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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

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

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.

For each brain region, they compared brain volume changes in three ways. First, they showed that the symptomatic SCA3 group has reduced brain volume in the cerebellum, brainstem, striatum, and spinal cord when compared to healthy controls. This is consistent with the findings of SCA3 post-mortem brain studies.

What makes this dataset more compelling, however, are the remaining two comparisons between pre-ataxia SCA3 individuals to symptomatic and control groups. A subset of these brain regions including the spinal cord, brain stem, and anterior regions of the cerebellum are much smaller in the symptomatic SCA3 group compared to the pre-ataxia group. This suggests that these areas have a worsening volume loss as symptoms develop. If true, this could make them key areas to watch over time in an individual with SCA3.

Finally, the authors found that the spinal cord, medulla, and pons have significant volume reduction in the pre-ataxia group compared to healthy controls. These results could indicate areas that could serve as a biomarker even before symptoms begin to show in SCA3 mutation carriers. 

Notably, all regions changed in the pre-ataxia group vs controls were also changed in the symptomatic group vs controls. Lack of significant volume loss in the posterior cerebellum and striatum of pre-ataxia individuals could indicate that certain areas degenerate at different times in SCA3. It is also possible that volume changes occur more slowly in these areas compared to others. This would lead to changes in volume that are too slight to pick up in a large group study that doesn’t follow individuals over time.

Several of the same regions, including the brainstem and spinal cord, appeared in every one of the above comparisons. This could suggest that these areas show change over the course of SCA3. To further assess whether the size of a brain area was related to worsening SCA3, the authors plotted the relative loss of volume in pre-ataxia and symptomatic SCA3 groups compared to controls across a predicted timeline of symptom onset.

For the ataxia group, the time since symptom onset was determined through clinical history. For the pre-ataxia group, the authors used a combination of the individual’s age and CAG repeat length to predict when symptom onset would occur. They found that the pons and midbrain areas had the steepest decline across this predicted timeline. This timeline ranged from approximately 20 years before symptom onset to 20 years after symptom onset. Without following the same individual over time, we cannot say definitively that this reduction in brain area volume is happening within patients over this critical time period, but the larger trend of the cohort is promising.

Moreover, the relative loss of volume of these areas correlated with CAG repeat length, age, and SARA score. These are all known factors associated with SCA3 symptom onset and disease progression. Thus, the volume loss of the pons and midbrain worsens in a way that correlates to other measures that we know are predictive of SCA3 progression and thus may be predictive themselves.

Together, these data suggest that the size of certain brain areas could be used as a biomarker for pre-ataxia as well as symptomatic SCA3 patients. If clinical trials for SCA3 seek to treat patients before the onset of symptoms, the relative volume of the pons could be helpful to include in these analyses. This measure would be even more powerful with follow-up evidence that these changes can be seen in individual SCA3 mutation carriers over time as they pass from pre-ataxia to ataxia stages.

It is worth noting that recent work has shown that the size of the pons is a valuable predictive measure in a related ataxia, SCA1 (Deelchand et al 2019). This may suggest that MRI could be a valuable tool for assessing disease progression in more ataxias. In addition, MRI measures could be further supplemented by other biomarkers associated with neurodegeneration for an even stronger body of evidence within clinical trials. One such biomarker is blood plasma levels of a protein called neurofilament light chain (NfL) which has been indicated to be increased in a number of SCAs and Huntington’s Disease (Coarelli et al 2021).

Key Terms

Quantitative: Measurable in terms of the quantity or amount of something rather than by a description. This could include something like the amount of a protein in a sample or the area of a brain region. Some data can be measured by applying a number to an observed quality as with the SARA score, this is considered “semi-quantitative” because the score is ultimately up to a clinician’s assessment and could vary across clinicians.

Neurodegenerative: Any condition that causes the loss of neurons and worsens with age.

Post-mortem: After death. In this instance, refers to donated tissue that scientists have received from a patient at end of life. These donations are used to understand which regions are most affected by neurodegenerative disease and to help connect findings in disease models to what we might see in patients.

Anterior: Towards the front. In the brain, certain subregions within a larger area (like the cerebellum) are identified by where they’re located. If something is labelled as anterior, this means it’s toward the “front” of that brain area or, to put it another way, closer to the nose than to the back of the head.

Posterior: Towards the rear or back. Similar to anterior only indicating the opposite direction- aka this specific part of a brain area is closer to the back of the head than it is to the nose.

Pons: A region of the brainstem important for regulating many basic functions including breathing and sleep. Serves as a connection point between the cerebellum, spinal cord, and the rest of the brain.

Symptomatic: Individuals who are experiencing symptoms of ataxia

Conflict of Interest Statement

The author and editor declare no conflict of interest.

Citation of Article Reviewed

Faber J, Schaprian T, Berkan K, Reetz K, França MC Jr, de Rezende TJR, Hong J, Liao W, van de Warrenburg B, van Gaalen J, Durr A, Mochel F, Giunti P, Garcia-Moreno H, Schoels L, Hengel H, Synofzik M, Bender B, Oz G, Joers J, de Vries JJ, Kang JS, Timmann-Braun D, Jacobi H, Infante J, Joules R, Romanzetti S, Diedrichsen J, Schmid M, Wolz R, Klockgether T. Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3. Mov Disord. 2021 Oct;36(10):2273-2281. doi: 10.1002/mds.28610. Epub 2021 May 5. PMID: 33951232.

Additional Citations

Deelchand DK, Joers JM, Ravishankar A, Lyu T, Emir UE, Hutter D, Gomez CM, Bushara KO, Lenglet C, Eberly LE, Öz G. Sensitivity of Volumetric Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy to Progression of Spinocerebellar Ataxia Type 1. Mov Disord Clin Pract. 2019 Jul 10;6(7):549-558. doi: 10.1002/mdc3.12804. PMID: 31538089; PMCID: PMC6749810.

Coarelli G, Darios F, Petit E, Dorgham K, Adanyeguh I, Petit E, Brice A, Mochel F, Durr A. Plasma neurofilament light chain predicts cerebellar atrophy and clinical progression in spinocerebellar ataxia. Neurobiol Dis. 2021 Jun;153:105311. doi: 10.1016/j.nbd.2021.105311. Epub 2021 Feb 23. PMID: 33636389.

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