Department of Radiology and Imaging Sciences Works

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The 2014 Moreton Lecture: A Rebuttal
(Elsevier, 2015-07) Borthakur, Gitasree; Kerridge, William D.; Ballenger, Zachary; Gunderman, Richard B.; Department of Radiology and Imaging, IU School of Medicine
2014 Update of the Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception
(Elsevier, 2016-06-01) Weiner, Michael W.; Veitch, Dallas P.; Aisen, Paul S.; Beckett, Laurel A.; Cairns, Nigel J.; Cedarbaum, Jesse; Green, Robert C.; Harvey, Danielle; Jack, Clifford R.; Jagust, William; Luthman, Johan; Morris, John C.; Petersen, Ronald C.; Saykin, Andrew J.; Shaw, Leslie; Shen, Li; Schwarz, Adam; Toga, Arthur W.; Trojanowski, John Q.; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of Medicine
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU, and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world.
2016 Advances in Renal Imaging Symposium
(Indiana University School of Medicine/IUPUI, 2016-11-15) IUPUI Imaging Research Symposium
The primary objective of the “Advances in Renal Imaging” symposium is to provide a forum for nephrology researchers and imaging scientists to come together and discuss needed kidney imaging biomarkers and explore the development of imaging technologies designed to address specific renal imaging needs. The Symposium includes three sessions of oral presentations with invited speakers addressing the following general themes: 1) Need for advances in renal imaging and the identification of potential imaging biomarker targets; 2) Advances in renal microscopy methods for basic science renal research; 3) Advances in molecular, perfusion, and structural renal imaging.
[68Ga]Ga-P16-093 as a PSMA-Targeted PET Radiopharmaceutical for Detection of Cancer: Initial Evaluation and Comparison with [68Ga]Ga-PSMA-11 in Prostate Cancer Patients Presenting with Biochemical Recurrence
(SpringerLink, 2020-06) Green, Mark A.; Hutchins, Gary D.; Bahler, Clinton D.; Tann, Mark; Mathias, Carla J.; Territo, Wendy; Sims, Justin; Polson, Heather; Alexoff, David; Eckelman, William C.; Kung, Hank F.; Fletcher, James W.; Radiology and Imaging Sciences, School of Medicine
Purpose: This study was undertaken to evaluate radiation dosimetry for the prostate-specific membrane antigen targeted [68Ga]Ga-P16-093 radiopharmaceutical, and to initially assess agent performance in positron emission tomography (PET) detection of the site of disease in prostate cancer patients presenting with biochemical recurrence. Procedures: Under IND 133,222 and an IRB-approved research protocol, we evaluated the biodistribution and pharmacokinetics of [68Ga]Ga-P16-093 with serial PET imaging following intravenous administration to ten prostate cancer patients with biochemical recurrence. The recruited subjects were all patients in whom a recent [68Ga]Ga-PSMA-11 PET/X-ray computed tomography (CT) exam had been independently performed under IND 131,806 to assist in decision-making with regard to their clinical care. Voided urine was collected from each subject at ~ 60 min and ~ 140 min post-[68Ga]Ga-P16-093 injection and assayed for Ga-68 content. Following image segmentation to extract tissue time-activity curves and corresponding cumulated activity values, radiation dosimetry estimates were calculated using IDAC Dose 2.1. The prior [68Ga]Ga-PSMA-11 PET/CT exam (whole-body PET imaging at 60 min post-injection, performed with contrast-enhanced diagnostic CT) served as a reference scan for comparison to the [68Ga]Ga-P16-093 findings. Results: [68Ga]Ga-P16-093 PET images at 60 min post-injection provided diagnostic information that appeared equivalent to the subject's prior [68Ga]Ga-PSMA-11 scan. With both radiopharmaceuticals, sites of tumor recurrence were found in eight of the ten patients, identifying 16 lesions. The site of recurrence was not detected with either agent for the other two subjects. Bladder activity was consistently lower with [68Ga]Ga-P16-093 than [68Ga]Ga-PSMA-11. The kidneys, spleen, salivary glands, and liver receive the highest radiation exposure from [68Ga]Ga-P16-093, with estimated doses of 1.7 × 10-1, 6.7 × 10-2, 6.5 × 10-2, and 5.6 × 10-2 mGy/MBq, respectively. The corresponding effective dose from [68Ga]Ga-P16-093 is 2.3 × 10-2 mSv/MBq. Conclusions: [68Ga]Ga-P16-093 provided diagnostic information that appeared equivalent to [68Ga]Ga-PSMA-11 in this limited series of ten prostate cancer patients presenting with biochemical recurrence, with the kidneys found to be the critical organ. Diminished tracer appearance in the urine represents a potential advantage of [68Ga]Ga-P16-093 over [68Ga]Ga-PSMA-11 for detection of lesions in the pelvis.
90Y Radioembolization for Hepatic Malignancy in Patients with Previous Biliary Intervention: Multicenter Analysis of Hepatobiliary Infections
(Radiological Society of North America, 2018-05-08) Devulapalli, Kavi K.; Fidelman, Nicholas; Soulen, Michael C.; Miller, Matthew; Johnson, Matthew S.; Addo, Eric; El-Haddad, Ghassan; Nutting, Charles; Morrison, James; Farsad, Khashayar; Lokken, R. Peter; Gaba, Ron C.; Fleming, Jacob; Brown, Daniel B.; Kwan, Sharon W.; Rose, Steven C.; Pennycooke, Kevin A.; Liu, David M.; White, Sarah B.; Gandhi, Ripal; Lazar, Ann A.; Kerlan, Robert K.; Radiology and Imaging Sciences, School of Medicine
PurposeTo determine the frequency of hepatobiliary infections after transarterial radioembolization (TARE) with yttrium 90 (90Y) in patients with liver malignancy and a history of biliary intervention.Materials and MethodsFor this retrospective study, records of all consecutive patients with liver malignancy and history of biliary intervention treated with TARE at 14 centers between 2005 and 2015 were reviewed. Data regarding liver function, 90Y dosimetry, antibiotic prophylaxis, and bowel preparation prophylaxis were collected. Primary outcome was development of hepatobiliary infection.ResultsOne hundred twenty-six patients (84 men, 42 women; mean age, 68.8 years) with primary (n = 39) or metastatic (n = 87) liver malignancy and history of biliary intervention underwent 180 procedures with glass (92 procedures) or resin (88 procedures) microspheres. Hepatobiliary infections (liver abscesses in nine patients, cholangitis in five patients) developed in 10 of the 126 patients (7.9%) after 11 of the 180 procedures (6.1%; nine of those procedures were performed with glass microspheres). All patients required hospitalization (median stay, 12 days; range, 2–113 days). Ten patients required percutaneous abscess drainage, three patients underwent endoscopic stent placement and stone removal, and one patient needed insertion of percutaneous biliary drains. Infections resolved in five patients, four patients died (two from infection and two from cancer progression while infection was being treated), and one patient continued to receive suppressive antibiotics. Use of glass microspheres (P = .02), previous liver resection or ablation (P = .02), and younger age (P = .003) were independently predictive of higher infection risk.ConclusionInfectious complications such as liver abscess and cholangitis are uncommon but serious complications of transarterial radioembolization with 90Y in patients with liver malignancy and a history of biliary intervention.© RSNA, 2018Online supplemental material is available for this article.
A carbon-11 labeled imidazo[1,2- a]pyridine derivative as a new potential PET probe targeting PI3K/mTOR in cancer
(e-Century Publishing, 2023-06-25) Liu, Wenqing; Ma, Wenjie; Wang, Min; Wang, Zhuangzhuang; Grega, Shaun D.; Zheng, Qi-Huang; Xu, Zhidong; Radiology and Imaging Sciences, School of Medicine
The PI3K/Akt/mTOR pathway is frequently dysregulated in cancer due to its central role in cell growth, survival, and proliferation. Overactivation of the PI3K/Akt/mTOR pathway may occur through varying mechanisms including mutations, gene amplification, and upstream signaling events, ultimately resulting in cancer. Therefore, PI3K/Akt/mTOR pathway has emerged as an attractive target for cancer therapy and imaging. A promising approach to inhibit this pathway involves a simultaneous inhibition of both PI3K and mTOR using a dual inhibitor. Recently, a potent dual PI3K/mTOR inhibitor, 2,4-difluoro-N-(2-methoxy-5-(3-(5-(2-(4-methylpiperazin-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (7), was discovered and demonstrated excellent kinase selectivity IC50 (PI3K/mTOR) = 0.20/21 nM; good cellular growth inhibition IC50 (HCT-116 cell) = 10 nM, modest plasma clearance, and acceptable oral bioavailability. Expanding on this discovery, here we present the synthesis of the carbon-11 labeled imidazo[1,2-a]pyridine derivative 2,4-difluoro-N-(2-methoxy-5-(3-(5-(2-(4-[11C]methylpiperazin-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (N-[11C]7) as a new potential radiotracer for the biomedical imaging technique positron emission tomography (PET) imaging of PI3K/mTOR in cancer. The reference standard 7 and its N-demethylated precursor, 2,4-difluoro-N-(2-methoxy-5-(3-(5-(2-(piperazin-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide (11), were synthesized in 7 and 8 steps with 10% and 7% overall chemical yield, respectively. N-[11C]7 was prepared from 11 using [11C]methyl triflate ([11C]CH3OTf) through N-11C-methylation and isolated by high-performance liquid chromatography (HPLC) and solid-phase extraction (SPE) formulation in 40-50% radiochemical yield decay corrected to end of bombardment (EOB) based on [11C]CO2. The radiochemical purity was > 99% and the molar activity (Am) at EOB was in the range of 296-555 GBq/µmol (n = 5).
A composite score using quantitative magnetic resonance cholangiopancreatography predicts clinical outcomes in primary sclerosing cholangitis
(Elsevier, 2023-06-29) Vuppalanchi, Raj; Are, Vijay; Telford, Alison; Young, Liam; Mouchti, Sofia; Ferreira, Carlos; Kettler, Carla; Gromski, Mark; Akisik, Fatih; Chalasani, Naga; Radiology and Imaging Sciences, School of Medicine
Background & aims: Magnetic resonance cholangiopancreatography (MRCP) for evaluation of biliary disease currently relies on subjective assessment with limited prognostic value because of the lack of quantitative metrics. Artificial intelligence-enabled quantitative MRCP (MRCP+) is a novel technique that segments biliary anatomy and provides quantitative biliary tree metrics. This study investigated the utility of MRCP+ as a prognostic tool for the prediction of clinical outcomes in primary sclerosing cholangitis (PSC). Methods: MRCP images of patients with PSC were post-processed using MRCP+ software. The duration between the MRCP and clinical event (liver transplantation or death) was calculated. Survival analysis and stepwise Cox regression were performed to investigate the optimal combination of MRCP+ metrics for the prediction of clinical outcomes. The resulting risk score was validated in a separate validation cohort and compared with an existing prognostic score (Mayo risk score). Results: In this retrospective study, 102 patients were included in a training cohort and a separate 50 patients formed a validation cohort. Between the two cohorts, 34 patients developed clinical outcomes over a median duration of 3 years (23 liver transplantations and 11 deaths). The proportion of bile ducts with diameter 3-5 mm, total bilirubin, and aspartate aminotransferase were independently associated with transplant-free survival. Combined as a risk score, the overall discriminative performance of the MRCP+ risk score (M+BA) was excellent; area under the receiver operator curve 0.86 (95% CI: 0.77, 0.95) at predicting clinical outcomes in the validation cohort with a hazard ratio 5.8 (95% CI: 1.5, 22.1). This was superior to the Mayo risk score. Conclusions: A composite score combining MRCP+ with total bilirubin and aspartate aminotransferase (M+BA) identified PSC patients at high risk of liver transplantation or death. Prospective studies are warranted to evaluate the clinical utility of this novel prognostic tool. Impact and implications: Primary sclerosis cholangitis (PSC) is a disease of the biliary tree where inflammation and fibrosis cause areas of narrowing (strictures) and expansion (dilatations) within the biliary ducts leading to liver failure and/or cancer (cholangiocarcinoma). In this study, we demonstrate that quantitative assessment of the biliary tree can better identify patients with PSC who are at high risk of either death or liver transplantation than a current blood-based risk score (Mayo risk score).
A cross‐sectional study of α‐synuclein seed amplification assay in Alzheimer's disease neuroimaging initiative: Prevalence and associations with Alzheimer's disease biomarkers and cognitive function
(Wiley, 2024) Tosun, Duygu; Hausle, Zachary; Iwaki, Hirotaka; Thropp, Pamela; Lamoureux, Jennifer; Lee, Edward B.; MacLeod, Karen; McEvoy, Sean; Nalls, Michael; Perrin, Richard J.; Saykin, Andrew J.; Shaw, Leslie M.; Singleton, Andrew B.; Lebovitz, Russ; Weiner, Michael W.; Blauwendraat, Cornelis; Alzheimer’s Disease Neuroimaging Initiative; Radiology and Imaging Sciences, School of Medicine
Introduction: Alzheimer's disease (AD) pathology is defined by β-amyloid (Aβ) plaques and neurofibrillary tau, but Lewy bodies (LBs; 𝛼-synuclein aggregates) are a common co-pathology for which effective biomarkers are needed. Methods: A validated α-synuclein Seed Amplification Assay (SAA) was used on recent cerebrospinal fluid (CSF) samples from 1638 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 78 with LB-pathology confirmation at autopsy. We compared SAA outcomes with neuropathology, Aβ and tau biomarkers, risk-factors, genetics, and cognitive trajectories. Results: SAA showed 79% sensitivity and 97% specificity for LB pathology, with superior performance in identifying neocortical (100%) compared to limbic (57%) and amygdala-predominant (60%) LB-pathology. SAA+ rate was 22%, increasing with disease stage and age. Higher Aβ burden but lower CSF p-tau181 associated with higher SAA+ rates, especially in dementia. SAA+ affected cognitive impairment in MCI and Early-AD who were already AD biomarker positive. Discussion: SAA is a sensitive, specific marker for LB-pathology. Its increase in prevalence with age and AD stages, and its association with AD biomarkers, highlights the clinical importance of α-synuclein co-pathology in understanding AD's nature and progression. Highlights: SAA shows 79% sensitivity, 97% specificity for LB-pathology detection in AD. SAA positivity prevalence increases with disease stage and age. Higher Aβ burden, lower CSF p-tau181 linked with higher SAA+ rates in dementia. SAA+ impacts cognitive impairment in early disease stages. Study underpins need for wider LB-pathology screening in AD treatment.
A DAT1 gene and APOE ε4 interaction is associated with apathy and structural brain changes in Alzheimer’s Disease
(Wiley, 2025-01-09) Malik, Rubina; Beaton, Derek; Saykin, Andrew J.; Nho, Kwangsik; Finger, Elizabeth; Radiology and Imaging Sciences, School of Medicine
Background: Apathy in patients with Alzheimer’s disease (AD) is associated with significant morbidity. We examined whether interactions between genetic variants related to neurotransmitter systems and regional brain atrophy are associated with apathy in patients with mild cognitive impairment (MCI) and AD. Method: For 1162 participants in the Alzheimer’s Disease Neuroimaging Initiative, including those with AD, MCI and cognitively normal individuals, a partial least squares correspondence analysis (PLS‐CA) modeled interactions between single nucleotide polymorphisms (SNPs), structural whole‐brain imaging variables, and apathy. Result: An interaction between apathy, the possession of an APOE (apolipoprotein E) ε4 allele combined with minor homozygosity for the DAT1 (dopamine transporter 1) gene, and brain atrophy. Conclusion: The results point to an association of a dopaminergic genetic marker and apathy in AD and may inform future design of clinical trials of apathy, as well as new treatment targets.
A deep learning framework identifies dimensional representations of Alzheimer’s Disease from brain structure
(Springer Nature, 2021-12-03) Yang, Zhijian; Nasrallah, Ilya M.; Shou, Haochang; Wen, Junhao; Doshi, Jimit; Habes, Mohamad; Erus, Guray; Abdulkadir, Ahmed; Resnick, Susan M.; Albert, Marilyn S.; Maruff, Paul; Fripp, Jurgen; Morris, John C.; Wolk, David A.; Davatzikos, Christos; iSTAGING Consortium; Baltimore Longitudinal Study of Aging (BLSA); Alzheimer’s Disease Neuroimaging Initiative (ADNI); Radiology and Imaging Sciences, School of Medicine
Heterogeneity of brain diseases is a challenge for precision diagnosis/prognosis. We describe and validate Smile-GAN (SeMI-supervised cLustEring-Generative Adversarial Network), a semi-supervised deep-clustering method, which examines neuroanatomical heterogeneity contrasted against normal brain structure, to identify disease subtypes through neuroimaging signatures. When applied to regional volumes derived from T1-weighted MRI (two studies; 2,832 participants; 8,146 scans) including cognitively normal individuals and those with cognitive impairment and dementia, Smile-GAN identified four patterns or axes of neurodegeneration. Applying this framework to longitudinal data revealed two distinct progression pathways. Measures of expression of these patterns predicted the pathway and rate of future neurodegeneration. Pattern expression offered complementary performance to amyloid/tau in predicting clinical progression. These deep-learning derived biomarkers offer potential for precision diagnostics and targeted clinical trial recruitment.

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