Explorations into the structural and molecular cerebral differences between tremor dominant and non-tremor Parkinson*s Disease

Resting tremor is a core symptom of Parkinson*s disease (PD), which is seen in
about 75% of patients. Aside from the appearance of tremor, these patients also
show a difference in disease progression than non-tremor PD patients: they have
less cognitive decline and a slower overall disease progression. The reason for
this variability is unclear, preventing treatment and development of new
therapies. Post-mortem studies suggest different patterns of (dopaminergic)
cell loss in the midbrain of tremor-dominant and non-tremor PD patients, but in
vivo evidence is lacking. These structural differences may in turn produce
downstream functional changes in the basal ganglia and thalamus. Here we test
this hypothesis in patients with PD, using both structural and functional MRI
scanning. Our structural scans will look at the structural integrity of deep
brain (dopaminergic) nuclei, and our functional scans will be focused on
thalamic GABA, which is the most important inhibitory neurotransmitter in the
human brain and strongly linked to the expression of tremor. Finally, we will
test the consequences of these underlying structural and functional changes for
behavioural performance using cognitive testing.

We hypothesize that PD patients with and without tremor have different patterns
of midbrain structural integrity in (dopaminergic) nuclei, different patterns
of functional connectivity from midbrain to basal ganglia, differences in
GABA-ergic tone in the thalamus, and differences in dopamine-specific
behavioural performance.

This research will combined with a previous study (CMO: NL47614.091.14
/2014-014), where we measured two groups of tremor-dominant PD patients
(dopamine-resistant and dopamine-responsive) and one group of matched controls.
The non-tremor group will undergo a very similar procedure, making them fully
comparable with the previous groups. This entails: testing all patients twice,
i.e. without their normal medication and after a single dose of
Levodopa-Benserazide 250 mg. The participants will undergo the following MR
scans: (1) diffusion tensor imaging (DTI; 15 min) and a high-resolution
localizer scan (SWI; 5 min) to quantify the structural integrity of deep brain
regions; (2) magnetic resonance spectroscopy (MRS; 30 min) to measure GABA
concentrations in the thalamus (and control regions) (3) fMRI resting state (10
min) to measure functional connectivity;. Outside the scanner, we will measure
cognitive performance on 2 behavioural tasks (40 min) measuring
dopamine-dependent and dopamine-independent cognitive performance.

The intervention includes two fMRI sessions per subject. The patients are
measured both OFF their own dopaminergic drugs, and ON 250 mg
Levodopa-Benserazide + 10 mg Domperidone. During the OFF condition, patients
will receive a placebo with the same physical appearance. Patients (but not
researchers) will be blinded to the intervention.

The experimental protocol will consist of clinical and behavioural measurements
plus anatomical and functional scans in the MRI scanner. These measurements
will be performed on 2 mornings (duration: 4 hours per session). Patients will
arrive in a practically defined OFF state, i.e. at least 12 hours after having
taken their last dopaminergic medication. At the end of the measurement, they
will resume their normal medication regime. When OFF-medication, their
Parkinson symptoms may temporarily worsen, which can lead to discomfort. On one
out of two sessions, patients will receive a dose of Levodopa-Benserazide (250
mg) that may be higher than the patient's usual dose. This may sometimes lead
to side effects such as nausea or dizziness. For this reason, patients will
receive 10 mg Domperidone, which is a standard clinical treatment to avoid such
side effects. Finally, the noise in the fMRI scanner, and lying in a small
space, may lead to discomfort. If all security measures are fulfilled, then
there is not risk for the patients.