New approaches for the quantification and targeting of noradrenergic dysfunction in Alzheimer’s disease
File(s)
Accepted version
Author(s)
David, Michael
Malhotra, Paresh
Type
Journal Article
Abstract
There is clear, early noradrenergic dysfunction in Alzheimer’s disease. This is likely secondary to pathological tau deposition in the locus coeruleus, the pontine nucleus that produces and releases noradrenaline, prior to involvement of cortical brain regions. Disruption of noradrenergic pathways affects cognition, especially attention, impacting memory and broader functioning. Additionally, it leads to autonomic and neuropsychiatric symptoms.
Despite the strong evidence of noradrenergic involvement in Alzheimer’s, there are no clear trial data supporting the clinical use of any noradrenergic treatments. Several approaches have been tried, including proof-of-principle studies and (mostly small scale) randomised controlled trials. Treatments have included pharmacotherapies as well as stimulation. The lack of clear positive findings is likely secondary to limitations in gauging locus coeruleus integrity and dysfunction at an individual level. However, the recent development of several novel biomarkers holds potential and should allow quantification of dysfunction. This may then inform inclusion criteria and stratification for future trials. Imaging approaches have improved greatly following the development of neuromelanin-sensitive sequences, enabling the use of structural MRI to estimate locus coeruleus integrity. Additionally, functional MRI scanning has the potential to quantify network dysfunction. As well as neuroimaging, EEG, fluid biomarkers and pupillometry techniques may prove useful in assessing noradrenergic tone.
Here we review the development of these biomarkers and how they might augment clinical studies, particularly randomised trials, through identification of patients most likely to benefit from treatment. We outline the biomarkers with most potential, and how they may transform symptomatic therapy for people living with Alzheimer’s disease.
Despite the strong evidence of noradrenergic involvement in Alzheimer’s, there are no clear trial data supporting the clinical use of any noradrenergic treatments. Several approaches have been tried, including proof-of-principle studies and (mostly small scale) randomised controlled trials. Treatments have included pharmacotherapies as well as stimulation. The lack of clear positive findings is likely secondary to limitations in gauging locus coeruleus integrity and dysfunction at an individual level. However, the recent development of several novel biomarkers holds potential and should allow quantification of dysfunction. This may then inform inclusion criteria and stratification for future trials. Imaging approaches have improved greatly following the development of neuromelanin-sensitive sequences, enabling the use of structural MRI to estimate locus coeruleus integrity. Additionally, functional MRI scanning has the potential to quantify network dysfunction. As well as neuroimaging, EEG, fluid biomarkers and pupillometry techniques may prove useful in assessing noradrenergic tone.
Here we review the development of these biomarkers and how they might augment clinical studies, particularly randomised trials, through identification of patients most likely to benefit from treatment. We outline the biomarkers with most potential, and how they may transform symptomatic therapy for people living with Alzheimer’s disease.
Date Acceptance
2022-02-25
Citation
Annals of Clinical and Translational Neurology, 9 (4)
ISSN
2328-9503
Publisher
Wiley Open Access
Journal / Book Title
Annals of Clinical and Translational Neurology
Volume
9
Issue
4
Copyright Statement
© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Sponsor
Medical Research Council (MRC)
Identifier
https://onlinelibrary.wiley.com/doi/10.1002/acn3.51539
Grant Number
MR/W016095/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences
Neurosciences & Neurology
VAGUS NERVE-STIMULATION
LOCUS-COERULEUS ACTIVITY
FUNCTIONAL CONNECTIVITY
PUPIL DIAMETER
ELECTROENCEPHALOGRAPHIC ACTIVITY
SUBSTANTIA-NIGRA
EMOTIONAL MEMORY
ADAPTIVE GAIN
BRAIN-STEM
OLD-AGE
Alzheimer Disease
Biomarkers
Humans
Locus Coeruleus
Magnetic Resonance Imaging
Norepinephrine
Locus Coeruleus
Humans
Alzheimer Disease
Norepinephrine
Magnetic Resonance Imaging
Biomarkers
1103 Clinical Sciences
1109 Neurosciences
Publication Status
Published