Quantitative Imaging Goals for NIDDK

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1 Quantitative Imaging Goals for NIDDK Maren R. Laughlin Senior Advisor Quantitative Imaging Goals for NIDDK Monitor progression and response to therapy of disease in liver kidney and urological organs bone marrow bowel exocrine pancreas Measure pancreatic islet beta cell mass and inflammation to monitor diabetes progression and response to therapy Monitor mass and activity of human brown and beige fat Enable brain research in metabolic diseases Regulation of energy balance and metabolism Alterations caused by disease state 1

2 Quantitative Imaging Goals for NIDDK Monitor progression and response to therapy of disease in liver kidney and urological organs bone marrow bowel exocrine pancreas Goal: replace diagnostic biopsy with independent measures of the common events in disease progression fat deposition inflammation fibrosis changes in architecture dysfunction dysregulated proliferation (cancer) NIDDK Activities focused on tissue fibrosis Nonalcoholic Steatohepatitis Clinical Research Network Clinical trials in adults and children Elucidate disease pathogenesis fat & fibrosis imaging Improve diagnosis, treatment and clinical management ChiLDReN: Childhood Liver Disease Network Biliary Atresia Research Consortium (BARC) Cholestatic Liver Disease Consortium (CLiC) Cystic Fibrosis Liver Disease (CFLD) Hepatitis B Clinical Research Network Drug-induced Liver Injury Network (DILIN) NIDDK Fibrosis Biomarker Consortium RFA-DK biomarkers of fibrosis in kidney, urological and bone marrow disease (4 sites) Upcoming NIDDK Workshop: Advances in Biomedical Imaging, Bioengineering and Related Technologies for the Development of Biomarkers of Pancreatic Disease July 22, 2013 University of Pittsburgh 2

3 Common Causes of Liver Disease Nonalcoholic Fatty Liver Disease (~80M in US) Nonalcoholic Steatohepatitis (10-15M in US) Liver Injury Alcohol & other diseases Hepatitis B Virus ~300M worldwide Hepatitis C Virus ~300M worldwide Hepatic stellate cells (HSCs): activation in response to liver injury inactivation with therapy Youngmin A Lee et al. Gut 2015;64: Can we image disease progression and regression? 3

4 Many mechanisms for fibrosis regression have been identified Youngmin A Lee et al. Gut 2015;64: Major studies with liver fibrosis as primary or co-primary endpoint Trautwein C. J Hepatol Apr;62(1S):S15-S24 4

5 Urgent need for a toolkit of validated biomarkers of liver fibrosis US shear-wave elastography MR Molecular Imaging of mouse liver collagen (fibrosis) MR elastography Tang A 1, Cloutier G, Szeverenyi NM, Sirlin CB. Am J Roentgenol Apr 23:W1-W11. Ultrasound Elastography and MR Elastography for Assessing Liver Fibrosis: Part 1, Principles and Techniques. Fuchs BC et al, J Hepatology (2013) 59: Quantitative Imaging Goals for NIDDK Monitor progression and response to therapy of disease in liver kidney and urological organs bone marrow bowel exocrine pancreas Measure pancreatic islet beta cell mass and inflammation to monitor diabetes progression and response to therapy Monitor mass and activity of human brown and beige fat Enable brain research in metabolic diseases Regulation of energy balance and metabolism Alterations caused by disease state 5

6 PET/SPECT Tracers Show Promise for Endogenous Human Cell Mass 18 F-FP-(+)-DTBZ 111 In-labelled Exendin [ 11 C]5-HTP T1 Diabetes T1 Diabetes T1 Diabetes Healthy Healthy Healthy Healthy T1D T1D Healthy Healthy T1D. Normandin M D et al. J Nucl Med 2012;53:908 Brom M et al. Diabetologia :950 Eriksson O et al. Diabetes 2014;63:3428 Barriers to validation: Beta cell mass is non-zero in T1D Many (54/74) T1D patients secrete c-peptide cells/cm 2 Many T1D have c-peptide. Oram RA, Diabetologia. (2014) 57(1): cell mass (insulin stain) in long duration (1-35 yrs) T1D avg non-dm BCM T1DM T2DM non-dm Adult range Many pancreata from T1D have islets with cells. Therefore, data in T1D are insufficient for validation of cell mass biomarkers R. Gianani et al Diabetologia (4):

7 Quantitative Imaging Goals for NIDDK Monitor progression and response to therapy of disease in liver kidney and urological organs bone marrow bowel exocrine pancreas Measure pancreatic islet beta cell mass and inflammation to monitor diabetes progression and response to therapy Monitor mass and activity of human brown and beige fat Enable brain research in metabolic diseases Regulation of energy balance and metabolism Alterations caused by disease state Human brown fat can be detected using FDG-PET lean person room temp (72º F) lean person cool temp (61º F) obese person cool temp (61º F) NIDDK Workshop, Bethesda, MD, November 4, 2014: Consensus Recommendations for Standardized FDG-PET of Human Brown Fat (manuscript in preparation) Lichtenbelt, New Engl J Med, 360: ,

8 Novel detection techniques for hbat mass and/or activity NET ligand 11 C-MRB detects inactive hbat 11 C-MRB PET 18 F-FDG PET Hwang JJ et al, Metabolism Jun;64(6): Imaging human brown adipose tissue under room temperature conditions with (11)C-MRB, a selective norepinephrine transporter PET ligand. Quantitative Imaging Goals for NIDDK Monitor progression and response to therapy of disease in liver kidney and urological organs bone marrow bowel exocrine pancreas Measure pancreatic islet beta cell mass and inflammation to monitor diabetes progression and response to therapy Monitor mass and activity of human brown and beige fat Enable brain research in metabolic diseases Regulation of energy balance and metabolism Alterations caused by disease state 8

9 Brain research in metabolic disease Key challenges: Adequate temporal/spatial resolution for structure, biochemistry, function Standardized protocols to relate metabolism, cognition and quantitative neuroimaging Diabetes is associated with impaired cognition, but does diabetic microvascular dysfunction interfere with functional imaging outcomes? DMN resting state functional connectivity reduced in T2DM despite unimpaired cognition T2DM Con Con T2DM Reduced working memory BOLD activation in MetS, despite unimpaired cognition Con MetS Con MetS Con MetS MTG Precuneus MEDFG K.F. Hoth et al. AJNR Am J Neuroradiol 2011;32: Gail Musen et al. Diabetes 2012;61:

10 MR Imaging Shows Promise for Measures of Pancreatic Inflammation Visualizing Pancreatic Inflammation Recent onset T1D Healthy High Low MRI Inflammation Signal Gaglia JL et al, Proc Natl Acad Sci U S A Feb 17;112(7):