Objective: To determine the effects of lithium therapy on blood-based biomarkers in Parkinson’s disease (PD).

Background: Lithium has multiple neuroprotective actions and may account for the 77% reduced rate of PD in smokers. Nurr1 is a transcription factor essential for dopamine cell maintenance and survival and is decreased by about 61% in PD substantia nigra and peripheral blood mononuclear cells (PBMCs). Nurr1 can also increase the expression of superoxide dismutase-1 (SOD-1). Lithium increases Nurr1 by 180% and protects rotenone-treated PC12 cells. As a result, Nurr1 is a PD therapeutic target of interest.

Method: This open-label trial randomized 16 PD patients to high (n=5, lithium carbonate titrated to achieve serum level of 0.4-0.5mmol/L), medium (n=6, 45mg/day lithium aspartate) or low-dose (n=5, 15mg/day lithium aspartate) lithium therapy for 6 months. Three additional PD patients served as controls (Clinicaltrial.gov: NCT04273932). Blood-based biomarkers were assessed at baseline, 3 and 6 months.

Results: Two of the patients assigned to medium dose lithium withdrew from the study both due to side effects of confusion and sedation. No other side effects were reported by the other 14 patients receiving lithium. PBMC Nurr1 assessed by quantitative real-time PCR increased by 420%, 679%, 93% and 139% in the high, medium and low-dose lithium and control groups, respectively, after 6 months. Defining a “Nurr1 responder” as having a 6-month Nurr1 increase of >200%, the responder rates were 20%, 75%, 20% and 0%, respectively. Serum lithium levels at 6 months were 1282, 828, 195 and 0.73µg/L, respectively. PBMC SOD-1 increased by 18%, 127%, -1% and 8%, respectively, and by 125% and -21% in Nurr1 responders and non-responders, respectively, after 6 months. Lithium did not affect plasma alpha-synuclein levels.

Conclusion: This pilot study showed medium dose lithium aspartate therapy to most strongly engage PD therapeutic targets but to be poorly tolerated in 1/3 of patients despite having serum lithium levels 45% lower than the high dose lithium carbonate group. This suggests that lithium aspartate may have greater physiological effects at a lower serum lithium level than lithium carbonate. Further clinical research is merited on identifying the lithium dose and formulation that is well tolerated and maximally engages PD therapeutic targets.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/low-dose-lithium-therapy-associated-with-increased-pbmc-nurr1-and-sod1-expression-in-parkinsons-disease-a-pilot-study/