Lithium for Parkinson's Disease - SUNY Buffalo Trial (NCT06339034)

Overview

This Phase 1/2 clinical trial investigates the repurposing of lithium as a potential disease-modifying therapy for Parkinson's disease (PD). Conducted at SUNY Buffalo under the leadership of Dr. Thomas Guttuso, the study builds on prior observational research suggesting that low-dose lithium may significantly reduce PD risk and slow disease progression.

Trial Details

Overview

This Phase 1/2 clinical trial investigates the repurposing of lithium as a potential disease-modifying therapy for Parkinson's disease (PD). Conducted at SUNY Buffalo under the leadership of Dr. Thomas Guttuso, the study builds on prior observational research suggesting that low-dose lithium may significantly reduce PD risk and slow disease progression.

Trial Details

| Attribute | Value |
|-----------|-------|
| NCT Number | NCT06339034 |
| Title | Repurposing Lithium for Parkinson's Disease: a RCT |
| Official Title | Repurposing Lithium as a Disease-modifying Therapy in Parkinson's Disease: A Randomized Controlled Trial |
| Status | Active, Not Recruiting |
| Phase | Phase 1/2 |
| Study Type | Interventional |
| Design | Randomized, Double-blind, Placebo-controlled |
| Allocation | Parallel Group |
| Masking | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Enrollment | 20 patients (estimated) |
| Sponsor | State University of New York at Buffalo |
| Collaborator | Cure Parkinson's |
| Principal Investigator | Thomas Guttuso, MD, Professor of Neurology |
| Location | UBMD Neurology, Williamsville, NY, United States |
| Start Date | July 3, 2024 |
| Primary Completion | December 2025 (estimated) |
| Completion | February 2026 (estimated) |

Rationale

Epidemiological Evidence

Large observational studies have demonstrated that low-dose lithium use is associated with a 77% reduced risk of developing Parkinson's disease. This compelling epidemiological data provides a strong rationale for testing lithium in a prospective clinical trial.

Preclinical Evidence

Lithium has demonstrated neuroprotective effects in multiple PD animal models:

• Prevents neuronal death
• Reduces behavioral symptoms
• Modulates key signaling pathways implicated in neurodegeneration

Prior Pilot Data

The research team previously conducted a 24-week pilot study of low-dose lithium in PD patients, which showed improvements in both MRI and blood-based biomarkers. These preliminary findings suggest lithium may slow disease progression, though the sample size was limited (3 of 4 patients receiving MRIs)[@guttuso2023].

Intervention

Treatment Arm (Lithium)

• Drug: Lithium (Dietary Supplement)
• Dose: 10mg elemental lithium per capsule
• Administration: 2 capsules daily (20mg/day total)
• Duration: 24 weeks

Placebo Arm

• Drug: Placebo
• Composition: Identical capsules filled with cellulose
• Administration: 2 capsules daily
• Duration: 24 weeks

Outcome Measures

Primary Outcomes

| Measure | Description | Timeframe |
|---------|-------------|-----------|
| MRI-derived free water (FW) levels | FW in posterior substantia nigra (pSN), dorsomedial nucleus of the thalamus (DMN-T), and nucleus basalis of Meynert (nbM) | Change from baseline to 24 weeks |
| PBMC Nurr1 mRNA expression | Peripheral blood mononuclear cell nuclear receptor-related 1 protein (Nurr1) expression using Taqman PCR | Change from baseline to 24 weeks |
| Serum neurofilament light chain (NfL) | Assessed using SIMOA platform by Quanterix | Change from baseline to 24 weeks |

Secondary Outcomes

| Measure | Description | Timeframe |
|---------|-------------|-----------|
| PBMC SOD-1 mRNA expression | Superoxide dismutase type-1 expression using Taqman PCR | Change from baseline to 24 weeks |
| PBMC pS9/total GSK-3β ratio | Glycogen synthase kinase-3β phosphorylation ratio (ELISA) | Change from baseline to 24 weeks |
| PBMC pThr308 and pS473/total Akt ratios | Protein kinase B phosphorylation ratios (ELISA) | Change from baseline to 24 weeks |
| Serum interleukin-6 | Pro-inflammatory cytokine (ELISA) | Change from baseline to 24 weeks |
| Serum GFAP | Glial fibrillary acidic protein (SIMOA platform) | Change from baseline to 24 weeks |
| MDS-UPDRS Part III | Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Motor Examination (score 0-132, higher = worse) | Change from baseline to 24 weeks |
| MoCA | Montreal Cognitive Assessment (score 0-30, higher = better) | Change from baseline to 24 weeks |
| Parkinson's Anxiety Scale | Score 0-48, higher = worse | Change from baseline to 24 weeks |
| Geriatric Depression Scale-15 | Score 0-15, higher = worse | Change from baseline to 24 weeks |
| Fatigue Severity Scale | Score 9-63, higher = worse | Change from baseline to 24 weeks |
| Insomnia Severity Index | Score 0-28, higher = worse | Change from baseline to 24 weeks |
| PDQ-8 | Parkinson's Disease Questionnaire-8 (score 0-32, higher = worse) | Change from baseline to 24 weeks |
| LEDD | Levodopa equivalent daily dose | Change from baseline to 24 weeks |

Other Outcomes

• Adverse events: Number of patients with any and serious adverse events, and withdrawals throughout the 24-week study

Eligibility Criteria

Inclusion Criteria

• Diagnosed with Parkinson's disease by a movement disorder specialist
• PD duration less than 4 years
• Normal thyroid and renal function at screening
• No previous lithium therapy
• No history of brain surgery
• No brain imaging findings suggesting another neurological condition besides PD
• No tobacco or THC product use for more than 1 year
• Stable PD medications for more than 30 days without current need for adjustments
• Stable psychiatric and diuretic medications for more than 60 days with no anticipated changes for at least 24 weeks
• No active medical or psychiatric condition that may interfere with study procedures

Exclusion Criteria

• PD duration greater than 4 years
• Abnormal thyroid or renal function at screening
• Previous lithium therapy
• History of brain surgery
• Brain imaging findings suggesting another neurological condition besides PD
• Tobacco or THC use within the past year
• PD medication adjustments within 30 days or anticipated need for adjustments
• Psychiatric or diuretic medication changes within the last 60 days or anticipated changes over 24 weeks
• Active medical or psychiatric condition that may interfere with study procedures

Demographics

• Sex: All
• Minimum Age: 40 years
• Maximum Age: 80 years
• Healthy Volunteers: No

Mechanism of Action

Lithium may exert disease-modifying effects in Parkinson's disease through multiple mechanisms:

Neurotrophic Effects

• Nurr1 activation: Lithium increases expression of Nurr1 (Nuclear Receptor-Related 1 protein), a transcription factor critical for dopaminergic neuron survival and function
• BDNF modulation: May enhance brain-derived neurotrophic factor signaling

Anti-inflammatory Effects

• IL-6 modulation: Reduces pro-inflammatory interleukin-6 levels
• Microglial regulation: May decrease microglial activation in the substantia nigra
• GFAP reduction: Lowers glial fibrillary acidic protein, a marker of astrocyte activation

Neuroprotective Signaling

• GSK-3β inhibition: Lithium inhibits glycogen synthase kinase-3β, a kinase implicated in tau phosphorylation and alpha-synuclein toxicity
• Akt activation: Enhances Akt signaling, promoting cell survival
• SOD-1 modulation: Affects superoxide dismutase-1 expression, potentially reducing oxidative stress

Biomarker Rationale

Free water MRI: The free water imaging technique measures extracellular water in the substantia nigra, which increases as dopaminergic neurons degenerate. Changes in free water may serve as an early marker of neuronal loss.

NfL (Neurofilament Light Chain): A blood biomarker indicating neuronal damage. Lower NfL levels suggest reduced neurodegeneration.

Scientific Context

Lithium in Neurodegeneration

Lithium has been studied extensively in Alzheimer's disease and other neurodegenerative conditions. Its mechanisms include:

• GSK-3β inhibition
• Anti-apoptotic effects
• Autophagy promotion
• Neurotrophic factor modulation

Why Low-Dose Lithium?

The 20mg/day dose used in this trial is significantly lower than doses used for bipolar disorder (typically 600-1200mg/day). This low-dose approach:

• Minimizes side effects
• Maintains neuroprotective mechanisms without mood effects
• Represents a paradigm of drug repurposing for disease modification

References