# Heterogeneity in FTD Clinical Trials: New Mechanisms and Measures

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $350,231

## Abstract

PROJECT SUMMARY—Heterogeneity in FTD Clinical Trials: New Mechanisms and Measures (Project 4)
Clinical trials in frontotemporal dementia (FTD) depend on robust and reliable tracking of disease over time.
Although all variants of FTD show measurable longitudinal decline, heterogeneity across FTD patients, and FTD
subtypes, poses a significant challenge for clinical trials. Rates of decline differ significantly across patients,
impacting power for trials. In addition, our group has noted that, despite fairly linear reductions in brain volume
in FTD over time, rates of clinical decline can vary dramatically across patients. One potentially important
contributor to this phenomenon is cognitive resilience (CR), which can be defined as the degree to which a
person’s clinical status remains better than predicted by measures of neurodegeneration, such as MRI. CR is a
naturally-occurring phenomenon evident in aging and several neurodegenerative diseases, yet it has been
understudied in FTD. Prior studies have identified a number of factors, including several modifiable lifestyle
behaviors, that influence CR, and preliminary data from our group and others suggest that several of these,
including sex, variation in the TEM106B gene, and exercise, may influence CR and rates of clinical decline in
FTD. A major goal of this project will be to identify the major factors, including modifiable behaviors, that influence
CR in FTD, and to create multifactor models for predicting who will decline more rapidly or slowiy, which can be
used for planning clinical trials. In addition, variation in symptom profiles across patients, even those who harbor
the same underlying proteinopathy, is another factor hindering trials in FTD. An individual affected by one of the
major FTD proteinopathies, TDP-43 or tau, can manifest behavioral, language, and/or motor symptoms. Thus,
another goal of this project will be to develop a new outcome measure, based on an approach called Goal
Attainment Scaling (GAS), for FTD clinical trials. GAS establishes individualized clinical outcomes based on
participant and caregiver ratings of the most troublesome symptoms, and is therefore ideal for trials of protein-
specific interventions that would enroll patients with a variety of clinical syndromes. To accomplish these goals,
we will leverage the baseline and longitudinal clinical, imaging, and biomarker data collected across the PPG
cores and examine the relationship between our hypothesized predictors, including genetic variants, exercise,
sleep, and vascular health, on CR over time. We will pursue the following specific aims: Aim 1. Determine the
influence of inherited and modifiable factors on CR in FTD; Aim 2. Determine the brain network physiology
associated with CR in FTD; Aim 3. Identify molecular markers that influence CR in FTD; Aim 4. Determine the
optimal combination of predictors that best account for CR in FTD; Aim 5. Develop Goal Attainment Scaling
(GAS) for FTD clinical trials. T...

## Key facts

- **NIH application ID:** 10556182
- **Project number:** 2P01AG019724-21A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** HOWARD J ROSEN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $350,231
- **Award type:** 2
- **Project period:** 2002-09-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10556182

## Citation

> US National Institutes of Health, RePORTER application 10556182, Heterogeneity in FTD Clinical Trials: New Mechanisms and Measures (2P01AG019724-21A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10556182. Licensed CC0.

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