Neurology: Changes in peripheral neurofilament light (NFL) levels may be an effective biomarker for spinocerebellar ataxia type 1 (SCA1) pre-ataxia and ataxia stages!

Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disorder characterized by a rapid and irreversible decline in motor function in middle age, caused by translational expansion of CAG repeats in the ATXN1 gene
.
The ataxia prophase of SCA1 may offer a unique opportunity to delay or even prevent the neurodegenerative process through early therapeutic intervention, now that targeted molecular therapy is available
.
In particular, antisense oligonucleotide (ASO) intervention targeting mutant ATXN1 showed promising results for the first time in alleviating molecular, pathological, and behavioral phenotypes in a mouse model of SCA1
.
Such ASO intervention may halt the neurodegenerative process even before clinical symptoms appear
.
However, to pave the way for upcoming clinical trials of these treatments, objective and readily available biomarkers are needed for both the pre-ataxia and ataxia stages of SCA1
.
Particularly useful for stratifying pre-ataxia subjects close to future clinical onset, early detection of neuronal decline, and capture of treatment response
.

The researchers propose serum neurofilament light (SNFL) levels as an objective and readily available blood biomarker for pre-ataxia disease stratification and detection of early neuronal decline in SCA1
.
Neurofilaments are neuron-specific cytoskeletal proteins that are released upon neuronal injury and can be reliably quantified in peripheral blood by ultrasensitive analysis
.
A previous single-center study in a mixed cohort of repetitive dilated spinocerebellar ataxias (SCA) demonstrated elevated blood NFL levels in multisystem repetitive dilated SCA during the ataxia disease stage
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However, these studies lack detailed cohort assessments of the pre-ataxia and outcome stages of SCA1, lack of validation of blood NFL levels by cerebrospinal fluid (CSF) NFL (CNfL) measurements, and lack of samples from treatment trials with NFL as the outcome variable Quantity estimate
.
Utilizing a multicenter cohort of pre-SCA1 and ataxia subjects and longitudinal follow-up assessments—including not only predicted but actually observed onset of ataxia
.
Recently, a study published in Neurology hypothesized that NFL levels in SCA1 could serve as (1) a peripheral biomarker close to the onset of clinical ataxia, (2) early neuronal decline in the pre-ataxia phase, and (3) Objective trial outcome variables that allow for a reduction in the sample size required in treatment trials
.
Increased NFL levels in serum and cerebrospinal fluid are expected to be already in pre-ataxia - SNFL elevation in pre-ataxia subjects precedes signs of brain atrophy on volume MRI and increases further closer to the onset of ataxia , even further elevated in the ataxia disease stage
.
The study questioned whether NFL levels are increased in SCA1 in ataxia and pre-ataxia, and whether NFL levels are associated with approaching ataxia onset
.

We assessed serum (SNFL) and cerebrospinal fluid (CNfL) NFL levels in pre-ataxia and ataxia SCA1 patients using multicenter cohorts recruited at six European university centers and clinical follow-up data, including actual observations (rather than actual observations).
prediction only) transition to the ataxia stage
.
Serum sNFL and cNfL levels were detected by single molecule array (SIMOA) and enzyme-linked immunosorbent assay (ELISA), respectively
.

• A total of 40 SCA1 subjects (23 pre-ataxia, 17 ataxia) and 89 control subjects, including 11 pre-ataxia subjects, were included in the study
  .
  
• In the pre-ataxia (15.
  5 pg/ml (10.
  5-21.
  1), median and interquartile range) and ataxia stage (31.
  6 pg/ml (26.
  237.
  7) compared with the control group (6.
  0 pg/ml ( 4.
  7-8.
  6)), higher SNFL levels produced higher age-adjusted effect sizes (pre-ataxia: r=0.
  62, ataxia: r=0.
  63)
  .
  
• During the pre-ataxia and ataxia phases, the elevation of SNFL paralleled the elevation of cNFL
  .
  
• In subjects with pre-ataxia, SNFL levels increased as the predicted time of onset of ataxia approached, significantly increased 5 years before onset of ataxia, and when ataxia onset was actually observed confirmed in subjects with pre-disorder
  .
  
• Increased SNFL has been detected in pre-ataxia SCA1 subjects without cerebellar or pontine volume atrophy, suggesting that SNFL may be more sensitive to early pre-ataxia neurodegeneration than the most sensitive changes currently known in volumetric MRI area is more sensitive
  .
  
• Using longitudinal SNFL measures, the sample size of clinical trials with SNFL reduction as the endpoint was estimated
  .
  

SNFL levels may provide readily accessible peripheral biomarkers in pre-ataxia and ataxia SCA1, allowing pre-ataxia subjects to be stratified near pre-onset and detect neurodegeneration early even before volumetric MRI changes , and potentially capture treatment responses in clinical trials
.

This study provides class III evidence that NFL levels are increased in SCA1 in both ataxia and pre-ataxia and are associated with the onset of ataxia
.

Source: Wilke C, Mengel D, Schöls L, et al.
Levels of Neurofilament Light at the Preataxic and Ataxic Stages of Spinocerebellar Ataxia Type 1 [published online ahead of print, 2022 Mar 9].
Neurology.
2022;10.
1212/WNL.
0000000000200257.
doi:10.
1212/WNL.
0000000000200257