Network Patterns in SCA3 and SCA6 Imaged by DWI, fMRI, MRI-T1 and FDG-PET

The Spinocerebellar Ataxias (SCA) constitute a group of hereditary
neurodegenerative disorders that share the clinical feature of ataxia as their
most prominent characteristic. Neuropathologically, the various genetic
subtypes are all associated with cerebellar atrophy, but apart from this,
specific subtypes display specific clinical features and patterns of
neurodegeneration that affect other parts of the central and peripheral nervous
system. E.g., while the SCA6 genotype manifests clinically as a *pure
cerebellar syndrome*, SCA3 is characterized by multiple extracerebellar
features. But due to the rarity of these diseases and their protracted disease
courses that span many years to decades, the amount of information on the
extent of neuropathological alterations, particularly in early disease stages,
is scarce.
Although the cerebellum is traditionally considered to be involved in motor
coordination, its role in cognitive and emotional processing has received
increasing attention in the past two decades. In line with this notion, people
with spinocerebellar ataxia often complain not only about motor impairment and
coordination problems, but also about cognitive and emotional changes and
fatigue. In a recent study, we demonstrated language impairment in SCA6
patients, not only in expression but also in perception, which was related to
the severity of ataxia (paper submitted). An important issue here is whether
these symptoms are caused by the cerebellar degeneration itself, or by
associated neuropathological changes outside the cerebellum, e.g. in the basal
ganglia or the cortex.
To gain more insight in the extent of cerebellar vs. extracerebellar pathology
this study aims to employ multimodal brain imaging in patients with two
genetically distinct forms of spinocerebellar ataxia, SCA6 and SCA3, as well as
in controls. To that end, various Magnetic Resonance Imaging (MRI) modalities
will be combined with Positron Emission Tomography (PET) imaging. Diffusion
Weighted Imaging (DWI) will be used to study white matter (WM) tracts whose
structural integrity may be particularly sensitive to degeneration. Structural
MRI, Resting State Functional MRI (RS-fMRI) and FluoroDeoxyGlucose PET (FDG
PET) will help to assess grey matter (GM) integrity. In addition, a number of
tests that assess language and cognitive executive functioning will be applied
to subjects, in order to confirm our previous findings of language impairment
in SCA6 patients.

The main objective of this study is to characterize the features and the
extent of extracerebellar structural pathology in SCA3 and SCA6 patients.
Secondary objectives are:
- To explore the sensitivity of DWI and other imaging modalities in detecting
neuropathological features in SCA3 and SCA6.
- To establish correlations between findings of the various imaging modalities
employed (DWI, VBM, RS-fMRI and FDG PET, i.e. to examine the WM/GM
correlation).
- To establish correlations between abnormalities found by the various imaging
modalities and the clinical, neuropsychological and genetic characteristics of
the included patients.

A cross-sectional study of patients with SCA3 and SCA6 as well as healthy
control subjects who will undergo neurological and neuropsychological
examination, a MRI scan (acquiring T1, T2, DWI, RS-fMRI and Fluid Attenuated
Inversion Recovery (FLAIR)) and a FDG-PET scan.

The risks associated with participation are considered negligible and the
burden can be considered minimal as there is ample experience with these PET
and MRI investigations. Subjects will undergo 1 MRI scan (+/- 1 hour), 1
FDG-PET scan (+/- 45 minutes), 1 neurological examination (+/- 10 minutes) and
1 cognitive examination (+/- 1.5 hour). Taken into account the switches between
the diverse locations where the various examinations will be performed, as well
as rest moments in between, the total examination time will come down to one
visit to the UMCG lasting a maximum of 8 hours (or, under exceptional
circumstances when planning will not permit, to two visits to the UMCG lasting
a maximum of 4 hours each).