Clinicopathological MRI and CSF correlates of iron accumulation, neurodegeneration and neuroinflammation in Huntington*s disease.

Huntington's disease (HD) is a rare autosomal dominant inherited progressive
neurodegenerative disorder caused by a pathological cytosine-adenine-guanine
(CAG) repeat expansion within exon 1 of the Huntingtin (HTT) gene on chromosome
4. The disease typically manifests at a mean age at onset of 30-50 years and is
characterized by a variety of motor disturbances (typically chorea and
dystonia), cognitive impairment and behavioural changes.

Neurodegeneration in HD is a direct result of the CAG repeat expansion, which
results in intracellular aggregation of the mutant huntingtin protein (mHTT),
thereby causing neuronal dysfunction and neuronal loss of the medium spiny
neurons of the striatum. In addition to the well-documented neurodegenerative
aspect of HD, strong evidence suggests a significant role for both iron
accumulation and neuroinflammation, two mechanisms that often go hand in hand.
MRI has been extensively used to visualize brain iron accumulation based on
tissue susceptibility effects on T2*-weighted MRI images showing increased iron
values in patients with HD.

Technical limitations of these imaging methods limit their sensitivity
and specificity to disease*related tissue iron changes. The recent
development of quantitative susceptibility mapping (QSM) overcomes these
technical difficulties, providing a direct measure of tissue magnetic
susceptibility. QSM has been shown to correlate linearly with the tissue iron
content in gray matter, with high sensitivity and specificity to tissue iron
changes, as demonstrated by post-mortem studies.

However, no study in any neurodegenerative disease so far has linked the
observed increase of brain iron accumulation as measured by QSM with direct,
well-established clinical measures for iron accumulation as cerebrospinal fluid
(CSF). Moreover, previous studies focusing on iron accumulation in
neurodegenerative diseases as Alzheimer*s disease as well as HD have shown that
iron appears to be taken up by activated microglia, the resident macrophages of
the brain. It is therefore thought that cerebral iron-accumulation in humans is
mostly explained by iron-accumulating microglia in affected brain regions,
linking iron to inflammation, a key pathological mechanism. Also here, no study
so far has linked between brain iron accumulation and well-established CSF
markers for neuroinflammation in HD.
We will also investigate the pathomchanism of neuroinflammation with MRI-scans,
using (Diffusion Weighted)-Magnetic Resonance Spectroscopy (DW-MRS). With these
method we can measure levels and compare characteristics of metabolites which
are specifc for neuroinflammation.

As both iron and neuroinflammation are known to be involved in HD pathogenesis,
iron imaging using QSM might be a potential imaging biomarker for disease state
in HD possibly reflecting neuroinflammation in HD.

1. To quantify brain iron accumulation in patient with HD using quantitative
susceptibility mapping (QSM) at ultrahigh field (7T) as compared to healthy
controls (case-control design).
2. To link QSM results with specific and well-known clinical CSF markers for
iron, neurodegeneration, and neuroinflammation.
3. To quantify levels and characteristics of neuroinflammation metabolties,
using (Diffusion Weighted-)Magnetic Resonance Spectroscopy ((DW-)MRS).
4. To link QSM results with neuroinflammation metabolites, using (DW-)MRS.
5. To investigate the relationship between brain iron accumulation as detected
by QSM and clinical and genetic characteristics of HD, assessed with valdiated
scales, formulas and tests, to assess quality of biomarker for disease state,
progression and ability to predict disease progression.
6. To follow-up these markers, using MRI and CSF, two years after baseline,
to conclude if they change during disease progression and aging. This is of
utmost importance, since an ideal biomarker should change along disease
progression.

We will perform an observational cross-sectional and longitudinal study in a
cohort of HD patients and age and sex matched control subjects. This study
will take place in the LUMC. The cross-sectional part contains a two day visit
for each participant and will include the following procedures: a 7T MRI scan
of maximal 60 minutes, short motor, cognitive, psychological and functional
assessments (45-60 minutes), a lumbar puncture and blood tests.
One year later we will follow-up the participants clinically, by assessing the
same neuropsychological tests and neurological examinations as on Baseline.
This visit will take 2 hours at the maximum and can be combined with other
reasons for visiting the LUMC, like participating in the Enroll-study or seeing
the neurologist for a yearly check.
Two years after baseline, the participant will be followed-up using the same
assessments as they had during baseline: a 7T MRI scan of maximal 60 minutes,
short motor, cognitive, psychological and functional assessments (45-60
minutes), a lumbar puncture and blood tests. These assessments will be obtained
during a two day visit, like during baseline.
Three years after baseline the participant are invited for another clinical
follow-up, in which the same neuropsychological tests and neurological
examinations are assessed as during the first follow-up. This visit will take 2
hours at the maximum.

This is a non-therapeutic group relatedness study. The study day consists of a
7T MRI scan, which has no consequence for the health of the participants. In
addition, a lumbar puncture will be performed. If the participant is in a good
position, with head, neck, arms, and legs flexed as much as possible and if the
participant has a normal anatomy of the vertebrae, a lumbar puncture is a
minimal burdening to participants. Contra-indications for both MRI and lumbar
puncture 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.

The ultrahigh field MRI system is widely used in research setting and since its
first introduction in the 1990s no SAEs have been reported. Important temporary
side-effects are vertigo, nausea and involuntary eye motion due to forces on
ion currents in the semicircular loops. All individuals entering the 7 T MRI
are provided adequate sound protection to reduce the acoustic noise for
protecting the ears and increase patient comfort during MRI. Since magnetic
metal is attracted by the static field of the 7 T MRI a safety screening
questionnaire determines whether it is safe for the patient to have the MRI.
The Investigational Medical Device Dossier (IMDD) describes the risks analysis
in more detail.