Daniels Christine, Steigerwald Frank, Capetian Philipp, Matthies Cordula, Malzahn Uwe, Heuschmann Peter U, Volkmann Jens
Department of Neurology, University Hospital Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany.
Department of Neurosurgery, University Hospital Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany.
Neurol Res Pract. 2020 Oct 19;2:41. doi: 10.1186/s42466-020-00086-w. eCollection 2020.
Dementia in Parkinson's disease (PDD) is a common non-motor symptom of advanced disease, associated with pronounced neocortical cholinergic deficits due to neurodegeneration of the nucleus basalis of Meynert (NBM) and its cholinergic terminals. In advanced PD, patients often require advanced therapies such as infusion therapy or deep brain stimulation (DBS) to improve motor control. However, patients with associated dementia are commonly excluded from DBS because of potential deterioration of cognitive functions. Yet marked reductions in dopaminergic medication and the subsequent risk of side effects (e.g., cognitive decline, psychosis, delirium) suggest that critical re-consideration of DBS of the subthalamic nucleus (STN-DBS) for advanced stages of PD and PDD is worthwhile. In this Phase 1b study, we will provide STN-DBS to a cohort of PDD patients with severe motor fluctuations and combine two additional electrodes for augmentative neurostimulation of the NBM.
We aim to include 12 patients with mild-to-moderately severe PDD who fulfill indication criteria regarding motor symptoms for STN-DBS. Eligible patients will undergo implantation of a neurostimulation system with bilateral electrodes in both the STN and NBM. After 12 weeks of STN-DBS (visit 1/V1), participants will be randomized to receive either effective neurostimulation of the NBM (group 1) or sham stimulation of the NBM (group 2). NBM-DBS will be activated in all participants after 24 weeks of blinded treatment (visit 2/V2). The primary outcome will be the safety of combined bilateral STN- and NBM-DBS, determined by spontaneously-reported adverse events. Other outcome measures will comprise changes on scales evaluating cognition, activities of daily living functioning and clinical global impression, as well as motor functions, mood, behavior, caregiver burden and health economic aspects, and several domain-specific cognitive tests. Changes in scores (V1 - V2) for both treatment arms will undergo analysis of covariances, with baseline scores as covariates.
The feasibility and safety of combined STN-NBM-DBS in patients with PDD will be assessed to determine whether additional NBM-DBS improves or slows the progression of cognitive decline. Positive results would provide a basic concept for future studies evaluating the efficacy of NBM-DBS in larger PDD cohorts. Indirectly, proof-of-safety of STN-DBS in PDD might influence patient selection for this standard treatment option in advanced PD.
ClinicalTrials.gov identifier (NCT number): NCT02589925.
帕金森病痴呆（PDD）是晚期疾病常见的非运动症状，与因Meynert基底核（NBM）及其胆碱能终末神经变性导致的明显新皮质胆碱能缺陷有关。在晚期帕金森病中，患者常需接受如输液治疗或脑深部电刺激（DBS）等先进疗法以改善运动控制。然而，伴有痴呆的患者通常因认知功能可能恶化而被排除在DBS治疗之外。但多巴胺能药物显著减少及其随后的副作用风险（如认知衰退、精神病、谵妄）表明，对于帕金森病和帕金森病痴呆晚期患者，重新审慎考虑丘脑底核DBS（STN-DBS）是值得的。在这项1b期研究中，我们将为一组有严重运动波动的帕金森病痴呆患者提供STN-DBS，并结合另外两个电极对NBM进行增强神经刺激。
我们旨在纳入12例轻度至中度严重帕金森病痴呆患者，这些患者符合STN-DBS运动症状的入选标准。符合条件的患者将接受在丘脑底核和NBM双侧植入电极的神经刺激系统。在STN-DBS治疗12周后（访视1/V1），参与者将被随机分组，分别接受NBM有效神经刺激（第1组）或NBM假刺激（第2组）。在盲法治疗24周后（访视2/V2），所有参与者的NBM-DBS将被激活。主要结局将是联合双侧丘脑底核和NBM-DBS的安全性，通过自发报告的不良事件来确定。其他结局指标将包括评估认知、日常生活功能、临床总体印象、运动功能、情绪、行为、照料者负担和健康经济方面的量表变化，以及多项特定领域的认知测试。两个治疗组的评分变化（V1 - V2）将以基线评分为协变量进行协方差分析。
将评估联合丘脑底核- NBM-DBS在帕金森病痴呆患者中的可行性和安全性，以确定额外的NBM-DBS是否能改善或减缓认知衰退的进展。阳性结果将为未来评估NBM-DBS在更大帕金森病痴呆队列中疗效的研究提供基本概念。间接地，帕金森病痴呆患者中丘脑底核DBS的安全性证据可能会影响晚期帕金森病患者对这种标准治疗方案的选择。
ClinicalTrials.gov标识符（NCT编号）：NCT02589925。
