The Dutch Parkinson-GBA Cohort Study (DUPARG)
Cognitive and cholinergic function analysis in Dutch Parkinson*s patients with GBA variations.

Parkinson's disease (PD) is a multifactorial disorder, with both environmental
and genetic risk factors playing important roles in its etiology and
progression. The most common genetic risk factor for PD involve mutation of the
GBA1 (GBA) gene, encoding the lysosomal enzyme glucocerebrosidase (GCase).
Approximately, 15% of Dutch PD patients has one or more GBA mutation. PD
patients who carry GBA mutations putatively comprise a distinct clinical
subtype, with a younger age at onset and faster progression of the disease.
GBA-PD is associated with more severe cognitive impairment, mood disorders,
postural instability and gait disorders (PIGD) and hyposmia. The GBA-PD
phenotype bears similarity with cholinergic system degeneration symptomatology,
which is an important but variable feature of PD, in particular the cognitive
impairment and postural instability and gait disorders (PIGD). Here, we will
explore using PET-imaging techniques if GBA mutations lead to preferential
degeneration of the cholinergic system. Additionally, the contribution of
reduced Case activity to the clinical status of PD subjects will be assessed.

The primary objective of this study is to compare cholinergic innervation of
the cerebral cortex of GBA-PD and non-GBA-PD patients, using [18]FEOBV PET
imaging of the brain.

We propose a cross-sectional study design, to compare cholinergic innervation
of GBA-PD - with non-GBA-PD patients.
The proposed study will include PD subjects with a known GBA mutation. These
GBA-PD subjects stem from two already existing study cohorts and by creating a
new GBA-PD cohort The first cohort contains of a Dutch national cohort of >500
GBA-PD patients, identified through a nation-wide screening in the Netherlands
(GBA-NLD) (Den Heijer et al, 2020)(1).. Participants from the Dutch Parkinson
Cohort (DUPARC) [METc 2017/142; NL60540.042.17]: a longitudinal cohort study of
150 de novo PD subjects will be enrolled. The measurements to perform in this
study are already approved by the METc for the DUPARC participants and
permission had been given by the patients to use their research data.
Additional participants will be recruited by cooperation of a collaborative
network of PD treating neurologist in the northern part of the Netherlands
(Parkinson Platform Northern Netherlands, PPNN). Patients treated by
neurologist of the PPNN will be informed about the study. Patients will be
asked to collect a saliva sample to analyse the GBA carrier status. Patients
with a GBA mutation who meet the in- and exclusion criteria are asked to
participate in the study after giving informed consent. Also specified subjects
with L444P GBA carrier status and E326K GBA carrier status will be enrolled to
compare the cholinergic innervation and cognitive functioning between these
mild and severe GBA variants, based on the clinical data so far.
The GBA-NLD subjects and additional subjects enrolled through the PPNN receive
measurements in concordance with the DUPARC protocol. Patients will undergo the
following measurements and questionnaires: Demographics, detailed medical
history, extensive neuropsychological assessment (NPA), GCase activity using
peripheral mononuclear blood cells (PBMCs) and imaging including FEOBV PET,
F-DOPA, MRI brain. METc persmission has already been granted to perform the
measurements on the DUPARC participants and permission had been given by the
patients to use their research data. This METc application asking permission to
perform the measurement for the GBA-NLD participants and participants enrolled
through the PPNN.

Participants from the GBA-NLD study and the participants enrolled through the
PPNN will undergo additional questionnaires and assessments. Those patients
will receive measurements in concordance with the DUPARC three-year follow-up
protocol.
This will include: FEOBV PET, FDOPA PET and a MRI. In addition, 60ml of blood
for the assessment of Gcase activity, neuropsychological assessment (NPA),
and motor assessments (UPDRS). The total examination will take two full-day
visits to the UMCG.
The radiation burden of the FEOBV-PET is 4,6mSv (with 200 MBq injection). For
attenuation correction a low-dose CT is also added to each PET scan performed.
This accounts for an addition radiation burden of 1,5 mSv.
To provide insight in the presynaptic dopaminergic integrity and related
disease activity, F-DOPA PET scans will be performed. The radiation burden of
the F-DOPA PET scan is 5,2 mSV (with 200 MBq injection) and an added 1,5 mSv
low-dose CT for attenuation correction. In total, the radiation burden of both
scans will be 12,8 mSv. There are no benefits associated for the participants
with participation.
Contrary to previous research, the current proposal provides the unique
opportunity for in-depth phenotyping of large numbers of GBA-PD subjects in a
homogenous, single-center, study protocol. In itself, thorough phenotyping will
provide health care professionals with reliable data to offer useful prognostic
information and personalized treatment, in particular regarding cognitive
deterioration, a major concern amongst PD subjects. Besides more solid data of
the clinical subtype of GBA-PD, this will also be the first study to use
various imaging parameters of GBA-PD, including cholinergic PET imaging using
FEOBV. As the clinical manifestation of GBA-PD suggest cholinergic involvement,
FEOBV-PET imaging will provide valuable insights in the neuro-anatomical
structures underlying the GBA-PD subtype. Moreover, it can inform treatment
decisions concerning cholinergic supplementation in both GBA-PD and non GBA-PD
subjects with cognitive impairments.
The clinical spectrum of GBA-PD seems less heterogeneous compared to non GBA-PD
with faster clinical progression, making GBA-PD interesting subtype for
disease-modifying trials, in particular aimed at increasing GCase activity.
Stratification according to GBA status might therefore reduce the sample sizes
and follow-up required for well-powered clinical trials. Besides GBA status,
the current proposal also allows for stratification according to biomarker
profiles, including GCase activity and brain cholinergic innervation, that are
putatively relevant for both GBA-PD and non GBA-PD.