Familial frontotemporal lobar degeneration (f-FTLD) represents a critical group to target for clinical trials in FTLD. F-FTLD accounts for 30 to 50% of all FTLD. Three mutations account for the majority of known mutations that cause f-FTLD. Mutations in the tau gene (MAPT) lead to FTLD-tau pathology, and mutations in the progranulin (GRN) or chromosome 9 open reading frame 72 (C90RF72 ) genes both lead to TDP-43 proteinopathy. Because each mutation is highly predictive of the underlying proteinopathy, clinical trials of new therapies directed at these specific biochemical targets would be guaranteed a homogeneous population if they focused on f-FTLD. In addition, f-FTLD is the only context in which patients affected by FTLD can be identified in the presymptomatic and early symptomatic stages, which are becomign increasingly important in models of treatment for neurodegenerative disease. However, little is known about the natural history of presymptomatic f-FTLD. The proposed study will quantify rates of clinical decline in both symptomatic and presymptomatic f-FTLD and examine rates of brain MR imaging changes in presymptomatic individuals. We will enroll 455 asymptomatic individuals age 30 or older from families with a known FTLD-causative mutation and anticipate that approximately half will be mutation carriers, as well as 455 symptomatic individuals. Clinical assessments including cognitive testing and functional evaluations will be performed at baseline and one year in all participants. In asymtomatic patients, we will obtain T1-MR1 (and additional imaging sequences) at baseline and one year.
The Aims for the project are: 1. To establish the magnitude and variance across subjects of clinical decline over one year in symptomatic (CDR>=0.5) f- FTLD due to known mutations, 2. To examine the relationship between medical comorbidities, lifestyle factors and natural history in f-FTLD, and 3. To establish the magnitude and variance across subjects of changes in imaging and clinical measures in presymptomatic (CDR=0) f-FTLD. Accomplishment of these Aims will provide much needed data for planning clinical trials in f-FTLD.

Public Health Relevance

A substantial portion of FTLD is caused by specific mutations that have already been identified, allowing researchers to know the biological mechanism leading to brain disease in such patients (familial FTLD, or f-FTLD). F-FTLD patients are a very important group for enrollment in clinical trials. To prepare for these trials, this project will quantify change over one year in f-FTLD using cognitive testing and imaging.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZTR1-CI-8 (01))
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Sutherland, Margaret L
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University of California San Francisco
San Francisco
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