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

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.

• 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.