Cerebellum, Pons, and Medulla- Oh my! Which brain regions can help us assess SCA3 progression?

Written by Carrie Sheeler Edited by Dr. Hayley McLoughlin

Researchers use Magnetic Resonance Imaging (MRI) to determine if brain volume can be a biomarker for SCA3

There are two goals of preclinical research. First, to understand the cause of a disease. Second, to develop treatments to stop or slow its effects. As understanding of the underlying causes of spinocerebellar ataxias (SCAs) has grown, researchers have begun to develop strategies for treating or slowing the progression of this family of diseases. The next question is how to best move these potential therapies from the lab space to the clinic, which we do through clinical trials.

Clinical trials are essentially enormous multi-phase experiments run largely by drug companies. Clinical trials ask two main questions. First, is this drug/therapy safe? Then, how well does this drug/therapy work? Many potential therapies for neurodegenerative diseases have been unsuccessful in the past decade. These attempts have failed to demonstrate that they are effective in changing the progression of diseases, such as Alzheimer’s and Parkinson’s. There is concern that lack of drug effectiveness may come from starting treatment too late in the progression of the disease. Later in disease, irreversible damage may have already happened that is too much to fix. This is difficult to avoid in cases where the main measure of drug success (known as “primary endpoint”) is determined by clinical assessment in which a patient treated with a drug already has symptoms. An example of this in ataxia clinical trials is using the scale for assessment and rating of ataxia, also known as the SARA score.

To add more quantitative strength to clinical assessments that may also allow researchers to predict when symptoms will start to occur, scientists are seeking out new ataxia biomarkers. Examples of biomarkers include changes in brain volume or the concentration of certain proteins in blood. These studies may allow for a greater timeframe within which clinicians can combat disease progression

Abstract blue brain
The volume of different brain regions could be used as biomarkers for SCA3 clinical trials. Photo used under license by Butusova Elena/Shutterstock.com.

This paper examined if the volume of specific areas of the brain may be used as a biomarker for spinocerebellar ataxia type 3 (SCA3). To accomplish this aim, they assessed brain images from 210 symptomatic SCA3 individuals, 48 pre-ataxia SCA3 individuals, and 63 healthy controls. The designation of ataxia vs pre-ataxia was done using SARA score. Pre-ataxia individuals had a score of less than three, while symptomatic patients had a score greater than or equal to 3. The images were taken using magnetic resonance imaging (MRI). Images were taken of 122 distinct brain regions, covering the entirety of the brain and the upper regions of the spinal cord.

The average ages for all three groups were 46 for symptomatic individuals with SCA3, 38 for pre-ataxia individuals with SCA3, and 43 for controls. Notably, each patient received only one MRI. This means the comparisons made in this study rely on comparisons between individuals, rather than within the same individual over time. This is important because it means that the results listed below are a representation of changes in the brain across a population of SCA3 mutation carriers. This is not a representation of what is happening in one individual over time. But it is quite similar to what you might measure during a clinical trial.

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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/Shutterstock.com.
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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/Shutterstock.com.

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.

Snapshot: What is Cerebrospinal Fluid (CSF)?

Public transit may not be the first thing that comes to mind when we think about the brain, but it’s a great way to understand how all the parts of the central nervous system work together. Nutrients, hormones, and other important molecules (the passengers) need to get on and off at different stations to do their work. They might first stop at the large internal chambers within the brain, called ventricles. From the ventricles, they can get to the central canal in the spinal cord, as well as the subarachnoid space. The subarachnoid space is a space between two membranes that surround the brain and spinal cord. It provides a stable structure for a network of veins and arteries.

The passengers are shuttled from station to station by the cerebrospinal fluid (CSF), a clear, colourless fluid that provides the central nervous system with necessary nutrients and hormones while carrying away waste products. CSF also cushions the brain and spinal cord by circulating between layers of tissues surrounding them. The whole public transit system is enclosed: the subarachnoid space and the ventricles are connected to the central canal in the spinal cord, forming a single reservoir for CSF.

Cerebrospinal fluid written in colorful letters under a Stethoscope on wooden background
Photo used under license by Sohel Parvez Haque/Shutterstock.com.

CSF is made by the choroid plexus, a collection of tiny blood vessels called capillaries. Capillaries filter the blood and secrete it into the ventricles. When the pressure of CSF is less than the pressure in the capillaries, CSF flows out and into the ventricles. When the pressure of CSF is greater than that of the bloodstream, the extra fluid is absorbed from the subarachnoid space and into sinuses (large areas filled with blood), where it can flow into the surrounding veins. The blood supply in the central nervous system tightly regulates the movement of molecules or cells between the blood and brain. This blood-brain barrier is crucial for protecting the brain from toxins and pathogens. Dysfunction of this specific system contributes to the development of neurological diseases.

Anatomical labeled scheme with human head and inside of skull, including superior sigittal sinus, ventricles, arachnoid Villi and spinal cord central canal.
Structure of the ventricles and central canal components that contribute to the public transit system. Photo used under license by VectorMine/Shutterstock.com.

Why is CSF Important for Neurodegenerative Diseases?

In neurodegenerative diseases like Spinocerebellar Ataxias, CSF contains molecules that can be used as biomarkers. Biomarkers are disease-specific proteins that change in concentration depending on disease stages. Biomarkers provide information on disease progression, with or without the impact of therapeutics. They are also crucial for understanding how disease processes work and assist in developing treatments.

The development of intrathecal injections, injecting into the central canal for distribution to the central nervous system (for example, spinal anesthesia), has been monumental for administering drugs in neurodegenerative diseases. In other words, not only can the public transit system of the central nervous system be investigated to see what passengers are associated with the disease, but it can be used to deliver “medicine passengers” to the place where the disease occurs.

If you would like to learn more about Cerebrospinal Fluid, take a look at these resources by MedlinePlus and WebMD.

Snapshot written by Kaitlyn Neuman and edited by Dr. Tamara Maiuri.

Four diseases, One Gene: CACNA1A

Written by Dr. Judit Pérez Edited by Dr. David Bushart

A new case report describes how a new mutation in the CACNA1A gene causes ataxia with seizures.

Genes and their diseases

Hereditary ataxias are caused by mutations in different genes that affect how different parts of the brain and spinal cord work. Usually, the affected genes predict how one would expect the patient’s clinical signs and symptoms to look. The reverse can also be true. For example, a set of clinical signs and symptoms may raise suspicion of a known genetic disease, which allows doctors to perform focused genetic testing to confirm the diagnosis. These correlations are helpful for doctors and patients in understanding the diagnostic process and disease outlook.

New mutation, new disease

A study by Stendel and colleagues was inspired by a patient who developed ataxia in mid-adulthood that slowly worsened over the next decades of his life. The progression resembled that of spinocerebellar ataxias with repeat expansions in their genes as the culprits. However, when doctors performed the usual genetic testing for ataxia genes, they did not find a match. Nevertheless, suspicion for an ataxia gene playing a role remained high. The patient had experienced seizures as a child (called “absence seizures”), which didn’t entirely fit the picture of known SCAs. Where to go from here? The scientists next broadened their search to include 118 genes that are known to cause ataxia or other diseases that include ataxia symptoms.  To their surprise, they found a previously unidentified mutation in a well-known ataxia gene called CACNA1A.

Human brain digital illustration. Electrical activity, flashes and lightning on a blue background.
CACNA1A is a gene that instructs brain cells to make a protein called Cav2.1, which helps neurons communicate. But now mutations in the CACNA1A gene are now connected to four different diseases. Photo used under license by Yurchanka Siarhei/Shutterstock.com.
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