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Scientists develop a new approach to assessing Ataxia at home

Written by Ziyang Zhao Edited by Dr. Hayley McLoughlin

A newly developed smartphone application will allow patients to assess ataxia at home.

There’s an interesting problem in science that’s often overshadowed in the scientific community. It’s not as flashy or as newsworthy as most scientific headlines, like the eradication of Polio or the creation of the coronavirus vaccine, but its importance looms nonetheless. That problem is the monumental task of getting people to assess themselves.

Take this interesting bit: The American Cancer Society found that nearly 100% of Americans are aware of the benefits of monthly screenings for Colorectal Cancer — a preventable and treatable form of cancer, if detected early — yet nearly 50,000 Colorectal Cancer-related deaths occur each year in the United States (American Cancer Society, 2016). Alongside that first statistic, the American Cancer Society had also asked why an unscreened individual chooses to remain so. An important reason, they noted, was patient concern over the complexities of taking a test: taking time off from work, getting a ride home, and high out-of-pocket expenses.

In Ataxia-based diseases, testing is similarly cumbersome and accessibility for assessment is not readily available. The most common way to measure the degree of one’s level of Ataxia is through the Scale for assessment and rating of ataxia (SARA) score, which evaluates 9 ataxia-affected abilities to produce a composite score. The problem, however, is that the SARA test is cumbersome. It’s a costly assessment that requires the patient to travel to their local hospital and meet with a testing expert.

Camera on tripod takng a video — The SARA^home test involves a person performing a series of physical tests. They record themselves using a tablet or smartphone on top of a tripod. Photo used under license by Mascha Tace/Shutterstock.com.

In this study, the researchers devised an Ataxia assessment matching the SARA test that can be performed at home, which they call SARA^home. While the original SARA test assessed 8 attributes, this new Ataxia test only assessed 5, including gait, stance, speech, nose-finger test, fast alternating hand movements. To make SARA^home even easier to take at home, the researchers also incorporated some modifications to their selected 5 tests from the original SARA test, including reducing required walking distances, performing fast-alternating movement and nose-finger tests on a chair, and replacing an investigator’s finger in the nose finger test with a tape-mark on the wall. These video recordings would be sent to an experienced rater, who would subsequently produce the score.

Snapshot: What is Nystagmus?

Nystagmus, also known as ocular ataxia, is a term that refers to uncontrollable eye movement- usually a repetitive cycle of slow movement in a specific direction followed by a quick adjustment back to center. The root of this movement lies in a normal reflex that we use every day: the vestibulo-ocular reflex. This reflex controls how our sense of balance and head movement (our ‘vestibular’ sense) directs the movement of our eyes (the ‘ocular’ component refers to the eye muscles).

For example, if we look at something like the space bar on our keyboard and move our head slowly back and forth, our eyes are usually able to remain fixed on the space bar without much conscious effort. This is occurring because of constant communication between our inner ear and our eye muscles as our head is moving in space.

To get slightly more technical about how this works, we have special sensory organs called “semicircular canals” in the inner ear which serve as a biological gyroscope. As you turn your head in a given direction, fluid in these canals shifts in relation to your movement. The shifting of this fluid activates specialized neurons that in turn activate other neurons to get the information of how you are turning from the ear, to the cerebellum, to the muscles that control the eye. However, there are circumstances where this line of communication may become overwhelmed or disrupted. This disruption causes our eyes to move even though our heads are still. When this happens, we get nystagmus.

For example, here is a video of someone experiencing the vestibulo-ocular reflex while spinning in a chair and nystagmus after spinning in a chair. In this instance, nystagmus happens when the person stops spinning in the chair because the fluid in the inner ear continues moving for a short time even though the head has stopped.

women is looking into the camera, her eyes show shee is looking to the side. — As seen in the video, nystagmus can cause uncontrollable eye movement after head movement has already stopped. Photo used under license by Olena Yakobchuk/Shutterstock.com.

Ataxia, the loss of coordinated movement, is caused by degeneration of the cerebellum. One of the main roles of the cerebellum is as an integration center for how we use incoming sensory information (touch, sight, balance, etc.) to direct how we move in space. Thus, we see that as ataxia worsens, complex voluntary movements like walking become harder to control. This can also disrupt how reflexes using balance and head movement, like the vestibulo-ocular reflex, work. As one’s head moves, the information on how the head is moving initially goes to a specific area of the cerebellum which then tells the eye muscles how to move.

When the cerebellar Purkinje cells of that area stop working properly, this channel of communication becomes overactive. The eye muscles begin to move sporadically as though the head was moving or swivelling even though it is staying still. This is an important symptom to address in patients with ataxia. Nystagmus disrupts sight and is tied to secondary symptoms such as dizziness and nausea. This combination of symptoms severely impedes a person’s independence and reduces their quality of life.

If you would like to learn more about nystagmus, take a look at these resources by Johns Hopkins and the American Academy of Ophthalmology.

Snapshot written by Carrie Sheeler and edited by Dr. Siddharth Nath.

“Expanding” the therapeutic promise for SCA1

Written by Dr. Judit M Perez Ortiz Edited by Dr. Maria do Carmo Costa

A druggable target in Spinocerebellar Ataxia type 1 (SCA1) shows promise in treating cerebellar and non-cerebellar aspects of disease.

Spinocerebellar Ataxia type 1 (SCA1) is a neurodegenerative disease that typically starts with coordination difficulties (ataxia) in mid- to late-adulthood, worsens over time, and shortens life expectancy. SCA1 runs in families, as it is caused by a genetic mutation in a gene called Ataxin-1. The gene’s instructions make a protein conveniently also termed “ataxin-1”. Healthy ataxin-1 is important in orchestrating important processes in brain cells.

In SCA1, mutant ataxin-1 drives disease by affecting these important cellular processes. In patients with SCA1, their ataxin-1 protein has a polyglutamine repeat expansion mutation that makes the protein behave in toxic ways. The disarray caused by mutant ataxin-1 protein slowly deteriorates and ultimately compromises the health of the brain areas involved. Research on this topic is very rich and increasingly exciting. SCA1 treatments under investigation explore different strategies to minimize the insult caused by mutant ataxin-1.

New work by Nitschke and colleagues takes previous efforts a step further towards this goal by delving deeper into the promises and limitations of an exciting therapeutic “angle” in the ataxin-1 protein itself.

Experimental mice are placed on the rotating rod to animal test in the Laboratory — Research in SCA1 mice shows preventing S776 phosphorylation improved muscle strength, respiratory function, and prolonged lifespan. Photo used under license by unoL/Shutterstock.com.

Snapshot: What is Transcranial Direct Current Stimulation (tDCS)?

Transcranial Direct Current Stimulation (tDCS) is a non-invasive method of brain stimulation. It promotes or inhibits activities in specific parts of the brain. tDCS is an experimental treatment that has been shown to result in changes in motor, cognitive and behavioural activities. It may be a valuable tool for the treatment of neurological disorders including cerebellar ataxia.

How it works

Neurons communicate with each other is through an electrical event called the action potential. The cell membrane of neurons can create differences in the concentration of charged molecules, called ions, inside and outside the cell. This separation of ions creates a voltage called the membrane potential. When a signal needs to be transduced to other neurons, a series of voltage changes in the membrane potential called the action potential occurs. The action potential propagates along the arms of the neuron, like sending a message through the cell. Once the message reaches the end of the arm where it meets up with other neurons, the initial neuron releases its neurotransmitters that deliver the message to the next neuron. And thus, the cycle continues!

tDCS works by stimulating the neurons with a weak electrical current, through electrodes placed on the scalp of the patient. These electrodes can slightly increase or decrease the resting membrane potential. This process can make it easier or harder for an action potential to occur. This either promotes or inhibits activities in specific brain regions.

Artist's depiction fo the human brain. Electrical energy is swirling around it. — tDCS is a non-invasive method of brain stimulation that promotes or inhibits activities in specific parts of the brain. Photo used under license by Andrus Ciprian/Shutterstock.com.

Application in ataxia

Due to the ability of tDCS to reversibly modulate brain activity, clinical trials have been conducted in many neurological and psychiatric disorders. Notably, a randomized, double-blind trial in 61 patients with multiple subtypes of ataxia came to completion in March 2021. After treatment with tDCS, a significant improvement in both the motor and cognitive symptoms of ataxia was observed. Patients also self-reported improvement in quality of life. The clinical assessment for motor functions was done through the scale for the assessment and rating of ataxia and the international cooperative ataxia rating scale. Assessment for cognitive functions was done through the cerebellar cognitive affective syndrome scale.

The study found that patients who went through two repeated treatment sessions with ten weeks in between had significantly better improvement when compared to patients who went through only one session of treatment. Also, the improvements persisted on average 3 to 6 months post-treatment. This means that the benefits of tDCS might last longer than previously thought.

Risks and benefits

TDCS is considered non-invasive and since its initial application in 1998, no serious or ongoing side effects have been reported. Studies have also shown that the electrical current will not interfere with vital functions of the heart and the brain stem. However, tDCS is still in its infancy. More research needs to be conducted to improve our understanding of potential risks and benefits. Temporary side effects including a mild burning/itching sensation at the stimulation sites, headache, and moderate fatigue were reported in around 17% of the patients. On the flip side, the technique uses equipment that is available on the market for other medical purposes. This makes the procedure relatively inexpensive, easily administered, and using easily replaceable equipment. TDCS could also be used in combination with other treatment methods. However, more research on combination treatments needs to be conducted to test safety and effectiveness.

If you would like to learn more about Transcranial Direct Current Stimulation, take a look at these resources by Johns Hopkins Medicine and Neuromodec.

Snapshot written by Christina (Yi) Peng and edited by Dr. David Bushart.

Snapshot: What is Riluzole?

Riluzole, often sold under the trade name Rilutek, is a medication used for the treatment of amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disease that mainly affects neurons controlling muscle movements. The drug was approved by the FDA (1995), Health Canada (1997), and the European Commission (1996). It helps slow down disease progression and may extend patient survival. The medication is available in tablet and liquid form, generally well-tolerated. There are sometimes mild side effects, which may include loss of appetite, nausea, and abdominal pain.

Close up of a woman taking a pill with water — Riluzole has been used to treat ALS, and research has suggested it may also help with forms of ataxia. It is currently being tested in clinical trials. Photo used under license by fizkes/Shutterstock.com.

How does it work?

Exactly how Riluzole slows disease progression remains unknown. However, it is thought that its neuroprotective effects likely stem from reducing a phenomenon known as excitotoxicity.

Neurons communicate with each other through chemical messengers called neurotransmitters. The signalling of these messengers needs to be tightly controlled. Too little or too much signaling will disrupt normal functions of the brain and cause damage to cells. Excitotoxicity is the result of excessive signaling by glutamate, one of the most abundant neurotransmitters in the brain. Glutamate is also associated with many neurodegenerative diseases.

Riluzole prevents this excessive signaling through several mechanisms. It is hypothesized that the effectiveness of riluzole in ALS treatment is the result of this neuroprotective property.

Riluzole for Ataxia

The neuroprotective function of riluzole has been a point of interest for the treatment of other neurodegenerative diseases since its approval. Multiple clinical trials have been conducted for patients with neurodegenerative diseases including Parkinson’s disease, Huntington’s disease, multiple system atrophy, and ataxia.

In 2010, a pilot trial was conducted with 40 patients with cerebellar ataxia who showed a lower level of motor impairment, measured by the International Cooperative Ataxia Rating Scale. A follow-up trial was then performed in 2015 for 55 patients with spinocerebellar ataxia (SCA) or Friedreich’s ataxia. Similarly, patient impairment had improved by an alternative measurement using the Scale for the Assessment and Rating of Ataxia. These findings indicate the possibility of riluzole being an effective treatment for cerebellar ataxia. However, more long-term studies and ones that are specific to different types of SCA need to be conducted to confirm the results.

Riluzole in Development

Even though riluzole was discovered more than 25 years ago, variations of the drug are still under development. As ALS often affects a patient’s ability to swallow, a new formulation of riluzole that is absorbed by placing it under your tongue is being developed under the name Nurtec.

Another prodrug version of riluzole, named Troriluzole (BHV-4157), may be better absorbed by the body with fewer side effects. Troriluzole is currently in phase three clinical trial for patients with different types of SCA. The trial is expected to be complete by November 30, 2021, and will hopefully provide more insight into the effectiveness of Troriluzole in SCA patients.

If you would like to learn more about Riluzole, take a look at these resources by the ClinicalTrials.gov and the Mayo Clinic.

Snapshot written by Christina (Yi) Peng and edited by Terry Suk.