Recruitment, Retainment, and Biomarkers of Response; A Pilot Trial of Lithium in Humans With Mild Cognitive Impairment.

Ashleigh Duthie,Cara Macdonald,Jennifer Gallagher,Alison Mcneilly,Simon Lovestone,Calum Sutherland,John Geddes,Lidy Van Aalten

doi:10.3389/fnmol.2019.00163

Abstract

Lithium has been used for decades to treat Bipolar Disorder. Some of its therapeutic benefits may be through inhibition of Glycogen Synthase Kinase (GSK)-3. Enhanced GSK3 activity associates with development of Alzheimer’s disease (AD), therefore lithium is a currently used therapeutic with potential to be repurposed for prevention of Dementia. An important step toward a clinical trial for AD prevention using lithium is to establish the dose of lithium that blocks GSK3 in Mild Cognitive Impairment (MCI), a high-risk condition for progression to AD. We investigated volunteer recruitment, retention, and tolerance in this population, and assessed biomarkers of GSK3 in MCI compared to control and after lithium treatment. Recruitment was close to target, with higher than anticipated interest. Drop out was not related to lithium blood concentration. Indeed, 33% of the withdrawals were in the first week of very low dose lithium. Most made it through to the highest dose of lithium with no adverse events. We analyzed 18 potential biomarkers of GSK3 biology in rat PBMCs, but only four of these gave a robust reproducible baseline signal. The only biomarker that was modified by acute lithium injection in the rat was the inhibitory phosphorylation of Ser9 of GSK3beta (enhanced in PBMCs) and this associated with reduced activity of GSK3beta. In contrast to the rat PBMC preparations the protein quality of the human PBMC preparations was extremely variable. There was no difference between GSK3 biomarkers in MCI and control PBMC preparations and no significant effect of chronic lithium on the robust GSK3 biomarkers, indicating that the dose reached may not be sufficient to modify these markers. In summary, the high interest from the MCI population, and the lack of any adverse events, suggest that it would be relatively straightforward and safe to recruit to a larger clinical trial within this dosing regimen. However, it is clear that we will need an improved PBMC isolation process along with more robust, sensitive, and validated biomarkers of GSK3 function, in order to use GSK3 pathway regulation in human PBMC preparations as a biomarker of GSK3 inhibitor efficacy, within a clinical trial setting.

Highlights

The pharmacological treatment of Dementia is limited to the treatment of symptoms, primarily due to the ever increasing number of failed clinical trials (Hardy, 2009; Wang et al, 2016; Amanatkar et al, 2017), while the paucity of non-amyloid targeting drugs in development is highly concerning (Cummings et al, 2017)
The study had several research goals, firstly to validate which of the numerous potential biomarkers of Glycogen Synthase Kinase-3 (GSK3) biology could be detected in Peripheral Blood Mononuclear cells (PBMCs), secondly to establish whether expression of these detectable biomarkers was affected by a diagnosis of Mild Cognitive Impairment (MCI), thirdly, to investigate whether expression of these biomarkers was modified by treatment with lithium, at a dose up to that used to treat Bipolar disorder, and to add to the growing information on tolerance of lithium in the MCI population
There are a host of potential biomarkers for GSK3 function in cells and tissues, none are, in themselves, ideal for accurate and complete assessment of GSK3 activity

Summary

Introduction

The pharmacological treatment of Dementia is limited to the treatment of symptoms, primarily due to the ever increasing number of failed clinical trials (Hardy, 2009; Wang et al, 2016; Amanatkar et al, 2017), while the paucity of non-amyloid targeting drugs in development is highly concerning (Cummings et al, 2017). GSK3 activation is directly linked to the development of cognitive impairment independent of AD pathology (King et al, 2013). This implies that GSK3 inhibition could have clinical benefits from early stage development right through to late stage disease. The wide spectrum of important biological actions influenced by GSK3 activity has questioned the clinical safety of a global GSK3 inhibition approach, especially as genetic ablation of GSK3 has serious health implications including disruption of brain development and repair (Jiang et al, 2005; Kim et al, 2009). GSK3 in human dementia is related to abnormally high GSK3 activity in adults, and no GSK3 inhibitor toxicology studies have been reported in an adult preclinical model with excessive GSK3 activity

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