Lithium's effects on therapeutic targets and MRI biomarkers in Parkinson's disease: A pilot clinical trial

Thomas Guttuso Jr, Rachel Shepherd, Luciana Frick, M Laura Feltri, Valerie Frerichs, Murali Ramanathan, Robert Zivadinov, Niels Bergsland, Thomas Guttuso Jr, Rachel Shepherd, Luciana Frick, M Laura Feltri, Valerie Frerichs, Murali Ramanathan, Robert Zivadinov, Niels Bergsland

Abstract

Background: 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.

Methods: This open-label pilot clinical trial randomized 16 PD patients to "high-dose" (n = 5, lithium carbonate titrated to achieve serum level of 0.4-0.5 mmol/L), "medium-dose" (n = 6, 45 mg/day lithium aspartate) or "low-dose" (n = 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.

Results: 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.

Conclusion: 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.

Keywords: Biomarker; Clinical trial; Cognition; Free water; Lithium; Progression.

Conflict of interest statement

Authors’ Conflicts of Interest for previous 12 months: Thomas Guttuso, Jr.: President of e3 Pharmaceuticals, Inc. Support from UCB for clinical trial patient enrollment. Rachel Shepherd: None. Luciana Frick: None. Laura Feltri: None. Valerie Frerichs: None. Murali Ramanathan: None. Robert Zivadinov: Received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Novartis, Sanofi, 415 Capital, Mapi Pharma and Janssen for speaking and consultant fees. He received financial support for research activities from Bristol Myers Squibb, Sanofi, Novartis, EMDSerono, V-WAVE Medical, Mapi Pharma, CorEvitas and Protembis. Niels Bergsland: None.

© 2023 The Authors.

Figures

Fig. 1
Fig. 1
Individual patient changes in FW after 24 weeks of high, medium or low-dose lithium therapy. FW: free water, DMN-T: dorsomedial nucleus of the thalamus, nbM: nucleus basalis of Meynert, pSN: posterior substantia nigra.

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