Tammie Benzinger - US grants

Core G: Imaging Summary The imaging data set collected in the Dominantly Inherited Alzheimer Network (DIAN) participants to date represents a highly valuable resource for Alzheimer's disease (AD) research. It has supported cross sectional analysis of PET and MRI data to develop a timeline for imaging biomarkers in autosomal dominant AD (ADAD). With this renewal application, the DIAN Imaging Core will continue to obtain and analyze longitudinal imaging data that is fully integrated with clinical, psychometric and cerebrospinal fluid (CSF) biomarkers, and will allow for mutation-specific genotype-phenotype analysis. Imaging Core will be responsible for the acquisition, quality control, and analysis of the MRI and PET neuroimaging for DIAN. Carriers of AD-causing mutations and their non-carrier siblings are enrolled and followed in the Clinical Core through the international DIAN performance sites. Participants will undergo structural and functional MRI, amyloid PET, tau PET, and metabolic PET imaging every 2 years, in conjunction with their clinical visits. The source imaging data and post-processed data will be available to collaborating and outside investigators and will be distributed by the Informatics and Biostatistics cores. For tau PET, we will now obtain scans with the tracers [18F]-MK-6240, [18F]-AV-1451 (aka Flortaucipir, T807), and [18F]-PI-2620. Because no single tracer has the international distribution to reach all sites, each site is assigned one for the three tau PET tracers. Using multiple tracers maximizes the number of DIAN sites that can perform tau PET imaging. Including multiple tracers across the study diminishes the risk of choosing one tracer for such a large, international study of unique participants. Approximately 1/3 of participants will undergo imaging with each tracer. We recognize the limitations of using multiple tracers in the same study and have taken steps to minimize this risk. Based upon our preliminary work, each tracer is independently powered to detect significant effects (see Project 2, Approach). Further, our current proposal is adaptive. If our immunohistochemistry and autoradiographic work (Project 2) demonstrates that one candidate tracer is unsuitable (i.e. THK-5351 binding to monoamine oxidase B44), it will be replaced with another. Over the course of the proposal we will also work with Pharma partners to strengthen tracer availability to a wider international network.

A. Project summary/abstract The goal of this project is to develop positron emission tomography (PET) tracers which quantitatively measure the expression of the sphingosine-1-phosphate receptor 1 (S1P1). Sphingosine 1-phosphate (S1P) is a membrane-derived lysophospholipid that plays critical regulatory roles in inflammatory diseases through modulating five S1P receptor subtypes. S1P1 is one of the most abundant receptors in this family. Dysregulation of S1P1 signaling is associated with inflammatory diseases in multiple organ systems, including the central nervous system (CNS). The FDA approved S1P-modulator, FTY720 (fingolimod), has been widely used for treatment of relapsing-remitting multiple sclerosis (RR-MS); fingolimod has high affinity to all S1P subtypes except S1P2, but its function mainly relies on its binding with S1P1. Although positive results in treating RR-MS with fingolimod illustrate the importance of this pathway in chronic inflammatory disease, the mechanisms by which S1P1 mediates pathological changes in MS as well as in other diseases are still not well understood. A PET tracer with high affinity and selectivity for S1P1 would provide a unique imaging tool to quantify S1P1 expression in inflamed tissue, thus helping physicians monitor the therapeutic efficacy of S1P1 inhibition in individual patients by assessing changes in S1P1 expression post-treatment. To test this hypothesis, we radiosynthesized the known S1P1 inhibitor, 11C-TZ3321 (IC50 = 2.13 ± 1.63 nM for S1P1, >1000 nM for S1P2- 5). Our preclinical data from three different animal models of inflammatory diseases suggest 11C-TZ3321 can be used to quantify S1P1 expression in vivo. We subsequently identified several lead compounds for future 18F- labeling that have high potency (IC50 < 20 nM for S1P1) and selectivity (IC50 >1000 nM for S1P2-5). We have proposed two specific aims to achieve our goal. Specific aim #1 is to translate 11C-TZ3321 into clinical investigation for proof of mechanism studies in RR-MS patients. Our multi-disciplinary team will carry out translational 11C-TZ3321 PET studies in MS patients and healthy volunteers to determine if S1P1 expression reflects the severity of MS and if changes of S1P1 expression reflect the therapeutic efficacy of treating MS with fingolimod. Specific aim #2 is to develop an 18F-labeled S1P1 specific PET radiotracer. We will optimize the lead structures of S1P1 compounds and perform in vitro binding assay to identify potent and selective compounds that can be 18F-labeled. Upon the success of 18F-labeling, we will perform in the rat EAE model of MS will be used for the preclinical evaluation of new 18F-labeled S1P1 PET tracers. We anticipate identifying a candidate 18F-labeled S1P1 specific radiotracer for future translational investigation of inflammatory response in human disease.

Project Summary/Abstract The Charles F. and Joanne Knight Alzheimer's Disease Research Center (Knight ADRC) at Washington University was founded as the Memory and Aging Project in 1979. Since that year, it has received continuous funding from the National Institutes of Health (NIH) and now supports an active cohort of nearly 800 participants who undergo longitudinal clinical and biomarker assessments for preclinical and symptomatic Alzheimer's disease (AD). The Knight ADRC is supported by three major NIH awards, the ADRC center grant (P50AG05681, JC Morris PI), the Healthy Aging and Senile Dementia (HASD; AG03991, JC Morris PI, Imaging Core Leader T Benzinger), and the Adult Children Study (ACS, P01 AG026276, JC Morris PI, Project 4 Leader T Benzinger). With this R01, we request funding for a new initiative which will add a novel biomarker of neuroinflammation in AD, diffusion basis spectrum imaging (DBSI) magnetic resonance imaging (MRI). Members of our research team have previously established the validity of DBSI MRI for neuroinflammation in multiple sclerosis, including both in vivo and ex vivo mouse and human studies. We now extend this research to AD, and will perform in vivo validation using positron emission tomography (PET) and ex vivo validation in human post mortem samples, including immunohistochemistry and autoradiography. Our preliminary data supports the predictive value of neuroinflammation markers in the progress from normal cognition to dementia, and in particularly, the promise of DBSI MRI for this, findings which we will validate in this larger study. We hypothesize that DBSI MRI will correspond to regional neuroinflammation in PET scans and that will correspond to areas of microglial infiltration in the autopsy specimens. We hypothesize that this relationship will be present in the earliest preclinical stages of AD, when cerebrospinal fluid (CSF) has abnormally low levels of A? but does not yet demonstrate abnormal levels of tau. Because DBSI MRI requires only Food and Drug Administration (FDA) approved MRI sequences, it could be rapidly extended to clinical trials or clinical populations.

Core E: Imaging Project Summary The Imaging Core of the Program Project Grant Healthy Aging and Senile Dementia (HASD) will provide quantitative imaging results for magnetic resonance imaging (MRI), amyloid positron emission tomography (PET) using [11C]-Pittsburgh Compound B (PiB), and tau PET using [18F]-AV-1451 (T807, flortaucipir) to support the affiliated Projects and Cores. Quantitative MRI measures will include volumetric MRI, quantitative and qualitative evaluations of vascular pathology including white matter hyperintensitites (WMH) and cerebral infarctions and microhemorrhages. Amyloid and tau PET will include summary statistics for standardized regions and voxelwise z-score analyses for overall burden and change over time. Exploratory measures will continue to include resting state functional connectivity MRI (rs-fcMRI), diffusion basis spectrum imaging (DBSI) for neuroinflammation, and arterial spin labelling (ASL) for blood flow using protocols compatible with the Alzheimer Disease Neuroimaging Initiative (ADNI-3) and the Dominantly Inherited Alzheimer Network (DIAN). We will continue to explore new MRI and PET options as these become available, such as alternative PET tracers for tau pathology or synaptic imaging, when relevant to the HASD Projects and Cores. We will also continue to promote sharing of the HASD imaging data through updated releases of the Open Access Series of Imaging Studies (OASIS) project.

ABSTRACT/PROJECT SUMMARY In this proposal we explore the transition from preclinical to symptomatic Alzheimer disease (AD) by incorporating the novel tau imaging tracer ([18F]-AV-1451) within the biomarker-rich protocol of the Dominantly Inherited Alzheimer Network (DIAN). We leverage the existing infrastructure of DIAN and a collaboration with Avid Radiopharmaceuticals to initiate tau positron emission tomography (PET) imaging in this unique cohort. DIAN provides fundamental support to the hypothesis that AD consists of a preclinical stage in which accumulation of beta-amyloid (A?) plaques and tau neurofibrillary tangle (NFT) gradually lead to neuronal dysfunction and cognitive impairment. However, key gaps remain in our understanding of the temporal and spatial interactions that occur between A? and tau during the transition from preclinical to clinical symptoms. This proposal answers these fundamental questions through three aims. Aim 1 studies the temporal dynamics of tau deposition (using AV-1451) in relation to estimated years to symptom onset (EYO) and existing biomarkers in DIAN (including cerebrospinal fluid, neuroimaging, and cognitive performance). Aim 2 studies the spatial (both local and distributed) changes of tau deposition (using AV-1451). Aim 3 studies the relationship between in vivo tau deposition (using AV-1451) and neuropathology. Unique to autosomal dominant AD (ADAD), the young age of the DIAN participants eliminates overlap with potential age-related neuropathology or tauopathy (PART). Our overall hypothesis is that conversion from cognitively normal to symptomatic AD can be accurately predicted by neuroimaging biomarkers, in particular by AV-1451 PET. Results from this proposal are fundamental for our understanding of PET tau as not only a diagnostic indicator of disease but also a therapeutic marker to evaluate the clinical efficacy of future interventions in ADAD.