Thursday, April 3, 2025
4/3/2025
Identifying and targeting the neural basis of depression in Parkinson's disease - PROJECT ABSTRACT Depression affects half of those suffering from Parkinson's disease (PD), significantly reducing quality of life, increasing disability and accelerating disease progression. However, traditional antidepressants are largely ineffective in PD and there are no targeted, effective treatments for depression in Parkinson's disease (dPD). Identifying new targets and evaluating new interventions for dPD is therefore critically important. A loss of synapses in neural circuitry responsible for movement is central to the pathology of PD, secondary to a toxic build-up of alpha-synuclein. Depression often occurs before the onset of motor symptoms in PD, reflecting the presence of pathology beyond motor circuitry. dPD is therefore likely neuroanatomically distinct from PD and from major depressive disorder (MDD). We will identify the synaptic- and network-level mechanisms that are unique to dPD, which could represent important new treatment targets. Specifically, we will use PET to measure synaptic density (Aim 1), and fMRI functional connectivity to measure network function (Aim 2) across dPD, PD (no depression), MDD and HC groups, allowing for the identification of synaptic- and network-level mechanisms that are unique to dPD. The proposed study builds on our existing PET/fMRI work in PD and in MDD showing a) almost 50% lower synaptic density in the substantia nigra in PD compared to HCs and b) lower synaptic density is associated with higher severity depression, as well as network dysfunction, in MDD. Further, our pilot data supports our hypothesis that there is a distinct pattern of synaptic loss in PD depression – specifically in mood- related circuitry. We also propose to target synaptic deficits in dPD using the rapid-acting antidepressant ketamine, whose primary mechanism of action is thought to be an increase in synaptic connections (Aim 3). We have shown that in MDD individuals with a synaptic deficit, a single dose of ketamine resulted in a robust increase in synaptic (SV2A) density. This increase in synaptic density was associated with a reduction in depression severity, providing the first in vivo evidence that an increase in synaptic connections underlies ketamine's therapeutic actions in humans. We will use PET to quantify synaptic density before and 24-hours after a single subanesthetic dose of ketamine in a subset of individuals with dPD to examine the antidepressant and mechanistic effects of ketamine in PD for the first time. Taking together the strong mechanistic rationale, the limitations of traditional antidepressants in PD and the substantial untapped potential of ketamine to alleviate depression in PD, the proposed work is highly significant and timely. We firmly believe that this innovative work will drive forward discovery of critically-needed targeted, effective treatments for depression in PD.
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