Neuroimaging Markers of Spreading Frontotemporal Degeneration Pathology

Lay Summary

Imaging how degeneration spreads in the brain of young-onset dementia to aid clinical trials

Investigators will use MRI imaging techniques to determine which of two proposed pathways young-onset degenerative diseases use to spread in the brain, and to identify key brain changes (biomarkers) that can be used to see if experimental therapies arrest disease progression.

When young-onset dementia, a degenerative disease that can occur in a person’s 50’s, affects the brain’s frontal and temporal regions it is called “frontotemporal lobar degeneration” (FTLD). Patients with these diseases often develop behavioral problems and relentless declines in language and some motor skills. The most common of these FTLD diseases is frontotemporal dementia. Patients are apathetic, lose empathy, have inappropriate behaviors, and they have problems with language, such as finding the right words or being able to portray their thoughts correctly in sentences. Other FTLD diseases include progressive supranuclear palsy, which produces balance and visual focus problems in addition to the behavioral alterations; amyotrophic lateral sclerosis (ALS or “Lou Gehrig’s disease”) occurring with frontotemporal dementia; and two specific types of aphasias (problems understanding or using language).

Unlike Alzheimer’s disease, which is associated with several brain factors, FTLD diseases arise only with a malfunction of a single protein. Some FTLD diseases involve abnormal accumulations of the protein called “TDP-43.” Others result when a protein called “Tau” misfolds in brain cells and induces Tau in nearby brain cells to similarly misfold, eventually blocking cellular communication and causing cells to die. For each FTLD disease, knowing where the protein problem originates in the brain, how the ensuing degenerative process spreads in the brain, and whether these patterns differ among FTLD diseases should substantially improve the ability to develop therapies that can arrest disease progression.

Each FTLD disease probably starts at an “epicenter” (single place) in the brain rather than in multiple centers, according to these investigators who care for large numbers of FTLD patients. That is their first hypothesis. The question is: how does degeneration spread in the brain? The investigators hypothesize that FTLD diseases spread cell-to-cell to adjacent areas in the brain, termed the “trans-neuronal model,” rather than spreading to various neural networks that are highly active, called the “Hub” model of disease spread.

First, they will use statistical modeling techniques to conduct proof-of-concept research in autopsied brain tissue from each FTLD disease type to test their hypothesis that each FTLD disease starts at an epicenter. Then, in a total of 300 patients, each with one of the FTLD diseases, they will use statistical modeling and imaging repeatedly over time to see how degeneration is spreading. They will use MRI imaging of the brain’s grey matter (brain cells) to see if changes are occurring in networks that are adjacent to one another rather than in highly active networks that may be far apart. Similarly, they will use DTI (diffusion-tensor) imaging in the brain’s white matter to see whether or not changes there are occurring in adjacent areas. If imaging shows that degeneration is spreading locally, from cell-to-cell in FTLD diseases, and that certain changes in white matter and grey matter are particularly associated with disease progression, the study will have identified biomarkers of disease progression. Clinical trials of experimental therapies then can use imaging of these biomarkers to assess whether experimental therapies are having an effect on arresting disease progression.

Significance: If biomarkers—key brain changes associated with disease progression—are found, clinical investigators can use imaging during clinical trials to determine early on whether specific experimental therapies are helping to arrest degeneration in FTLD diseases.