Longitudinal multi-modality imaging in non-fluent/agrammatic primary progressive aphasia

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PROJECT SUMMARY The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) is a neurodegenerative disorder defined by the presence of agrammatic aphasia and/or apraxia of speech that commonly results from a 4- repeat tauopathy. During the previous 2 cycles of the R01 we used neuroimaging to characterize the patterns of neurodegeneration and structural and functional breakdowns in connectivity associated with nfvPPA. However, little is known about how these brain changes are related to, or driven by, underlying biological processes. Two important biological mechanisms relevant to nfvPPA are deposition of the protein tau and neuroinflammation. In the 2nd cycle of the R01 we assessed tau deposition in vivo using PET. In the 3rd cycle we will focus on assessing the role of neuroinflammation and other biological processes. The first aim of the grant is to characterize the patterns of neuroinflammation in the brain using PET imaging with the 3rd generation ligand 11C-ER176 and determine whether neuroinflammation changes over time and is associated with clinical disease severity. The second aim is to determine whether biomarkers of pathological processes measured from blood plasma, including neurofilament light chain, plasma glial fibrillary acidic protein, tau, and inflammation biomarkers, are abnormal in nfvPPA. We will also assess whether these biomarkers change over time and are associated with clinical disease severity. These first two aims will determine whether neuroinflammation PET and blood plasma biomarkers are useful disease biomarkers in nfvPPA, and we will determine whether these measures could be useful prognostic markers of future clinical decline. Our third objective is to build upon knowledge gained from the first 2 cycles and determine how structural and functional abnormalities in the brain, measured using structural MRI, diffusion tractography and resting state fMRI, are related to neuroinflammation PET and blood plasma biomarkers. This aim will help model the degree to which these biological processes relate to other more established breakdowns in brain structure and function. To accomplish these aims we will recruit 50 patients with nfvPPA, and each participant will undergo three serial assessments one year apart. At each assessment, patients will have a neurological and speech-language assessment, 11C-ER176 neuroinflammation PET and a 3T magnetic resonance imaging scan that will include resting-state functional MRI and diffusion tensor imaging sequences. A blood sample will be collected from all patients at both visits. Blood samples were also collected in the 2nd cycle of the R01 and hence blood plasma biomarkers will be measured in 100 nfvPPA patients. We will also recruit 50 cognitively normal healthy controls who will undergo identical neuroimaging and provide a blood sample. This renewal is highly significant as results gained will be critical to understand the biology of nfvPPA and mechanisms of disease spread. Furthermore, this work may also help provide potential mechanistic treatment targets for nfvPPA and establish disease biomarkers for prognosis and for future research studies and clinical trials in patients with nfvPPA.