Serotonin Degeneration and Amyloid-β Deposition in Mild Cognitive Impairment: Relationship to Cognitive Deficits

Abstract

Background
Neuropathological and neuroimaging studies have demonstrated degeneration of the serotonin system in Alzheimer’s disease (AD). Neuroimaging studies have extended these observations to the preclinical stages of AD, mild cognitive impairment (MCI). Serotonin degeneration has been observed also in transgenic amyloid mouse models, prior to widespread cortical distribution of amyloid-β (Aβ).

Objective
The present study evaluated the regional distribution of the serotonin transporter (5-HTT) and of Aβ in individuals with MCI and healthy older controls, as well as the contribution of 5-HTT and Aβ to cognitive deficits.

Methods
Forty-nine MCI participants and 45 healthy older controls underwent positron emission tomography (PET) imaging of 5-HTT and Aβ, structural magnetic resonance imaging and neuropsychological assessments.

Results
Lower cortical, striatal, and limbic 5-HTT and higher cortical Aβ was observed in MCIs relative to healthy controls. Lower 5-HTT, mainly in limbic regions, was correlated with greater deficits in auditory-verbal and visual-spatial memory and semantic, not phonemic fluency. Higher cortical A β was associated with greater deficits in auditory-verbal and visual-spatial memory and in semantic, not phonemic fluency. When modeling the association between cognition, gray matter volumes and Aβ, inclusion of 5-HTT in limbic and in select cortical regions significantly improved model fit for auditory-verbal and visual-spatial memory and semantic, but not phonemic fluency.

Conclusions
These results support the role of serotonin degeneration in the memory and semantic fluency deficits observed in MCI.

Full text

Journal of Alzheimer’s Disease 96 (2023) 215–227
DOI 10.3233/JAD-230570
IOS Press
215
Serotonin Degeneration and Amyloid-␤
Deposition in Mild Cognitive Impairment:
Relationship to Cognitive Deficits
Gwenn S. Smitha,b,∗, Hiroto Kuwabarab, Haijuan Yana, Najlla Nasseryc, Mark Yoona,
Vidya Kamatha, Michael Krautd, Neda F. Goulda, Alena Savonenkoe, Jennifer M. Coughlina,b,
Martin Lodgeb, Martin G. Pompera,b, Ayon Nandib, Daniel Holtb, Robert F. Dannalsb
and Jeannie M. Leoutsakosa,f
aDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore,
MD, USA
bDivision of Nuclear Medicine and Molecular Imaging, Russell H. Morgan Department of Radiology and
Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
cDivision of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine,
Baltimore, MD, USA
dDivision of Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns
Hopkins University School of Medicine, Baltimore, MD, USA
eDepartment of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD,
USA
fDepartment of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
Handling Associate Editor: Jordi A. Matias-Guiu
Accepted 14 August 2023
Pre-press 13 September 2023
Abstract.
Background: Neuropathological and neuroimaging studies have demonstrated degeneration of the serotonin system in
Alzheimer’s disease (AD). Neuroimaging studies have extended these observations to the preclinical stages of AD, mild
cognitive impairment (MCI). Serotonin degeneration has been observed also in transgenic amyloid mouse models, prior to
widespread cortical distribution of amyloid-␤(A␤).
Objective: The present study evaluated the regional distribution of the serotonin transporter (5-HTT) and of A␤in individuals
with MCI and healthy older controls, as well as the contribution of 5-HTT and A␤to cognitive deficits.
Methods: Forty-nine MCI participants and 45 healthy older controls underwent positron emission tomography (PET) imaging
of 5-HTT and A␤, structural magnetic resonance imaging and neuropsychological assessments.
Results: Lower cortical, striatal, and limbic 5-HTT and higher cortical A␤was observed in MCIs relative to healthy controls.
Lower 5-HTT, mainly in limbic regions, was correlated with greater deficits in auditory-verbal and visual-spatial memory and
semantic, not phonemic fluency. Higher cortical A␤was associated with greater deficits in auditory-verbal and visual-spatial
memory and in semantic, not phonemic fluency. When modeling the association between cognition, gray matter volumes
and A␤, inclusion of 5-HTT in limbic and in select cortical regions significantly improved model fit for auditory-verbal and
visual-spatial memory and semantic, but not phonemic fluency.
∗Correspondence to: Gwenn S. Smith, PhD, Richman Family
Professor of Alzheimer’s and Related Dementias, Department of
Psychiatry and Behavioral Sciences, Division of Geriatric Psy-
chiatry and Neuropsychiatry, Johns Hopkins University School
of Medicine, Johns Hopkins Bayview Medical Center, 5300
Alpha Commons Drive, 4th floor, Baltimore, MD 21224, USA.
Tel.: +1 410 550 6207; Fax: +1 410 550 1407; E-mail: gsmith95@
jhmi.edu.
ISSN 1387-2877/$35.00 © 2023 – IOS Press. All rights reserved.