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

Ashleigh Duthie, Lidy van Aalten, Cara MacDonald, Alison McNeilly, Jennifer Gallagher, John Geddes, Simon Lovestone, Calum Sutherland (Lead / Corresponding author)

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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.

Original languageEnglish
Article number163
Pages (from-to)1-16
Number of pages16
JournalFrontiers in Molecular Neuroscience
Volume12
DOIs
Publication statusPublished - 28 Jun 2019

Fingerprint

Lithium
Biomarkers
Alzheimer Disease
Clinical Trials
Cognitive Dysfunction
Glycogen Synthase Kinase 3
Bipolar Disorder
Population
Dementia
Volunteers
Therapeutics
Phosphorylation
Injections

Keywords

  • Biomarker
  • Clinical trial
  • GSK3
  • Lithium
  • Safety

Cite this

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title = "Recruitment, Retainment, and Biomarkers of Response: A Pilot Trial of Lithium in Humans With Mild Cognitive Impairment",
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.",
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Recruitment, Retainment, and Biomarkers of Response : A Pilot Trial of Lithium in Humans With Mild Cognitive Impairment. / Duthie, Ashleigh; van Aalten, Lidy; MacDonald, Cara ; McNeilly, Alison; Gallagher, Jennifer; Geddes, John ; Lovestone, Simon ; Sutherland, Calum (Lead / Corresponding author).

In: Frontiers in Molecular Neuroscience, Vol. 12, 163, 28.06.2019, p. 1-16.

Research output: Contribution to journalArticle

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T2 - A Pilot Trial of Lithium in Humans With Mild Cognitive Impairment

AU - Duthie, Ashleigh

AU - van Aalten, Lidy

AU - MacDonald, Cara

AU - McNeilly, Alison

AU - Gallagher, Jennifer

AU - Geddes, John

AU - Lovestone, Simon

AU - Sutherland, Calum

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