Tracking longitudinal change in presymptomatic genetic prion disease (TLC-Pre-gPrD)

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Project Summary/Abstract The main goal of this project is to identify and develop biomarkers for treatment trials in presymptomatic genetic prion disease (PreSx gPrD). Most PrDs are potentially transmissible and rapidly progressive; all are fatal. As has been shown in a related disorder, Alzheimer’s disease, it is critical to develop early detection methods and biomarkers so that potential treatments can be given in early pre-presymptomatic (pre-clinical) phases when they have the best chance of working. Approximately 15% of human prion diseases (PrDs) are genetic, caused by mutations in the prion protein gene, PRNP. Because a simple genetic blood test can identify PRNP mutation carriers from families with gPrD, we can identify those with mutations prior to their developing symptoms (presymptomatic; PreSx); this group is an ideal target for therapeutic trials, to delay or even prevent, clinical onset. Similar methods are being used in autosomal dominant forms of genetic Alzheimer’s disease, such as with the Alzheimer’s Disease Prevention Initiative (API) and the Dominantly Inherited Alzheimer’s Disease Network (DIAN) studies. Therapies for PrD are currently under development, but to prepare for these trials it is necessary to identify markers sensitive to biological changes in pre-clinical stages, when symptoms have not yet developed. Our preliminary data suggest that such biological changes (biomarkers) can be measured in PreSx gPrDs and include brain volume, MRI mean diffusivity, cognitive & quantified motor assessments, retinal layer thickness and possibly CSF and plasma proteins. Over five years, we will recruit ~80 PreSx gPrD mutation carriers and ~40 age & gender-matched controls without PRNP mutations (non-carriers) from gPrD families. Subjects will have serial annual visits, for at least three years, that include: neurological exam, neuropsychological testing, functional scores, blood and CSF collection, olfactory mucosal swabbings, skin biopsies, brain MRI, and optical coherence tomography. We will establish rates of change of various biomarkers in PreSx mutation carriers vs. controls, to determine the best outcome measures for PreSx gPrD treatment trials. Our aims are: Aim 1. Characterize the rates of biomarker change in PreSx Slow-gPrD. We hypothesize that, compared with controls, PreSx Slow-gPrD will show greater rates of: A) cortical MD elevation, B) decline on quantitative motor testing, & C) decline in processing speed. Aim 2. Characterize the rates of biomarker change in PreSx Fast-gPrD. We hypothesize that, compared with controls, PreSx Fast-gPrD will show great rates of: A) deep nuclei (putaminal) MD reduction, B) Greater rates of decline on quantified motor testing, & C) decline in processing speed Exploratory Aims. A) We hypothesize that subjects with positive RT-QuIC assays will have more rapid imaging and clinical changes than RT-QuIC negative subjects. B) Fast and Slow PreSx gPrD will have greater rates of 1. elevation of certain CSF & serum biomarkers, 2. cognitive & motor decline, and 3. cortical volume loss, whereas only PreSx Slow gPrD will have a greater rate of decline in INL thickness, than controls.