Objective: The TRIP proof-of-concept study examines functioning of the hippocampal DG/CA3 subregion as a biomarker and therapeutic target for memory impairment in Parkinson’s Disease (PD).

Background: Mild memory impairment, termed amnestic Mild Cognitive Impairment (aMCI), is associated with greater functional impairment and rapid progression toward dementia in PD. There is currently no treatment for PD-aMCI. Studies have shown hyperactivation of hippocampal subfields during an episodic memory task to be a marker of aMCI predictive of disease progression in Alzheimer’s disease. Based on its effective use in Alzheimer’s disease, this study will investigate the efficacy of the repurposed antiepileptic drug, levetiracetam, in low doses as a putative treatment to target and reduce DG/CA3 hyperactivation and improve episodic memory deficits in PD-aMCI.

Method: Twenty-eight PD patients with PD-aMCI, 28 PD patients with no memory impairment (PD-nMI) and 28 healthy controls (HC) will be recruited. PD-aMCI participants will undertake a 12-week randomized- placebo-controlled double-blind cross-over trial (clinicaltrials.org: NCT04643327) with 14-day treatment of 125mg levetiracetam or placebo twice daily, separated by a four-week washout period. After each treatment period, participants will complete an episodic memory task designed to tax hippocampal subregion specific function during high-resolution functional Magnetic Resonance Imaging (fMRI). PD-nMI and healthy control participants will undergo the fMRI protocol only, to compare baseline DG/CA3 subfield activity.

Results: Episodic memory task performance and functional activation in the DG/CA3 subfield during the task obtained during the fMRI session will be used as primary outcome measures. Global cognition, Parkinson’s disease severity, and adverse events will be measured as secondary outcomes.

Conclusion: Based on previous work in Alzheimer’s MCI, it is hypothesized that: a) PD-aMCI participants will exhibit greater activation in the DG/CA3 region during episodic memory function compared to PD-nMI participants and HC; and b) levetiracetam treatment will normalize DG/CA3 overactivation in PD-aMCI participants and improve memory performance in these patients.

Abstract previously presented at the Herston Health Precinct Symposium [07/12/2020] and BioNetwork Annual Research Symposium on Dementia [15/09/2020].

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MDS Abstracts - https://www.mdsabstracts.org/abstract/therapy-to-reduce-dementia-risk-in-parkinsons-disease-trip-proof-of-concept-trial/