Neuroimaging biomarkers in Huntington*s Disease after 16 years of disease progression

Huntington*s Disease (HD) is a rare autosomal dominant inherited progressive
neurodegenerative disorder, caused by a CAG repeat expansion of exon 1 in the
HTT gene on chromosome 4. The disease typically manifests at an age at onset
between 30 and 50 years old and is characterized by a variety of motor
disturbances (mainly chorea and dystonia), cognitive impairment and behavioral
changes.

There have been multiple neuroimaging studies showing pathophysiological
changes in the brain during the course of Huntington*s Disease. One of the most
common findings in neuroimaging studies is striatal atrophy, studied with
structural MR imaging. Volume changes seem to start in the striatum, years
before clinical onset and spreads throughout the brain during the manifest
stages, affecting widespread regions of the grey and white matter. There are
also other MRI sequences that have proved to be of value in assessing disease
progression in HD, such as diffusion tensor imaging (DTI) which have assessed
microstructural changes in the white matter, Magnetic Resonance Spectroscopy
(MRS) that show pathophysiological mechanisms like increased neuroinflammation
and iron sensitive sequences which show an increased iron accumulation in
certain regions of the brain.

An important limitation of most of the neuroimaging studies in HD, is the lack
of longitudinal follow-up. Most of the longitudinal studies that have been
performed so far, have followed participants up to 30-72 months (resp. IMAGE-HD
and TRACK-HD. A longitudinal follow-up after 16 years has never been performed
and is therefore extremely valuable. Therefore, we will follow-up the
participants who participated in TRACK-HD in the LUMC at least at baseline in
2008, with a follow-up MRI and clinical assessments to assess disease
progression with MRI and clinical characteristics. These data combined will
show a long intra-individual progress of disease progression, which will add
information to a huge gap of knowledge in neuroimaging studies.

Our primary objective is to compare neuroimaging markers on a 3T MRI-scan with
the MRI-scans that were performed during TRACK-HD in 2008-2011. We will assess
the following neuroimaging markers, starting with the most important marker:
1. Structural neuroimaging; volume of regions such as the caudate nucleus,
putamen, and cortex.
a. To assess atrophy in the brain
b. Compare the findings with earlier results from TRACK-HD to
evaluate the progression of this neuroimaging marker
2. Iron sensitive MRI; quantification of iron levels in regions such as
the basal ganglia and cortex.
a. To assess iron accumulation in the brain
b. Compare the findings with earlier results from TRACK-HD to
evaluate the progression of this neuroimaging marker
3. Magnetic Resonance Spectroscopy (MRS); measurement of metabolites level
in the putamen.
a. To assess neuroinflammation in the brain
b. Compare the findings with earlier results from TRACK-HD to
evaluate the progression of this neuroimaging marker
4. Diffusion Tensor Imaging (DTI): measuring microstructural tracts
in the white matter
a. To evaluate microstructural differences
b. Compare the findings with earlier results from TRACK-HD
to evaluate the progression of this neuroimaging marker

Secondary Objectives:
In addition to the course of neuroimaging markers during intra-individual
disease progression, we would like to analyse the clinical characteristics of
these participants during this study, during TRACK-HD and in between the
neuroimaging timepoints, to add multiple extra timepoints with clinical data.

This is a cross-sectional study in which we perform clinical assessments and a
3T MRI-scan of the brain on participants who have participated in TRACK-HD in
the LUMC. This will be added to the data of TRACK-HD which included clinical
assessments and a yearly 3T MRI-scan of the brain during the period 2008-2011.
This study will include one visit in which we perform clinical assessments and
a 50-minute 3T MRI-scan. The clinical assessments include a short motor
assessment, psychological and functional assessments. Before these assessments
are performed, the patient needs to sign an informed consent. All together this
visit will take around 3 hours.

This is a non-therapeutic group relatedness study. Before the study assessments
participants have to give informed consent. The study days consists of a 3T MRI
scan and short motor, functional, and neuropsychological assessments, which
have no consequences for the health of the participants. Contra-indications for
MRI will be carefully checked per subject to minimize the risks. Burden will be
kept at a minimum by using short protocols and breaks in between.