Tagged: antibodies

The road ahead: Parkinson’s research in 2018

The great ice hockey player Wayne Gretzky once said “A good hockey player plays where the puck is. A great hockey player plays where the puck is going to be” (the original quote actually came from his father, Walter). 

At the start of each year, it is a useful practise to layout what is planned for the next 12 months. This can help us better anticipate where ‘the puck’ will be, and allow us to prepare for things further ahead.

2017 was an incredible year for Parkinson’s research, and there is a lot already in place to suggest that 2018 is going to be just as good (if not better).

In this post, we will lay out what we can expect over the next 12 months with regards to the Parkinson’s-related clinical trials research of new therapies.


Charlie Munger (left) and Warren Buffett. Source: Youtube

Many readers will be familiar with the name Warren Buffett.

The charming, folksy “Oracle of Omaha” is one of the wealthiest men in the world. And he is well known for his witticisms about investing, business and life in general.

Warren Buffett. Source: Quickmeme

He regularly provides great one liners like:

“We look for three things [in good business leaders]: intelligence, energy, and integrity. If they don’t have the latter, then you should hope they don’t have the first two either. If someone doesn’t have integrity, then you want them to be dumb and lazy”

“Work for an organisation of people you admire, because it will turn you on. I always worry about people who say, ‘I’m going to do this for ten years; and if I really don’t like it very much, then I’ll do something else….’ That’s a little like saving up sex for your old age. Not a very good idea”

“Choosing your heroes is very important. Associate well, marry up and hope you find someone who doesn’t mind marrying down. It was a huge help to me”

Mr Buffett is wise and a very likeable chap.

Few people, however, are familiar with his business partner, Charlie Munger. And Charlie is my favourite of the pair.

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The Llama-nation of Parkinson’s disease

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The clustering of a protein called alpha synuclein is one of the cardinal features of the brain of a person with Parkinson’s disease.

Recently published research has demonstrated that tiny antibodies (called nanobodies) derived from llamas (yes, llamas) are very effective at reducing this clustering of alpha synuclein in cell culture models of Parkinson’s disease. 

In today’s post, we will discuss the science, review the research and consider what it could all mean for Parkinson’s disease.


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Llama. Source: Imagesanimals

Ok, I confess: This post has been partly written purely because I really like llamas. And I’m not ashamed to admit it either.

I mean, look at them! They are fantastic:

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Source: Vogue

Very cute. But what does this have to do with Parkinson’s disease?

Indeed. Let’s get down to business.

This post has also been written because llamas have a very interesting biological characteristic that is now being exploited in many areas of medical research, including for Parkinson’s disease.

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The autoimmunity of Parkinson’s disease?

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In this post we discuss several recently published research reports suggesting that Parkinson’s disease may be an autoimmune condition. “Autoimmunity” occurs when the defence system of the body starts attacks the body itself.

This new research does not explain what causes of Parkinson’s disease, but it could explain why certain brain cells are being lost in some people with Parkinson’s disease. And such information could point us towards novel therapeutic strategies.


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The first issue of Nature. Source: SimpleWikipedia

The journal Nature was first published on 4th November 1869, by Alexander MacMillan. It hoped to “provide cultivated readers with an accessible forum for reading about advances in scientific knowledge.” It has subsequently become one of the most prestigious scientific journals in the world, with an online readership of approximately 3 million unique readers per month (almost as much as we have here at the SoPD).

Each Wednesday afternoon, researchers around the world await the weekly outpouring of new research from Nature. And this week a research report was published in Nature that could be big for the world of Parkinson’s disease. Really big!

On the 21st June, this report was published:

Nature
Title: T cells from patients with Parkinson’s disease recognize α-synuclein peptides
Authors: Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A
Journal: Nature. 2017 Jun 21. doi: 10.1038/nature22815.
PMID: 28636593

In their study, the investigators collected blood samples from 67 people with Parkinson’s disease and from 36 healthy patients (which were used as control samples). They then exposed the blood samples to fragments of proteins found in brain cells, including fragments of alpha synuclein – this is the protein that is so closely associated with Parkinson’s disease (it makes regular appearances on this blog).

What happened next was rather startling: the blood from the Parkinson’s patients had a strong reaction to two specific fragments of alpha synuclein, while the blood from the control subjects hardly reacted at all to these fragments.

In the image below, you will see the fragments listed along the bottom of the graph (protein fragments are labelled with combinations of alphabetical letters). The grey band on the plot indicates the two fragments that elicited a strong reaction from the blood cells – note the number of black dots (indicating PD samples) within the band, compared to the number of white dots (control samples). The numbers on the left side of the graph indicate the number of reacting cells per 100,000 blood cells.

Table1

Source: Nature

The investigators concluded from this experiment that these alpha synuclein fragments may be acting as antigenic epitopes, which would drive immune responses in people with Parkinson’s disease and they decided to investigate this further.

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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:

Accuracy

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:
Blood1

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).

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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.