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

Article type: Research Article

Authors: Smith, Gwenn S.^{a; b; *} | Kuwabara, Hiroto^b | Yan, Haijuan^a | Nassery, Najlla^c | Yoon, Mark^a | Kamath, Vidya^a | Kraut, Michael^d | Gould, Neda F.^a | Savonenko, Alena^e | Coughlin, Jennifer M.^{a; b} | Lodge, Martin^b | Pomper, Martin G.^{a; b} | Nandi, Ayon^b | Holt, Daniel^b | Dannals, Robert F.^b | Leoutsakos, Jeannie M.^{a; f}

Affiliations: [a] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [b] Division of Nuclear Medicine and Molecular Imaging, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [c] Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [d] Division of Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA | [e] Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, USA | [f] Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

Correspondence: [*] Correspondence to: Gwenn S. Smith, PhD, Richman Family Professor of Alzheimer’s and Related Dementias, Department of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry 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.

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.

Keywords: Aging, Alzheimer’s disease, amyloid-β, mild cognitive impairment, positron emission tomography, serotonin transporter

DOI: 10.3233/JAD-230570

Journal: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 215-227, 2023