Levetiracetam for the treatment of mild cognitive impairment in Parkinson's disease: a double-blind controlled proof-of-concept trial protocol

Abstract

Background: Mild memory impairment, termed amnestic mild cognitive impairment (aMCI), is associated with rapid progression towards dementia in Parkinson's disease (PD). Studies have shown hyperactivation of hippocampal DG/CA3 subfields during an episodic memory task as a biomarker of aMCI related to Alzheimer's disease. This project investigates the feasibility of a trial to establish the efficacy of a repurposed antiepileptic drug, levetiracetam, in low doses as a putative treatment to target DG/CA3 hyperactivation and improve episodic memory deficits in aMCI in PD. Based on previous work, it is hypothesized that levetiracetam will normalize DG/CA3 overactivation in PD-aMCI participants and improve memory performance.

Methods: Twenty-eight PD-aMCI participants, 28 PD participants without memory impairment (PD-nMI), and 28 healthy controls will be recruited. PD-aMCI participants will undertake a 12-week randomized, placebo-controlled, double-blind cross-over trial with a 14-day treatment of 125 mg levetiracetam or placebo twice daily, separated by a 4-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 controls 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 fMRI task will be primary outcome measures. Global cognition, PD severity, and adverse events will be measured as secondary outcomes. Recruitment, eligibility, and study completion rates will be explored as feasibility outcomes.

Conclusions: This study, the first of its kind, will establish hippocampal subregion functional impairment and proof of concept of levetiracetam as an early therapeutic option to reduce dementia risk in PD.

Trial registration: ClinicalTrials.gov, NCT04643327 . Registered on 25 November 2020.

Keywords: Dementia; Episodic memory; Hippocampus; Levetiracetam; Parkinson’s disease; fMRI.

Fig. 1

Study procedure flow chart. Legend: T = Time, PD = Parkinson’s disease, aMCI = amnestic mild cognitive impairment, nMI = no memory impairment, HC = healthy controls, fMRI = functional magnetic resonance imaging

Fig. 2

Pattern separation task. Legend: Participants are shown a series of pictures of everyday objects and asked to determine if the item is “new” in the context of the experiment, “old” (exact repetition of a previously shown item), or “similar” but not exactly the same, termed “lure” trials. Correct identification of the critical lure trials is thought to depend on hippocampal subregion dentate gyrus (DG)/CA3-mediated functions shown to be associated with age-related memory impairment and memory impairment in amnestic mild cognitive impairment [12]