Looking beyond the central nervous system in SCA3: nerve and muscle ultrasound as potential imaging markers to quantify and monitor peripheral nervous system degeneration

Spinocerebellar ataxia type 3 (SCA3) is a progressive multisystemic disorder
that severely impacts quality of life. Besides degeneration of the cerebellum,
brainstem, spinal cord, and basal ganglia, the disease is characterized by
widespread involvement of peripheral nervous system (PNS) components, including
the dorsal root ganglia, peripheral nerves, and anterior horn cells.
Degeneration of these structures not only leads to bothersome complaints that
impair patients* daily functioning and quality of life (e.g., muscle cramps,
pain, tingling, numbness, and muscle atrophy), but may also importantly add to
sensory ataxia severity and therefore accelerate overall ataxia progression.
Nonetheless, the vast majority of studies looking for potential biomarkers
focused on the central nervous system, most notably cerebellar and pontine MRI
volumes and cerebrospinal fluid proteins. Driven by this lack of PNS markers
and the extensive application of peripheral nerve and muscle ultrasound for
patients with neuromuscular disorders in our center, we aim to investigate
whether both imaging techniques can yield reliable diagnostic and monitoring
biomarkers of PNS involvement in SCA3.

An additional subcomponent of this study is aimed to examine the feasibility of
implementing the 'Goal Attainment Scale' (GAS), an alternative clinical outcome
measure, within this specific patient population. We will explore its
correlation with other clinical outcome measures obtained in this study, and
also evaluate associations between patient-reported outcome measures obtained
in this study and passive and proactive coping capacities.

To investigate whether peripheral nerve and muscle ultrasound can be used as
reliable diagnostic and monitoring biomarkers of PNS involvement in SCA3.
Specifically, we will examine:

1) Whether peripheral nerve and muscle ultrasound are able to adequately
differentiate SCA3 mutation carriers from healthy controls without a neuropathy
or myopathy (i.e., if these techniques could serve as diagnostic biomarkers of
PNS degeneration).
2) Whether peripheral nerve and muscle ultrasound are able to detect
abnormalities already in pre-ataxic SCA3 mutation carriers.
3) Whether peripheral nerve ultrasound is able to already detect abnormalities
in individuals without electrophysiological evidence of nerve dysfunction.
4) Whether peripheral nerve and muscle imaging abnormalities correlate with
ataxia severity, disease duration, activities of daily living, patient-reported
cramp and neuropathy severity score, cerebellar cognitive affective syndrome
scale score, health-related quality of life, fatigue, mood, restless legs
severity, sleep quality, and PROM-Ataxia score.
5) Whether nerve and muscle imaging abnormalities correlate with serum
neurofilament light chain concentrations, which is a marker of damage to
large-caliber myelinated axons.
6) Whether nerve and muscle ultrasound are able to detect changes at a
follow-up measurement after 1 year (i.e., if they could serve as monitoring
biomarkers of PNS degeneration).
7) Whether the Goal Attainment Scale is applicable to SCA3 patients and what
factors should be considered for its future use in a trial setting.
8) Whether there is a relationship between a patient's coping strategy and the
outcomes of patient-reported outcome measures (such as EQ-5D-5L, PHQ-9, and
PROM-ataxia)

Prospective longitudinal study.

The burden for participants consists of two study visits. All measurements are
without significant side effects ("negligible risk").