Measuring neurodegeneration in spinocerebellar ataxias

Written by Dr Hannah K Shorrock Edited by Dr. Maria do Carmo Costa

Neurofilament light chain predicts cerebellar atrophy across multiple types of spinocerebellar ataxia

A team led by Alexandra Durr at the Paris Brain Institute identified that the levels of neurofilament light chain (NfL) protein are higher in SCA1, 2, 3, and 7 patients than in the general population. The researchers also discovered that the level of NfL can predict the clinical progression of ataxia and changes in cerebellar volume. Because of this, identifying patients’ NfL levels may help to provide clearer information on disease progression in an individualized manner. This in turn means that NfL levels may be useful in refining inclusion criteria for clinical trials.

The group enrolled a total of 62 SCA patients with 17 SCA1 patients, 13 SCA2 patients, 19 SCA3 patients, and 13 SCA7 patients alongside 19 age-matched healthy individuals (“controls”) as part of the BIOSCA study. Using an ultrasensitive single-molecule array, the group measured NfL levels from blood plasma that was collected after the participants fasted.

The researchers found that NfL levels were significantly higher in SCA expansion carriers than in control participants at the start of the study (baseline). In control individuals, the group identified a correlation between age and NfL level that was not present among SCA patients. This indicates that disease stage rather than age plays a larger role in NfL levels in SCAs.

Looking at each disease individually, the group was able to generate an optimal disease cut-off score to differentiate between control and SCA patients. By comparing the different SCAs, the research group found that SCA3 had the highest NfL levels among the SCAs studied. As such, SCA3 had the most accurate disease cut-off level with 100% sensitivity and 95% specificity of defining SCA3 patients based on NfL levels.

Artist's drawing of a group of Laboratory Scientist sturying a larger-than life human brain
A team from the Paris Brain Institute identify that SCA1, 2, 3, and 7 patients have higher levels of NfL protein than the general population. Photo used under license by ivector/
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Snapshot: What is the International Cooperative Ataxia Rating Scale?

The International Cooperative Ataxia Rating Scale (ICARS) is an assessment of the degree of impairment in patients with cerebellar ataxia. It was developed in 1997 by the Committee of the World Federation of Neurology. The goal of ICARS is to provide a standardized clinical rating score to measure the efficacy of potential treatments. The scale was intended for patients with cerebellar ataxia. But ICARS has also been validated for patients with focal cerebellar lesions, spinocerebellar, and Friedrich’s ataxia.

How Does it Work?

The ICARS is a semi-quantitative examination that translates the symptomatology of cerebellar ataxia into a scoring system out of 100. The assessment is designed to be completed within 30 minutes, and higher scores indicate a higher level of disease impairment. The assessment consists of 19 items and four subscales of postural and gait disturbances, limb movement disturbances, speech disorders, and oculomotor disorders. Detailed descriptions of the scoring metrics are also provided to reduce scoring variability between the examiners.

Advantages and Drawbacks

Since its development, multiple studies have validated the ICARS. It has also been widely used in clinical assessment for ataxia rating of different diseases. One such study accessed 14 instruments of ataxia assessment and identified the ICARS to be highly reproducible and internally consistent.

However, the scale also does not account for some ataxia symptoms, such as hypotonia (muscle weakness), that are difficult to access clinically. Some subscales also have a considerable ceiling effect, where many patients reach the maximum score for a category. This means symptoms are not being accessed past a certain severity.

Doctor writing down patient notes on a clipboard using a checklist while sitting at a desk.
The ICARS is a semi-quantitative examination that translates the symptomatology of cerebellar ataxia into a scoring system out of 100. Photo used under license by eggeegg/

Other Ataxia Rating Scales

The Scale for the Assessment and Rating of Ataxia (SARA) is another semi-quantitative assessment of impairment levels. It consists of only eight items, making it easier to perform for frequent assessments. However, the simplification of the scale excludes some important symptomatology, including oculomotor impairment.

A pilot study has also been conducted for the development of SARAhome, a video-based variation of SARA that can be conducted independently at home, showing promise for the digitization of ataxia assessment.

Another assessment scale that is even more toned-down is the Brief Ataxia Rating Scale (BARS). The scale consists of five items that assess gait, speech, eye movement, and limb mobility, and the estimated assessment time is only five minutes.

All the assessments described above have been validated and each has its own benefits and drawbacks. However, none of them provides the minimal important difference, which is an important clinical measurement used to determine the effectiveness of potential treatment. Therefore, we are still in need of developing better tools for measuring disease impairment in ataxia patients.

If you would like to learn more about ICARS, take a look at this resource by Physiopedia.

Snapshot written by Christina (Yi) Peng and edited by Dr. Hayley McLoughlin.

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 SARAhome 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/

In this study, the researchers devised an Ataxia assessment matching the SARA test that can be performed at home, which they call SARAhome. 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 SARAhome 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.

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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/

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/

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 and the Mayo Clinic.

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