The Dutch Parkinson and Cognition Study (DUPARC):
A prospective study on cognitive pathology in de novo Parkinson*s disease

Parkinson*s disease (PD) is characterized by both motor and non-motor symptoms,
including cognitive decline. Mild cognitive impairment (PD-MCI) is already
present at time of diagnosis in 24-36% of PD patients. Cognitive impairment in
PD is associated with both cholinergic and dopaminergic deficiencies in the
brain. Although dopaminergic neuronal degeneration is quite well established in
relationship to the motor impairment, the rate and extent of the cholinergic
neuronal degeneration in the course of PD is unknown. It is also unclear how
cholinergic and dopaminergic degeneration contributes to cognitive deficits
found in early and more advanced PD and its role in the progression over time.

The primary objective is to establish the relationship between cognitive
impairment and cholinergic neurodegeneration in de novo PD patients, by
studying cholinergic imaging using [18F]Fluoroethoxy-Benzovesamicol
([18F]FEOBV) PET and neuropsychological performance over time.

The secondary objectives are:
- to analyse the relationship between cognitive impairment as measured by
extensive neuropsychological assessment (NPA) and dopaminergic
neurodegeneration, using F-DOPA-PET
- to analyse the (progression of the) cognitive profile of de novo PD patients
compared to control subjects, and determine the incidence of Mild Cognitive
Impairment (PD-MCI) in this patient group.
- To compare cholinergic innervation in de novo PD patients with severe
cognitive impairment with more PD patients with dementia (PDD) at a longer
disease duration
- to analyse the relationship between resting-state functional connectivity and
both cholinergic and dopaminergic innervation.
- to investigate possible predictive factors related to the progression of
cognitive impairment, using optical coherence tomography (OCT).
- To investigate the influence of levodopa on retinal cell layers with OCT.
- To analyse cognitive decline and cholinergic neurodegeneration over time,
correcting for possible confounders, e.g. systemic inflammation, disease
history, and clinical-genetic subtyping, in particular in relation to
GBA1-mutations and GCase activity.

This study is designed as a prospective cohort study of 150 de novo PD
patients, selected from hospitals in the 3 northern provinces from the
Netherlands.
At baseline patients will undergo the following investigations and
questionnaires:
Demographics, detailed medical history, neuropsychological assessment, imaging
including MRI brain, F-DOPA PET and FEOBV PET, and OCT. 3 year follow up
includes neuropsychological assessment, OCT, MRI and both F-DOPA and FEOBV PET
imaging. 6 year follow up includes neuropsychological assesment, MRI and FEOBV
PET imaging.
At 3 months follow-up, a subgroup of 40 subjects will undergo ophthalmological
assessment.
A subset of 40 healthy controls will undergo a one-time FDOPA PET and MRI to
serve as a reference for MRI and dopaminergic analyses.

Burden:
Part of baseline measurements are considered as clinical care after diagnosing
a patient with PD, including MRI scan and F-DOPA scan. In addition, subjects
will undergo, FEOBV-PET scan, OCT and neuropsychological assessment at
baseline. The total baseline examination (including standard measurements) will
take two full-day visits to the UMCG. One-year follow-up will include one visit
to the UMCG of approximately 4 hours. 3 year follow-up will take two days. 6
year follow-up will take one day visit to the UMCG. Participants willing to
donate blood for analysis of inflammation, immune status, and GCase activity,
will donate a total of 60mL at the three year and six year follow-up.


Risk:
Baseline measurements includes two PET scans, of which the F-DOPA scan is
considered clinical protocol. In addition to the F-DOPA scan patients will
undergo FEOBV PET imaging with a radiationburden of 4,6 mSv + 1,5 mSv low-dose
CT.
3 year follow-up includes F-DOPA PET and FEOBV PET with a total burden of
respectively 5,2 mSv and 4,6 mSv and additional 2 low-dose CT of 1,5 mSv. 6
year follow-up includes FEOBV PET with a total burden of 6,1 mSv.
The overall radiation burden therefore is 31,7 mSv in 6 years and falls in a
moderate risk category (1-10mSV per year).

The total radiation exposure of the healthy controls for F-DOPA PET scan 6.7
mSv and thus falls into the risk category IIb moderate.


Benefit for the patient:
In comparison to current clinical care, the patient will get a more extensive
baseline measurement of imaging, motor and non-motor (including cognitive)
assessments. This will allow the treating physician to better track patient's
complaints and symptoms over the course of the disease. By having a solid
baseline measurment, changes can better be objectived and treatment can be
adjusted if needed. In particular the non-motor symptoms, including cognitive
impairment, or often less well recognized in current care due to the subjective
character. By assessing patients at baseline and following up symptoms and
complaints, patients can receive better care and treatment.

Benefits for research:
Including both dopaminergic and cholinergic PET imaging in combination with
both motor and non-motor assessments (including cognitive assessment), we
create a unique oppurtinity to investigate the individual roles of both
neurotransmitter systems in de development of the disease, with special focus
on cognitive decline over time. With a better understanding of the underlying
pathology and the progression over time, it will give the possibility to better
predict cognitive decline; which patients are expected to decline more rapidly
and the type of cognitive decline can be objectivied. This can be of great
importance to possible early treatment in case of cognitive decline.
In addition, by combining the imaging and neuropsychological assessment, more
information will be available for other, related, neurodegenerative diseases.