Effects of Lithium Therapy on Blood-based Therapeutic Targets in Parkinson's Disease.

This study aims to determine if one of three low doses of lithium therapy for 6 months can engage one or more blood-based therapeutic targets implicated in Parkinson's disease (PD) pathophysiology. Results of this study will help to determine if lithium therapy is worthwhile to further investigate as a potential disease-modifying therapy in PD, the optimal dose to study and the optimal PD subgroup most likely to benefit from lithium therapy.

Lithium belongs to a class of kinase-targeting therapies, including the diabetes medication exenatide and the cancer medication nilotinib, that have demonstrated promise as disease-modifying therapies for Parkinson's disease (PD). Exenatide was recently shown to engage protein kinase B (Akt) and provide significant symptomatic and possible disease-modifying benefit in PD in a phase 2 randomized controlled trial (RCT). Nilotinib engages c-Abelson kinase (c-Abl) and its disease-modifying effects are currently being investigated in two, phase 2 PD RCTs. Lithium targets Akt, glycogen synthase kinase-3 beta (GSK-3B, a downstream target of Akt) and cyclin-dependent kinase 5 (cdk5, a downstream target of c-Abl) in manners that recapitulate those of exenatide and nilotinib. Also, lithium inhibits inositol monophosphate leading to enhanced autophagy and reduced intracellular levels of alpha-synuclein (a-synuclein), which is believed to be a primary mediator of the progressive neurodegeneration in PD. In addition to a-synuclein, genome-wide association studies (GWAS) have implicated oligomeric tau in the pathogenesis of PD. Pathological mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of a late-onset parkinsonism that is clinically indistinguishable from sporadic PD and very similar pathologically. Pathological LRRK2 mutations affect the activities of Akt, GSK-3B and cdk5 to greatly increase the formation of phosphorylated tau (p-tau) - the precursor to tau oligomer formation - and decrease the activity of the transcriptional cofactor B-catenin - which mediates the transcription of neuronal survival genes implicated in PD such as nuclear receptor related 1 (Nurr1). Through its ability to inhibit GSK-3B, lithium can enhance B-catenin-mediated activity and Nurr1 expression. Lithium was also effective in several PD animal models. Finally, both clinical trial and epidemiologic data suggest that lithium exposures of even <1mg a day may provide significant disease-modifying effects in neurodegenerative diseases including PD. The investigators propose to assess the effects of 3 lithium dosages for 6 months on the above targets measured in blood in a randomized, parallel design, proof of concept clinical trial among 18 PD patients. In addition, 2 PD patients will serve as controls and not receive lithium therapy.

The dose will be titrated based on weekly blood tests to achieve a target serum level of 0.40-0.50mmol/L, which represents an elemental lithium dose of about 85-170mg a day.

Plasma alpha-synuclein assessed by ultra-sensitive, immunomagnetic reduction assay (MagQu, LLC, Surprise, AZ).

Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Part III (Motor Examination) and question 1.11 (Constipation Problems) in the "on" state

Diagnosed with PD according to the UK Brain Bank Criteria. 45-80yo. Clinical Dementia Rating Scale score of 0 or 0.5. Stable PD medications for previous 30 days and no current need for changes in the opinion of the PI. No formed visual hallucinations or delusions for previous year. Never taken prescription or over-the-counter lithium. Stable or no diuretics for past 4 weeks and no need for changes for at least 6 months, in the PI's opinion. Stable doses of antidepressants, antihypertensives and non-steroidal anti-inflammatory medications (NSAIDs) for previous 60 days and no current need to adjust such medications. No history of cardiac arrhythmias besides atrial fibrillation that is rate controlled. No unstable cardiac, medical or psychiatric condition in the opinion of the PI. No current use of illicit drugs or current alcohol abuse in the opinion of the PI. No history of hypothyroidism, not receiving thyroid replacement therapy and normal thyroid stimulating hormone (TSH) level at screening visit. Estimated renal glomerular filtration rate ≥50 at screening visit. No history of receiving or planning to receive nilotinib or a glucagon-like peptide-1 agonist medication such as exenatide. No use of tobacco products for the previous year. No deep brain stimulation (DBS) or possible need for DBS for at least 1-year in the opinion of the PI. Women with child bearing potential will need a negative pregnancy test and not be nursing an infant at screening. Women with child bearing potential will need to report using barrier method or hormonal contraception. Not enrolled in another clinical trial. Willing and able to sign informed consent and follow study procedures.

Guttuso T Jr, Shepherd R, Frick L, Feltri ML, Frerichs V, Ramanathan M, Zivadinov R, Bergsland N. Lithium's effects on therapeutic targets and MRI biomarkers in Parkinson's disease: A pilot clinical trial. IBRO Neurosci Rep. 2023 May 7;14:429-434. doi: 10.1016/j.ibneur.2023.05.001. eCollection 2023 Jun.