Structural and functional MRI in Parkinson*s disease and healthy carriers with GBA mutation, an exploratory study

Parkinson*s disease (PD) is the second most common neurodegenerative disease
worldwide. Clinically, PD is characterized by motor slowing (bradykinesia),
stiffness (rigidity) and resting tremor. A mutation in the glucocerebrosidase
(GBA) gene represents the most common strong risk for developing (PD), although
only a relatively small proportion of patients carry this mutation in Western
Europe (5-10%). PD patients with a GBA mutation likely manifest worse disease
evolution and high progression rates of motor and cognitive symptoms. However,
clinical characterization of different PD phenotypes remains challenging given
the lack of studies combining extensive genetic and (longitudinal) clinical
data. In the prospective open-end Luxembourg Parkinson*s study (NCER-PD
program: National Centre for Excellence in Research in Parkinson*s Disease),
both these datatypes are combined for extensive phenotyping with stratified
treatment as end-goal. In the study proposed here, we add neuroimaging measures
to the Luxembourg Parkinson*s study. This allows insight into
pathophysiological mechanisms underlying different PD phenotypes (with and
without GBA gene mutations). This knowledge will help to understand why GBA
variants carriers follow a different clinical course compared to non-GBA
variants carriers. This may form the basis for new future treatments, and
personalised medicine.

Identifying the genotype-phenotype-imaging correlates in GBA mutation carriers
with and without Parkinson*s disease using functional and structural magnetic
resonance imaging (MRI).

Cross-sectional observational study, which will be combined with the
prospective longitudinal Luxembourg Parkinson*s study.

The load on the patients consist of travelling, time spent on this project, and
potentially a temporary worsening of symptoms caused by withholding medication.
Participants will be asked to travel to the Donders Centre for Cognitive
Neuroimaging from Luxembourg, since MRI facilities are lacking in Luxembourg.
The Luxembourg study team will arrange all transport and hotel stays. A
qualified medical team member (neurologist or specialized PD nurse) will join
all participants during their travel. Travel and hotel costs are covered.
Healthy controls will be measured once (one hotel night) and PD patients will
be measured on two consecutive days (ON and OFF dopaminergic medication, two
hotel nights). For the OFF-medication measurement, the antiparkinsonian
medication will be temporarily stopped once overnight to reach at least 12
hours OFF medication state. Immediately after the measurements, participants
will resume their normal medication regime. For ON-medication measurements,
patients will take their own regular dopaminergic medication. All measurements
are non-invasive, painless, and without nuclear radiation. Individual
participants do not directly benefit from participation. However, we expect
that this study will improve our knowledge about the cerebral mechanisms
underlying symptoms in PD patients with GBA mutations. This may lead to new
biomarkers for disease progression and new ways of treating this relatively
malignant form of Parkinsonism.