Evaluation of a semi-automated approach for FDG PET image analysis for routine clinical application in patients with multiple myeloma.

Background: FDG PET/CT is a tool for assessing response to therapy in various cancers, and may provide an earlier biomarker of clinical response. We developed a novel semi-automated approach for analyzing FDG PET/CT images in patients with multiple myeloma (MM) to standardize FDG PET application.

Methods: Patients (n = 8) with relapsed/refractory MM from the Phase 2 study (NCT02899052) of venetoclax plus carfilzomib and dexamethasone underwent FDG PET/CT at baseline and up to two timepoints during treatment.

Application of Aligned-UMAP to longitudinal biomedical studies.

High-dimensional data analysis starts with projecting the data to low dimensions to visualize and understand the underlying data structure. Several methods have been developed for dimensionality reduction, but they are limited to cross-sectional datasets. The recently proposed Aligned-UMAP, an extension of the uniform manifold approximation and projection (UMAP) algorithm, can visualize high-dimensional longitudinal datasets.

Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency: A Randomized Clinical Trial.

Importance: Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations.

Objective: To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency.

Convective forces increase rostral delivery of intrathecal radiotracers and antisense oligonucleotides in the cynomolgus monkey nervous system.

Background: The intrathecal (IT) dosing route introduces drugs directly into the CSF to bypass the blood-brain barrier and gain direct access to the CNS. We evaluated the use of convective forces acting on the cerebrospinal fluid as a means for increasing rostral delivery of IT dosed radioactive tracer molecules and antisense oligonucleotides (ASO) in the monkey CNS. We also measured the cerebral spinal fluid (CSF) volume in a group of cynomolgus monkeys.

Intrathecal Tc-DTPA imaging of molecular passage from lumbar cerebrospinal fluid to brain and periphery in humans.

Introduction: Cerebrospinal fluid (CSF) molecular exchange with brain interstitial fluid (ISF) and periphery is implicated in neurological disorders but needs better quantitative clinical assessment approaches.

Methods: Following intrathecal (ITH) dosing via lumbar puncture, Technetium-99 m (Tc-) diethylenetriaminepentaacetic acid (DTPA) imaging was used to quantify neuraxial spread, CSF-brain molecular exchange, and CSF-peripheral clearance in 15 normal human volunteers. The effect of experimental convection manipulation on these processes was also assessed.

Neurophysiological Biomarkers of Parkinson's Disease.

Background: There is a need for reliable and robust Parkinson's disease biomarkers that reflect severity and are sensitive to disease modifying investigational therapeutics.

Objective: To demonstrate the utility of EEG as a reliable, quantitative biomarker with potential as a pharmacodynamic endpoint for use in clinical assessments of neuroprotective therapeutics for Parkison's disease.

Methods: A multi modal study was performed including aquisition of resting state EEG data and dopamine transporter PET imaging from Parkinson's disease patients off medication and compared against age-matched controls.

Rethinking bomb threat response.

Understanding the explosive threat landscape is paramount to having a sound evacuation protocol. Security procedures and response to threats can no longer be static and uniformly applied; rather, they must be tailored to ever-evolving terrorist and criminal tactics. This paper introduces recent statistics regarding the decreasing number of domestic bombings in the USA.

Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging.

Intrathecal (IT) delivery and pharmacology of antisense oligonucleotides (ASOs) for the CNS have been successfully developed to treat spinal muscular atrophy. However, ASO pharmacokinetic (PK) and pharmacodynamic (PD) properties remain poorly understood in the IT compartment. We applied multimodal imaging techniques to elucidate the IT PK and PD of unlabeled, radioactively labeled, or fluorescently labeled ASOs targeting ubiquitously expressed or neuron-specific RNAs.

Treatment of internuclear ophthalmoparesis in multiple sclerosis with fampridine: A randomized double-blind, placebo-controlled cross-over trial.

Aim: To examine whether the velocity of saccadic eye movements in internuclear ophthalmoparesis (INO) improves with fampridine treatment in patients with multiple sclerosis (MS).

Methods: Randomized, double-blind, placebo-controlled, cross-over trial with fampridine in patients with MS and INO. Horizontal saccades were recorded at baseline and at multiple time points post-dose.

In-DANBIRT Molecular Imaging of Inflammatory Cells in Atherosclerosis.

Atherosclerosis-related morbidity and mortality remain a global concern. Atherosclerotic disease follows a slow and silent progression, and the transition from early-stage lesions to vulnerable plaques remains difficult to diagnose. Inflammation is a key component of the development of atherosclerotic plaque and consequent life-threatening complications.

Dual-Isotope Cryoimaging Quantitative Autoradiography: Investigating Antibody-Drug Conjugate Distribution and Payload Delivery Through Imaging.

In vitro properties of antibody-drug conjugates (ADCs) such as binding, internalization, and cytotoxicity are often well characterized before in vivo studies. Interpretation of in vivo studies might be significantly enhanced by molecular imaging tools. We present here a dual-isotope cryoimaging quantitative autoradiography (CIQA) methodology combined with advanced 3-dimensional imaging and analysis allowing for the simultaneous study of both antibody and payload distribution in tissues of interest in a preclinical setting.

Noninvasive PK11195-PET Image Analysis Techniques Can Detect Abnormal Cerebral Microglial Activation in Parkinson's Disease.

Background And Purpose: Neuroinflammation has been implicated in the pathophysiology of Parkinson's disease (PD), which might be influenced by successful neuroprotective drugs. The uptake of [ C](R)-PK11195 (PK) is often considered to be a proxy for neuroinflammation, and can be quantified using the Logan graphical method with an image-derived blood input function, or the Logan reference tissue model using automated reference region extraction. The purposes of this study were (1) to assess whether these noninvasive image analysis methods can discriminate between patients with PD and healthy volunteers (HVs), and (2) to establish the effect size that would be required to distinguish true drug-induced changes from system variance in longitudinal trials.

Sclerostin and DKK1 Inhibition Preserves and Augments Alveolar Bone Volume and Architecture in Rats with Alveolar Bone Loss.

Alveolar bone is a mechanosensitive tissue that provides structural support for teeth. Alveolar bone loss is common with aging, menopause, tooth loss, and periodontitis and can lead to additional tooth loss, reduced denture fixation, and challenges in placing dental implants. The current studies suggest that sclerostin and DKK1, which are established osteocyte-derived inhibitors of bone formation, contribute to alveolar bone loss associated with estrogen ablation and edentulism in rats.

The Expansion of Heterotopic Bone in Fibrodysplasia Ossificans Progressiva Is Activin A-Dependent.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder that is characterized by episodic yet cumulative heterotopic ossification (HO) in skeletal muscles, tendons, and ligaments over a patient's lifetime. FOP is caused by missense mutations in the type I bone morphogenetic protein (BMP) receptor ACVR1. We have determined that the formation of heterotopic bone in FOP requires activation of mutant ACVR1 by Activin A, in part by showing that prophylactic inhibition of Activin A blocks HO in a mouse model of FOP.

A phase one, single-dose, open-label, clinical safety and PET/MR imaging study of Ga-DOTATOC in healthy volunteers.

This prospective pilot study provides a dynamic whole body PET/MR image database, clinical safety, biodistribution profile and dosimetry of Ga-DOTATOC in healthy subjects, to establish a baseline and standard reference for its use in diagnosis and treatment response evaluation among patients with somatostatin receptor expressing neoplastic diseases. Dynamic whole body PET/MR imaging was performed in 12 healthy subjects (male/female: 8/4) after injection of 242.39 ± 53.

Advancing Drug Discovery and Development Using Molecular Imaging (ADDMI): an Interest Group of the World Molecular Imaging Society and an Inaugural Session on Positron Emission Tomography (PET).

Multi-modality molecular imaging techniques have expanded the role of imaging biomarkers in the pharmaceutical industry and are beginning to streamline the drug discovery and development process. The World Molecular Imaging Society (WMIS) serves as a forum for discussing innovative and exploratory multi-modal, interdisciplinary molecular imaging research with a mission of bridging the gap between pathology and in vivo imaging. To formalize the role of the WMIS in pharmaceutical research efforts, members of the society have formed an interest group entitled Advancing Drug Discovery and Development using Molecular Imaging (ADDMI).

High-throughput high-volume nuclear imaging for preclinical in vivo compound screening.

Background: Preclinical single-photon emission computed tomography (SPECT)/CT imaging studies are hampered by low throughput, hence are found typically within small volume feasibility studies. Here, imaging and image analysis procedures are presented that allow profiling of a large volume of radiolabelled compounds within a reasonably short total study time. Particular emphasis was put on quality control (QC) and on fast and unbiased image analysis.

Three-Dimensional Dosimetry for Radiation Safety Estimates from Intrathecal Administration.

Intrathecal administration is of growing interest for drug delivery, and its utility is being increasingly investigated through imaging. In this work, the 3-dimensional Voxel-Based Internal Dosimetry Application (VIDA) and 4D Extended Cardiac Torso Phantom (XCAT) were extended to provide radiation safety estimates specific to intrathecal administration. The 3-dimensional VIDA dosimetry application Monte Carlo simulation was run using a modified XCAT phantom with additional and edited cerebrospinal fluid (CSF) regions to produce voxel-level absorbed dose per unit cumulated activity maps for 9 selected source regions.

Automated segmentation of MR imaging to determine normative central nervous system cerebrospinal fluid volumes in healthy volunteers.

An accurate non-invasive method to determine total body cerebrospinal fluid volume has a number of potential diagnostic and therapeutic applications. Herein we describe a technique for automated segmentation of total body MRI data to determine cranial and spinal CSF volume in 15 healthy adults. These in vivo estimates of CSF volume exceed the standard reported volume of 150mL in human adults and provide normative data for diagnosis of disease states such as hydrocephalus and therapy including pharmacologic dosimetry.

Dynamic dual-isotope molecular imaging elucidates principles for optimizing intrathecal drug delivery.

The intrathecal (IT) dosing route offers a seemingly obvious solution for delivering drugs directly to the central nervous system. However, gaps in understanding drug molecule behavior within the anatomically and kinetically unique environment of the mammalian IT space have impeded the establishment of pharmacokinetic principles for optimizing regional drug exposure along the neuraxis. Here, we have utilized high-resolution single-photon emission tomography with X-ray computed tomography to study the behavior of multiple molecular imaging tracers following an IT bolus injection, with supporting histology, autoradiography, block-face tomography, and MRI.

SIRT1 Mediates Depression-Like Behaviors in the Nucleus Accumbens.

Unlabelled: Depression is a recurring and life-threatening illness that affects up to 120 million people worldwide. In the present study, we show that chronic social defeat stress, an ethologically validated model of depression in mice, increases SIRT1 levels in the nucleus accumbens (NAc), a key brain reward region. Increases in SIRT1, a well characterized class III histone deacetylase, after chronic social defeat suggest a role for this enzyme in mediating depression-like behaviors.

Micro-CT imaging: Developing criteria for examining fetal skeletons in regulatory developmental toxicology studies - A workshop report.

During the past two decades the use and refinements of imaging modalities have markedly increased making it possible to image embryos and fetuses used in pivotal nonclinical studies submitted to regulatory agencies. Implementing these technologies into the Good Laboratory Practice environment requires rigorous testing, validation, and documentation to ensure the reproducibility of data. A workshop on current practices and regulatory requirements was held with the goal of defining minimal criteria for the proper implementation of these technologies and subsequent submission to regulatory agencies.

A gradient-loadable (64)Cu-chelator for quantifying tumor deposition kinetics of nanoliposomal therapeutics by positron emission tomography.

Effective drug delivery to tumors is a barrier to treatment with nanomedicines. Non-invasively tracking liposome biodistribution and tumor deposition in patients may provide insight into identifying patients that are well-suited for liposomal therapies. We describe a novel gradient-loadable chelator, 4-DEAP-ATSC, for incorporating (64)Cu into liposomal therapeutics for positron emission tomographic (PET).