# Depression and accelerated brain aging: A PET imaging study

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $1,159,114

## Abstract

PROJECT SUMMARY: Normal aging slowly affects the brain via alterations in synaptic transmission and
plasticity through various processes including changes in dendritic spine morphologies and loss of synaptic
proteins. Major depressive disorder (MDD) is the most prevalent and disabling psychiatric disorder worldwide
and is associated with reduced synaptic signaling proteins, such as presynaptic neurotransmitter vesicle-
associated proteins and postsynaptic structural and functional proteins. Converging evidence from human
clinical and postmortem studies, and preclinical work suggests that depression may accelerate brain aging, as
evidenced by neuronal atrophy, and reduced synaptic and synaptic vesicle protein densities, and vesicle
trafficking and growth, particularly in the hippocampus (HIP) and dorsolateral prefrontal cortex (dlPFC), and
may thus represent a prodrome to dementia. In animal and postmortem work, changes in synaptic density
have been robustly evaluated via quantification of synaptic vesicle proteins. In vivo quantification of synaptic
density in humans was recently made possible with the development of a novel radioligand 11C-UCB-J, which
quantifies the density of synaptic vesicle glycoprotein 2A (SV2A), a ubiquitously expressed marker of synaptic
density, using positron emission tomography (PET) imaging. In this study, we will conduct the first known in
vivo human examination of whether MDD may accelerate synaptic aging over a 25-year span (ages 40-65), as
well as how MDD-related changes in synaptic density relate to cognitive functioning and the heterogeneous
clinical presentation of this disorder. Our preliminary data from a large normative sample of healthy adults
suggest a systematic age-related decline in synaptic density in the HIP and dlPFC, which becomes more
pronounced as a function of increasing age. They further reveal a substantially more pronounced decline in
synaptic density in the HIP and dlPFC in individuals with MDD compared to age-matched healthy controls. In
the proposed study, we will employ a novel accelerated longitudinal design that builds on these initial results by
evaluating whether MDD accelerates synaptic aging by examining in vivo changes in synaptic density in the
HIP and dlPFC compared to healthy controls across the middle-to-older age spectrum. We will also evaluate
how synaptic density in these brain regions relates to the endophenotypic and phenotypic expression of MDD
using state-of-the-art objective laboratory, structured clinical interview, and neuropsychological measures.
Results of the proposed study will provide the first human in vivo data on the role of MDD as a potential
accelerator of synaptic aging, as well as the effect of MDD-related changes in synaptic density on the clinical
expression of this multi-faceted disorder. They will also inform pathophysiologic models of how MDD
contributes to synaptic aging, and yield new insight into a novel “upstream” mechanism-based target for
therapi...

## Key facts

- **NIH application ID:** 10001643
- **Project number:** 5R01MH118728-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Irina Esterlis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,159,114
- **Award type:** 5
- **Project period:** 2019-08-23 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001643

## Citation

> US National Institutes of Health, RePORTER application 10001643, Depression and accelerated brain aging: A PET imaging study (5R01MH118728-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001643. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*