Evaluation of Lithium as a Glycogen-Synthase-Kinase-3 (GSK-3) Inhibitor in Mild Cognitive Impairment

Overview

The project is designed to generate critical information to design and justify a robust trial on lithium prevention of the onset of Alzheimer's disease (AD). Lithium exerts and inhibitory effect on Glycogen synthase kinase 3 (GSK-3) a brain biomarker of neuroprotection. The study consists of 3 phases: 1. Phase 1 investigates rats to establish a reliable method to measure brain biomarker activity levels from blood biomarker activity. 2. Phase 2 will determine whether the GSK3 enzyme activity is significantly different in subjects with MCI compared to normal individuals. 3. Phase 3 investigates patients with MCI taking lithium to establish the minimum lithium dose required to inhibit the activity of GSK-3.

Lithium has been used for decades to treat Bipolar Affective Disorder. Some of its therapeutic benefits are through the inhibition of the enzyme Glycogen Synthase Kinase-3 (GSK-3). GSK3 activity is associated with the development of several aspects of AD and thus lithium can regulate an enzyme linked to AD development. As an important step towards designing a clinical trial to investigate the potential of lithium for AD prevention the investigators propose to establish the minimum dose of lithium needed to block GSK3 in people with Mild Cognitive Impairment (MCI), a high-risk condition for progression to AD. The study will establish whether GSK3 activity is altered in MCI and monitor lithium regulation of GSK3 biomarkers in this population. At the same time the study will investigate how GSK3 measured in blood relates to GSK3 activity in the brain in a small animal study. In further preparation for a future large scale trial, this pilot study will generate technical data to develop the technique of using Magnetic Resonance Spectroscopy (MRS) as a biomarker to detect the earliest brain changes of AD. Recruitment will be shared between the two sites for this study, Dundee and Oxford. The study will involve 12 patients with MCI and 12 controls, who will be asked for two sets of blood tests, and 20 patients with MCI who consent to take Lithium who will be asked for blood tests at regular intervals. For all participants the study period is 12 weeks.