Natural history and biomarker identification in Spinocerebellar Ataxia type 1

Spinocerebellar ataxia type 1 (SCA1) is a rare, autosomal dominant
neurodegenerative disease, affecting the cerebellum and connected brain regions
with devastating consequences. The cause of SCA1 is an expanded polyglutamine
repeat in the ataxin-1 protein, which provides a clear target for therapy
development. Previous studies showed that downregulation of mutant ataxin-1 can
improve behavior and brain pathology in SCA1 mouse models.

Currently patients only receive symptomatic treatment, which is often
ineffective against progressive loss of mobility and independence and an early
death. Development of a gene therapy that can halt or reverse disease
progression is urgently awaited, and as patients say; *there is finally hope
for a treatment*. To prepare for the development of such a therapy, insights
into the natural course of the disease, as well as validated biomarkers are
mandatory. As it is suspected that there is already irreversible brain damage
at the onset of ataxia, preclinical mutation carriers and mildly affected
patients represent an appropriate target population for future interventional
trials. Whereas validated clinical outcome measures for ataxia have been
developed, the dynamics of these and their sensitivity to change in the Dutch
SCA1 population are unknown. Also, there is an almost complete lack of
biomarkers for SCA1, while the availability of validated biomarkers is an
essential precondition for interventional studies, in particular of
interventions that target molecular mechanisms of SCA1 and aim at modifying the
disease course rather than temporarily improving ataxia symptoms. Therefore,
development and validation of innovative disease biomarkers will be a major
focus of this project.

Primary Objective
- To identify (a combined set of) clinical and non-clinical markers most
sensitive to disease progression in Dutch SCA1 mutation carriers.

Secondary Objectives:
- To quantify the annual change in disease-relevant clinical scales and
patient-reported outcome measures in Dutch SCA1 patients.
- To establish the utility of automated speech analysis as a surrogate motor
biomarker in SCA1.
- To establish the utility of structural MRI and MR spectroscopy measurements
as surrogate disease progression markers
- To develop and establish the utility of biochemical disease and progression
markers
- To establish the utility of sensor measurements of walking and balance
as surrogate disease progression markers.
- To generate a natural history data set of clinical parameters, MRI, speech,
and biochemical biomarker measurements in SCA1 that can be exploited for
further collaborative research in SCA1.
- To explore the predictive value of short-term biomarker changes
(one-year) on longer term changes in clinical and patient-reported outcome
measures.

This prospective cohort study will capture the natural history of Dutch SCA1
patients over the course of 2 (optionally 4) years. We will include 50 SCA1
patients (40 symptomatic and 10 preclinical) and 20 matched controls. All study
participants will undergo detailed annual assessments at baseline, 1 year after
baseline and 2 years after baseline, with a possible follow-up visit after 4
years.

Participants will visit the study centre once a year for two consecutive years.
These three visits include a clinical assessment battery, including validated
ataxia-scales and tests to assess cognitive function, mood, activities of daily
living, walk/balance performance and quality of life. MRI-scans (lasting about
45 minutes to complete) and blood samples will be acquired at each visit.
Patients will be asked to optionally undergo a lumbar puncture twice (baseline
and after 1 year), to obtain a cerebrospinal fluid sample. Controls will
receive a similar assessment protocol, with clinical assessments, MRI-scans and
blood sampling, but without the lumbar puncture. 4 years after baseline an
extra study visit will be planned for assessment of clinical and
patient-reported outcome measures (duration 1.5 hours)