# AD-specific changes in the MTL: Novel biomarkers using in vivo / ex vivo imaging

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $682,315

## Abstract

Alzheimer's disease (AD) is one of the greatest challenges facing our society. Finding a cure will almost
certainly require gaining a better understanding of the biological mechanisms that cause AD and distinguishing
their effects from aging and commonly comorbid non-AD pathologies. Furthermore, drug trials in AD can
benefit from more powerful biomarkers, particularly biomarkers that can better identify individuals who have
incipient preclinical AD pathology and are likely to progress to the active neurodegenerative phase of AD in a
short timeframe, as well as biomarkers that can act as surrogate measures of outcome by measuring the
effects of a drug on subtle changes in the brain's structural integrity. This project will address these challenges
by focusing on the medial temporal lobe (MTL), the area of the brain where the earliest AD-related neuronal
injury occurs. The project will use a combination of ex vivo and in vivo imaging, including ex vivo and in vivo
imaging in the same subjects, to characterize the effects of AD and non-AD pathology on the MTL and to
identify “hot spots” in the MTL where changes observable on in vivo MRI are specific to AD pathology. Novel
biomarkers of AD that leverage this information will be developed and evaluated using the recently funded
Phase 3 of the Alzheimer's Disease Neuroimaging Initiative (ADNI3).
Aim 1 will image 80 intact MTL autopsy specimens using ultra high-resolution 9.4 Tesla MRI and serial
histological imaging with immunohistochemical staining for tau, beta-amyloid, TDP43, and alpha-synuclein
pathologies. Brains from these autopsies will also be assessed for evidence of cerebrovascular disease.
Histology data will be co-registered to the MRI, and MRI of all specimens will be co-registered to a novel ex
vivo MRI template. Statistical mapping in the template space will be used to describe spatial distributions of AD
and non-AD pathologies, to characterize the morphological effects of these pathologies, and to identify regions
of the MTL where changes in structural integrity (i.e., gray matter thickness) specifically correlate with AD
pathology. Aim 2 will extend prior work on automatic multi-atlas segmentation and quantification of MTL
subregions in high-resolution T2-weighted in vivo MRI scans of the MTL with a novel atlas that combines ex
vivo and in vivo imaging in the same subjects (n=40). This unique in vivo/ex vivo dataset will allow histological
validation of MTL subregion segmentation protocols and algorithms, but will also serve as a conduit for
mapping distributions of pathology and other rich information defined in the ex vivo template in Aim 1 into the
space of in vivo imaging. Aim 3 will develop in vivo imaging biomarkers based on the cross-sectional and
longitudinal analysis of high-resolution T2-weighted in vivo MRI. These biomarkers will incorporate information
on the patterns of AD and non-AD pathology in the MTL derived in Aim 1. The proposed biomarkers will be
evaluated using hig...

## Key facts

- **NIH application ID:** 10144342
- **Project number:** 5R01AG056014-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Paul A. Yushkevich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $682,315
- **Award type:** 5
- **Project period:** 2017-05-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10144342

## Citation

> US National Institutes of Health, RePORTER application 10144342, AD-specific changes in the MTL: Novel biomarkers using in vivo / ex vivo imaging (5R01AG056014-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10144342. Licensed CC0.

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