Anhedonic depression and alterations in the dopaminergic neurocircuitry in Parkinson’s disease

Rationale: Parkinson’s Disease (PD) is the second most prevalent neurodegenerative brain disease, characterized by degeneration of dopaminergic (DA) neurons. In PD, depression is very common (35%) with a high disease burden. Although the etiology of PD-depression is likely multifactorial, specific brain regions and neurotransmitters have been implicated, includ-ing dopamine. Despite increasing interest in identifying underlying mechanisms of depression in PD, we still lack insight needed to tailor individual treatments. Moreover, studies in (non-PD) depression indicate the need to distinguish psychiatric phenotypes of depression. The anhedonic subtype is of particular interest in PD. Anhedonia is defined as a decreased moti-vation for and sensitivity to rewarding experiences and is linked to aberrant DA neurotrans-mission. Prior clinical research in PD-depression was hampered by three limitations: psychiat-ric assessment was not consequently performed according to the art, clinical heterogeneity was not considered, and radiotracers not selective for DAT were used. In the present study, we explicitly focus on clinically carefully defined subgroups, anhedonic vs. non-anhedonic depression, and use a selective DAT tracer.

Objective: First aim is to quantify DA function of meso-limbic/cortical DA pathways (meas-ured with 18F-FE-PE2I Position Emission Tomography (PET) in PD-depression with or without anhedonia (vs. non-depressed PD). Second aim is to associate these DAT findings with dif-ferences in functional connectivity (measured by resting state functional Magnetic Reso-nance Imaging (fMRI) (vs. non-depressed PD) in these networks.

Study design: This observational cross-sectional multimodal neuroimaging study combines fMRI with a novel, highly selective DAT PET tracer (18F-FE-PE2I) in a comparison of three groups of PD-patients.

Study population: The current CMO application concerns 75 (+15 in case of drop-out) pa-tients with PD (who are included in the Personalized Parkinson’s Project (in total 650 PD pa-tients will be included, NL59694.091.16). Eligible are those who score >=14 on Beck Depres-sion Inventory and fulfill the criteria of a depression, or -in contrast- score <=8 and do not ful-fill the depression-criteria. Depressed patients are stratified in 2 different phenotypes: anhe-donic (n=25, +5 in case of drop-out) and non-anhedonic depression (n=25, +5). Subtyping of the depression will be established by a psychiatrist’s evaluation of the anhedonia criterion in DSM-5. These groups will be contrasted with a control group of non-depressed PD patients (n=25, +5).To explain additional variance, self-report questionnaires and a behavioral task assessing various aspects of anhedonia will be obtained.

Intervention (if applicable): Not applicable.

Main study parameters/endpoints:
Differences between (anhedonic and non-anhedonic) depressed PD patients and non-depressed PD patients in: (1) Baseline DAT-availability measured with PET; (2) Functional connectivity from seeds with aberrant DAT-availability compared to non-depressed PD.

Secondary parameters
Differences between (anhedonic and non-anhedonic) depressed PD patients and non-depressed PD patients in effort-reward weighting on an effort-reward-choice-task (ERCT), fMRI-based BOLD signal when performing the ERCT during the decisional phase, fMRI-based BOLD signal when performing a reinforcement learning task, neuromelanin, and subjective self-report measurements assessing depression, anhedonia, apathy and anxiety.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Participants will attend screening session with a psychiatric interview of approximately 90 minutes, followed by two study days of approximately 5-6 hours each; entailing two assess-ments with fMRI, questionnaires and behavior tasks and one PET-session. At least 12 hours preceding one of the two fMRI sessions, participants will have to refrain from dopaminergic medication, and as such, patients will arrive in a practically defined OFF state. At the end of the measurement, they will resume their normal medication regime.
The load on participants consists of the time spent on this project, potentially a temporary worsening of symptoms caused by withholding medication, and the low-dose nuclear radiation due to the PET session. Individual participants do not directly benefit from participation. We expect that this study will improve our knowledge about the cerebral mechanisms under-lying (anhedonic versus non-anhedonic) depression in PD, which may lead to new ways of treating depression in PD, a disease with high burden on patients and their relatives.

Primary Objective:
Our first aim is to quantify dopaminergic function in mesolimbic/mesocortical dopaminergic pathways (measured with 18F-FE-PE2I PET) in PD-depression with or without anhedonia. We hypothesize that lower DAT-availability (i.e. more dopamine depletion) exists in ventral stria-tum and brainstem (i.e. meso-limbic pathway) with potentially less disturbances in the prefron-tal cortex) in the anhedonic depressive subtype versus the non-anhedonic subtype. In con-trast, in the non-anhedonic subtype we expect less differences in DAT availability compared to non-depressed PD in the ventral striatum and brainstem and potentially more pronounced differences in the prefrontal cortex (meso-cortical pathway).

Secondary Objective(s):
Our second aim is to associate these DAT-findings with differences in functional connectivity (measured by fMRI) in these mesolimbic/mesocortical networks and examine differences in functional connectivity between groups (anhedonic versus non-anhedonic versus non-depressed PD patients). We expect decreased functional connectivity in the mesolimbic pathway especially in anhedonic PD-depression, while we expect decreased connectivity in the mesocortical pathway in the non-anhedonic subtype. Finally, we expect the decreases in connectivity to be largest when DAT-availability in the pathway is lowest.

This is a cross-sectional study, so there is only one time point; the assessments are obtained within three sessions, planned closely together.

not applicable