Publications by authors named "Rainer Hinz"

63 Publications

Kinetic modeling and parameter estimation of TSPO PET imaging in the human brain.

Eur J Nucl Med Mol Imaging 2021 Mar 11. Epub 2021 Mar 11.

Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.

Purpose: Translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET) is widely used in research studies of brain diseases that have a neuro-immune component. Quantification of TSPO PET images, however, is associated with several challenges, such as the lack of a reference region, a genetic polymorphism affecting the affinity of the ligand for TSPO, and a strong TSPO signal in the endothelium of the brain vessels. These challenges have created an ongoing debate in the field about which type of quantification is most useful and whether there is an appropriate simplified model.

Methods: This review focuses on the quantification of TSPO radioligands in the human brain. The various methods of quantification are summarized, including the gold standard of compartmental modeling with metabolite-corrected input function as well as various alternative models and non-invasive approaches. Their advantages and drawbacks are critically assessed.

Results And Conclusions: Researchers employing quantification methods for TSPO should understand the advantages and limitations associated with each method. Suggestions are given to help researchers choose between these viable alternative methods.
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http://dx.doi.org/10.1007/s00259-021-05248-9DOI Listing
March 2021

Αlpha 5 subunit-containing GABA receptors in temporal lobe epilepsy with normal MRI.

Brain Commun 2021 7;3(1):fcaa190. Epub 2021 Jan 7.

Centre for Neuroscience, Department of Medicine, Imperial College London, London W12 0NN, UK.

GABA receptors containing the α5 subunit mediate tonic inhibition and are widely expressed in the limbic system. In animals, activation of α5-containing receptors impairs hippocampus-dependent memory. Temporal lobe epilepsy is associated with memory impairments related to neuron loss and other changes. The less selective PET ligand [C]flumazenil has revealed reductions in GABA receptors. The hypothesis that α5 subunit receptor alterations are present in temporal lobe epilepsy and could contribute to impaired memory is untested. We compared α5 subunit availability between individuals with temporal lobe epilepsy and normal structural MRI ('MRI-negative') and healthy controls, and interrogated the relationship between α5 subunit availability and episodic memory performance, in a cross-sectional study. Twenty-three healthy male controls (median ± interquartile age 49 ± 13 years) and 11 individuals with MRI-negative temporal lobe epilepsy (seven males; 40 ± 8) had a 90-min PET scan after bolus injection of [C]Ro15-4513, with arterial blood sampling and metabolite correction. All those with epilepsy and six controls completed the Adult Memory and Information Processing Battery on the scanning day. 'Bandpass' exponential spectral analyses were used to calculate volumes of distribution separately for the fast component [; dominated by signal from α1 (α2, α3)-containing receptors] and the slow component (; dominated by signal from α5-containing receptors). We made voxel-by-voxel comparisons between: the epilepsy and control groups; each individual case versus the controls. We obtained parametric maps of and measures from a single bolus injection of [C]Ro15-4513. The epilepsy group had higher in anterior medial and lateral aspects of the temporal lobes, the anterior cingulate gyri, the presumed area tempestas (piriform cortex) and the insulae, in addition to increases of ∼24% and ∼26% in the ipsilateral and contralateral hippocampal areas ( < 0.004). This was associated with reduced : ratios within the same areas ( < 0.009). Comparisons of for each individual with epilepsy versus controls did not consistently lateralize the epileptogenic lobe. Memory scores were significantly lower in the epilepsy group than in controls (mean ± standard deviation -0.4 ± 1.0 versus 0.7 ± 0.3;  = 0.02). In individuals with epilepsy, hippocampal did not correlate with memory performance on the Adult Memory and Information Processing Battery. They had reduced in the hippocampal area, which was significant ipsilaterally ( = 0.03), as expected from [C]flumazenil studies. We found increased tonic inhibitory neurotransmission in our cohort of MRI-negative temporal lobe epilepsy who also had co-morbid memory impairments. Our findings are consistent with a subunit shift from α1/2/3 to α5 in MRI-negative temporal lobe epilepsy.
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http://dx.doi.org/10.1093/braincomms/fcaa190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811756PMC
January 2021

Brain Microglial Activation Increased in Glucocerebrosidase (GBA) Mutation Carriers without Parkinson's disease.

Mov Disord 2021 03 5;36(3):774-779. Epub 2020 Dec 5.

Department of Clinical and Movement Neurosciences, Institute of Neurology, UCL, London, UK.

Background: Glucocerebrosidase gene mutations are a common genetic risk factor for Parkinson's disease. They exhibit incomplete penetrance. The objective of the present study was to measure microglial activation and dopamine integrity in glucocerebrosidase gene mutation carriers without Parkinson's disease compared to controls.

Methods: We performed PET scans on 9 glucocerebrosidase gene mutation carriers without Parkinson's disease and 29 age-matched controls. We measured microglial activation as C-(R)-PK11195 binding potentials, and dopamine terminal integrity with F-dopa influx constants.

Results: The C-(R)-PK11195 binding potential was increased in the substantia nigra of glucocerebrosidase gene carriers compared with controls (Student t test; right, t = -4.45, P = 0.0001). Statistical parametric mapping also localized significantly increased C-(R)-PK11195 binding potential in the occipital and temporal lobes, cerebellum, hippocampus, and mesencephalon. The degree of hyposmia correlated with nigral C-(R)-PK11195 regional binding potentials (Spearman's rank, P = 0.0066). Mean striatal F-dopa uptake was similar to healthy controls.

Conclusions: In vivo C-(R)-PK11195 PET imaging detects neuroinflammation in brain regions susceptible to Lewy pathology in glucocerebrosidase gene mutation carriers without Parkinson's. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048428PMC
March 2021

P-glycoprotein overactivity in epileptogenic developmental lesions measured in vivo using (R)-[ C]verapamil PET.

Epilepsia 2020 07 6;61(7):1472-1480. Epub 2020 Jul 6.

Department of Clinical and Experimental Epilepsy, University College London Queen Square Institute of Neurology, London, UK.

Objective: Overexpression of the drug transporter P-glycoprotein (P-gp) is thought to be involved in drug-resistance in epilepsy by extrusion of antiepileptic drugs (AEDs). We used positron emission tomography (PET) and the P-gp substrate radiotracer (R)-[ C]verapamil (VPM) together with the third-generation P-gp inhibitor tariquidar (TQD) to evaluate P-gp function in individuals with drug-resistant epileptogenic developmental lesions.

Methods: Twelve healthy controls (7 male, median age 45, range 35-55 years), and two patients with epileptogenic developmental lesions (2 male, aged 24 and 62 years) underwent VPM-PET scans before and 60 minutes after a 30-minute infusion of 2 and 3 mg/kg TQD. The influx rate constant, VPM-K , was estimated from the first 10 minutes of dynamic data using a single-tissue compartment model with a VPM plasma input function. Statistical parametric mapping (SPM) analysis was used to compare individual patients with the healthy controls.

Results: At baseline, SPM voxel-based analysis revealed significantly lower uptake of VPM corresponding to the area of the epileptogenic developmental lesion compared to 12 healthy controls (P < .048). This was accentuated following P-gp inhibition with TQD. After TQD, the uptake of VPM was significantly lower in the area of the epileptogenic developmental lesion compared to controls (P < .002).

Significance: This study provides further evidence of P-gp overactivity in patients with drug-resistant epilepsy, irrespective of the type of lesion. Identifying P-gp overactivity as an underlying contributor to drug-resistance in individual patients will enable novel treatment strategies aimed at overcoming or reversing P-gp overactivity.
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http://dx.doi.org/10.1111/epi.16581DOI Listing
July 2020

Neuroinflammation as measured by positron emission tomography in patients with recent onset and established schizophrenia: implications for immune pathogenesis.

Mol Psychiatry 2020 Jun 30. Epub 2020 Jun 30.

Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK.

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), which is upregulated in activated microglia, is a method for investigating whether immune activation is evident in the brain of adults with schizophrenia. This study aimed to measure TSPO availability in the largest patient group to date, and to compare it between patients with recent onset (ROS) and established (ES) schizophrenia. In total, 20 ROS patients (14 male), 21 ES (13 male), and 21 healthy controls completed the study. Patients were predominantly antipsychotic-medicated. Participants underwent a PET scan using the TSPO-specific radioligand [C](R)-PK11195. The primary outcome was binding potential (BP) in the anterior cingulate cortex (ACC). Secondary outcomes were BP in six other regions. Correlations were investigated between TSPO availability and symptom severity. Data showed that mean BP was higher in older (ES and controls) compared with younger (ROS and controls) individuals, but did not significantly differ between ROS or ES and their respective age-matched controls (ACC; ANOVA main effect of diagnosis: F = 0.407, p = 0.526). Compared with controls, BP was lower in antipsychotic-free (n = 6), but not in medicated, ROS patients. BP in the ES group was negatively correlated with positive symptoms, and positively correlated with negative symptom score. Our data suggest ageing is associated with higher TSPO but a diagnosis of schizophrenia is not. Rather, subnormal TSPO levels in drug-free recent-onset patients may imply impaired microglial development and/or function, which is counteracted by antipsychotic treatment. The development of novel radioligands for specific immune-mechanisms is needed for further clarification.
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http://dx.doi.org/10.1038/s41380-020-0829-yDOI Listing
June 2020

Decreased GABA-A Receptor Binding in Association With β-Lactam Antibiotic Use.

Clin Nucl Med 2019 Dec;44(12):981-982

School of Biomedical Engineering & Imaging Sciences, King's College London, and Guy's and St Thomas' PET Centre, St Thomas' Hospital.

β-Lactam antibiotics are proconvulsive. In laboratory animals, this effect seems to be predominantly mediated through inhibition of GABA-A receptors, but it has not been demonstrated in humans in vivo. We report images of a [C]Ro15-4513 PET from a 40-year-old man who had completed a 1-week course of flucloxacillin before it. Relative to healthy controls, the participant had significantly lower mean gray matter binding. These novel data suggest that, in humans, the proconvulsive effect of β-lactam antibiotics is mediated via either competition for the same benzodiazepine-binding site as [C]Ro15-4513 or downregulation of GABA-A receptor expression.
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http://dx.doi.org/10.1097/RLU.0000000000002811DOI Listing
December 2019

Tau Aggregation Correlates with Amyloid Deposition in Both Mild Cognitive Impairment and Alzheimer's Disease Subjects.

J Alzheimers Dis 2019 ;70(2):455-465

Neurology Imaging Unit, Department of Medicine, Imperial College London, London, UK.

Background: Amyloid plaque and tau-containing neurofibrillary tangles are important features of Alzheimer's disease (AD). However, the relationship between these processes is still debated.

Objective: We aimed to investigate local and distant relationships between tau and amyloid deposition in the cortex in mild cognitive impairment (MCI) and AD using PET imaging.

Methods: Seventy-nine subjects (51 controls, 13 amyloid-positive MCI subjects, and 15 amyloid positive AD subjects) underwent MRI and 18F-flutemetamol PET. All MCI/AD subjects and 8 healthy controls as well as 33 healthy control subjects from the ADNI dataset also had 18F-AV1451 PET. Regional and distant correlations were examined after sampling target-to-cerebellar ratio images. Biological parametric mapping was used to evaluate voxel level correlations locally.

Results: We found multiple clusters of voxels with highly significant positive correlations throughout the association cortex in both MCI and AD subjects.

Conclusion: The multiple clusters of positive correlations indicate that tau and amyloid may interact locally and be involved in disease progression. Our findings suggest that targeting both pathologies may be required.
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http://dx.doi.org/10.3233/JAD-181168DOI Listing
October 2020

Microglial activation in early Alzheimer trajectory is associated with higher gray matter volume.

Neurology 2019 03 22;92(12):e1331-e1343. Epub 2019 Feb 22.

From the Department of Medicine (G.D.F., M.D., M.W., Z.F., V.C., R.A., D.J.B., P.E.), Imperial College London; Department of Psychology (T.E.), University of London, London; Wolfson Molecular Imaging Centre (R.H.), University of Manchester, UK; and Department of Nuclear Medicine (D.J.B.), Aarhus University, Denmark.

Objective: To investigate the influence of microglial activation in the early stages of Alzheimer's disease trajectory, we assessed the relationship between microglial activation and gray matter volume and hippocampal volume in patients with mild cognitive impairment (MCI).

Methods: In this study, 55 participants (37 with early stages of MCI and 18 controls) underwent [C]PBR28 PET, a marker of microglial activation; volumetric MRI to evaluate gray matter and hippocampal volumes as well as clinical and neuropsychometric evaluation. [C]PBR28 V (volume of distribution) was calculated using arterial input function and Logan graphical analysis. Gray matter volume and hippocampal volumes were calculated from MRI for each participant. Statistical parametric mapping software was used to perform voxel-wise correlations and biological parametric mapping analysis. Amyloid status was assessed using [F]flutemetamol PET.

Results: Higher [C]PBR28 V in different cortical areas correlated with higher gray matter volume in both amyloid-positive and -negative MCI. In addition, higher hippocampal volume correlated with higher cortical [C]PBR28 Logan V.

Conclusions: In this in vivo study, we have demonstrated that microglial activation quantified using [C]PBR28 PET was associated with higher gray matter volume and higher hippocampal volume in patients with MCI. This might suggest that microglial activation may not always be associated with neuronal damage, and indeed it may have a beneficial effect in the early stages of the Alzheimer trajectory. While further longitudinal studies are necessary, these findings have significant implications on therapeutic strategies targeting microglial activation.
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http://dx.doi.org/10.1212/WNL.0000000000007133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511099PMC
March 2019

[18F]Florbetapir positron emission tomography: identification of muscle amyloid in inclusion body myositis and differentiation from polymyositis.

Ann Rheum Dis 2019 05 13;78(5):657-662. Epub 2019 Feb 13.

The National Institute for Health Research Manchester Musculoskeletal Biomedical Research Centre, Manchester University Hospitals NHS FoundationTrust, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.

Objectives: With the tools available currently, confirming the diagnosis of inclusion body myositis (IBM) can be difficult. Many patients are initially misdiagnosed with polymyositis (PM). In this observational study at a UK adult neuromuscular centre, we investigated whether amyloid positron emission tomography could differentiate between IBM and PM.

Methods: Ten patients with IBM and six with PM underwent clinical review, [18F]florbetapir positron emission tomography and MRI of skeletal musculature. Differences in [18F]florbetapir standardised uptake value ratios in skeletal muscle regions of interest were evaluated. Relationships between [18F]florbetapir standardised uptake value ratios and measures of disease severity (clinical and by MRI of skeletal muscle) were assessed.

Results: [18F]florbetapir standardised uptake value ratios were significantly higher in those with IBM compared with PM for all assessed regions (total-[18F]florbetapir standardised uptake value ratio 1.45 (1.28 to 2.05) vs 1.01 (0.80 to 1.22), p=0.005). For total-[18F]florbetapir standardised uptake value ratios≥1.28, sensitivity and specificity for IBM was 80% and 100%, respectively.

Conclusions: [18F]florbetapir amyloid positron emission tomography differentiates IBM from PM. Successful development could facilitate accurate diagnosis, inclusion in clinical trials and help avoid unnecessary exposure to potentially harmful treatments.
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http://dx.doi.org/10.1136/annrheumdis-2018-214644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517800PMC
May 2019

Dual-phase [18F]florbetapir in frontotemporal dementia.

Eur J Nucl Med Mol Imaging 2019 02 19;46(2):304-311. Epub 2018 Dec 19.

Wolfson Molecular Imaging Centre, Faculty of Medicine, Biology and Health, University of Manchester, 27 Palatine Road, Manchester, M20 3LJ, UK.

Purpose: The PET tracer [18F]florbetapir is a specific fibrillar amyloid-beta (Aβ) biomarker. During the late scan phase (> 40 min), it provides pathological information about Aβ status. Early scan phase (0-10 min) can provide FDG-'like' information. The current investigation tested the feasibility of using florbetapir as a dual-phase biomarker in behavioural variant frontotemporal dementia (bvFTD).

Methods: Eight bvFTD patients underwent [18F]florbetapir and [18]FDG-PET scans. Additionally, ten healthy controls and ten AD patients underwent florbetapir-PET only. PET data were acquired dynamically for 60-min post-injection. The bvFTD PET data were used to define an optimal time window, representing blood flow-related pseudo-metabolism ('pseudo-FDG'), of florbetapir data that maximally correlated with the corresponding real FDG SUVR (40-60 min) in a composite neocortical FTD region.

Results: A 2 to 5-min time window post-injection of the florbetapir-PET data provided the largest correlation (Pearson's r = 0.79, p = 0.02) to the FDG data. The pseudo-FDG images demonstrated strong internal consistency with actual FDG data and were also visually consistent with the bvFTD patients' hypometabolic profiles. The ability to identify bvFTD from blind visual rating of pseudo-FDG images was consistent with previous reports using FDG data (sensitivity = 75%, specificity = 85%).

Conclusions: This investigation demonstrates that early phase florbetapir uptake shows a reduction of frontal lobe perfusion in bvFTD, similar to metabolic findings with FDG. Thus, dynamic florbetapir scans can serve as a dual-phase biomarker in dementia patients to distinguish FTD from AD and cognitively normal elderly, removing the need for a separate FDG-PET scan in challenging dementia cases.
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http://dx.doi.org/10.1007/s00259-018-4238-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333719PMC
February 2019

Resilience to cognitive impairment in the oldest-old: design of the EMIF-AD 90+ study.

BMC Geriatr 2018 11 26;18(1):289. Epub 2018 Nov 26.

Department of Medicine and Aged Care, @AgeMelbourne, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia.

Background: The oldest-old (subjects aged 90 years and older) population represents the fastest growing segment of society and shows a high dementia prevalence rate of up to 40%. Only a few studies have investigated protective factors for cognitive impairment in the oldest-old. The EMIF-AD 90+ Study aims to identify factors associated with resilience to cognitive impairment in the oldest-old. In this paper we reviewed previous studies on cognitive resilience in the oldest-old and described the design of the EMIF-AD 90+ Study.

Methods: The EMIF-AD 90+ Study aimed to enroll 80 cognitively normal subjects and 40 subjects with cognitive impairment aged 90 years or older. Cognitive impairment was operationalized as amnestic mild cognitive impairment (aMCI), or possible or probable Alzheimer's Disease (AD). The study was part of the European Medical Information Framework for AD (EMIF-AD) and was conducted at the Amsterdam University Medical Centers (UMC) and at the University of Manchester. We will test whether cognitive resilience is associated with cognitive reserve, vascular comorbidities, mood, sleep, sensory system capacity, physical performance and capacity, genetic risk factors, hallmarks of ageing, and markers of neurodegeneration. Markers of neurodegeneration included an amyloid positron emission tomography, amyloid β and tau in cerebrospinal fluid/blood and neurophysiological measures.

Discussion: The EMIF-AD 90+ Study will extend our knowledge on resilience to cognitive impairment in the oldest-old by extensive phenotyping of the subjects and the measurement of a wide range of potential protective factors, hallmarks of aging and markers of neurodegeneration.

Trial Registration: Nederlands Trial Register NTR5867 . Registered 20 May 2016.
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http://dx.doi.org/10.1186/s12877-018-0984-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258163PMC
November 2018

Inflammation and vascular permeability correlate with growth in sporadic vestibular schwannoma.

Neuro Oncol 2019 02;21(3):314-325

Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

Background: Inflammation is hypothesized to be a key event in the growth of sporadic vestibular schwannoma (VS). In this study we sought to investigate the relationship between inflammation and tumor growth in vivo using the PET tracer 11C-(R)-PK11195 and dynamic contrast enhanced (DCE) MRI derived vascular biomarkers.

Methods: Nineteen patients with sporadic VS (8 static, 7 growing, and 4 shrinking tumors) underwent prospective imaging with dynamic 11C-(R)-PK11195 PET and a comprehensive MR protocol, including high temporal resolution DCE-MRI in 15 patients. An intertumor comparison of 11C-(R)-PK11195 binding potential (BPND) and DCE-MRI derived vascular biomarkers (Ktrans, vp, ve) across the 3 different tumor growth cohorts was undertaken. Tissue of 8 tumors was examined with immunohistochemistry markers for inflammation (Iba1), neoplastic cells (S-100 protein), vessels (CD31), the PK11195 target translocator protein (TSPO), fibrinogen for vascular permeability, and proliferation (Ki-67). Results were correlated with PET and DCE-MRI data.

Results: Compared with static tumors, growing VS displayed significantly higher mean 11C-(R)-PK11195 BPND (-0.07 vs 0.47, P = 0.020), and higher mean tumor Ktrans (0.06 vs 0.14, P = 0.004). Immunohistochemistry confirmed the imaging findings and demonstrated that TSPO is predominantly expressed in macrophages. Within growing VS, macrophages rather than tumor cells accounted for the majority of proliferating cells.

Conclusion: We present the first in vivo imaging evidence of increased inflammation within growing sporadic VS. Our results demonstrate that 11C-(R)-PK11195 specific binding and DCE-MRI derived parameters can be used as imaging biomarkers of inflammation and vascular permeability in this tumor group.
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http://dx.doi.org/10.1093/neuonc/noy177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380424PMC
February 2019

Comment on " In Vivo [F]GE-179 Brain Signal Does Not Show NMDA-Specific Modulation with Drug Challenges in Rodents and Nonhuman Primates".

ACS Chem Neurosci 2019 01 11;10(1):768-772. Epub 2018 Oct 11.

School of Biomedical Engineering and Imaging Sciences , King's College London , London SE1 7EH , United Kingdom.

Schoenberger and colleagues ( Schoenberger et al. ( 2018 ) ACS Chem. Neurosci. 9 , 298 - 305 ) recently reported attempts to demonstrate specific binding of the positron emission tomography (PET) radiotracer, [F]GE-179, to NMDA receptors in both rats and Rhesus macaques. GE-179 did not work as expected in animal models; however, we disagree with the authors' conclusion that "the [F]GE-179 signal seems to be largely nonspecific". It is extremely challenging to demonstrate specific binding for the use-dependent NMDA receptor intrachannel ligands such as [F]GE-179 in animals via traditional blocking, due to its low availability of target sites ( B). Schoenberger and colleagues anesthetized rats and Rhesus monkeys using isoflurane, which has an inhibitory effect on NMDA receptor function and thus would be expected to further reduce the B. The extent of glutamate release achieved in the provocation experiments is uncertain, as is whether a significant increase in NMDA receptor channel opening can be expected under anesthesia. Prior data suggest that the uptake of disubstituted arylguanidine-based ligands such as GE-179 can be reduced by phencyclidine binding site antagonists, if injection is performed in the absence of ketamine and isoflurane anesthesia, e.g., with GE-179's antecedent, CNS 5161 ( Biegon et al. ( 2007 ) Synapse 61 , 577 - 586 ), and with GMOM ( van der Doef et al. ( 2016 ) J. Cereb. Blood Flow Metab. 36 , 1111 - 1121 ). However, the extent of nonspecific uptake remains uncertain.
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http://dx.doi.org/10.1021/acschemneuro.8b00246DOI Listing
January 2019

The EMIF-AD PreclinAD study: study design and baseline cohort overview.

Alzheimers Res Ther 2018 08 4;10(1):75. Epub 2018 Aug 4.

Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Amsterdam, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.

Background: Amyloid pathology is the pathological hallmark in Alzheimer's disease (AD) and can precede clinical dementia by decades. So far it remains unclear how amyloid pathology leads to cognitive impairment and dementia. To design AD prevention trials it is key to include cognitively normal subjects at high risk for amyloid pathology and to find predictors of cognitive decline in these subjects. These goals can be accomplished by targeting twins, with additional benefits to identify genetic and environmental pathways for amyloid pathology, other AD biomarkers, and cognitive decline.

Methods: From December 2014 to October 2017 we enrolled cognitively normal participants aged 60 years and older from the ongoing Manchester and Newcastle Age and Cognitive Performance Research Cohort and the Netherlands Twins Register. In Manchester we included single individuals, and in Amsterdam monozygotic twin pairs. At baseline, participants completed neuropsychological tests and questionnaires, and underwent physical examination, blood sampling, ultrasound of the carotid arteries, structural and resting state functional brain magnetic resonance imaging, and dynamic amyloid positron emission tomography (PET) scanning with [F]flutemetamol. In addition, the twin cohort underwent lumbar puncture for cerebrospinal fluid collection, buccal cell collection, magnetoencephalography, optical coherence tomography, and retinal imaging.

Results: We included 285 participants, who were on average 74.8 ± 9.7 years old, 64% female. Fifty-eight participants (22%) had an abnormal amyloid PET scan.

Conclusions: A rich baseline dataset of cognitively normal elderly individuals has been established to estimate risk factors and biomarkers for amyloid pathology and future cognitive decline.
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http://dx.doi.org/10.1186/s13195-018-0406-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091034PMC
August 2018

Microglial activation correlates in vivo with both tau and amyloid in Alzheimer's disease.

Brain 2018 09;141(9):2740-2754

Neurology Imaging Unit, Department of Medicine, Imperial College London, Hammersmith Hospital, UK.

Alzheimer's disease is characterized by the histopathological presence of amyloid-β plaques and tau-containing neurofibrillary tangles. Microglial activation is also a recognized pathological component. The relationship between microglial activation and protein aggregation is still debated. We investigated the relationship between amyloid plaques, tau tangles and activated microglia using PET imaging. Fifty-one subjects (19 healthy controls, 16 mild cognitive impairment and 16 Alzheimer's disease subjects) participated in the study. All subjects had neuropsychometric testing, MRI, amyloid (18F-flutemetamol), and microglial (11C-PBR28) PET. All subjects with mild cognitive impairment and Alzheimer's disease and eight of the controls had tau (18F-AV1451) PET. 11C-PBR28 PET was analysed using Logan graphical analysis with an arterial plasma input function, while 18F-flutemetamol and 18F-AV1451 PET were analysed as target:cerebellar ratios to create parametric standardized uptake value ratio maps. Biological parametric mapping in the Statistical Parametric Mapping platform was used to examine correlations between uptake of tracers at a voxel-level. There were significant widespread clusters of positive correlation between levels of microglial activation and tau aggregation in both the mild cognitive impairment (amyloid-positive and amyloid-negative) and Alzheimer's disease subjects. The correlations were stronger in Alzheimer's disease than in mild cognitive impairment, suggesting that these pathologies increase together as disease progresses. Levels of microglial activation and amyloid deposition were also correlated, although in a different spatial distribution; correlations were stronger in mild cognitive impairment than Alzheimer's subjects, in line with a plateauing of amyloid load with disease progression. Clusters of positive correlations between microglial activation and protein aggregation often targeted similar areas of association cortex, indicating that all three processes are present in specific vulnerable brain areas. For the first time using PET imaging, we show that microglial activation can correlate with both tau aggregation and amyloid deposition. This confirms the complex relationship between these processes. These results suggest that preventative treatment for Alzheimer's disease should target all three processes.
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http://dx.doi.org/10.1093/brain/awy188DOI Listing
September 2018

In vivo quantification of glial activation in minipigs overexpressing human α-synuclein.

Synapse 2018 12 12;72(12):e22060. Epub 2018 Aug 12.

Department of Nuclear Medicine and PET Center, Institute of Clinical Medicine, Aarhus University and Hospital, Aarhus, Denmark.

Parkinson's disease is characterized by a progressive loss of substantia nigra (SN) dopaminergic neurons and the formation of Lewy bodies containing accumulated alpha-synuclein (α-syn). The pathology of Parkinson's disease is associated with neuroinflammatory microglial activation, which may contribute to the ongoing neurodegeneration. This study investigates the in vivo microglial and dopaminergic response to overexpression of α-syn. We used positron emission tomography (PET) and the 18 kDa translocator protein radioligand, [ C](R)PK11195, to image brain microglial activation and (+)-α-[ C]dihydrotetrabenazine ([ C]DTBZ), to measure vesicular monoamine transporter 2 (VMAT2) availability in Göttingen minipigs following injection with recombinant adeno-associated virus (rAAV) vectors expressing either mutant A53T α-syn or green fluorescent protein (GFP) into the SN (4 rAAV-α-syn, 4 rAAV-GFP, 5 non-injected control minipigs). We performed motor symptom assessment and immunohistochemical examination of tyrosine hydroxylase (TH) and transgene expression. Expression of GFP and α-syn was observed at the SN injection site and in the striatum. We observed no motor symptoms or changes in striatal [ C]DTBZ binding potential in vivo or striatal or SN TH staining in vitro between the groups. The mean [ C](R)PK11195 total volume of distribution was significantly higher in the basal ganglia and cortical areas of the α-syn group than the control animals. We conclude that mutant α-syn expression in the SN resulted in microglial activation in multiple sub- and cortical regions, while it did not affect TH stains or VMAT2 availability. Our data suggest that microglial activation constitutes an early response to accumulation of α-syn in the absence of dopamine neuron degeneration.
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http://dx.doi.org/10.1002/syn.22060DOI Listing
December 2018

Does inflammation precede tau aggregation in early Alzheimer's disease? A PET study.

Neurobiol Dis 2018 09 11;117:211-216. Epub 2018 Jun 11.

Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark; Division of Neuroscience, Newcastle University, Newcastle, UK.

Objective: Our aim was to assess with positron emission tomography (PET) the temporal and spatial inter-relationships between levels of cortical microglial activation and the aggregated amyloid-β and tau load in mild cognitive impairment (MCI) and early Alzheimer's disease (AD).

Methods: Six clinically probable AD and 20 MCI subjects had inflammation (C-(R)-PK11195), amyloid (C-PiB) and tau (F-flortaucipir) PET, magnetic resonance imaging (MRI) and a neuropsychological assessment. Parametric images of tracer binding were interrogated at a voxel level and by region of interest analyses.

Results: 55% of MCI and 83% of AD subjects had a high amyloid-β load. We have previously reported that clusters of correlated amyloid and inflammation levels are present in cortex. Here we found no correlation between levels of inflammation (C-(R)-PK11195 BP) and tau (F-flortaucipir SUVR) or MMSE scores in high amyloid-β cases.

Interpretation: While correlated levels of amyloid-β and inflammation can be seen in MCI, we did not detect an association between levels of cortical tau tangles and inflammation in our series of high amyloid-β cases. High levels of inflammation could be seen in amyloid-β positive MCI cases where F-flortaucipir signals were low suggesting microglial activation precedes tau tangle formation. Inflammation levels were higher in high amyloid-β MCI than in early AD cases, compatible with it initially playing a protective role.
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http://dx.doi.org/10.1016/j.nbd.2018.06.004DOI Listing
September 2018

Simplifying [F]GE-179 PET: are both arterial blood sampling and 90-min acquisitions essential?

EJNMMI Res 2018 Jun 11;8(1):46. Epub 2018 Jun 11.

Division of Brain Sciences, Imperial College London, London, UK.

Introduction: The NMDA receptor radiotracer [F]GE-179 has been used with 90-min scans and arterial plasma input functions. We explored whether (1) arterial blood sampling is avoidable and (2) shorter scans are feasible.

Methods: For 20 existing [F]GE-179 datasets, we generated (1) standardised uptake values (SUVs) over eight intervals; (2) volume of distribution (V) images using population-based input functions (PBIFs), scaled using one parent plasma sample; and (3) V images using three shortened datasets, using the original parent plasma input functions (ppIFs).

Results: Correlations with the original ppIF-derived 90-min Vs increased for later interval SUVs (maximal ρ = 0.78; 80-90 min). They were strong for PBIF-derived Vs (ρ = 0.90), but between-subject coefficient of variation increased. Correlations were very strong for the 60/70/80-min original ppIF-derived Vs (ρ = 0.97-1.00), which suffered regionally variant negative bias.

Conclusions: Where arterial blood sampling is available, reduction of scan duration to 60 min is feasible, but with negative bias. The performance of SUVs was more consistent across participants than PBIF-derived Vs.
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http://dx.doi.org/10.1186/s13550-018-0396-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995767PMC
June 2018

Parametric mapping using spectral analysis for C-PBR28 PET reveals neuroinflammation in mild cognitive impairment subjects.

Eur J Nucl Med Mol Imaging 2018 07 9;45(8):1432-1441. Epub 2018 Mar 9.

Department of Medicine, Neurology Imaging Unit, Imperial College London, London, W12 0NN, UK.

Purpose: Neuroinflammation and microglial activation play an important role in amnestic mild cognitive impairment (MCI) and Alzheimer's disease. In this study, we investigated the spatial distribution of neuroinflammation in MCI subjects, using spectral analysis (SA) to generate parametric maps and quantify C-PBR28 PET, and compared these with compartmental and other kinetic models of quantification.

Methods: Thirteen MCI and nine healthy controls were enrolled in this study. Subjects underwent C-PBR28 PET scans with arterial cannulation. Spectral analysis with an arterial plasma input function was used to generate C-PBR28 parametric maps. These maps were then compared with regional C-PBR28 V (volume of distribution) using a two-tissue compartment model and Logan graphic analysis. Amyloid load was also assessed with F-Flutemetamol PET.

Results: With SA, three component peaks were identified in addition to blood volume. The C-PBR28 impulse response function (IRF) at 90 min produced the lowest coefficient of variation. Single-subject analysis using this IRF demonstrated microglial activation in five out of seven amyloid-positive MCI subjects. IRF parametric maps of C-PBR28 uptake revealed a group-wise significant increase in neuroinflammation in amyloid-positive MCI subjects versus HC in multiple cortical association areas, and particularly in the temporal lobe. Interestingly, compartmental analysis detected group-wise increase in C-PBR28 binding in the thalamus of amyloid-positive MCI subjects, while Logan parametric maps did not perform well.

Conclusions: This study demonstrates for the first time that spectral analysis can be used to generate parametric maps of C-PBR28 uptake, and is able to detect microglial activation in amyloid-positive MCI subjects. IRF parametric maps of C-PBR28 uptake allow voxel-wise single-subject analysis and could be used to evaluate microglial activation in individual subjects.
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http://dx.doi.org/10.1007/s00259-018-3984-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993844PMC
July 2018

Microglial activation, white matter tract damage, and disability in MS.

Neurol Neuroimmunol Neuroinflamm 2018 May 6;5(3):e443. Epub 2018 Mar 6.

Turku PET Centre (E.R., J.T., M.S., J.R., J.O.R.), Division of Clinical Neurosciences (E.R., M.S., J.O.R., L.A.), Department of Biostatistics (T.V.), and Medical Imaging Centre of Southwest Finland (T.P., R.P.), Turku University Hospital and University of Turku, Finland; Division of Neuroscience and Experimental Psychology (A.G.), University of Manchester, United Kingdom; Department of Nuclear Medicine and Geriatric Medicine (A.G.), University Hospital Essen, Germany; and Wolfson Molecular Imaging Centre (R.H., P.S.T.), University of Manchester, United Kingdom.

Objective: To investigate the relationship of in vivo microglial activation to clinical and MRI parameters in MS.

Methods: Patients with secondary progressive MS (n = 10) or relapsing-remitting MS (n = 10) and age-matched healthy controls (n = 17) were studied. Microglial activation was measured using PET and radioligand [C]()-PK11195. Clinical assessment and structural and quantitative MRI including diffusion tensor imaging (DTI) were performed for comparison.

Results: [C]()-PK11195 binding was significantly higher in the normal-appearing white matter (NAWM) of patients with secondary progressive vs relapsing MS and healthy controls, in the thalami of patients with secondary progressive MS vs controls, and in the perilesional area among the progressive compared with relapsing patients. Higher binding in the NAWM was associated with higher clinical disability and reduced white matter (WM) structural integrity, as shown by lower fractional anisotropy, higher mean diffusivity, and increased WM lesion load. Increasing age contributed to higher microglial activation in the NAWM among patients with MS but not in healthy controls.

Conclusions: PET can be used to quantitate microglial activation, which associates with MS progression. This study demonstrates that increased microglial activity in the NAWM correlates closely with impaired WM structural integrity and thus offers one rational pathologic correlate to diffusion tensor imaging (DTI) parameters.
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http://dx.doi.org/10.1212/NXI.0000000000000443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840890PMC
May 2018

Assessing Inflammation in Acute Intracerebral Hemorrhage with PK11195 PET and Dynamic Contrast-Enhanced MRI.

J Neuroimaging 2018 03 24;28(2):158-161. Epub 2017 Oct 24.

Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.

Background And Purpose: Studies in animal models suggest that inflammation is a major contributor to secondary injury after intracerebral hemorrhage (ICH). Direct, noninvasive monitoring of inflammation in the human brain after ICH will facilitate early-phase development of anti-inflammatory treatments. We sought to investigate the feasibility of multimodality brain imaging in subacute ICH.

Methods: Acute ICH patients were recruited to undergo multiparametric MRI (including dynamic contrast-enhanced measurement of blood-brain barrier transfer constant (K ) and PET with [ C]-(R)-PK11195). [ C]-(R)-PK11195 binds to the translocator protein 18 kDa (TSPO), which is rapidly upregulated in activated microglia. Circulating inflammatory markers were measured at the time of PET.

Results: Five patients were recruited to this feasibility study with imaging between 5 and 16 days after onset. Etiologies included hypertension-related small vessel disease, cerebral amyloid angiopathy (CAA), cavernoma, and arteriovenous malformation (AVM). [ C]-(R)-PK11195 binding was low in all hematomas and 2 (patient 2 [probable CAA] and 4 [AVM]) cases showed widespread increase in binding in the perihematomal region versus contralateral. All had increased K in the perihematomal region (mean difference = 2.2 × 10 minute ; SD = 1.6 × 10 minute ) versus contralateral. Two cases (patients 1 [cavernoma] and 4 [AVM]) had delayed surgery (3 and 12 months post-onset, respectively) with biopsies showing intense microglial activation in perilesional tissue.

Conclusions: Our study demonstrates for the first time the feasibility of performing complex multimodality brain imaging for noninvasive monitoring of neuroinflammation for this severe stroke subtype.
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http://dx.doi.org/10.1111/jon.12477DOI Listing
March 2018

Assessing Inflammation in Acute Intracerebral Hemorrhage with PK11195 PET and Dynamic Contrast-Enhanced MRI.

J Neuroimaging 2018 03 24;28(2):158-161. Epub 2017 Oct 24.

Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.

Background And Purpose: Studies in animal models suggest that inflammation is a major contributor to secondary injury after intracerebral hemorrhage (ICH). Direct, noninvasive monitoring of inflammation in the human brain after ICH will facilitate early-phase development of anti-inflammatory treatments. We sought to investigate the feasibility of multimodality brain imaging in subacute ICH.

Methods: Acute ICH patients were recruited to undergo multiparametric MRI (including dynamic contrast-enhanced measurement of blood-brain barrier transfer constant (K ) and PET with [ C]-(R)-PK11195). [ C]-(R)-PK11195 binds to the translocator protein 18 kDa (TSPO), which is rapidly upregulated in activated microglia. Circulating inflammatory markers were measured at the time of PET.

Results: Five patients were recruited to this feasibility study with imaging between 5 and 16 days after onset. Etiologies included hypertension-related small vessel disease, cerebral amyloid angiopathy (CAA), cavernoma, and arteriovenous malformation (AVM). [ C]-(R)-PK11195 binding was low in all hematomas and 2 (patient 2 [probable CAA] and 4 [AVM]) cases showed widespread increase in binding in the perihematomal region versus contralateral. All had increased K in the perihematomal region (mean difference = 2.2 × 10 minute ; SD = 1.6 × 10 minute ) versus contralateral. Two cases (patients 1 [cavernoma] and 4 [AVM]) had delayed surgery (3 and 12 months post-onset, respectively) with biopsies showing intense microglial activation in perilesional tissue.

Conclusions: Our study demonstrates for the first time the feasibility of performing complex multimodality brain imaging for noninvasive monitoring of neuroinflammation for this severe stroke subtype.
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http://dx.doi.org/10.1111/jon.12477DOI Listing
March 2018

Brain inflammation accompanies amyloid in the majority of mild cognitive impairment cases due to Alzheimer's disease.

Brain 2017 Jul;140(7):2002-2011

Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark.

See Kreisl (doi:10.1093/awx151) for a scientific commentary on this article.Subjects with mild cognitive impairment associated with cortical amyloid-β have a greatly increased risk of progressing to Alzheimer's disease. We hypothesized that neuroinflammation occurs early in Alzheimer's disease and would be present in most amyloid-positive mild cognitive impairment cases. 11C-Pittsburgh compound B and 11C-(R)-PK11195 positron emission tomography was used to determine the amyloid load and detect the extent of neuroinflammation (microglial activation) in 42 mild cognitive impairment cases. Twelve age-matched healthy control subjects had 11C-Pittsburgh compound B and 10 healthy control subjects had 11C-(R)-PK11195 positron emission tomography for comparison. Amyloid-positivity was defined as 11C-Pittsburgh compound B target-to-cerebellar ratio above 1.5 within a composite cortical volume of interest. Supervised cluster analysis was used to generate parametric maps of 11C-(R)-PK11195 binding potential. Levels of 11C-(R)-PK11195 binding potential were measured in a selection of cortical volumes of interest and at a voxel level. Twenty-six (62%) of 42 mild cognitive impairment cases showed a raised cortical amyloid load compared to healthy controls. Twenty-two (85%) of the 26 amyloid-positive mild cognitive impairment cases showed clusters of increased cortical microglial activation accompanying the amyloid. There was a positive correlation between levels of amyloid load and 11C-(R)-PK11195 binding potentials at a voxel level within subregions of frontal, parietal and temporal cortices. 11C-(R)-PK11195 positron emission tomography reveals increased inflammation in a majority of amyloid positive mild cognitive impairment cases, its cortical distribution overlapping that of amyloid deposition.
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http://dx.doi.org/10.1093/brain/awx120DOI Listing
July 2017

Test-retest reproducibility of quantitative binding measures of [C]Ro15-4513, a PET ligand for GABA receptors containing alpha5 subunits.

Neuroimage 2017 05 11;152:270-282. Epub 2017 Mar 11.

Centre for Neuroscience, Department of Medicine, Imperial College London, London, UK; Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London, UK; Division of Imaging Sciences & Biomedical Engineering, King's College London, London, UK; The Neurodis Foundation, CERMEP - Imagerie du Vivant, Lyon, France.

Introduction: Alteration of γ-aminobutyric acid "A" (GABA) receptor-mediated neurotransmission has been associated with various neurological and psychiatric disorders. [C]Ro15-4513 is a PET ligand with high affinity for α5-subunit-containing GABA receptors, which are highly expressed in limbic regions of the human brain (Sur et al., 1998). We quantified the test-retest reproducibility of measures of [C]Ro15-4513 binding derived from six different quantification methods (12 variants).

Methods: Five healthy males (median age 40 years, range 38-49 years) had a 90-min PET scan on two occasions (median interval 12 days, range 11-30 days), after injection of a median dose of 441 MegaBequerels of [C]Ro15-4513. Metabolite-corrected arterial plasma input functions (parent plasma input functions, ppIFs) were generated for all scans. We quantified regional binding using six methods (12 variants), some of which were region-based (applied to the average time-activity curve within a region) and others were voxel-based: 1) Models requiring arterial ppIFs - regional reversible compartmental models with one and two tissue compartments (2kbv and 4kbv); 2) Regional and voxelwise Logan's graphical analyses (Logan et al., 1990), which required arterial ppIFs; 3) Model-free regional and voxelwise (exponential) spectral analyses (SA; (Cunningham and Jones, 1993)), which also required arterial ppIFs; 4) methods not requiring arterial ppIFs - voxelwise standardised uptake values (Kenney et al., 1941), and regional and voxelwise simplified reference tissue models (SRTM/SRTM2) using brainstem or alternatively cerebellum as pseudo-reference regions (Lammertsma and Hume, 1996; Gunn et al., 1997). To compare the variants, we sampled the mean values of the outcome parameters within six bilateral, non-reference grey matter regions-of-interest. Reliability was quantified in terms of median absolute percentage test-retest differences (MA-TDs; preferentially low) and between-subject coefficient of variation (BS-CV, preferentially high), both compounded by the intraclass correlation coefficient (ICC). These measures were compared between variants, with particular interest in the hippocampus.

Results: Two of the six methods (5/12 variants) yielded reproducible data (i.e. MA-TD <10%): regional SRTMs and voxelwise SRTM2s, both using either the brainstem or the cerebellum; and voxelwise SA. However, the SRTMs using the brainstem yielded a lower median BS-CV (7% for regional, 7% voxelwise) than the other variants (8-11%), resulting in lower ICCs. The median ICCs across six regions were 0.89 (interquartile range 0.75-0.90) for voxelwise SA, 0.71 (0.64-0.84) for regional SRTM-cerebellum and 0.83 (0.70-0.86) for voxelwise SRTM-cerebellum. The ICCs for the hippocampus were 0.89 for voxelwise SA, 0.95 for regional SRTM-cerebellum and 0.93 for voxelwise SRTM-cerebellum.

Conclusion: Quantification of [C]Ro15-4513 binding shows very good to excellent reproducibility with SRTM and with voxelwise SA which, however, requires an arterial ppIF. Quantification in the α5 subunit-rich hippocampus is particularly reliable. The very low expression of the α5 in the cerebellum (Fritschy and Mohler, 1995; Veronese et al., 2016) and the substantial α1 subunit density in this region may hamper the application of reference tissue methods.
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http://dx.doi.org/10.1016/j.neuroimage.2016.12.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440177PMC
May 2017

Flutriciclamide (18F-GE180) PET: First-in-Human PET Study of Novel Third-Generation In Vivo Marker of Human Translocator Protein.

J Nucl Med 2016 Nov 3;57(11):1753-1759. Epub 2016 Jun 3.

Neurology Imaging Unit, Imperial College London, Hammersmith Hospital, London, United Kingdom

Neuroinflammation is associated with neurodegenerative disease. PET radioligands targeting the 18-kDa translocator protein (TSPO) have been used as in vivo markers of neuroinflammation, but there is an urgent need for novel probes with improved signal-to-noise ratio. Flutriciclamide (F-GE180) is a recently developed third-generation TSPO ligand. In this first study, we evaluated the optimum scan duration and kinetic modeling strategies for F-GE180 PET in (older) healthy controls.

Methods: Ten healthy controls, 6 TSPO high-affinity binders, and 4 mixed-affinity binders were recruited. All subjects underwent detailed neuropsychologic tests, MRI, and a 210-min F-GE180 dynamic PET/CT scan using metabolite-corrected arterial plasma input function. We evaluated 5 different kinetic models: irreversible and reversible 2-tissue-compartment models, a reversible 1-tissue model, and 2 models with an extra irreversible vascular compartment. The minimal scan duration was established using 210-min scan data. The feasibility of generating parametric maps was also investigated using graphical analysis.

Results: F-GE180 concentration was higher in plasma than in whole blood during the entire scan duration. The volume of distribution (V) was 0.17 in high-affinity binders and 0.12 in mixed-affinity binders using the kinetic model. The model that best represented brain F-GE180 kinetics across regions was the reversible 2-tissue-compartment model (2TCM4k), and 90 min resulted as the optimum scan length required to obtain stable estimates. Logan graphical analysis with arterial input function gave a V highly consistent with V in the kinetic model, which could be used for voxelwise analysis.

Conclusion: We report for the first time, to our knowledge, the kinetic properties of the novel third-generation TSPO PET ligand F-GE180 in humans: 2TCM4k is the optimal method to quantify the brain uptake, 90 min is the optimal scan length, and the Logan approach could be used to generate parametric maps. Although these control subjects have shown relatively low V, the methodology presented here forms the basis for quantification for future PET studies using F-GE180 in different pathologies.
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http://dx.doi.org/10.2967/jnumed.115.169078DOI Listing
November 2016

Comparative Evaluation of Three TSPO PET Radiotracers in a LPS-Induced Model of Mild Neuroinflammation in Rats.

Mol Imaging Biol 2017 02;19(1):77-89

Wolfson Molecular Imaging Centre, University of Manchester, 27 Palatine Road, Manchester, M20 3LJ, UK.

Purpose: Over the past 20 years, neuroinflammation (NI) has increasingly been recognised as having an important role in  many neurodegenerative diseases, including Alzheimer's disease. As such, being able to image NI non-invasively in patients is critical to monitor pathological processes and potential therapies targeting neuroinflammation. The translocator protein (TSPO) has proven a reliable NI biomarker for positron emission tomography (PET) imaging. However, if TSPO imaging in acute conditions such as stroke provides strong and reliable signals, TSPO imaging in neurodegenerative diseases has proven more challenging. Here, we report results comparing the recently developed TSPO tracers [F]GE-180 and [F]DPA-714 with (R)-[C]PK11195 in a rodent model of subtle focal inflammation.

Procedures: Adult male Wistar rats were stereotactically injected with 1 μg lipopolysaccharide in the right striatum. Three days later, animals underwent a 60-min PET scan with (R)-[C]PK11195 and [F]GE-180 (n = 6) or [F]DPA-714 (n = 6). Ten animals were scanned with either [F]GE-180 (n = 5) or [F]DPA-714 (n = 5) only. Kinetic analysis of PET data was performed using the simplified reference tissue model (SRTM) with a contralateral reference region or a novel data-driven input to estimate binding potential BP. Autoradiography and immunohistochemistry were performed to confirm in vivo results.

Results: At 40-60 min post-injection, [F]GE-180 dual-scanned animals showed a significantly increased core/contralateral uptake ratio vs. the same animals scanned with (R)-[C]PK11195 (3.41 ± 1.09 vs. 2.43 ± 0.39, p = 0.03); []DPA-714 did not (2.80 ± 0.69 vs. 2.26 ± 0.41). Kinetic modelling with a contralateral reference region identified significantly higher binding potential (BP) in the core of the LPS injection site with [F]GE-180 but not with [F]DPA-714 vs. (R)-[C]PK11195. A cerebellar reference region and novel data-driven input to the SRTM were unable to distinguish differences in tracer BP.

Conclusions: Second-generation TSPO-PET tracers are able to accurately detect mild-level NI. In this model, [F]GE-180 shows a higher core/contralateral ratio and BP when compared to (R)-[C]PK11195, while [F]DPA-714 did not.
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http://dx.doi.org/10.1007/s11307-016-0984-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5209405PMC
February 2017

The 18-kDa mitochondrial translocator protein in human gliomas: an 11C-(R)PK11195 PET imaging and neuropathology study.

J Nucl Med 2015 Apr 26;56(4):512-7. Epub 2015 Feb 26.

Wolfson Molecular Imaging Center, University of Manchester, Manchester, United Kingdom

Unlabelled: The 18-kDa mitochondrial translocator protein (TSPO) is upregulated in high-grade astrocytomas and can be imaged by PET using the selective radiotracer (11)C-(R)PK11195. We investigated (11)C-(R)PK11195 binding in human gliomas and its relationship with TSPO expression in tumor tissue and glioma-associated microglia/macrophages (GAMs) within the tumors.

Methods: Twenty-two glioma patients underwent dynamic (11)C-(R)PK11195 PET scans and perfusion MR imaging acquisition. Parametric maps of (11)C-(R)PK11195 binding potential (BPND) were generated. Coregistered MR/PET images were used to guide tumor biopsy. The tumor tissue was quantitatively assessed for TSPO expression and infiltration of GAMs using immunohistochemistry and double immunofluorescence. The imaging and histopathologic parameters were compared among different histotypes and grades and correlated with each other.

Results: BPND of (11)C-(R)PK11195 in high-grade gliomas was significantly higher than in low-grade astrocytomas and low-grade oligodendrogliomas. TSPO in gliomas was expressed predominantly by neoplastic cells, and its expression correlated positively with BPND in the tumors. GAMs only partially contributed to the overall TSPO expression within the tumors, and TSPO expression in GAMs did not correlate with tumor BPND.

Conclusion: PET with (11)C-(R)PK11195 in human gliomas predominantly reflects TSPO expression in tumor cells. It therefore has the potential to effectively stratify patients who are suitable for TSPO-targeted treatment.
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http://dx.doi.org/10.2967/jnumed.114.151621DOI Listing
April 2015

18F-florbetapir PET in patients with frontotemporal dementia and Alzheimer disease.

J Nucl Med 2015 Mar 5;56(3):386-91. Epub 2015 Feb 5.

Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, United Kingdom

Unlabelled: Pathologic deposition of amyloid β (Aβ) protein is a key component in the pathogenesis of Alzheimer disease (AD) but not a feature of frontotemporal dementia (FTD). PET ligands for Aβ protein are increasingly used in diagnosis and research of dementia syndromes. Here, we report a PET study using (18)F-florbetapir in healthy controls and patients with AD and FTD.

Methods: Ten healthy controls (mean age ± SD, 62.5 ± 5.2 y), 10 AD patients (mean age ± SD, 62.6 ± 4.5), and 8 FTD patients (mean age ± SD, 62.5 ± 9.6) were recruited to the study. All patients underwent detailed clinical and neuropsychologic assessment and T1-weighted MR imaging and were genotyped for apolipoprotein E status. All participants underwent dynamic (18)F-florbetapir PET on a high-resolution research tomograph, and FTD patients also underwent (18)F-FDG PET scans. Standardized uptake value ratios (SUVRs) were extracted for predefined gray and white matter regions of interest using cerebellar gray matter as a reference region. Static PET images were evaluated by trained raters masked to clinical status and regional analysis.

Results: Total cortical gray matter (18)F-florbetapir uptake values were significantly higher in AD patients (median SUVR, 1.73) than FTD patients (SUVR, 1.13, P = 0.002) and controls (SUVR, 1.26, P = 0.04). (18)F-Florbetapir uptake was also higher in AD patients than FTD patients and controls in the frontal, parietal, occipital, and cingulate cortices and in the central subcortical regions. Only 1 FTD patient (homozygous for apolipoprotein E ε4) displayed high cortical (18)F-florbetapir retention, whereas (18)F-FDG PET demonstrated mesiofrontal hypometabolism consistent with the clinical diagnosis of FTD. Most visual raters classified 1 control (10%) and 8 AD (80%) and 2 FTD (25%) patients as amyloid-positive, whereas ratings were tied in another 2 FTD patients and 1 healthy control.

Conclusion: Cortical (18)F-florbetapir uptake is low in most FTD patients, providing good discrimination from AD. However, visual rating of FTD scans was challenging, with a higher rate of discordance between interpreters than in AD and control subjects.
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http://dx.doi.org/10.2967/jnumed.114.147454DOI Listing
March 2015

P-glycoprotein expression and function in patients with temporal lobe epilepsy: a case-control study.

Lancet Neurol 2013 Aug 18;12(8):777-85. Epub 2013 Jun 18.

Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.

Background: Studies in rodent models of epilepsy suggest that multidrug efflux transporters at the blood-brain barrier, such as P-glycoprotein, might contribute to pharmacoresistance by reducing target-site concentrations of antiepileptic drugs. We assessed P-glycoprotein activity in vivo in patients with temporal lobe epilepsy.

Methods: We selected 16 patients with pharmacoresistant temporal lobe epilepsy who had seizures despite treatment with at least two antiepileptic drugs, eight patients who had been seizure-free on antiepileptic drugs for at least a year after 3 or more years of active temporal lobe epilepsy, and 17 healthy controls. All participants had a baseline PET scan with the P-glycoprotein substrate (R)-[(11)C]verapamil. Pharmacoresistant patients and healthy controls then received a 30-min infusion of the P-glycoprotein-inhibitor tariquidar followed by another (R)-[(11)C]verapamil PET scan 60 min later. Seizure-free patients had a second scan on the same day, but without tariquidar infusion. Voxel-by-voxel, we calculated the (R)-[(11)C]verapamil plasma-to-brain transport rate constant, K1 (mL/min/cm(3)). Low baseline K1 and attenuated K1 increases after tariquidar correspond to high P-glycoprotein activity.

Findings: Between October, 2008, and November, 2011, we completed (R)-[(11)C]verapamil PET studies in 14 pharmacoresistant patients, eight seizure-free patients, and 13 healthy controls. Voxel-based analysis revealed that pharmacoresistant patients had lower baseline K1, corresponding to higher baseline P-glycoprotein activity, than seizure-free patients in ipsilateral amygdala (0·031 vs 0·036 mL/min/cm(3); p=0·014), bilateral parahippocampus (0·032 vs 0·037; p<0·0001), fusiform gyrus (0·036 vs 0·041; p<0·0001), inferior temporal gyrus (0·035 vs 0·041; p<0·0001), and middle temporal gyrus (0·038 vs 0·044; p<0·0001). Higher P-glycoprotein activity was associated with higher seizure frequency in whole-brain grey matter (p=0·016) and the hippocampus (p=0·029). In healthy controls, we noted a 56·8% increase of whole-brain K1 after 2 mg/kg tariquidar, and 57·9% for 3 mg/kg; in patients with pharmacoresistant temporal lobe epilepsy, whole-brain K1 increased by only 21·9% for 2 mg/kg and 42·6% after 3 mg/kg. This difference in tariquidar response was most pronounced in the sclerotic hippocampus (mean 24·5% increase in patients vs mean 65% increase in healthy controls, p<0·0001).

Interpretation: Our results support the hypothesis that there is an association between P-glycoprotein overactivity in some regions of the brain and pharmacoresistance in temporal lobe epilepsy. If this relation is confirmed, and P-glycoprotein can be identified as a contributor to pharmacoresistance, overcoming P-glycoprotein overactivity could be investigated as a potential treatment strategy.

Funding: EU-FP7 programme (EURIPIDES number 201380).
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http://dx.doi.org/10.1016/S1474-4422(13)70109-1DOI Listing
August 2013