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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT03185208
Other study ID # PRO17030527
Secondary ID R01AG055389-01
Status Active, not recruiting
Phase Phase 4
First received
Last updated
Start date September 1, 2017
Est. completion date August 31, 2024

Study information

Verified date May 2024
Source University of Pittsburgh
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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.


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).


Recruitment information / eligibility

Status Active, not recruiting
Enrollment 80
Est. completion date August 31, 2024
Est. primary completion date August 31, 2024
Accepts healthy volunteers No
Gender All
Age group 60 Years and older
Eligibility 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)

Study Design


Related Conditions & MeSH terms


Intervention

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

Locations

Country Name City State
United States University of Pittsburgh Medical Center Pittsburgh Pennsylvania

Sponsors (2)

Lead Sponsor Collaborator
Ariel Gildengers, MD National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Primary California Verbal Learning Test II Change from baseline on the California Verbal Learning Test II measured annually over 2 years. Negative change over time indicates clinical worsening of verbal memory. At baseline and annually for 2 years
Primary Brief Visuospatial Memory Test - Revised Change from baseline on the Brief Visuospatial Memory Test - Revised measured annually over 2 years. Negative change over time indicates clinical worsening of visual memory. At baseline and annually for 2 years
Primary NIH Toolbox Change from baseline on NIH Toolbox performance measured annually over 2 years. At baseline and annually for 2 years
Primary Preclinical Alzheimer Cognitive Composite composed of Memory and other cognitive tests Change from baseline cognitive testing measures over 2 years on a composite of memory, executive function, processing speed, activities of daily living, and general cognition tests. At baseline and annually for 2 years
Primary GSK-3ß activity Change from baseline values over 2 years on blood based biomarkers At baseline and annually for 2 years
Primary Brain-derived Neurotrophic Factor Change from baseline values over 2 years on blood based biomarkers At baseline and annually for 2 years
Primary Change from baseline brain volume values over 2 years as measured by structural imaging (7T MRI) Total volume, Grey & White matter volume, regional volumes At baseline and annually for 2 years
Secondary Change from baseline brain integrity measures over 2 years as measured by structural imaging (7T MRI) lower level of microbleeds, higher white matter integrity, better network connectivity At baseline and annually for 2 years
Secondary Change from baseline cerebrospinal phospho tau levels over 2 years CSF At baseline and annually for 2 years
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