cells die off or become less efficient. This lower threshold is in contrast to the more well known cell loss of the dopamine producing neurons in the midbrain, where approximately 50-70 percent of the dopamine neurons disappear before the classical motor features of Parkinson’s start to appear. Their theory suggests that this part of the brain has a larger reserve, and thus higher threshold.
Hence the reason why this is being called the ‘threshold theory’.
Some groups of cells may have a higher threshold in Parkinson’s disease. Source: Cell
Some cells may have a low threshold and only require a few cells to be lost before the clinical features associated with those cells begin to appear. These symptoms would obviously appear earlier than those features associated with a high threshold population of cells, which required substantial loss before symptoms appear.
This idea would explain differing results seen in research findings regarding, for example, vagotomies (the cutting of the vagus nerve to the gut – click here to read more about this). This new theory would suggest that the procedure might not have any impact at all on lowering the risk of Parkinson’s disease.
Both scientists insist that searching for treatments that slow or block the aggregation of alpha synuclein is still necessary.
“Instead of studying how proteins move from one neuron to another and searching for compounds that prevent the ‘spread’ of aggregated alpha-synuclein, we need to study why alpha-synuclein accumulates within neurons and how these neurons die in the disease, and search for compounds that prevent the general neuronal dysfunction,” – Dr Engelender
(Source: Science Daily)
So are there any problems with this new theory?
The new theory is a very interesting idea and deserves consideration. It solves some of the problems with the “ascending theory” discussed further above. But it also faces some of the same problems that the ascending theory has to deal with.
For example, in one large autopsy study which investigated 904 brains, the investigators blindly collected all of the brains that had alpha synuclein present in the groups of neurons that are affected in Parkinson’s disease (eg. the dorsal motor nucleus of vagus, substantia nigra, and/or basal forebrain nuclei.). They found that alpha synuclein was observed in 11.3% (or 106 cases). But when the researchers then looked at the clinical notes associated with those cases, only 32 (30%) had been diagnosed with a neurodegenerative disorder. The rest had demonstrated no clinical features.
Another study found that 8.3% of the aged control brains had alpha synuclein present in them. In addition, the presence of alpha synuclein is not specific to Parkinson’s disease – approximately 50% of people who die with Alzheimer’s disease have been found to have Lewy bodies. These results suggest that alpha synuclein aggregation can be present in both healthy and diseased brains. But if this is so, what role is alpha synuclein playing in Parkinson’s disease?
(You see the sort of problems we are dealing with in research when trying to come up with a theory of how something complicated is actually working?)
What does it all mean?
The central job of a scientist is to test hypotheses.
A hypothesis is a true or false statement (for example, hypothesis: the sun will come up tomorrow – easy to test as the sun either will or won’t come up; the statement is either true or false). In building one hypothesis on top of another hypothesis, we develop theories about how the world around us works.
Sometimes our hypotheses can unwittingly take us in a particular direction, depending on different variables. The danger in this process (one which must be met with discipline and control procedures) is that one can start to look for results that support a hypothesis or theory. It is a very human characteristic to become blind to any evidence to the contrary.
A new theory of Parkinson’s disease has been proposed. It suggests that rather than the condition starting in one location and progressively moving higher into the brain, Parkinson’s disease may actually start everywhere and it is the varying levels of tolerance between different types of cells that determines which cells die first.
It is certainly a new take of the available evidence and the research community is considering it. It will be interesting to see what kind of feedback results from this article, and we will post updates on that feedback as they become available.
The banner for today’s post was sourced from Sott
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.
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.
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.
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.