Monitoring Parkinson’s: Let’s just sleep on it

Regular readers will be aware that here at the SoPD, we are on a mission to change the way we clinically test drugs (Click here for the most recent rant on this topic).  We have a lot of interesting drugs waiting in the pipeline to be clinically tested and an eager (read: desperate) population of individuals affected by Parkinson’s, but we are missing one critical part of the equation: better tools of assessment. How can we determine whether a drug is actually working or not? And how can we better monitor people over time on said drug? Our current methods assessing individuals with Parkinson’s rely heavily on clinical rating scales and brain imaging. These are basic tools at best, conducted episodically (annually in general, or once every 2-6 months during a clinical trial), and provide little in the way of useful objective data (on an individual basis). In today’s post, we will look at a single aspect of Parkinson’s – sleep – and try to nut-out a better/more informative method of assessing it over time.

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The Bluesky project. Source: Mirror

Last week tech industry giants Pfizer and IBM made an big announcement.

It was news that I have been quietly waiting to hear for some time.

It related to their “BlueSky Project” – a collaboration between the two companies to provide better methods of assessment/monitoring of Parkinson’s.

 

The two companies announced that they are now ready to start accepting the first participants for a new clinical trial.

And it is a really intriguing study for one simple reason:

The entire trial will take place inside one house.

The house that Parkinson’s built. Source: Mirror

The house – originally a farmhouse built in the early 19th century – is based on the IBM Thomas J Watson Research Center in Yorktown Heights (upstate New York).

And what makes the house unique is that the living space of the house is now packed with sensors for assessing Parkinson’s. It contains magnetometers, cameras, gyroscopes, and accelerometers that can monitor and measure the movements of the people living in the building.

Right down to each tremor and twitch.

The layout of the house (floor plan) looks like this:

Home sweet home. Source: Datamakespossible

I am currently not aware of the details of the trial protocol, but I guess it is safe to assume that participants will be required to spend a certain period of time (probably multiple visits) in the house as part of the study. They will also most likely be required to wear sensors on their body during their stay.

Putting on the wearable sensors. Source: Mirror

By combining both wearable sensors and ‘ambient sensors’ (fixed systems of measurement around the house), Pfizer and IBM hope that using this system they will be able to collect a huge amount of information about a person’s movements, from their ability to grasp a doorknob to the way they slide a chair out from under the table.

I’m not sure about the orange plates. Source: Mirror

Once dressed up with the wearable sensors, participants will probably be allowed to make themselves at home in the house, and their daily activities will be measured and assessed.

Sweet dreams. Source: Mirror

In addition to better monitoring of Parkinson’s, another goal of the Bluesky project is to train artificial intelligence (really smart computers) to assess the Parkinson’s symptoms that the system is picking up. The computers will be able to assess participants the same way a doctor would, but on a continuous basis.

In the long term, this will mean no more “once-every-12-months” appointments, but rather ongoing measurements being made as individuals goes about their lives. Continuous assessment.

This video explains the approach IBM and Pfizer are taking with this project:

So the system will be ‘watching’ me all the time?

Yeah, I appreciate that all of this technology may feel a little bit creepy/’Big brother’ to some readers (particularly in this age of Cambridge Analytica). But I actually really like certain aspects of this project.

I am not sure about the artificial living environment of a house in upstate New York, but if some of the assessment technology can be applied to an individual’s normal everyday home life, I think it could help us tremendously with both monitoring of Parkinson’s over time and within the context of clinical trials.

What do you mean?

This quote is copied from another article about the Bluesky project:

“When [a patient] finally gets their 20 minutes with the neurologist to review their meds schedule and symptoms and changes, what the health professional observes is not necessarily an accurate reflection of how that person’s life is,” says Holly Chaimov, executive director of advocacy group Parkinson’s Resources of Oregon. “This objective data could fill in the rest of the picture.”

Holly Chaimov. Source: Osugero

The ‘objective data’ in the last sentence is referring to the data being collected in the Bluesky project.

A lot of what we use at the moment in the diagnosis and assessment of Parkinson’s is ‘qualitative data’, information that hasn’t been (or can’t actually be) measured.

For example, how tired do you feel today? Your answer will be qualitative. Even if I ask you to give me a measure of how tired you feel (on a scale of 1 – 10, ten being absolutely exhausted), your response is subjective (based solely on your view of things) and still rather qualitative.

This is me when I am really tired (maybe, 8 on a scale of 1 to 10). Source: Theodysseyonline

A better way of assessing individuals with Parkinson’s over time would be continuous measurements, coming from technology that requires little or no effort from the person being monitored.

We have previously discussed wearable technology for Parkinson’s (Click here to read that post, and click here for a good review of wearable sensors for Parkinson’s), and more recently we have looked at using smart pills to monitor what is happening in the gastrointestinal tract (Click here to read that post):

Smart pills. Source: sfchronicle

Smart pills require little effort from the individual taking the pill, beyond actually remembering to take their medication in the morning (which is a daily habit for many).

Today we are going to discuss another component of life that is affected by Parkinson’s, which could definitely be better monitored using new technology.

That area of life: Sleep.

How is sleep affected in Parkinson’s?

Problems with sleep are some of the most common non-motor features of Parkinson’s, and many studies have demonstrated this.

A good example is the PRIAMO (PaRkinson And non Motor symptOms) study. It was an epidemiology study which aimed to assess the prevalence and incidence of non-motor features of Parkinson’s. It was a longitudinal 24 month observational study conducted by 59 Neurology Centres across Italy to establish the incidence of non-motor features in Parkinson’s. The study involved 1307 people with Parkinson’s.

Title: The PRIAMO study: A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease.
Authors: Barone P, Antonini A, Colosimo C, Marconi R, Morgante L, Avarello TP, Bottacchi E, Cannas A, Ceravolo G, Ceravolo R, Cicarelli G, Gaglio RM, Giglia RM, Iemolo F, Manfredi M, Meco G, Nicoletti A, Pederzoli M, Petrone A, Pisani A, Pontieri FE, Quatrale R, Ramat S, Scala R, Volpe G, Zappulla S, Bentivoglio AR, Stocchi F, Trianni G, Dotto PD; PRIAMO study group.
Journal: Mov Disord. 2009 Aug 15;24(11):1641-9.
PMID: 19514014

The PRIAMO study found that 98.6% of the participants reported the presence of non-motor features, and one of the most common was sleep problems – occurring in 64.1% of cases.

And these sleep related issues could be further broken down into:

• REM sleep behaviour disorder (29.6% of cases)
• Insomnia (36.8%)
• Excessive day time sleepiness (21.2%)
• Restless legs (15.2%)

These results have been replicated numerous times. In fact, the incidence of sleep problems in Parkinson’s is generally stated as occurring in 40% to 90% of cases (Click here for a good review on the topic).

What happens in the brain in Parkinson’s that causes sleep problems?

As you will be aware, sleep is an unconscious state that the body goes into when we lie down during the night. It is characterised by immobility and reduced responsiveness. There are two broad phases of sleep:

1. Rapid eye movement (REM) sleep
2. Non-rapid eye movement (NREM) sleep.

We pass through these phases in a wave-like cycles as we sleep:

Stages of sleep. Source: Wikipedia

In addition, there are different stages that make up these cycles (stage 1-4, on the left hand side of the image above), which we pass through on our way down to stage 4 (or NREM sleep) and back.

These stages exhibit different patterns of brain activity:

 

Brain activity during each stage of sleep. Source: Homesteadschools

The brain is very active during REM sleep (this is the period during which we dream), whereas during NREM sleep the brain goes through periods of synchronised neuronal activity (resulting in the ‘high peak’ activity you can see in stage 4 of the image above).

In many cases of Parkinson’s, the pattern of sleep can be slightly different.

Parkinson’s is associated with increased sleep latency (that is, the length of time that it takes to fall sleep – more specifically, to move from full wakefulness to stage 1 in the image above). It is also associated with increased amounts of stage I sleep and reduced levels of REM sleep:

The % of sleep time spent in stages 1-3 of non-REM sleep & REM. Source: Scialert

This abnormal pattern of sleep is multifactorial in origin. It can of course relate to the motor issues of Parkinson’s, such as stiffness. Nocturia (needing to urinate) and medication effects (for example, dopamine agonists) can also disrupt sleep.

The sleep issues can also stem from the cell loss associated with Parkinson’s.

It was once believed that the brain had a specific “sleep region” (in a central region called the hypothalamus). And working in opposition to this was a separate “wakefulness region” (in the brainstem). But recent research has demonstrated that this proposal is too simplistic. Now it appears that wakefulness is not centralised but regulated by a whole network of structures in the brainstem, hypothalamus and basal forebrain. 

The circuitry of sleep. Source: Howsleepworks

Unfortunately, some of the areas of the brain stem associated with sleep are badly affected in Parkinson’s. This is particularly evident in the REM stage of sleep.

Normally during REM sleep, reduced levels of serotonin activity in the brain leads to immobility of the body, through a network of brainstem neurons including the locus subcoeruleus and magnocellularis nucleus. But in Parkinson’s, some of these regions suffer cell loss which results in the body losing its immobility during REM. And this is why some people with very early Parkinson’s will act out their dreams.

Acting out of dreams is a feature of REM sleep behaviour disorder – a common precursor to Parkinson’s.

Click here for a very good review on the structures of the brain involved in sleep and how they are affected by Parkinson’s.

How is sleep currently assessed in Parkinson’s?

The most commonly used method of assessing sleep in Parkinson’s is the Movement Disorder Society-sponsored Unified Parkinson’s Disease Rating Scale (MDS-UPDRS).

It has two separate items for sleep:

1. Nighttime sleep-related problems (item 1.7) – ranging from 0 (not present) to 4 (severe) scores.
2. Daytime sleepiness (item 1.8) – ranging from 0 (not present) to 4 (severe) scores.

And that’s it.

An exhaustive assessment of sleep?

Other rating scales can and are being used. For example, the Epworth Sleepiness Scale (ESS) has been widely used but it is not specific to Parkinson’s. It is also a self-administered rating scale and measures only daytime somnolence (or sleepiness). Other rating scales include the Pittsburgh Sleep Quality Index, Stanford Sleepiness Scale, and Karolinska Sleepiness Scale. There is also the Parkinson’s Disease Sleep Scale – a 15-item measure of commonly reported symptoms associated with sleep disturbance in Parkinson’s.

So we are measuring sleep using just rating scales?

Basically: yes.

But there is a good reason for this. The gold standard for physiological measurements of sleep is polysomnography.

Polysomnography involves recording of your brain waves, the oxygen level in your blood, heart rate and breathing, as well as eye and leg movements during a period of sleep.

Polysomnography. Source: Sleep-apnea-guide

As you may appreciate, these tests require very specialised equipment that is needs to be calibrated and maintained in dedicated sleep laboratories, which is all rather expensive.

But it gives the participant and the investigators are very rich data set of information that can be used for analysis.

But what other options are there?

There are actually a lot of other alternatives. From simple apps that you can download onto your smart phone (although this form of data collection is a bit variable – Click here, here and here to read more about these methods of assessing sleep). This method of sleep assessment usually requires you to sleep with your phone lying on the mattress beside you.

There are more sophisticated options that one can simply lie on and these seem to be more accurate.

One example of this is the sleep monitor system from Beddit.

PLEASE NOTE: This is not a product endorsement, I am simply using Beddit (which is now owned by Apple) as an example. I have not tested this product, nor have I had any communication with the company. I am simply using it as an example of how sleep could be better and more continuously monitored.

The Beddit 3 Sleep monitor is a strap that lies across your mattress at the level of the sleeper’s heart. It hugs the mattress so the person sleeping apparently does not notice it.

Source: Gadgetsandwearables

Best of all it required very little effort from the individual being monitored. It just lies there continuously recording information.

And the system provides a huge amount of information that can is transferred to a smart phone or tablet, which provides reports.

Source: Multivu

The information collected deals with everything from your heart rate, breathing and snoring, to time asleep or restless and times out of bed. It can also give you bedroom humidity and temperature measures. It automatically senses when you go to bed, and it provides a smart alarm system that wakes you up at the best point in your sleep cycle.

Source: Appleinsider

Lots of information that could be collected and monitored over time. And that information could be used in a sleep-associated clinical trial to determine whether a treatment is having a beneficial effect.

I’m not suggesting that this is necessarily the way forward, but it certainly beats the two item clinical rating scale (UPDRS) or sleeping in a bedroom with cameras etc in upstate New York.

Right?

Are there any clinical trials for sleep issues in Parkinson’s?

Most clinical trials of new treatments for Parkinson’s disease will include sleep as part of their assessment. But there are also a lot of clinical trials focused solely on sleep issues in Parkinson’s (Click here for some examples).

One interesting example of them is a trial being conducted by Jazz Pharmaceuticals.

Jazz Pharma is currently conducting a 4-week long Phase II clinical study that will evaluate the safety, efficacy and pharmacokinetics of their experimental drug Solriamfetol (also known as JZP-110) in people with Parkinson’s and excessive daytime sleepiness (Click here to read more about this trial and click here to read the press release).

Solriamfetol (formerly known as ADX-N05, which Jazz acquired from Aerial Biopharma) is a phenylalanine derivative that acts as a norepinephrine–dopamine re-uptake inhibitor (this increases the level of dopamine floating around in the brain, without inhibiting serotonin or other monoamines).

We should know the results of this double-blind, placebo-controlled, randomised study before the end of this year, but Solriamfetol may be approved by the FDA before Christmas this year for the treatment of excessive sleepiness in patients with narcolepsy or obstructive sleep apnea (Click here to read more about this), which would help the drug being approved for other indications/purposes.

What does it all mean?

Technology is an amazing thing, especially when it is used in constructive and beneficial ways.

Recently Pfizer and IBM have announced the start of an interesting clinical study that will involve participants living in a purpose built house that will monitor and analyse many different components of their Parkinson’s symptoms. While this trial is taking a holistic approach, it will also hopefully highlight individual components of Parkinson’s that can be effectively monitored (ideally beyond the laboratory setting).

And it is absolutely crucial that we embrace this idea of better monitoring, for two reasons:

1. The treatment of Parkinson’s is going to become more personal. Everyone is different, so the treatments should be more individualised. But it is very difficult to assess individuals using just periodic rating scale assessments and the occasional brain scan (Click here for more on this).
2. We will be facing a dilemma in the not-so-distant future in which we will have semi-curative treatments that may only partially correct Parkinson’s (for example, Exenatide only affecting motor features – click here to read more about this), while leaving certain aspects still affected. Such a scenario will make future drug development/testing very difficult if we do not have better methods of assessment (Click here for more on this).

Sleep is a daily activity that appears to be relatively easy to measure and monitor. Disruption of sleep patterns is also a common feature of Parkinson’s. While efforts to assess tremor have proven very difficult (it is hard to differentiate between actual purposeful movements vs PD-related movements), the monitoring of sleep looks to be one component of Parkinson’s that deserves more attention.

And speaking of sleep: it’s time I got some.

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The banner for today’s post was sourced from Time