Researchers from Johns Hopkins Medicine have found that relatively lower levels of serotonin in certain brain regions of adults with mild cognitive impairment (MCI) may contribute to memory issues, including Alzheimer’s disease. The results come from comparing PET scans of over ninety adults with and without MCI.
These results add credence to mounting evidence that detectable brain alterations occur in individuals with mild memory impairments well before an Alzheimer’s diagnosis, and they may provide new targets for therapeutic interventions aimed at slowing or halting the disease’s progression.
“The study shows that people with mild cognitive impairment already display loss of the serotonin transporter. This measure that reflects serotonin degeneration is associated with problems with memory, even when we take into account in our statistical model MRI measures of neurodegeneration and PET measures of the amyloid protein that are associated with Alzheimer’s Disease,”
said Gwenn Smith, Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.
Reduced Serotonin Transporter Levels
The Hopkins researchers gathered 45 healthy adults 55 years of age and above and 49 MCI volunteers for the study. The participants underwent two PET scans and an MRI to determine changes in brain structure, as well as an MRI at Johns Hopkins between 2009 and 2022.
The researchers used PET scans to examine the serotonin transporter — a neurotransmitter or brain chemical traditionally associated with positive mood, hunger, and sleep — as well as the distribution of amyloid-beta protein in the brain. Amyloid-beta is hypothesized to be important in the pathogenesis of Alzheimer’s disease.
Studies in mice done at Johns Hopkins have shown that serotonin degeneration occurs before the development of widespread beta-amyloid deposits in the brain. Loss of serotonin is often associated with depression, anxiety, and psychological disorders.
Researchers found that MCI patients had lower levels of the serotonin transporter and higher levels of Aβ than healthy controls.
Antidepressant Therapy
In cortical and limbic regions, patients with mild cognitive impairment exhibited up to 25% lower serotonin transporter levels than healthy controls. Lower serotonin transporter levels were detected in cortical, limbic, and subcortical brain regions of MCI patients, areas specifically responsible for executive function, emotion, and memory.
“The correlation we observed between lower serotonin transporters and memory problems in MCI is important because we may have identified a brain chemical that we can safely target that may improve cognitive deficits and, potentially, depressive symptoms,”
said Smith.
Recently developed antidepressant medications may be an effective way to improve memory deficits and depressive symptoms and, if successful, may be a powerful way to slow the progression of the disease. This is especially true if researchers can demonstrate that serotonin loss over time is directly involved in the transition from MCI to AD.
Mild Cognitive Impairment
Mild cognitive impairment is the diagnostic stage that occurs between normal aging brain function and Alzheimer’s Disease (AD). MCI symptoms include frequent amnesia of recent events, trouble finding words, and loss of sense of smell.
Those with MCI may stay in this stage indefinitely or progress to more severe forms of cognitive deficits, giving urgency to the search for predictive markers and possible early prevention interventions, investigators say.
The researchers emphasized that their study found a link between reduced serotonin transporter levels and memory impairments in MCI but did not prove causation or the role of serotonin in the development from MCI to AD. Further research is needed to resolve these questions by studying healthy controls and persons with MCI over time to illustrate the function of serotonin in illness progression.
Researchers say future studies include longitudinal follow-up of individuals with MCI to compare serotonin degeneration to the increase in Aβ levels, as well as the increase in levels of the Tau protein that is also associated with AD compared to healthy adults. They are also studying multi-modal antidepressant drugs to treat depression and memory deficits in hopes of mitigating and halting symptoms.
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.
Reference:
- Smith, Gwenn S. et al. Serotonin Degeneration and Amyloid-β Deposition in Mild Cognitive Impairment: Relationship to Cognitive Deficits. Journal of Alzheimer’s Disease, 1 Jan. 2023 : 215 – 227