Lithium As a Treatment to Prevent Impairment of Cognition in Elders

Overview

Alzheimer's disease (AD) is the most common cause of dementia in adults 65 years and older. AD leads to a complete loss of memory and independent function, and presently there is no cure. Many studies suggest that lithium treatment may delay dementia onset or slow its progression. However, more research is needed to understand the extent of its anti-dementia properties if it will be deployed broadly in the general population. This study will examine whether lithium has anti-dementia properties in older adults who have mild cognitive impairment and are at risk of becoming demented.

Full Title of Study: “Evaluation of Brain and Cognitive Changes in Older Adults With MCI Taking Lithium to Prevent Alzheimer Type Dementia”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: March 31, 2022

Detailed Description

Alzheimer's disease (AD) is the most common cause of dementia in adults 65 years and older. Unchecked, the disease will reach epidemic proportions in the United States and worldwide by 2050, and presently, there is no intervention that has shown a clear effect on AD progression. Over the past several years, there has been increasing interest in re-purposing the use of lithium for diseases involving neurodegeneration. Lithium treatment has been associated with neurogenesis in the hippocampus, up-regulation of important neurotrophic factors such as B-cell lymphoma 2 (Bcl-2) and brain-derived neurotrophic factor (BDNF), and inhibition of glycogen synthase kinase 3 (GSK-3) isoforms α and β. In particular, GSK-3α interacts with gamma-secretase playing a critical role in the conversion of amyloid precursor protein (APP) to amyloid-beta (Aβ); lithium has been shown to reduce Aβ production and memory deficits in AD transgenic mouse models. GSK-3β phosphorylates tau, a critical step in the formation of neurofibrillary tangles, and lithium has been shown to reduce tau phosphorylation in vivo and in vitro. That lithium may alter the AD trajectory is supported by numerous observational reports showing delay of dementia onset in those treated with it. However, the results of the few human lithium trials conducted have been mixed. Additional research is needed to determine whether lithium has a role as an anti-dementia agent. In contrast to previous studies, we will implement an Randomized Controlled Trial (RCT) with a more integrative, comprehensive approach than done before involving state-of-the-art ultra-high field (7T) human Magnetic Resonance Imaging (MRI), neurocognitive assessment, and blood- and Cerebrospinal Fluid (CSF)- based biomarker measurement to investigate the role of lithium as an anti-dementia agent. The specific aim of this pilot-feasibility study is to examine the potential disease modifying properties of lithium in individuals with mild cognitive impairment (MCI) in delaying conversion to dementia. The study will enroll and randomly assign 80 individuals 60 years and older with MCI to take lithium, titrated to a maximally tolerated blood level (0.5 to 0.8 meq/L), or placebo for two years to assess lithium's effects on preserving cognition and delaying conversion to dementia. Participants will receive annual neurocognitive assessment, blood- and CSF-based biomarker measurement, and 7T MRI of structural brain volumes (e.g., hippocampal, total cortical gray). At baseline, all subjects who are able will undergo Positron Emission Tomography (PET) imaging for Aβ. The following hypotheses will be tested: H1: a) Participants randomized to take lithium for two years, compared to placebo, will better maintain cognitive function, primarily in memory, which b) will be associated with changes in biomarkers (e.g., GSK-3β, BDNF). H2: a) Participants randomized to take lithium, compared to placebo, will have larger hippocampal volumes and lower total gray matter thinning, which b) will be associated with changes in biomarkers and c) better cognitive function, primarily in memory. The exploratory aim examines whether lithium is related to additional markers of enhanced brain integrity (e.g., lower level of microbleeds, higher white matter integrity, better network connectivity, or decreased CSF phospho tau levels).

Interventions

  • Drug: Lithium Carbonate
    • See lithium carbonate arm
  • Drug: Placebo oral capsule
    • See placebo arm

Arms, Groups and Cohorts

  • Experimental: Lithium carbonate
    • Lithium carbonate will be initiated at 150 mg per day and increased based on blood levels until a steady blood level between 0.6 and 0.8 meq/L is achieved. Participants will continue at the dose achieved for 2 years with quarterly monitoring.
  • Placebo Comparator: placebo
    • Matching placebo will be initiated and increased based on pretend blood levels. Participants will take placebo for 2 years with quarterly monitoring.

Clinical Trial Outcome Measures

Primary Measures

  • Change from baseline cognitive testing measures over 2 years
    • Time Frame: At baseline and annually for 2 years
    • Preclinical Alzheimer Cognitive Composite composed of Memory and other cognitive tests
  • Change from baseline biomarker values over 2 years
    • Time Frame: At baseline and annually for 2 years
    • GSK-3β activity, BDNF
  • Change from baseline brain volume values over 2 years as measured by structural imaging (7T MRI)
    • Time Frame: At baseline and annually for 2 years
    • Total volume, Grey & White matter volume, regional volumes

Secondary Measures

  • Change from baseline brain integrity measures over 2 years as measured by structural imaging (7T MRI)
    • Time Frame: At baseline and annually for 2 years
    • lower level of microbleeds, higher white matter integrity, better network connectivity
  • Change from baseline cerebrospinal phospho tau levels over 2 years
    • Time Frame: At baseline and annually for 2 years
    • CSF

Participating in This Clinical Trial

Inclusion Criteria

1. 60 years or older

2. Diagnosis of Mild Cognitive Impairment

Exclusion Criteria

1. Major psychiatric illness (mild psychiatric illness may be included)

2. Major neurologic illness (e.g., multiple sclerosis)

3. Contraindication to lithium (e.g., renal insufficiency)

4. Unable to complete neuropsychological testing due to non-remediable impairment (e.g., blindness)

Gender Eligibility: All

Minimum Age: 60 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Ariel Gildengers, MD
  • Collaborator
    • National Institute on Aging (NIA)
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: Ariel Gildengers, MD, Associate Professor of Psychiatry – University of Pittsburgh
  • Overall Official(s)
    • Ariel Gildengers, MD, Principal Investigator, University of Pittsburgh
  • Overall Contact(s)
    • James Emanuel, 412-246-6004, emanuelje@upmc.edu

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