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.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease
• Intervention / Treatment: Drug: Lithium

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 Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Williamsville, New York, United States, 14221
      • University at Buffalo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

1. Diagnosed with PD according to the UK Brain Bank Criteria.
2. 45-80yo.
3. Clinical Dementia Rating Scale score of 0 or 0.5.
4. Stable PD medications for previous 30 days and no current need for changes in the opinion of the PI.
5. No formed visual hallucinations or delusions for previous year.
6. Never taken prescription or over-the-counter lithium.
7. Stable or no diuretics for past 4 weeks and no need for changes for at least 6 months, in the PI's opinion.
8. Stable doses of antidepressants, antihypertensives and non-steroidal anti-inflammatory medications (NSAIDs) for previous 60 days and no current need to adjust such medications.
9. No history of cardiac arrhythmias besides atrial fibrillation that is rate controlled.
10. No unstable cardiac, medical or psychiatric condition in the opinion of the PI.
11. No current use of illicit drugs or current alcohol abuse in the opinion of the PI.
12. No history of hypothyroidism, not receiving thyroid replacement therapy and normal thyroid stimulating hormone (TSH) level at screening visit.
13. Estimated renal glomerular filtration rate ≥50 at screening visit.
14. No history of receiving or planning to receive nilotinib or a glucagon-like peptide-1 agonist medication such as exenatide.
15. No use of tobacco products for the previous year.
16. No deep brain stimulation (DBS) or possible need for DBS for at least 1-year in the opinion of the PI.
17. 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.
18. Not enrolled in another clinical trial.
19. Willing and able to sign informed consent and follow study procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Measure Description	Time Frame
Trough, steady-state plasma lithium levels by ICP/MS		Change from baseline to 24 weeks
Patient tolerability	Assessed by patient reported adverse events.	Up to 24 weeks
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	Score range 0-132 with higher values indicating more severe symptoms.	Change from baseline to weeks 12 and 24.
Parkinson's Anxiety Scale	Score range 0-48 with higher values indicating more severe symptoms.	Change from baseline to weeks 12 and 24.
Geriatric Depression Scale-15	Score range 0-15 with higher values indicating more severe symptoms.	Change from baseline to weeks 12 and 24.
Fatigue Severity Scale	Score range 9-56 with higher values indicating more severe symptoms.	Change from baseline to weeks 12 and 24.
Insomnia Severity Index	Score range 0-28 with higher values indicating more severe symptoms.	Change from baseline to weeks 12 and 24.
Parkinson's Disease Questionnaire-8	Score range 0-32 with higher values indicating more severe symptoms.	Change from baseline to weeks 12 and 24.
Montreal Cognitive Assessment (MoCA)	Score range 0-30 with higher values indicating more severe symptoms.	Change from screening to week 24

Collaborators and Investigators

• Sponsor: State University of New York at Buffalo

Publications and helpful links

General Publications

• 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.

Helpful Links

• PubMed Link to study results

Study record dates

Study Major Dates

• Study Start (Actual): October 17, 2019
• Primary Completion (Actual): June 15, 2023
• Study Completion (Actual): August 12, 2023

Study Registration Dates

• First Submitted: October 31, 2019
• First Submitted That Met QC Criteria: February 14, 2020
• First Posted (Actual): February 18, 2020

Study Record Updates

• Last Update Posted (Actual): August 15, 2023
• Last Update Submitted That Met QC Criteria: August 12, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Lithium; Alpha-synuclein
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Antidepressive Agents; Antimanic Agents; Lithium Carbonate
• Other Study ID Numbers: STUDY00003688

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No