Robert A. Comley

Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging.

While emerging evidence suggests that neuroinflammation plays a crucial role in Alzheimers disease, the impact of the microglia response in Alzheimers disease remains a matter of debate. We aimed to study microglial activation in early Alzheimers disease and its impact on clinical progression using a second-generation 18-kDa translocator protein positron emission tomography radiotracer together with amyloid imaging using Pittsburgh compound B positron emission tomography. We enrolled 96 subjects, 64 patients with Alzheimers disease and 32 controls, from the IMABio3 study, who had both (11)C-Pittsburgh compound B and (18)F-DPA-714 positron emission tomography imaging. Patients with Alzheimers disease were classified as prodromal Alzheimers disease (n = 38) and Alzheimers disease dementia (n = 26). Translocator protein-binding was measured using a simple ratio method with cerebellar grey matter as reference tissue, taking into account regional atrophy. Images were analysed at the regional (volume of interest) and at the voxel level. Translocator protein genotyping allowed the classification of all subjects in high, mixed and low affinity binders. Thirty high+mixed affinity binders patients with Alzheimers disease were dichotomized into slow decliners (n = 10) or fast decliners (n = 20) after 2 years of follow-up. All patients with Alzheimers disease had an amyloid positive Pittsburgh compound B positron emission tomography. Among controls, eight had positive amyloid scans (n = 6 high+mixed affinity binders), defined as amyloidosis controls, and were analysed separately. By both volumes of interest and voxel-wise comparison, 18-kDa translocator protein-binding was higher in high affinity binders, mixed affinity binders and high+mixed affinity binders Alzheimers disease groups compared to controls, especially at the prodromal stage, involving the temporo-parietal cortex. Translocator protein-binding was positively correlated with Mini-Mental State Examination scores and grey matter volume, as well as with Pittsburgh compound B binding. Amyloidosis controls displayed higher translocator protein-binding than controls, especially in the frontal cortex. We found higher translocator protein-binding in slow decliners than fast decliners, with no difference in Pittsburgh compound B binding. Microglial activation appears at the prodromal and possibly at the preclinical stage of Alzheimers disease, and seems to play a protective role in the clinical progression of the disease at these early stages. The extent of microglial activation appears to differ between patients, and could explain the overlap in translocator protein binding values between patients with Alzheimers disease and amyloidosis controls.

Radioligand development for molecular imaging of the central nervous system with positron emission tomography

Positron emission tomography (PET) is routinely used to support the development of drugs to treat neurological and psychiatric disorders. PET radioligands must not only be selective for the target of interest but must also possess a range of physicochemical and pharmacological characteristics that allow them to be radiolabelled with short-lived positron-emitting isotopes, safely administered to humans, and for the degree of target binding to be quantified in vivo. We review the ligand development process, including target selection, radioligand discovery (in vitro and preclinical evaluation), radiochemistry and evaluation in humans.

Kinetic Modeling of the Tau PET Tracer 18F-AV-1451 in Human Healthy Volunteers and Alzheimer's Disease Subjects

18F-AV-1451 is currently the most widely used of several experimental tau PET tracers. The objective of this study was to evaluate 18F-AV-1451 binding with full kinetic analysis using a metabolite-corrected arterial input function and to compare parameters derived from kinetic analysis with SUV ratio (SUVR) calculated over different imaging time intervals. Methods: 18F-AV-1451 PET brain imaging was completed in 16 subjects: 4 young healthy volunteers (YHV), 4 aged healthy volunteers (AHV), and 8 Alzheimer disease (AD) subjects. Subjects were imaged for 3.5 h, with arterial blood samples obtained throughout. PET data were analyzed using plasma and reference tissue–based methods to estimate the distribution volume, binding potential (BPND), and SUVR. BPND and SUVR were calculated using the cerebellar cortex as a reference region and were compared across the different methods and across the 3 groups (YHV, AHV, and AD). Results: AD demonstrated increased 18F-AV-1451 retention compared with YHV and AHV based on both invasive and noninvasive analyses in cortical regions in which paired helical filament tau accumulation is expected in AD. A correlation of R2 > 0.93 was found between BPND (130 min) and SUVR-1 at all time intervals. Cortical SUVR curves reached a relative plateau around 1.0–1.2 for YHV and AHV by approximately 50 min, but increased in AD by up to approximately 20% at 110–130 min and approximately 30% at 160–180 min relative to 80–100 min. Distribution volume (130 min) was lower by 30%–35% in the YHV than AHV. Conclusion: Our data suggest that although 18F-AV-1451 SUVR curves do not reach a plateau and are still increasing in AD, an SUVR calculated over an imaging window of 80–100 min (as currently used in clinical studies) provides estimates of paired helical filament tau burden in good correlation with BPND, whereas SUVR sensitivity to regional cerebral blood changes needs further investigation.

Increased arterial inflammation in individuals with stage 3 chronic kidney disease

PurposeWhile it is well known that patients with chronic kidney disease (CKD) are at increased risk for the development and progression of atherosclerosis, it is not known whether arterial inflammation is increased in mild CKD. The aim of this study was to compare arterial inflammation using 18F-FDG PET/CT in patients with CKD and in matched controls.MethodsThis restrospective study included 128 patients undergoing FDG PET/CT imaging for clinical indications, comprising 64 patients with stage 3 CKD and 64 control patients matched by age, gender, and cancer history. CKD was defined according to guidelines using a calculated glomerular filtration rate (eGFR). Arterial inflammation was measured in the ascending aorta as FDG uptake on PET. Background FDG uptake (venous, subcutaneous fat and muscle) were recorded. Coronary artery calcification (CAC) was assessed using the CT images. The impact of CKD on arterial inflammation and CAC was then assessed.ResultsArterial inflammation was higher in patients with CKD than in matched controls (standardized uptake value, SUV: 2.41 ± 0.49 vs. 2.16 ± 0.43; p = 0.002). Arterial SUV correlated inversely with eGFR (r = −0.299, p = 0.001). Venous SUV was also significantly elevated in patients with CKD, while subcutaneous fat and muscle tissue SUVs did not differ between groups. Moreover, arterial SUV remained significantly elevated in patients with CKD compared to controls after correcting for muscle and fat background, and also remained significant after adjusting for clinical risk factors. Further, CKD was associated with arterial inflammation (SUV) independent of the presence of subclinical atherosclerosis (CAC).ConclusionModerate CKD is associated with increased arterial inflammation beyond that of controls. Further, the increased arterial inflammation is independent of presence of subclinical atherosclerosis. Current risk stratification tools may underestimate the presence of atherosclerosis in patients with CKD and thereby the risk of cardiovascular events.

Human Kinetic Modeling of the 5HT6 PET Radioligand 11C-GSK215083 and Its Utility for Determining Occupancy at Both 5HT6 and 5HT2A Receptors by SB742457 as a Potential Therapeutic Mechanism of Action in Alzheimer Disease

Antagonism of 5-hydroxytrypamine-6 (5HT6) receptors is associated with procognitive effects in preclinical species, suggesting a therapeutic potential for this mechanism in Alzheimer disease (AD) and other cognitive diseases. In a phase 2 dose study, SB742457, a novel 5HT6 antagonist, showed increasing procognitive effects in patients with AD as the dose increased, with a procognitive signal in AD patients at a dose of 35 mg/d superior to the other doses tested (5 and 15 mg/d). Methods: In this article, we describe the quantification and pharmacologic selectivity of a new 5HT6 PET ligand (11C-GSK215083) in healthy volunteers and its use to measure occupancies achieved at various doses of SB742457. Results: Kinetic analysis of 11C-GSK215083 uptake in the human brain demonstrated the multilinear model, MA2, to represent the method of choice when a blood input was available and the full tissue reference method when no input was available. Pharmacologic dissection of the in vivo 11C-GSK215083–specific binding showed the ligand bound mostly the 5HT6 in the striatum (blocked by SB742457 but not by the selective 5-hydroxytryptamine-2A (5HT2A) antagonist ketanserin) and the 5HT2A in the frontal cortex (blocked by both ketanserin and SB742457). Repeated administration of SB742457 (3, 15, and 35 mg/d) saturated the 5HT6 receptors at all doses. In the cortex, 5HT2A receptor occupancy was 24% ± 6% (3 mg/d), 35% ± 4% (15 mg/d), and 58% ± 19% (35 mg/d; mean ± SD), suggesting a progressive engagement of 5HT2A as the dose increased. Conclusion: Collectively, these data support the use of 11C-GSK215083 as a 5HT6 clinical imaging tool and suggest that blocking both the 5HT6 and the 5HT2A receptors may be required for the optimal therapeutic action of SB742457 in AD.

Quantification of [11C]Ro15-4513 GABAAα5 specific binding and regional selectivity in humans

[11C]Ro15-4513 has been introduced as a positron emission tomography radioligand to image the GABAAα5 receptor subtype thought to be important in learning, memory and addiction. However, the in vivo selectivity of the ligand remains unknown and a full assessment of different analysis approaches has yet to be performed. Using human heterologous competition data, with [11C]Ro15-4513 and the highly selective GABAAα5 selective negative allosteric modulator Basmisanil (RG1662), we quantify the GABAAα5 selectivity of [11C]Ro15-4513, assess the validity of reference tissues and evaluate the performance of four different kinetic analysis methods. The results show that [11C]Ro15-4513 has high but not complete selectivity for GABAAα5, with α5 representing around 60–70% of the specific binding in α5 rich regions. Competition data indicate that the cerebellum and pons are essentially devoid of α5 signal and might be used as reference regions under certain conditions. Off-target non-selective binding to other GABAA subtypes means that the choice of analysis method and the interpretation of outcome measures must be considered carefully. We discuss the merits of two tissue compartmental model analyses to derive both VT and VS, band-pass spectral analysis for estimation of V α 5 and the simplified reference tissue model for estimation of BP ND .

ON EVALUATION OF TAU ACCUMULATIONS IN LONGITUDINAL STUDIES OF ALZHEIMER’S DISEASE (AD): IMPLICATIONS FROM A PET STUDY WITH [18F]RO6958948

A1 19 A2 8 A3 22 A4 21 ACCUMULATIONS IN LONGITUDINAL STUDIES OFALZHEIMER’S DISEASE (AD): IMPLICATIONS FROMAPET STUDYWITH [18F]RO6958948 Hiroto Kuwabara, Edilio Borroni, Robert A. Comley, Joshua Roberts, Kelly Kitzmiller, Paul B. Rosenberg, Madhav Thambisetty, Michael Honer, Gregory Klein, Lorena Gapasin, Luca Gobbi, Dean F. Wong, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Roche Pharmaceutical Research and Early Development, Basel, Switzerland; Abbvie Inc., Chicago, IL, USA. Contact e-mail: hkuwaba1@jhmi.edu

Kinetic evaluation of three newly developed radioligands for human tau imaging

voxel-wise. Results: Peak SUV values were approximately 3, 1.5 and 3.5 for [C]RO6924963, [C]RO6931643, and [F] RO6958948, respectively. The retention of [C]RO6931643 and [F]RO6958948 in HS was much lower than that of [C] RO6924963. For [C]RO6931643 and [F]RO6958948 (in AD), highest uptake was seen in the frontal (Fr), temporal (Tp), parietal (Pa), occipital (Oc), and fusiform (Fs) cortices, and the entorhinal area (ER). SUVR60-90 values ranged from 1.22 (L. Fr) to 1.55 (L. Oc) for [C]RO6931643, and 1.39 (R.Fr) to 2.25 (L. Fs) for [F]RO6958948, and VT ranged from 2.28 (R. ER) to 3.14 (L. Tp), and 3.98 (R. ER) to 5.62 (L. Tp), respectively. Regional analysis of SUVR and VT for [ C]RO6931643 and [F]RO6958948 clearly allowed AD and HS to be distinguished. When compared to HS, the two tracers showed robust group effects (F>90; p1⁄4<10; two-way ANOVA) on SUVR and VT, and significant group differences (p<0.05 with Bonferroni correction; without overlap) in 6 of 12 regions for [C]RO6931643 and 4 of 12 for [F]RO6958948 (using SUVR). Voxel-wise analysis of SUVR revealed clusters of significantly higher uptake in AD compared to HS in Fs for [C]RO6931643 (7 AD vs. 5 HS), and [F] RO6958948 (5 AD vs. 5 HS). There were no radiolabelled metabolites nor defluorination of [F]RO6958948. Conclusions: Our data supports further evaluation of [F]RO6958948. Kinetic analysis is reported in detail in Kuwabara, AAIC 2015.

P341 NON-INVASIVE IMAGING OF KUPFFER CELL STATUS USING RADIOLABELLED MANNOSYLATED ALBUMIN

Background and Aims: Kupffer cells are responsible for maintaining liver homeostasis and have a vital role in chronic hepatotoxicity and various liver diseases. Positron Imaging Tomography (PET) is a non-invasive imaging technique that allows quantification and visualization of biochemical processes by monitoring the distribution of molecules labelled with positron imaging isotopes. We aimed to develop a methodology for noninvasive PET imaging of Kupffer cell status in liver. Methods: Our strategy was to target CD206 receptor that selectively takes up mannosylated albumin. Thus mannosylated albumin (mHSA) was synthesized and coupled to radionuclide-18F. Thereafter the pharmacological properties of this radiotracer were explored in a range of pre-clinical models including cells and wistar-rats. Whole-body PET images were acquired 30/60 minutes after injection of 5-15 MBq of radiotracer-[18F]B-mHSA. Results: Hepatic uptake at 30 and 60 min was high whereas accumulation in the kidney was even higher, due to metabolism in liver and renal clearance. Blocking studies with a 20 fold excess of unlabeled tracer revealed saturable tracer uptake. In immune-related organs such as the bone-marrow, spleen, and liver radio-tracer uptake was highest at 30 minutes post injection and decreased thereafter. Ex-vivo biodistribution indicated lowest tracer uptake in non-target organs. Tracer uptake reaches a plateau in 45 min for RAW cells and in 60 min for murine Kupffer cells. Conclusions: [18F]B-mHSA is readily labelled, is stable in plasma and displays binding affinity for the CD206 receptors. This method allows quantitative and non-invasive imaging of liver function by using expression of the Kupffer cell specific CD206 receptor with special interest in liver toxicity and the early events leading to liver fibrosis.