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.

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

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.
Continue reading “Measuring neurodegeneration in spinocerebellar ataxias”

Spotlight: The CMRR Ataxia Imaging Team

Location: University of Minnesota, MN, USA

Year Research Group Founded:  2008

What models and techniques do you use?

A photo of the CMRR Ataxia Imaging Team
A photo of the CMRR Ataxia Imaging Team in 2019. Front row, left to right – Diane Hutter, Christophe Lenglet (PI), Gulin Oz (PI), Katie Gundry, Jayashree Chandrasekaran Back row, left to right: Brian Hanna, James Joers, Pramod Pisharady, Kathryn France, Pierre-Gilles Henry (PI), Dinesh Deelchand, Young Woo Park, Isaac Adanyeguh (insert)

Research Group Focus

What shared research questions is your group investigating?

We use high field, multi-nuclear magnetic resonance imaging (MRI) and spectroscopy (MRS) to explore how diseases impact the central nervous system. These changes can be structural, functional, biochemical and metabolic alterations. For example, we apply advanced MRI and MRS methods in neurodegenerative diseases and diabetes.

We also lead efforts in research taking place at multiple different cities across the United States and the world. As you can imagine, studies spread out across such a big area require a lot of coordination and standardization. We design robust MRI and MRS methods to be used in clinical settings like these.

Another important question for our team is how early microstructural, chemical and functional changes can be detected in the brain and spinal cord by these advanced MR methods. We are interested in looking at these changes across all stages of disease.

Why does your group do this research?

The methods we use (MRI and MRS) can provide very helpful information to be used in clinical trials. These biomarkers we look at can provide quantitative information about how a disease is progressing or changing.

There is good evidence that subtle changes in the brain can be detected by these advanced MR technologies even before patients start having symptoms. If we better understand the earliest changes that are happening in the brain, this can in turn enable interventions at a very early stage. For example, we could treat people even before brain degeneration starts to take place.

Why did you form a research group connecting multiple labs?

We came together to form the CMRR Ataxia Imaging Team to benefit from our shared and complementary expertise, experience, and personnel. We can do more together than we could apart.

Are you recruiting human participants for research?

Yes, we are! We are looking for participants for multiple different studies. You can learn more about the research we are recruiting for at the following links: READISCA,  TRACK-FA, NAF Studies, and FARA Studies. More information is also available through the UMN Ataxia Center.

A photo of the CMRR Ataxia Imaging Team in 2016
A photo of the CMRR Ataxia Imaging Team in 2016, in front of the historic 4T scanner where the first functional MR images were obtained, in CMRR courtyard. Left to right – Christophe Lenglet (PI), Sarah Larson, Gulin Oz (PI), Dinesh Deelchand, Pierre-Gilles Henry (PI), James Joers, Diane Hutter

What Labs Make Up the CMRR Ataxia Imaging Team?

The Oz Lab

Principal Investigator:  Dr. Gulin Oz

Year Founded:  2006

Our focus is on MR spectroscopy, specifically neurochemistry and metabolism studies. We focus on spinocerebellar ataxias. Also, we have been leading MRS technology harmonization across different sites and vendors.

The Henry Lab

Principal Investigator: Dr. Pierre-Gilles Henry

Year Founded:  2006

We develop advanced methods for MR spectroscopy and motion correction. Then apply these new methods to the study of biochemistry and metabolism in the brain and spinal cord in various diseases. We have been working on ataxias since 2014.

Fun Fact about the Henry Lab: The French language can often be heard in discussions in our lab!

The Lenglet Lab

Principal Investigator:  Dr. Christophe Lenglet

Year Founded:  2011

We develop mathematical and computational strategies for human brain and spinal cord connectivity mapping. We do this using high field MRI. Our research aims at better understanding the central nervous system anatomical and functional connectivity. We are especially interested in looking at this in the context of neurological and neurodegenerative diseases.

Fun Fact

Members of our team have their roots in 7 countries (US, Turkey, France, India, Mauritius, South Korea, Ghana) and 4 continents (North America, Europe, Asia, Africa)

For More Information, check out the Center for Magnetic Resonance Research (CMRR) Website!


Written by Dr. Gulin Oz, Dr. Pierre-Gilles Henry, and Dr. Christophe Lenglet, Edited by Celeste Suart

A promising biomarker to track disease progression in SCA3

Written by Dr. Ambika Tewari Edited by Dr. Gulin Oz

Neurofilament light chain could provide a reliable readout of how far an SCA3 patient’s disease has progressed

How often have you heard that the most effective way to treat a disorder is early intervention? In reality, “early” is not possible for many disorders because patients receive a diagnosis only after the appearance of symptoms. But what if there was a way we could tell that a patient will develop a disease – even before they have any symptoms? Thankfully, that’s exactly what researchers in the field of biomarkers are trying to do. Biomarkers are biological indicators that are not only present in patients before the manifestation of symptoms, but can also be used to measure disease progression. In the SCA field, there have been a recent series of articles that have shed light on a promising biomarker for SCA3.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease, is the most common dominantly-inherited ataxia. It is caused by an expansion of CAG repeats (a small segment of DNA that codes for the amino acid glutamine) in the ATXN3 gene. An important feature of SCA3, as well as in other spinocerebellar ataxias, is the progressive development of symptoms. Symptoms usually occur across decades, and can be divided into three major phases: asymptomatic, preclinical, and symptomatic. In the asymptomatic phase, there is no evidence of clinical symptoms (even though the patient has had the SCA-causing mutation since birth). In the preclinical stage, patients show unspecified neurological symptoms such as muscle cramps and/or mild movement abnormalities. By the symptomatic (i.e., clinical) stage, patients have significant difficulty walking.

A Spinal Cord Motor Neuron sample stained purple.
Neurofilament light chain (NfL) is an important building block of neurons. But when neurons are damaged, NfL is released. Image of a spinal cord motor neuron courtesy of Berkshire Community College.

Currently in SCA research, disease progression is measured using the Scale for the Assessment and Rating of Ataxia (SARA). A score of 3 or more on the SARA differentiates clinical and preclinical groups. Structural and functional brain imaging methods (such as MRI) also track the progressive nature of the disease, like the SARA, but give us a visual picture of changes in the brain. Together, these methods have provided the SCA community with important insights into the clinical spectrum of each specific disease and its rate of progression. And, with the exciting progress we have recently made in the realm of SCA3 therapeutics, a biomarker that is cost-effective and easy to measure (like in a blood test) could provide a convenient way to assess how effective a potential treatment is.

Continue reading “A promising biomarker to track disease progression in SCA3”

Aperçu Rapide: Qu’est-ce que l’imagerie par résonance magnétique (IRM) ? A quoi sert elle dans l’Ataxie ?

Qu’est-ce que c’est?

L’imagerie par résonance magnétique (IRM) est un type de technologie utilisé pour prendre des photos détaillées du corps. Il est couramment utilisé pour détecter des anomalies dans le corps, diagnostiquer des maladies et surveiller régulièrement les patients en cours de traitement. Il peut générer des images tridimensionnelles de tissus non osseux, tels que le cerveau. Les procédures d’IRM sont non invasives, nécessitent une préparation minimale et ne sont pas associées à des risques pour la santé, car elles n’utilisent pas de types de rayonnement nocifs tels que les rayons X.

Comment ça marche?

Les tissus humains contiennent de l’eau, qui contient de très petites particules appelées protons qui se comportent comme de minuscules aimants. Un appareil d’IRM utilise de gros aimants puissants pour générer un champ magnétique qui peut modifier la rotation de ces particules dans votre corps, ce qui les aligne sur le champ magnétique. Des ondes radio non nuisibles sont ensuite émises par le patient, modifiant ainsi la direction de ces particules, de sorte qu’elles ne sont plus alignées sur le champ magnétique. Les ondes radio sont alors désactivées et les particules peuvent alors se réaligner avec le champ magnétique. Différents types de tissus et de structures dans le corps auront des particules qui se ré-alignent différemment, ce qui peut être détecté par la machine pour générer une image détaillée en noir et blanc de la zone balayée du corps. En plus de ces informations structurelles, les analyses IRM peuvent fournir des informations sur la manière dont le cerveau est câblé, les niveaux de produits chimiques importants, le flux sanguin, le métabolisme et les fonctions cérébrales en acquérant des informations différemment avec le même appareil.

Vue 3D d'un cerveau humain entier prise par IRM, sous deux angles.
Vue 3D d’un cerveau humain entier prise par 7 Tesla IRM. Photo offerte gracieusement par B.L. Edlow et al, bioRxiv, 2019

Comment se préparer pour une IRM ?

Étant donné que l’IRM utilise un gros aimant, les appareils électroniques et les objets métalliques, tels que les lunettes et les bijoux, doivent être retirés. Aucune autre préparation n’est généralement requise pour l’analyse. Les patients doivent rester immobiles pour générer une image claire. Les patients n’ont pas besoin d’être sous sédation, sauf s’ils ont du mal à rester allongés pendant l’intervention. Les examens d’IRM obtenus à des fins de recherche n’utilisent pas l’anesthésie pour éviter des risques inutiles aux participants à la recherche.

Que se passe-t-il lors d’une IRM?

Le patient s’allonge sur une table qui se déplacera dans la chambre en forme de tunnel. Le patient est généralement réveillé et restera dans la chambre après plusieurs analyses (environ 30 à 60 minutes). Au fur et à mesure de la numérisation, il y a souvent des bruits mécaniques forts. Des bouchons d’oreilles sont donc fournis pour la protection. Certains patients peuvent souffrir de claustrophobie ou être dérangés par les bruits. En vous familiarisant davantage avec la procédure, en écoutant de la musique ou en fermant les yeux, vous pourrez soulager l’inconfort pendant le scan.

Que recherchent les médecins chez les patients atteints d’une Ataxie spinocérébelleuse (SCA) ?

Les examens IRM sont souvent utilisés pour imager le cerveau afin de détecter les signes d’ataxie spinocérébelleuse (SCA), en particulier dans une région du cerveau appelée cervelet. Le SCA est associé à la perte de cellules cérébrales et se traduit par une réduction du volume de tissu cérébral dans l’image IRM.

Si vous souhaitez en savoir plus sur l’imagerie par résonance magnétique (IRM), jetez un œil à ces ressources de l’IRM Québec et de l’Université Laval.

Plus de ressources sur l’IRM en anglais peuvent être trouvées aux National Institutes of Health et à la Mayo Clinic.

Écrit par Dr. Claudia Hung, Édité par Dr. Gülin Öz, Traduction française par: L’Association Alatax, Publication initiale: 15 novembre 2019.