Guttuso Thomas, Shepherd Rachel, Frick Luciana, Feltri M Laura, Frerichs Valerie, Ramanathan Murali, Zivadinov Robert, Bergsland Niels
Department of Neurology, Clinical and Translational Science Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States.
Department of Chemistry, Clinical and Translational Science Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States.
IBRO Neurosci Rep. 2023 May 7;14:429-434. doi: 10.1016/j.ibneur.2023.05.001. eCollection 2023 Jun.
Lithium has a wide range of neuroprotective actions, has been effective in Parkinson's disease (PD) animal models and may account for the decreased risk of PD in smokers.
This open-label pilot clinical trial randomized 16 PD patients to "high-dose" ( = 5, lithium carbonate titrated to achieve serum level of 0.4-0.5 mmol/L), "medium-dose" ( = 6, 45 mg/day lithium aspartate) or "low-dose" ( = 5, 15 mg/day lithium aspartate) lithium therapy for 24-weeks. Peripheral blood mononuclear cell (PBMC) mRNA expression of nuclear receptor-related-1 (Nurr1) and superoxide dismutase-1 (SOD1) were assessed by qPCR in addition to other PD therapeutic targets. Two patients from each group received multi-shell diffusion MRI scans to assess for free water (FW) changes in the dorsomedial nucleus of the thalamus and nucleus basalis of Meynert, which reflect cognitive decline in PD, and the posterior substantia nigra, which reflects motor decline in PD.
Two of the six patients receiving medium-dose lithium therapy withdrew due to side effects. Medium-dose lithium therapy was associated with the greatest numerical increases in PBMC Nurr1 and SOD1 expression (679% and 127%, respectively). Also, medium-dose lithium therapy was the only dosage associated with mean numerical decreases in brain FW in all three regions of interest, which is the opposite of the known longitudinal FW changes in PD.
Medium-dose lithium aspartate therapy was associated with engagement of blood-based therapeutic targets and improvements in MRI disease-progression biomarkers but was poorly tolerated in 33% of patients. Further PD clinical research is merited examining lithium's tolerability, effects on biomarkers and potential disease-modifying effects.
锂具有广泛的神经保护作用，在帕金森病（PD）动物模型中有效，且可能是吸烟者患PD风险降低的原因。
这项开放标签的试点临床试验将16例PD患者随机分为“高剂量”组（n = 5，碳酸锂滴定至血清水平达到0.4 - 0.5 mmol/L）、“中剂量”组（n = 6，天冬氨酸锂45 mg/天）或“低剂量”组（n = 5，天冬氨酸锂15 mg/天），进行为期24周的锂治疗。除其他PD治疗靶点外，通过qPCR评估外周血单核细胞（PBMC）中核受体相关蛋白1（Nurr1）和超氧化物歧化酶1（SOD1）的mRNA表达。每组两名患者接受多壳扩散MRI扫描，以评估丘脑背内侧核、Meynert基底核（反映PD认知功能下降）和黑质后部（反映PD运动功能下降）的自由水（FW）变化。
接受中剂量锂治疗的6例患者中有2例因副作用退出。中剂量锂治疗使PBMC中Nurr1和SOD1表达的数值增加最大（分别为679%和127%）。此外，中剂量锂治疗是唯一与所有三个感兴趣区域的脑FW平均数值下降相关的剂量，这与PD中已知的纵向FW变化相反。
中剂量天冬氨酸锂治疗与基于血液的治疗靶点的参与以及MRI疾病进展生物标志物的改善相关，但33%的患者耐受性较差。值得进一步开展PD临床研究，以检验锂的耐受性、对生物标志物的影响以及潜在的疾病修饰作用。
