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.

At the two-year follow-up, the group found that, as expected, SCA patients performed worse on neurological examination indicating that their diseases had progressed. Control individuals did not show a change in performance on neurological examination. The researchers assessed patients’ ataxia symptoms with the scale for the assessment and rating of ataxia and the cerebellar functional severity score.

The levels of NfL did not significantly change between baseline and two-year follow-up for either SCA patients or control individuals in this study. This may suggest that longer follow-up times may be required to detect changes in NfL levels. However, because this study included patients with a wide range of diseases stages, it may be that NfL level changes would be detectable over this time-period in groups of patients at the same disease stage. This may be especially true early on in disease progression.

Importantly, at both baseline and follow-up for SCA patients, there was a significant correlation between NfL levels and measurements taken at the neurological examination. This shows that NfL is a clinically relevant biomarker that correlates with disease severity.

Interestingly, several premanifest expansion carriers who did not show ataxia symptoms on neurological examination at baseline were included in this study. By the two-year follow-up, the premanifest carriers who had NfL levels close to or above the disease cut-off concentrations had started to display symptoms of ataxia. These symptoms included both cerebellar and non-cerebellar manifestations of the disease. Only the carriers who had NfL levels in the range of control levels did not develop signs of disease. Therefore, NfL levels in premanifest expansion carriers could be a useful predictor for disease onset. This could help to refine inclusion criteria for clinical trials in expansion carriers who have very subtle signs of disease.

At both baseline and follow-up, volumes of the cerebellum and pons were measured by magnetic resonance imaging (MRI). As expected, SCA patients but not control individuals showed a decrease in volume of both brain regions studied between baseline and follow-up. For SCA patients, the higher the NfL, the lower the pons volume at baseline. Similarly, there was a correlation between NfL at baseline and the change in cerebellum volume between baseline and follow-up. Higher NfL levels at baseline predicted a decrease in cerebellar volume. Overall, in this study, the group found that the higher the baseline levels of plasma NfL, the greater the loss of cerebellar volume at the two-year follow-up. Patients with higher baseline levels of plasma NfL also had the worst performances at the follow-up neurological examination. Together, this shows that plasma NfL concentrations can predict disease progression in SCA expansion carriers.

There is currently a large focus on therapeutic development for SCAs. However, identifying biomarkers that can be used to assess how well a clinical trial is going and who should be included in the trial will be essential for the successful transition of these therapeutics into the clinic.

This study demonstrates that in a group of patients at variable stages of disease, NfL levels do not change enough over a two-year period to use for assessing how effective a treatment is during a clinical trial. However, it does show the usefulness of NfL levels as criteria for clinical trial inclusion.

As clinical measurements for neurological examination are perception dependent, they are not entirely accurate in detecting subtle disease progression. Measuring NfL levels would therefore provide patients with a more accurate estimation of disease progression. It could also help to refine the criteria for the inclusion of patients in clinical trials for therapy development.

Key Terms

Premanifest Expansion Carriers: Patients who have the mutation that causes a form of ataxia, but who are not yet having symptoms.

Neurofilament light chain (NfL): Neurofilament protein that is present in neurons and is released from neurons when they are damaged during neurodegeneration. The released NfL can be measured in the blood and cerebrospinal fluid and can be used as a biomarker. You can learn more about NfL in our past Snapshot.

Conflict of Interest Statement

The author and editor declare no conflict of interest.

Citation of Article Reviewed

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 153, 105311, 2021.105311 (2021). https://pubmed.ncbi.nlm.nih.gov/33636389/