# Longitudinal Molecular Imaging of Neuropathology and Serotonin in Mild Cognitive Impairment

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $960,234

## Abstract

Molecular imaging methods to visualize the neuropathology of Alzheimer’s disease (AD) in vivo provide an
unprecedented opportunity to understand early stage AD by testing hypotheses informed by human
neuropathology and animal models. A fuller understanding of the neurobiology of early AD and its clinical
progression is essential to identify individuals at risk and to identify targets for prevention and treatment. To
maximize the benefit from disease-modifying therapies, individuals must be identified and treated in the early
stages, including mild cognitive impairment (MCI). Only by doing so, is it possible to prevent progressive
spreading of neuropathology and emergence of cognitive deficits and neuropsychiatric symptoms (NPS).
Multi-radiotracer PET studies of Aβ and 5-HT by the PI and colleagues in amnestic, multi-domain, MCI (aMCI-
MD) and cognitively normal elderly demonstrated progressive, cortical and limbic 5-HT degeneration over the
course of MCI, linked to network dysfunction, that was greater and more widespread than cortical Aβ, cerebral
atrophy or cerebral blood flow deficits. Cortical and limbic 5-HT degeneration was a more powerful predictor of
cross-sectional and longitudinal memory impairment than Aβ. Human data and animal models show the
synergistic effect of Tau on both Aβ and 5-HT degeneration. Tau overlaps more than Aβ with loss of 5-HT in
cortical and 5-HT-rich limbic regions, is more temporally linked to cognitive deficits and decline and is better
correlated with cognitive impairment. Thus, in vivo imaging of 5-HT combined with Tau and Aβ, may represent
a powerful predictor of cognitive decline and emergence of NPS. Lower 5-HT transporters (SERT) overlapped
to a greater extent with Tau in limbic regions than Aβ. A longitudinal molecular imaging study is proposed in
normal aging and amnestic, multi-domain, MCI (aMCI-MD) with high resolution PET scans for 5-HT transporter
availability (SERT), Tau and Aβ. To evaluate SERT, and its relationship to Tau and Aβ, in aMCI-MD and
normal controls at baseline and longitudinal follow-up. 2. To evaluate SERT, Tau and Aβ in relation to cognitive
deficits and NPS, in aMCI-MD and normal controls at baseline and longitudinal follow-up. The hypotheses will
be tested that relative to healthy controls, patients with aMCI-MD will have lower baseline and longitudinal
decreases in SERT, higher baseline and greater increases in Tau and less baseline difference and less
change over time in Aβ .Lower SERT and decreases over time, in combination with greater increases in Tau,
in contrast to increases in Aβ, will be associated with greater cognitive deficits (episodic, verbal memory) and
NPS (affective cluster) and worsening of cognition and NPS to a greater extent in aMCI-MD compared to
controls. Elucidating the role of 5-HT in relation to Tau and Aβ in cognitive decline in aMCI-MD will have
fundamental implications for the design of prevention and intervention studies targeting 5-HT, studies of other...

## Key facts

- **NIH application ID:** 9846184
- **Project number:** 5R01AG059390-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Gwenn S Smith
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $960,234
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9846184

## Citation

> US National Institutes of Health, RePORTER application 9846184, Longitudinal Molecular Imaging of Neuropathology and Serotonin in Mild Cognitive Impairment (5R01AG059390-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9846184. Licensed CC0.

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