Reproducibility of findings in modern PET neuroimaging: insight from the NRM2018 grand challenge

The reproducibility of findings is a compelling methodological problem that the neuroimaging community is facing these days. The lack of standardized pipelines for image processing, quantification and statistics plays a major role in the variability and interpretation of results, even when the same data are analysed. This problem is well-known in MRI studies, where the indisputable value of the method has been complicated by a number of studies that produce discrepant results. However, any research domain with complex data and flexible analytical procedures can experience a similar lack of reproducibility. In this paper we investigate this issue for brain PET imaging. During the 2018 NeuroReceptor Mapping conference, the brain PET community was challenged with a computational contest involving a simulated neurotransmitter release experiment. Fourteen international teams analysed the same imaging dataset, for which the ground-truth was known. Despite a plurality of methods, the solutions were consistent across participants, although not identical. These results should create awareness that the increased sharing of PET data alone will only be one component of enhancing confidence in neuroimaging results and that it will be important to complement this with full details of the analysis pipelines and procedures that have been used to quantify data.ISSN:0271-678XISSN:1559-701

Quantitative imaging of mitochondrial and synaptic function in the human brain with 18F-BCPP-EF, 11C-SA-4503, and 11C-UCB-J

The ‘Molecular Imaging of Neurodegenerative Disease: Mitochondria, Associated Proteins & Synapses’ (MIND-MAPS) Consortium was formed to investigate three potential molecular markers of the mitochondrial/endoplasmic reticulum/synaptic axis dysfunction associated with neurodegeneration using positron emission tomography (PET) in the healthy human brain as well as across a number of neurodegenerative diseases. Mitochondrial complex-I (MC-I), sigma 1 receptor (S1R) and synaptic vesicle protein 2A (SV2A) can be quantified using PET radioligands 18F-BCPP-EF, 11C-SA-4503 and 11C-UCB-J, respectively, provided these ligands are selective for their targets, have suitable kinetics and produce a signal that can be analysed using an appropriate tracer kinetic model. The main contribution of this thesis was the identification and development of a set of optimal tracer kinetic models and PET image derived outcome measures for each of these radioligands to be implemented across the MIND-MAPS cohorts. The work presented on 18F-BCPP-EF (Chapter 4) was the first published quantification of this ligand in the human brain, and showed that the volume of distribution (VT), the VT normalised by the free plasma fraction (fp) and the distribution volume ratio (DVR) derived using either multilinear analysis 1 (MA1) or the two-tissue compartment model (2TC) can be reliably used to quantify MC-I with good reproducibility. The work presented on 11C-SA-4503 (Chapter 5) established MA1 as the optimal kinetic model for the quantification of S1R in the healthy human brain using either VT or VT/fp as outcome measures. Some of the drawbacks of the ligand including unreliable metabolite measurements and associated high intersubject variability of the outcome measures were elucidated and improvements suggested. The characterisation of 11C-UCB-J (Chapter 6) supported previous literature results by showing that the 1TC model is the optimal compartmental model to estimate VT with time stability results showing that scan time could be reduced to 60 minutes. VT/fp, DVR-1 (BPND=binding potential) and semiquantitative outcome measure SUVr-1 derived from a 20 minute static PET scan were also established as reliable outcome measures, adding confidence to the excellence of 11C-UCB-J as a tool for quantifying SV2A, and its suitability for regular use in clinical settings. In addition to establishing the appropriate tracer quantification methods, an investigation on the effects of healthy ageing on MC-I, S1R and SV2A (Chapter 7) demonstrated that there is age-related reduction of MC-I in the caudate as well in SV2A in both the caudate and thalamus regions, while S1R is mostly stable with age in healthy individuals. Altogether, the work presented in this thesis generated the optimal set of tracer kinetic modelling pipelines and outcome measures for the quantification of 18F-BCPP-EF, 11C-SA-4503 and 11C-UCB-J in humans, allowing for the implementation of consistent analytical methods across MIND-MAPS cohorts to enable the study of changes in the mitochondrial/endoplasmic reticulum/synaptic axis in ageing and neurodegeneration.Open Acces

Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: 18F-BCPP-EF, 11C-SA-4503, and 11C-UCB-J.

Mitochondrial complex 1 is involved in maintaining brain bioenergetics; σ-1 receptor responds to neuronal stress; and synaptic vesicle protein 2A reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here, we characterize the kinetic behavior of 3 PET radioligands-18F-BCPP-EF, 11C-SA-4503, and 11C-UCB-J-for the measurement of mitochondrial complex 1, σ-1 receptor, and synaptic vesicle protein 2A, respectively, and determine appropriate analysis workflows for their application in future studies of the in vivo molecular pathology of these diseases. Methods: Twelve human subjects underwent dynamic PET scans with each radioligand, including associated arterial blood sampling. A range of kinetic models was investigated to identify an optimal kinetic analysis method for each radioligand and a suitable acquisition duration. Results: All 3 radioligands readily entered the brain and yielded heterogeneous uptake consistent with the known distribution of the targets. The optimal models determined for the regional estimates of volume of distribution were multilinear analysis 1 (MA1) and the 2-tissue-compartment model for 18F-BCPP-EF, MA1 for 11C-SA-4503, and both MA1 and the 1-tissue-compartment model for 11C-UCB-J. Acquisition times of 70, 80, and 60 min for 18F-BCPP-EF, 11C-SA-4503, 11C-UCB-J, respectively, provided good estimates of regional volume of distribution values. An effect of age was observed on 18F-BCPP-EF and 11C-UCB-J signal in the caudate. Conclusion: These ligands can be assessed for their potential to stratify patients or monitor the progression of molecular neuropathology in neurodegenerative diseases

Endogenous dopamine release in the human brain as a pharmacodynamic biomarker:evaluation of the new GPR139 agonist TAK-041 with [¹¹C]PHNO PET

The use of positron emission tomography (PET) in early-phase development of novel drugs targeting the central nervous system, is well established for the evaluation of brain penetration and target engagement. However, when novel targets are involved a suitable PET ligand is not always available. We demonstrate an alternative approach that evaluates the attenuation of amphetamine-induced synaptic dopamine release by a novel agonist of the orphan G-protein-coupled receptor GPR139 (TAK-041). GPR139 agonism is a novel candidate mechanism for the treatment of schizophrenia and other disorders associated with social and cognitive dysfunction. Ten healthy volunteers underwent [(11)C]PHNO PET at baseline, and twice after receiving an oral dose of d-amphetamine (0.5 mg/kg). One of the post-d-amphetamine scans for each subject was preceded by a single oral dose of TAK-041 (20 mg in five; 40 mg in the other five participants). D-amphetamine induced a significant decrease in [(11)C]PHNO binding potential relative to the non-displaceable component (BP(ND)) in all regions examined (16–28%), consistent with increased synaptic dopamine release. Pre-treatment with TAK-041 significantly attenuated the d-amphetamine-induced reduction in BP(ND) in the a priori defined regions (putamen and ventral striatum: 26% and 18%, respectively). The reduction in BP(ND) was generally higher after the 40 mg than the 20 mg TAK-041 dose, with the difference between doses reaching statistical significance in the putamen. Our findings suggest that TAK-041 enters the human brain and interacts with GPR139 to affect endogenous dopamine release. [(11)C]PHNO PET is a practical method to detect the effects of novel drugs on the brain dopaminergic system in healthy volunteers, in the early stages of drug development

Mitochondrial Complex 1, Sigma 1, and Synaptic Vesicle 2A in Early Drug-Naive Parkinson's Disease

Background Dysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross‐sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug‐naive PD patients. Methods Twelve early drug‐naive PD patients and 16 healthy controls underwent a 3‐Tesla MRI and PET imaging to quantify volume of distribution of [11C]UCB‐J, [11C]SA‐4503, and [18F]BCPP‐EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1‐year follow‐up assessments. Results Reduced [11C]UCB‐J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug‐naive PD patients compared with healthy controls. [11C]UCB‐J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [11C]SA‐4503 and [18F]BCPP‐EF volume of distribution in PD compared with healthy controls. Lower brain stem [11C]UCB‐J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow‐up compared with baseline. Conclusions Our findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug‐naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow‐up will determine the validity of these PET markers to track disease progression. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia:a multimodal PET and magnetic resonance spectroscopy brain imaging study

Glutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ). Forty volunteers (SCZ n = 18, HV n = 22) underwent [(11)C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy ((1)H-MRS) imaging in the left hippocampus and anterior cingulate cortex (ACC) to index [(11)C]UCB-J distribution volume ratio (DVR), and creatine-scaled glutamate (Glu/Cr), glutamate and glutamine (Glx/Cr) and NAA (NAA/Cr). In healthy volunteers, but not patients, [(11)C]UCB-J DVR was significantly positively correlated with Glu/Cr, in both the hippocampus and ACC. Furthermore, in healthy volunteers, but not patients, [(11)C]UCB-J DVR was significantly positively correlated with Glx/Cr, in both the hippocampus and ACC. There were no significant relationships between [(11)C]UCB-J DVR and NAA/Cr in the hippocampus or ACC in healthy volunteers or patients. Therefore, an appreciable proportion of the brain (1)H-MRS glutamatergic signal is related to synaptic density in healthy volunteers. This relationship is not seen in schizophrenia, which, taken with lower synaptic marker levels, is consistent with lower levels of glutamatergic terminals and/or a lower proportion of glutamatergic relative to GABAergic terminals in the ACC in schizophrenia