Biomarkers in Intermediate Allele Carriers, Adult-, and Early-onset Huntington*s Disease Patients.

Huntington*s Disease (HD) is a rare autosomal dominant inherited progressive
neurodegenerative disorder caused by a pathological cytosine-adenine-guanine
(CAG) repeat expansion in the Huntingtin (HTT) gene on chromosome 4. A CAG
repeat length of 40 or more is invariably associated with HD. Alleles with a
CAG repeat length between 27-35 are called intermediate alleles (IA). CAG
repeat lengths under 35 are not considered to be associated with HD. However,
there are case reports that claim otherwise, although there is a lack of
convincing biological evidence, and no follow-up data on IA carriers with HD
symptoms. On the other side are patients with a very long CAG repeat length.
These patients tend to have an early disease onset, including Juvenile-onset HD
(JoHD). Early-onset HD (EoHD), including JoHD, patients present with
significantly different clinical phenotypes compared with adult-onset HD (AHD)
patients. IA carriers and patients with EoHD are often overlooked, since both
groups are extremes on the HD spectrum. This research project is part of the
*CureQ: Predict, Delay & Cure polyglutamine(Q) caused Neurodegeneration*
consortium. The main aim of CureQ is to better predict onset and progression of
disease, of HD and spinocerebellar ataxia, and enable polyQ targeted therapies.
In this study, we will build a national longitudinal clinical cohort of IA
carriers, AHD, EoHD patients, and controls for phenotyping and biomarker
research. Getting more insight in biomarkers that are associated with disease
processes will help clinicians to define disease onset as well as disease
progression, as early and precisely as possible. We will collect longitudinal
data on multiple promising biomarkers in blood and cerebrospinal fluid (CSF).
The two groups at the extreme ends of the HD spectrum (IA carriers and EoHD
patients) will be compared to the AHD group. The CureQ consortium investigates
disease mechanisms through cellular models based on patient-derived induced
pluripotent stem cells (iPSCs), which will be generated from peripheral blood
mononuclear cells (PBMCs). These disease models will provide insights in
disease processes, and can therefore contribute to the discovery of new
clinically relevant biomarkers, and new treatment strategies. Using
patient-derived iPSCs and differentiating them into neurons and glia cells is
the only way to make reliable disease models for HD, since existing animal
models are not representative due to their high CAG repeat length. Developing
these models will also reduce the need for animal testing.

The primary objective:
To identify fluid and radiological biomarkers, in IA carriers, AHD patients,
and EoHD patients, that can be linked to clinical outcome measures. We aim to
link longitudinal changes in these biomarkers to disease progression. Disease
progression will be measured using clinical outcomes measures. In addition, we
will compare the two extreme groups, IA carriers and EoHD patients, to the AHD
group (with regular HD disease characteristics), and the healthy control group.

Secondary Objectives:
- To phenotype IA carriers, and assess the potential presence of HD processes
in IA carriers, by measuring biomarkers and clinical outcome measures over 2
years, and comparing them with data from AHD patients, and aged-matched healthy
controls.
- To provide PBMCs that can be reprogrammed into iPSCs, and further
differentiated into disease-relevant cells (e.g., neurons, glia) and tissue
(e.g., brain organoids) for cellular phenotyping. PBMCs will be isolated from
blood from IA carriers, AHD patients, and EoHD patients.

A 3 year prospective cohort study without interventions. The annual assessments
will include biomarker analysis in blood and cerebrospinal fluid (CSF) samples,
as well as Magnetic Resonance Imaging (MRI). Participants will also undergo
detailed clinical assessment.

This is a non-therapeutic group relatedness study. This study has no immediate
benefits for the participants. However, HD patients may benefit from an
improved understanding of the pathophysiology of HD and the potential discovery
of clinically relevant biomarkers for HD. In addition, IA carriers might
benefit from a better understanding of their clinical phenotype, and a more
clear prognosis. Moreover, the potential risks of this study are very limited.
The methods proposed for this research are a minimal burden, and have low
risks. Only the lumbar puncture and venapuncture are invasive, although
minimally. Additionally, these are the best, and only methods, to accurately
assess disease progression in HD patients. The data that will be collected in
this research is of great importance to enable future research towards
therapeutic treatments.

This study consists of three assessments per participant, a baseline and two
follow-up assessments (after one and two years). An assessment includes:
clinical assessment, 3T MR imaging, lumbar puncture and a venapuncture. The 3T
MRI scan is widely used in clinical environments, and has no consequences for
the health of participants. If conducted by an experienced team after careful
consideration of any contraindications a lumbar puncture is a minimal burden to
the participant. Contraindications for both MRI and lumbar puncture will be
carefully checked per subject. The potential risks of this study are minimal,
and precautions will be taken to minimize them further.

MRI, lumbal puncture, venapuncture, and the neuropsychological tests are not
standard parts of the treatment for HD. There is no curative treatment, so the
only treatment patients receive is treatment of symptoms. Dependent on the
situation of the patient, MRI, lumbal puncture, venapuncture, and/or
neuropsychological tests can be included as part of the treatment. A lot of the
HD patients seen in the LUMC or MUMC+ are already part of scientific research,
like Enroll-HD, in which venapuncture and the neuropsychological tests are
standard practice. Therefore, these procedures will not be an additional burden
for those patients. The data from the neuropsychological test can be used for
both studies, and some additional blood will be drawn.

The study could potentially also include incapacitated participants. The EoHD
group is the only participant group that could potentially contain
incapacitated participants. It is important to conduct research with this group
of EoHD patients, since these patients have a significantly different clinical
phenotype than regular HD patients [18,20]. Consequently, results from studies
conducted with regular HD patients are only translatable to EoHD patients to a
very limited extent. Therefore, it is important to include EoHD patients in
research. Additionally, the potential risks of this study are very limited, as
described above. An MRI is widely used in clinical environments and is
non-invasive. A venipuncture can be perceived as painful, but has very minimal
risks. Incapacitated participants will be asked to consent to a lumbar
puncture. A lumbar puncture is a minimal burden if conducted by an experienced
team after careful consideration of any contraindications. The procedure itself
takes only 5 minutes, and it has minimal risks. The lumbar puncture will not be
an obligatory part of this study for incapacitated patients. These patients
might have a decreased understanding of this procedure. Physically, the lumbar
puncture is a minimal burden when conducted correctly. However, for this
vulnerable group of patients, the procedure may be stressful, due to a lack of
insight into the situation. It is important for this research to include
incapacitated patients, even if they prefer to forego the lumbar puncture. The
group of EoHD patients is scarce, and we cannot afford to lose these patients
for the other modalities (blood and MRI).