Dissanayaka Nadeeka, Pourzinal Dana, Byrne Gerard J, Yang Jihyun, McMahon Katie L, Pontone Gregory M, O'Sullivan John D, Adam Robert, Littleford Roberta, Chatfield Mark, Lehn Alexander, Mari Zoltan, Bakker Arnold
UQ Centre for Clinical Research, The University of Queensland, Herston, QLD, Australia.
Department of Neurology, Royal Brisbane & Women's Hospital, Herston, QLD, Australia.
Pilot Feasibility Stud. 2023 Nov 22;9(1):189. doi: 10.1186/s40814-023-01406-y.
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.
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.
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.
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.
ClinicalTrials.gov, NCT04643327 . Registered on 25 November 2020.
轻度记忆障碍，即遗忘型轻度认知障碍（aMCI），与帕金森病（PD）向痴呆的快速进展相关。研究表明，在情景记忆任务期间海马齿状回/海马体CA3亚区的过度激活是与阿尔茨海默病相关的aMCI的生物标志物。本项目调查一项试验的可行性，该试验旨在确定一种重新利用的抗癫痫药物左乙拉西坦低剂量作为一种假定治疗方法的疗效，以靶向齿状回/海马体CA3亚区的过度激活并改善PD中aMCI的情景记忆缺陷。基于先前的研究工作，假设左乙拉西坦将使PD-aMCI参与者的齿状回/海马体CA3亚区过度激活恢复正常并改善记忆表现。
将招募28名PD-aMCI参与者、28名无记忆障碍的PD参与者（PD-nMI）和28名健康对照者。PD-aMCI参与者将进行一项为期12周的随机、安慰剂对照、双盲交叉试验，每天两次接受14天的125毫克左乙拉西坦或安慰剂治疗，中间间隔4周的洗脱期。在每个治疗期后，参与者将在高分辨率功能磁共振成像（fMRI）期间完成一项旨在考验海马亚区特定功能的情景记忆任务。PD-nMI和健康对照者仅接受fMRI检查，以比较基线齿状回/海马体CA3亚区活动。
fMRI任务期间情景记忆任务表现和齿状回/海马体CA3亚区的功能激活将作为主要结局指标。整体认知、PD严重程度和不良事件将作为次要结局进行测量。招募、合格性和研究完成率将作为可行性结局进行探索。
本研究为首创性研究，将确定海马亚区功能损害以及左乙拉西坦作为降低PD痴呆风险的早期治疗选择的概念验证。
ClinicalTrials.gov，NCT(04643327)。于2020年11月25日注册。
