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...