Effects of Lithium Therapy on Blood-based Therapeutic Targets in Parkinson's Disease.
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Lithium aspartate 15mg a day 15mg of elemental lithium administered every morning by mouth. |
Drug: Lithium
Lithium aspartate of lithium carbonate will be administered by mouth.
|
| Experimental: Lithium aspartate 45mg a day 20mg every morning and 25mg every evening of elemental lithium administered by mouth. |
Drug: Lithium
Lithium aspartate of lithium carbonate will be administered by mouth.
|
| Experimental: Lithium carbonate 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. |
Drug: Lithium
Lithium aspartate of lithium carbonate will be administered by mouth.
|
| No Intervention: No lithium treatment Control arm |
Outcome Measures
Primary Outcome Measures
- 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
- Trough, steady-state plasma lithium levels by ICP/MS [Change from baseline to 24 weeks]
- Patient tolerability [Up to 24 weeks]
Assessed by patient reported adverse events.
- 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.
- Geriatric Depression Scale-15 [Change from baseline to weeks 12 and 24.]
Score range 0-15 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.
- Montreal Cognitive Assessment (MoCA) [Change from screening to week 24]
Score range 0-30 with higher values indicating more severe symptoms.
Eligibility Criteria
Criteria
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Diagnosed with PD according to the UK Brain Bank Criteria.
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45-80yo.
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Clinical Dementia Rating Scale score of 0 or 0.5.
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Stable PD medications for previous 30 days and no current need for changes in the opinion of the PI.
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No formed visual hallucinations or delusions for previous year.
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Never taken prescription or over-the-counter lithium.
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Stable or no diuretics for past 4 weeks and no need for changes for at least 6 months, in the PI's opinion.
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Stable doses of antidepressants, antihypertensives and non-steroidal anti-inflammatory medications (NSAIDs) for previous 60 days and no current need to adjust such medications.
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No history of cardiac arrhythmias besides atrial fibrillation that is rate controlled.
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No unstable cardiac, medical or psychiatric condition in the opinion of the PI.
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No current use of illicit drugs or current alcohol abuse in the opinion of the PI.
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No history of hypothyroidism, not receiving thyroid replacement therapy and normal thyroid stimulating hormone (TSH) level at screening visit.
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Estimated renal glomerular filtration rate ≥50 at screening visit.
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No history of receiving or planning to receive nilotinib or a glucagon-like peptide-1 agonist medication such as exenatide.
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No use of tobacco products for the previous year.
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No deep brain stimulation (DBS) or possible need for DBS for at least 1-year in the opinion of the PI.
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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.
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Not enrolled in another clinical trial.
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Willing and able to sign informed consent and follow study procedures.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University at Buffalo | Williamsville | New York | United States | 14221 |
Sponsors and Collaborators
- University at Buffalo
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- STUDY00003688