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MRI of TDP-43 Mice Model of Primary Progressive Aphasia

PI: Csernansky, Wang

Summary:
Using in vivo high-field MRI, we will characterize the changes in brain architecture in a TDP-43 overexpression mouse model of PPA.

Details:
Primary progressive aphasia (PPA) is one of the most profoundly disabling dementias of late life, yet the cause of PPA remains unknown. Studies of post-mortem brain tissue have shown that PPA can be associated with neuropathological changes consistent with frontotemporal lobar degeneration (FTLD), or changes that are more typical of Alzheimer’s disease (AD). Especially among the FTLD subform of PPA, there is baffling variation in the specific types of neuropathological findings and their relationships to specific types of behavioral changes. Thus, it appears that PPA may encompass a number of different specific dementing diseases, each of which may have a unique disease mechanism. Until we understand the specific disease mechanisms that underlie this complex syndrome, specific treatments that can slow or halt PPA are not likely to be discovered.

Ubiquitin-immunoreactive neuronal inclusions composed of TAR DNA binding protein of 43-kDA (TDP-43) are a major pathological feature of the most common form of FTLD, i.e., FTLD-TDP. Such inclusions appear to be associated with the degeneration and death of neurons in the language centers of the brain. In vivo studies with TDP-43 knockout mice have also suggested that TDP-43 plays a critical, although undefined role in development. The purpose of this research is to use a strain of transgenic mice that conditionally express wild-type human TDP-43 (hTDP-43) in the forebrain, to characterize the specific mechanism by which this inclusion causes neuronal death, the pattern of brain changes that results from this inclusion, and finally, how to recognize this pattern in living patients with PPA. Using this strategy, we will be able to identify and characterize a specific subform of PPA for the first time.

Using in vivo high-field MRI, we will characterize the changes in brain architecture in a TDP-43 overexpression mouse model.