Neuroimaging Markers of Spreading Frontotemporal Degeneration Pathology

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

Corey McMillan, Ph.D.

University of Pennsylvania

Funded in September, 2015: $200000 for 3 years


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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.   


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A defining characteristic of neurodegenerative diseases is their progressive nature. While seminal neuropathological studies provide “gold-standard” evidence of progressive neurodegeneration, these assessments only provide end-stage observations that cannot directly assess the trajectory of disease progression. In contrast, in vivo neuroimaging has the potential to monitor spreading disease longitudinally in human individuals throughout the disease course. This project specifically focuses on disease progression in frontotemporal lobar degeneration (FTLD), a progressive neurodegenerative form of young onset dementia. FTLD is pathologically characterized by either misfolded tau proteins (FTLD-tau) or inclusions of TAR DNA binding protein (FTLD-TDP). FTLD is clinically heterogeneous, including syndromes more commonly associated with FTLD-tau such as corticobasal syndrome, progressive supranuclear palsy, and nonfluent/agrammatic variant of primary progressive aphasia and syndromes more commonly associated with FTLD-TDP including amyotrophic lateral sclerosis with FTD and semantic variant of primary progressive aphasia (svPPA). However, the most common FTLD syndrome, behavioral variant frontotemporal dementia (bvFTD), is equally likely caused by FTLD-tau or FTLD-TDP and therefore clinical biomarkers must take into account the pathological source of disease. This proposal will use MRI and DTI neuroimaging to evaluate disease progression in pathological forms of FTLD in whole group and clinically-stratified analyses to test two competing models of pathological spread in neurodegenerative disease. The “hub” theory proposes that the amount of disease in a region is proportional to its metabolic demand and that disease first emerges in critical hub regions that are vulnerable to pathology. The “trans-neuronal spread” model implicates prion-like cell-to-cell spreading disease involving neurons and glia in FTLD spectrum pathology. To address the timely and clinical need to understand the progression of pathology in FTLD I propose three specific aims: (1) retrospective proof-of-concept “staging” of GM and WM neuroimaging in FTLD-tau and FTLD-TDP; (2) prospective longitudinal assessment of GM and WM; and (3) connectome and graph theoretic analysis of integrated GM and WM. Together, these aims will establish converging sources of in vivo neuroimaging evidence to elucidate our understanding of the transmission of neurodegenerative disease, provide prognostic markers to improve the treatment of these devastating diseases, and establish robust endpoint biomarkers for emerging clinical trials of disease-modifying agents.


Anatomy: Frontal lobe
Gray matter

White matter
Conditions: Dementia

Neurodegenerative disease
Development: Age, effects of
Technology: Diffusion tensor imaging