Effects of Lithium Therapy on Blood-based Therapeutic Targets in Parkinson's Disease.
- Registration Number
- NCT04273932
- Lead Sponsor
- State University of New York at Buffalo
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 19
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Lithium aspartate 15mg a day Lithium 15mg of elemental lithium administered every morning by mouth. Lithium aspartate 45mg a day Lithium 20mg every morning and 25mg every evening of elemental lithium administered by mouth. Lithium carbonate Lithium 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.
- Primary Outcome Measures
Name Time Method Plasma alpha-synuclein assessed by ultra-sensitive, immunomagnetic reduction assay (MagQu, LLC, Surprise, AZ). Change from baseline to 24 weeks Peripheral blood mononuclear cell (PBMC) Nurr1 mRNA levels by real-time polymerase chain reaction. Change from baseline to 24 weeks PBMC phosphorylated (p) and total (t) levels of pSerine9 and t-glycogen synthase kinase-3B Change from baseline to 24 weeks Plasma brain-derived neurotrophic factor (BDNF). Change from baseline to 24 weeks PBMC pThreonine308 and t-protein kinase B (Akt). Change from baseline to 24 weeks
- Secondary Outcome Measures
Name Time Method Patient tolerability Up to 24 weeks Assessed by patient reported adverse events.
Trough, steady-state plasma lithium levels by ICP/MS Change from baseline to 24 weeks Geriatric Depression Scale-15 Change from baseline to weeks 12 and 24. Score range 0-15 with higher values indicating more severe symptoms.
Montreal Cognitive Assessment (MoCA) Change from screening to week 24 Score range 0-30 with higher values indicating more severe symptoms.
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 Change from baseline to weeks 12 and 24. Score range 0-132 with higher values indicating more severe symptoms.
Parkinson's Anxiety Scale Change from baseline to weeks 12 and 24. Score range 0-48 with higher values indicating more severe symptoms.
Fatigue Severity Scale Change from baseline to weeks 12 and 24. Score range 9-56 with higher values indicating more severe symptoms.
Insomnia Severity Index Change from baseline to weeks 12 and 24. Score range 0-28 with higher values indicating more severe symptoms.
Parkinson's Disease Questionnaire-8 Change from baseline to weeks 12 and 24. Score range 0-32 with higher values indicating more severe symptoms.
Trial Locations
- Locations (1)
University at Buffalo
🇺🇸Williamsville, New York, United States