Tag: neurodegeneration

Isradipine: Posthoc analysis

~ Simon ~ 4 Comments

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Last year the results of the large STEADY-PD study were published. The investigators behind the Phase III clinical trial reported that the experimental treatment being tested had no effect on the progression of Parkinson’s in recently diagnosed individuals.

The treatment being evaluated was a calcium channel blocker called isradipine – it is used for treating high blood pressure.

Since publishing the results, some of the researchers behind the study have been conducting post hoc analysis of the data… and they have found something interesting: An effect.

In today’s post, we will look at why isradipine was evaluated in Parkinson’s, what the results of the STEADY-PD study were, and what the newly discovered effect could mean.

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Source: Medium

In the scientific world, post hoc analysis (from the Latin post hoc, meaning “after this”) consists of statistical analyses that are specified after the data has been seen. This type of analysis should only be considered for “hypothesis forming” exercises, and not be viewed as cherry-picking of the data in order to find an effect. 

And one must be careful with interpretation of data (eg. most people who are involved in car crashes have been reported as wearing clothes at the time of the incident, thus we should get rid of clothes to assess if this will reduce the incidence of automobile accidents).

Post hoc analyses of completed clinical trial data, however, can be very useful process of identifying interesting trends that could be explored in future studies.

A good example of this has recently been conducted on the STEADY-PD clinical trial study.

What was the STEADY-PD clinical trial about?

Continue reading “Isradipine: Posthoc analysis” →

What TDO about KMO?

~ Simon ~ 4 Comments

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New approaches for potentially slowing the progression of Parkinson’s are being announced on a regular basis. Some of them can not be independently replicated (such is the nature of science), while others open up whole new areas of research.

Recently scientists have reported that inhibiting certain aspects of the kynurenine pathway – which plays a critical role in generating energy in cells – can have neuroprotective results in models of Parkinson’s.

Many of the results have been independently replicated and the findings are now resulting in a new class of drug heading for clinical testing.

In today’s post, we will delve into what the kynurenine pathway is, explore how it relates to Parkinson’s, and discuss some of the approaches soon heading for the clinic.

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Structure of tryptophan. Source: Wikipedia

Tryptophan is one of eight essential amino acids.

Amino acids are the fundamental building blocks of proteins in biology, but the “essential” label in this case does not refer to its necessity (although it is necessary), but rather the fact that it cannot be made by our bodies. As a result, all essential amino acids must come from the food we consume.

Tryptophan has many functions within the body:

  • it is a precursor to the neurotransmitter serotonin (which influences your mood, cognition, and behaviour)
  • it is a precursor of the hormone melatonin (which governs your sleep-wake cycle)
  • it is a precursor of vitamin B3 (naicin)

Source: Wikimedia

More importantly, however, tryptophan is also involved in kynurenine synthesis.

What is kynurenine synthesis?

Continue reading “What TDO about KMO?” →

Monthly Research Review – February 2021

~ Simon ~ 4 Comments

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At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during February 2021.

The post is divided into eight parts based on the type of research:

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So, what happened during February 2021?

In world news:

February 4th – More injections than infections – more people have now been vaccinated against Covid-19 than infected worldwide (Source).

February 15th – Ngozi Okonjo-Iweala elected as the seventh Director-General of the World Trade Organisation – a first for women and a first for Africa (Source).

 

February 17th – Researchers reported a high-performance polyethylene plastic made from renewable oils that is chemically recyclable (Source).

February 18th – Nasa’s Perseverance (“Percy”) rover was safely delivered to the surface of Mars (Source).

24 February – Ghana becomes the first country to receive vaccines through the COVAX vaccine-sharing initiative.

 

In the world of Parkinson’s research, a great deal of new research and news was reported:

In February 2021, there were 1,228 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (2,463 for all of 2021 so far). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).

The top 5 pieces of Parkinson’s news

Continue reading “Monthly Research Review – February 2021” →

Forget Special K, maybe focus on LysoK

~ Simon ~ 1 Comment

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Over the last 20 years, researchers have identified a number of genetic variations that can confer an increased risk of developing Parkinson’s. Tiny alterations in regions of DNA (called genes) – which provide the instructions for making a protein – can increase one’s chances of Parkinson’s.

A better understanding of the biological pathways associated with these genetic risk factors is opening up vast new areas of research.

Recently researchers have been exploring the biology behind one particular genetic risk factor – involving a gene called TMEM175 – and they have discovered something quite unexpected: While one genetic variation in the TMEM175 gene increases the risk of Parkinson’s, another variation reduces it.

In today’s post, we will explore the biology of TMEM175, review what the results of the new research indicate, and consider why these findings might be interesting in terms of potential future therapeutic targets.

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Wadlow (back left). Source: Telegraph

Robert Pershing Wadlow was always in the back of school photos.

Born February 22nd 1918, Wadlow’s birth certificate indicated that he was “normal height and weight“, but from that point onwards, there was nothing normal about his rate of growth.

By the time, Robert was 8 years old, he was taller than his father (he was 6 foot/183cm). And eight years later when he turned 16, Robert was 8 foot 1 (2.47 m)… and he was still growing.

Here is a picture of him with his family at 19 years of age:

Source: Businessinsider

Robert was the tallest person in recorded history, and at the time of his death – at the tragically young age of 22 – Robert was almost 9 feet tall (8 ft 11; 2.72 m)… and still growing.

His incredible growth was caused by a condition called hyperplasia of his pituitary gland. This condition that results in an overactive pituitary gland which causes an abnormally high level of the human growth hormone to be produced.

Source: Britannica

Human growth hormone (or somatotropin) is a peptide hormone that belongs to a much larger group of molecules that are referred to as growth factors.

In general terms, growth factors are small molecule that plays an important and fundamental role in biology. They stimulate cell proliferation, wound healing, and occasionally cellular differentiation.

And Robert’s story is an example of how powerful the effect these tiny molecules can have.

Growth factors are secreted from one cell and they float around in the extracellular world until they interact with another cell and initiate survival- and growth-related processes.

Source: Wikimedia

We have often discussed growth factors on this website in the past, with posts of growth factors like GDNF (Click here to read a SoPD about this) and CDNF (Click here to read a SoPD post on this). These discussions have largely focused on how growth factors could have neuroprotective and regenerative potential for Parkinson’s, stimulating survival and growth of cells.

Recently, however, new research has been published that demonstrates how some of these growth factors could be influencing an entirely different aspect of cellular biology that is connected to Parkinson’s: lysosomal function.

What is lysosomal function?

Continue reading “Forget Special K, maybe focus on LysoK” →

Our approach to failure

~ Simon ~ 9 Comments

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Recently the results of two large clinical trials in Parkinson’s were announced. Both indicated that the therapies involved had not demonstrated any impact on the progression of Parkinson’s. This disappointing news resulted in the usual headlines (“Epic failure” & “Clinical trial tanks”) from news outlets whose editors have obviously never lost anyone they cared about.

In addition, there has also been a useful chorus of “I told you so” and “We’re going the wrong way” coming from the back seat of the car, despite the fact that we haven’t seen any actual trial data yet, or the fact that they can’t propose any viable alternative approaches.

What is missing in all of this noise, however, is a better approach to failure. Not only an open and honest postmortem of what worked and didn’t work in the studies, but also better, more respectful ways of communicating results.

In today’s post, we will discuss our approach to failure.

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PART 1. POSTMORTEM

The book I gift the most is Sherwin Nuland’s “How we die”.

As a rule, I am selective as to who I gift this to, never for Christmas or birthdays, and I always remind the receiver of the gift that “you should not judge a book by its cover”.

This book is so precious.

A poetic set of reflections from a medical doctor who has sent his entire career watching ‘life’s final chapter’. There is science, wisdom and beauty on every single page. Nuland has such a wonderful way with words, and I find myself constantly going back to this book and finding something new.

Sherwin Nuland (1930 – 2014). Source: Theparisreview

My favourite part of the entire book is chapter 11.

Throughout the first half of the book, Nuland pushes the argument for returning some dignity to our last days of life. Rather than prolonging suffering in a futile effort to extend life a few short months, he implores the reader to let nature simply take its course.

But all of this changes in chapter 11, where he describes the moment his brother Harvey called him on the phone and told him he had been diagnosed with terminal cancer.

Source: Lawtech

In an instant everything changed. The context had shifted, and instead of “let nature simply take its course”, Nuland recalls how his thinking immediately became “we have to do whatever it takes to keep my brother alive”. (And I’m not ruining the book by sharing this spoiler – there is so much more in this book. It should be required reading for first year medical students).

My second most gifted book is “Black box thinking: The Surprising Truth About Success“ by Matthew Syed.

Matthew Syed. Source: Amazon

It investigates how we approach failure, and the first chapter describes everything that is wrong with how we currently conduct clinical trials.

What does it say?

Continue reading “Our approach to failure” →

The basket case

~ Simon ~ 4 Comments

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One of the more interesting pieces of clinical trial news in 2020 was the publication of the results of a “basket study” for neurological conditions. This was a trial that involved a drug being tested on a selection of neurodegenerative conditions, rather than just one condition.

Between December 2013 to May 2017, researchers recruited a total of 29 individuals with Alzheimer’s, 14 with progressive supranuclear palsy (PSP) and 30 with corticobasal syndrome. These participants were intravenously injected with the same drug (TPI-287 – a microtubule stabilizer) once every 3 weeks for 9 weeks (with an optional 6-week open-label extension).

Although the findings of the study did not support further development of TPI-287 for tauopathies, the overall structure of the study represents an interesting example of how researchers are taking different approaches to investigating neurodegenerative conditions.

In today’s post, we will discuss novel clinical trial designs (“baskets and umbrella”) and other examples of research efforts to better understand neurodegeneration as a whole.

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Source: HuffPost

It was when my daughter turned 3 years old that the psychological warfare really started.

And I remember the moment of realisation very clearly: It began with her desire for a pet dog.

Up until that point in time, she had limited experience with dogs and her negotiation strategies centred solely around crying. I think she loved “the idea” of a dog, but she was generally quite timid around them. Regardless, she gradually began applying pressure (read: lots of crying) on us to get a dog.

And said pressure began to build rapidly (read: frequent episodes of lots of crying).

Source: Focus

Now my wife is definitely not a dog person (“wet, filthy, smelly things“). I on the other hand quite like dogs, but I was utterly, utterly, utterly opposed to getting one because I know full well who will be lumped with the mid-winter late night “walkies” two years down the line: me!

The pressure from our daughter continued to increase, however, until we finally had to sit down with her and explain that we were not going to be getting a dog. On the surface, it looked like she handled this news very well (that is to say: she did not cry). She simply accepted the situation, got up and left the room, saying “Ok”.

My wife and I looked at each other and thought “problem solved”.

The next morning, however, this picture was waiting for us on the kitchen table:

I kid you not.

That’s my daughter and her pet dog (“Linguine“) on the right, and I’m the big, cross-eyed, bad guy on the left.

Since that time the psychological manoeuvring has only become more sophisticated (the teenage years are still a few years away, but I am already absolutely terrified!).

Amusing, but what does this have to do with Parkinson’s?

Continue reading “The basket case” →

Trying to LIMP-2 the lysosome

~ Simon ~ 8 Comments

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Lysosomes are small bags of enzymes that are used to break down material inside of cells – digesting newly absorbed food or recycling old/used proteins and rubbish. Recently researchers have been discovering increasing evidence that points towards dysfunction in lysosomes as a key influential player in neurodegenerative conditions, like Parkinson’s.

There are several Parkinson’s genetic risk factors associated with lysosomal function (GBA being the obvious one), that can increase one’s risk of developing Parkinson’s.

But there is also data indicating that individuals without any of these risk factors may also have reduced lysosomal activity. And recently researchers have identified one possible explanation.

In today’s post, we will explore what lysosomes are, investigate how they maybe involved with Parkinson’s, review what the new data reports, and discuss how this information might be useful.

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Type of endocytosis. Source: Slidemodel

On a continual basis, cells inside your body are absorbing material from the world around them with the aim of collecting all that they need to survive. They do this predominantly via a process called endocytosis, in which a small part of the cell membrane envelopes around an object (or objects) and it is brought inside the cell.

As the section of cell membrane enters the interior of the cell, it detaches from the membranes and forms what is called an endosomes (sometimes it is also called a vacuole). Once inside, the endosome transported deeper into the interior of the cells where it will bind to another small bag that is full of digestive enzymes that help to break down the contents of the endosome.

This second bag is called a lysosome.

Lysosomes

How lysosomes work. Source: Prezi

Once bound, the lysosome and the endosome/vacuole will fuse together and the enzymes from the lysosome will be unleashed on the material contained in the vacuole. The digestion that follows will break down the material into more manageable components that the cell needs to function and survive.

This enzymatic process works in a very similar fashion to the commercial products that you use for washing your clothes.

Enzymatic degradation. Source: Samvirke

The reagents that you put into the washing machine with your clothes contain a multitude of enzymes, each of which help to break down the dirty, bacteria, flakes of skin, etc that cling to your clothes. Each enzyme breaks down a particular protein, fat or such like. And this situation is very similar to the collection of enzymes in the lysosome. Each enzyme has a particular task and all of them are needed to break down the contents of the endosome.

Interesting, but what does this have to do with Parkinson’s?

Continue reading “Trying to LIMP-2 the lysosome” →

Being ly-mphatic about drainage issues

~ Simon ~ 11 Comments

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The lymphatic network is an important part of our body’s defense system. It is made up of an enormous web of vessels and nodes which help to protect us from infection and disease.

This network transports a colourless fluid (called lymph), which serves two primary functions: 1.) it contains infection-fighting white blood cells that help in immune responses, and 2.) it functions as a ‘drainage system’ – allowing excess fluid from organs to be extracted and shifted to the blood system for excretion.

Recently, researchers reported something interesting about the lymphatic system in people with Parkinson’s: the rate of flow around the brain is slower.

In today’s post, we will discuss what the lymphatic system is, review what the new research found, and look at how this new information could potentially be used to help treat conditions like Parkinson’s.

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Source: Thinkery

So picture this if you will:

The weather reporter would later say that it was “a month of rain in the matter of an hour“, but in the midst of the summertime mêlée I was standing bare foot, ankle deep in my rapidly flooding courtyard, trying to clear the blocked storm drain with a long metal pole.

My tee-shirt and shorts were soaked, and… oh yeah, there was lots of thunder and (more importantly) lightning.

Source: KalingaTV

Now, I am a rather tall individual (6’8 ~ 2m 7cm on my good days), and looking back now I can appreciate that standing ankle deep in water holding a long metal pole high in the air (to gather enough downward force to unplug the drain) in the middle of a lightning storm was probably not one of my best moments.

Luckily, my neighbour – a plumber and 3-4 fold smarter than me – kindly decided to take pity on his slow-witted nearby resident. He leapt into the situation and resolved it all in the blink of an eye.

Source: Independent

Since that moment I have religiously maintained a clear storm drain, and taken to deriving great pleasure in keeping other drainage systems about the house clear and flowing free.

I’m happy for you, but what does this have to do with Parkinson’s?

Well, very recently researchers have reported that a different kind of drainage issue might be at play in many cases of Parkinson’s.

What on Earth do you mean?!?

Continue reading “Being ly-mphatic about drainage issues” →

Monthly Research Review – January 2021

~ Simon ~ 1 Comment

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At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during the previous 4 weeks.

The post is divided into eight parts based on the type of research:

Today’s post is a review of Parkinson’s research during the month of January 2021.

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So, what happened during January 2021?

In world news:

January 6th – the platypus genome was published. Reseachers explore how one of mother nature’s oddities became so odd (Click here to read more about this).

January 6th – Using a recently developed gene-editing technique, researchers reported that they could partially correct the accelerated aging disorder of progeria, extending the lifespan of mice with the associated genetic variation (Click here to read more about this).

January 7th – While the world is more focused on the rollout of the company’s COVID vaccine, researchers at BioNTech published a research report in which they had designed an mRNA vaccine that delayed the onset of and reduced the severity of multiple sclerosis-like disease in mice (Click here to read more about this).

January 26 – The number of confirmed COVID-19 cases exceeded 100 million worldwide.

January 28th – A day that some of the absurdity of the stock market was openly revealed. Wall Street institutions cried “it’s not fair if everyone else can manipulate the market”, as the GameStop share price rise messed up their own manipulations (Now we suddenly need regulation?!?). Free markets indeed (Click here to read more about this).

In the world of Parkinson’s research, a great deal of new research and news was reported:

In January 2021, there were 1,235 research articles added to the Pubmed website with the tag word “Parkinson’s ” attached (10,584 for all of 2020). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).

The top 6 pieces of Parkinson’s news

Continue reading “Monthly Research Review – January 2021” →

The age-associated changes of PARKIN

~ Simon ~ 4 Comments

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Tiny variations in a region of DNA referred to as “Parkin” are associated with an increased risk of developing Parkinson’s (particularly young onset forms of the conditions). The Parkin DNA provide the instructions for making a protein that is involved with many functions inside cells.

New research indicates that as we age, Parkin protein becomes less available. In fact, by the time we turn 50 years of age, “Parkin is largely insoluble”, meaning that the majority of the protein is no longer able to do its job.

This shift appears to involve oxidation changes.

In today’s post, we will discuss what Parkin and oxidation are, how Parkin might be affected by oxidation, and how this information might be useful to treating Parkin-associated Parkinson’s.

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Me (I wish) before 27. Source: Pinterest

I don’t know about you, but 27 was my peak.

Before my 27th birthday, I could run around all over the place – acting like an idiot, with all the energy in the world. I was invincible and having lots of fun. And yes, some vices might have been involved – I would drink myself blind on a Friday night, wake up fresh the next day and do it all merrily again.

Me before 27. Source: Thefix

But then, my 27th birthday came along and I woke up the next day tired and feeling… fatigued. Weary even. And definitely with less enthusiasm than I had before I passed out the night before. My father called it a “hang-over” (which up until that time I had naively/idiotically thought I was immune to).

Me, before (left) and after 27 (right). Source: Wanna-joke

But I gradually developed this sinking feeling that it was something else.

Something more sinister.

It was as though something had changed. Something inside of me.

And I distinctly remember a moment of realisation, when I asked “Am I getting old???”

My father saw my concern and gave me sage advice (“It’s like I always say, aging ain’t for sissies“), and with that I changed my ways.

Source: DS

Since that moment, I have been fascinated by the biology of aging, particularly in the context of Parkinson’s (age is the main correlate with neurodegenerative conditions like Parkinson’s and Alzheimer’s). So it was with great interest that I read a manuscript in November last year that had been posted on the openly-available preprint database bioRxiv.

What did the manuscript say?

Continue reading “The age-associated changes of PARKIN” →