348 results found
Wilson H, Dervenoulas G, Pagano G, et al., 2019, Evaluation of Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson's Disease: An in vivo [11C]BU99008 PET study, International Congress of Parkinson's Disease and Movement Disorders, Publisher: WILEY, Pages: S835-S836, ISSN: 0885-3185
Wilson H, Niccolini F, Dervenoulas G, et al., 2019, Evaluation of Imidazoline 2 binding sites reflecting astroglia pathology in Huntington's Disease: An in vivo [11C]BU99008 PET study, International Congress of Parkinson's Disease and Movement Disorders, Publisher: WILEY, Pages: S836-S836, ISSN: 0885-3185
Wilson H, Dervenoulas G, Pagano G, et al., 2019, Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson's disease: an in vivo11C-BU99008 PET study., Brain, Vol: 142, Pages: 3116-3128
Astroglia are multifunctional cells that regulate neuroinflammation and maintain homeostasis within the brain. Astroglial α-synuclein-positive cytoplasmic accumulations have been shown post-mortem in patients with Parkinson's disease and therefore astroglia may play an important role in the initiation and progression of Parkinson's disease. Imidazoline 2 binding sites are expressed on activated astroglia in the cortex, hippocampus, basal ganglia and brainstem; therefore, by measuring imidazoline 2 binding site levels we can indirectly evaluate astrogliosis in patients with Parkinson's disease. Here, we aimed to evaluate the role of astroglia activation in vivo in patients with Parkinson's disease using 11C-BU99008 PET, a novel radioligand with high specificity and selectivity for imidazoline 2 binding sites. Twenty-two patients with Parkinson's disease and 14 healthy control subjects underwent 3 T MRI and a 120-min 11C-BU99008 PET scan with volume of distribution (VT) estimated using a two-tissue compartmental model with a metabolite corrected arterial plasma input function. Parkinson's disease patients were stratified into early (n = 8) and moderate/advanced (n = 14) groups according to disease stage. In early Parkinson's disease, increased 11C-BU99008 VT uptake was observed in frontal (P = 0.022), temporal (P = 0.02), parietal (P = 0.026) and occipital (P = 0.047) cortical regions compared with healthy controls. The greatest 11C-BU99008 VT increase in patients with early Parkinson's disease was observed in the brainstem (52%; P = 0.018). In patients with moderate/advanced Parkinson's disease, loss of 11C-BU99008 VT was observed across frontal (P = 0.002), temporal (P < 0.001), parietal (P = 0.039), occipital (P = 0.024), and insula (P < 0.001) cortices; and in the subcortical regions of caudate (P < 0.001), putamen (P < 0.001) and thalamus (P < 0.001); and in the brainstem (P = 0.018) compared with healthy controls. In patients with Parkinson'
Sridharan S, Raffel J, Nandoskar A, et al., 2019, Confirmation of specific binding of the 18 kDa translocator protein (TSPO) radioligand [18F]GE-180: a blocking study using XBD173 in multiple sclerosis normal appearing white and grey matter, Molecular Imaging and Biology, Vol: 21, Pages: 935-944, ISSN: 1536-1632
Purpose: Positron emission tomography (PET) ligands exhibit different levels of non-displaceable binding in vivo. In the case of ligands for the 18 kDa translocator protein (TSPO), the component of non-displaceable binding for the most widely used radiotracer, [11C]-(R)-PK11195, is relatively high compared to that for newer TSPO ligands. Non-displaceable binding is not often quantified in humans in vivo, partially due to a lack of available ligands that are known to be safe with which to displace binding to the target receptor. Recently, however, a technique has been developed to quantify the non-displaceable binding of TSPO tracers in vivo, by blocking the receptor with the TSPO ligand XBD173 and comparing the total volume of distribution ( ) pre and post-blockade. Here, we used an occupancy plot to quantify the non-displaceable binding ( ) of the TSPO PET tracers [18F]GE-180 and [11C]PBR28 in cohorts of people with multiple sclerosis (MS). We also compared plots of subjects carrying both high and mixed binding affinity polymorphisms of TSPO to estimate while potentially avoiding the need for receptor blockade.Procedures: Twelve people with multiple sclerosis (MS) and high (HAB) or mixed (MAB) affinity binding for TSPO underwent baseline MRI and 90-minute dynamic [18F]GE-180 PET (n=6; 3 HAB and 3 MAB) or [11C]PBR28 PET (n=6; 3 HAB, 3 MAB). Either one week later ([18F]GE-180) or the same afternoon ([11C]PBR28), participants had repeat PET following a 90mg dose of XBD173. PET images were co-registered with T1 MR volumetric images and regions of interest (ROIs) were defined using the 83-region Hammers atlas. Arterial blood sampling was used to generate plasma input functions for the two-tissue compartment model to quantify . The non-displaceable fraction of the total volume of distribution ( ) was calculated using two independent methods: the occupancy plot (by modelling the differences in signal post XBD173), and the polymorphism plot (by modelling the differences in
Piccini P, Pagano G, Politis M, 2019, Comparison of phosphodiesterase 10A and dopamine transporter levels as markers of disease burden in early Parkinson's disease, Movement Disorders, Vol: 34, Pages: 1505-1515, ISSN: 0885-3185
BackgroundRecent work has shown loss of phosphodiesterase 10A levels in middle‐stage and advanced treated patients with PD, which was associated with motor symptom severity.ObjectivesTo assess phosphodiesterase 10A levels in early PD and compare with loss of dopamine transporter as markers of disease burden.MethodsSeventy‐eight subjects were included in this study (17 early de novo, 15 early l‐dopa–treated, 24 moderate‐advanced l‐dopa–treated patients with PD, and 22 healthy controls). All participants underwent [11C]IMA107 PET, [11C]PE2I PET, and 3‐Tesla MRI scan.ResultsEarly de novo PD patients showed loss of [11C]IMA107 and of [11C]PE2I binding in caudate and putamen (P < 0.001); early l‐dopa–treated PD patients showed additional loss of [11C]IMA107 in the caudate (P < 0.001; annual decline 3.6%) and putamen (P < 0.001; annual decline 2.8%), but loss of [11C]PE2I only in the putamen (P < 0.001; annual decline 6.8%). Lower [11C]IMA107 correlated with lower [11C]PE2I in the caudate (rho = 0.51; P < 0.01) and putamen (rho = 0.53; P < 0.01). Longer disease duration correlated with lower [11C]IMA107 in the caudate (rho = –0.72; P < 0.001) and putamen (rho = –0.48; P < 0.01), and with lower [11C]PE2I only in the putamen (rho = –0.65; P < 0.001). Higher burden of motor symptoms correlated with lower [11C]IMA107 in the caudate (rho = –0.42; P < 0.05) and putamen (rho = –0.41; P < 0.05), and with lower [11C]PE2I only in the putamen (rho = –0.69; P < 0.001).ConclusionOur findings demonstrate loss of phosphodiesterase 10A levels very early in the course of PD and is associated with the gradual and progressive increase of motor symptoms. Phosphodiesterase 10A imaging shows similar potential with dopamine transporter imaging to follow disease progression.
Gorgoraptis N, Li LM, Whittington A, et al., 2019, In vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury, Science Translational Medicine, Vol: 11, Pages: 1-14, ISSN: 1946-6234
Traumatic brain injury (TBI) can trigger progressive neurodegeneration, with tau pathology seen years after a single moderate-severe TBI. Identifying this type of posttraumatic pathology in vivo might help to understand the role of tau pathology in TBI pathophysiology. We used flortaucipir positron emission tomography (PET) to investigate whether tau pathology is present many years after a single TBI in humans. We examined PET data in relation to markers of neurodegeneration in the cerebrospinal fluid (CSF), structural magnetic resonance imaging measures, and cognitive performance. Cerebral flortaucipir binding was variable, with many participants with TBI showing increases in cortical and white matter regions. At the group level, flortaucipir binding was increased in the right occipital cortex in TBI when compared to healthy controls. Flortaucipir binding was associated with increased total tau, phosphorylated tau, and ubiquitin carboxyl-terminal hydrolase L1 CSF concentrations, as well as with reduced fractional anisotropy and white matter tissue density in TBI. Apolipoprotein E (APOE) ε4 genotype affected the relationship between flortaucipir binding and time since injury, CSF β amyloid 1–42 (Aβ42) concentration, white matter tissue density, and longitudinal Mini-Mental State Examination scores in TBI. The results demonstrate that tau PET is a promising approach to investigating progressive neurodegeneration associated with tauopathy after TBI.
Jolly AE, Raymont V, Cole JH, et al., 2019, Dopamine D2/D3 receptor abnormalities after traumatic brain injury and their relationship to post-traumatic depression, NeuroImage: Clinical, Vol: 24, ISSN: 2213-1582
ObjectiveTo investigate dopamine D2/D3 receptor availability following traumatic brain injury (TBI) and their relationship to the presence of DSM-IV Major Depressive Disorder (MDD) and patterns of axonal injury.MethodsTwelve moderate-severe TBI patients and 26 controls were imaged using [11C]PHNO positron emission tomography (PET) and structural magnetic resonance imaging (MRI). TBI patients and a second group of 32 controls also underwent diffusion tensor imaging (DTI) and neuropsychological assessment. Patients included six with post-injury MDD (TBI-MDD) and six without (TBI-NON). Non-displaceable binding potential (BPND) [11C]PHNO values were used to index D2/D3 receptor availability, and were calculated using a reference region procedure. Differences in BPND were examined using voxelwise and region-of-interest analyses. White matter microstructure integrity, quantified by fractional anisotropy (FA), was assessed and correlated with BPND.ResultsLower [11C]PHNO BPND was found in the caudate across all TBI patients when compared to controls. Lower [11C]PHNO BPND was observed in the caudate of TBI-MDD patients and increased [11C]PHNO BPND in the Amygdala of TBI-NON patients compared to controls. There were no significant differences in [11C]PHNO BPND between TBI-MDD and TBI-NON patients. Furthermore, DTI provided evidence of axonal injury following TBI. The uncinate fasciculus and cingulum had abnormally low FA, with the uncinate particularly affected in TBI-MDD patients. Caudate [11C]PHNO BPND correlated with FA within the nigro-caudate tract.Conclusions[11C]PHNO BPND is abnormal following TBI, which indicates post-traumatic changes in D2/D3 receptors. Patterns of [11C]PHNO BPND seen in patients with and without MDD suggest that further research would be beneficial to determine whether the use of dopaminergic treatment might be effective in the treatment of post-traumatic depression.
Mansur A, Rabiner EA, Comley RA, et al., 2019, Characterization of 3 PET tracers for Quantification of Mitochondrial and Synaptic function in Healthy Human Brain: 18F-BCPP-EF, 11C-SA-4503, 11C-UCB-J, Journal of Nuclear Medicine, ISSN: 1535-5667
Mitochondrial complex 1 (MC1) is involved in maintaining brain bioenergetics, the sigma 1 receptor (σ1R) responds to neuronal stress and synaptic vesicle protein 2A (SV2A) reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here we characterise the kinetic behaviour of three positron emission tomography (PET) radioligands 18F-BCPP-EF, 11C-SA-4503 and 11CUCB- J, for the measurement of MC1, σ1R and SV2A, 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 including associated arterial blood sampling with each radioligand. A range of kinetic models were investigated to identify an optimal kinetic analysis method for each radioligand and a suitable acquisition duration. Results: All three 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 (VT) were multilinear analysis 1 (MA1) and the 2-tissue compartment (2TC) model for 18F-BCPP-EF, MA1 for 11C-SA- 4503, and both MA1 and the 1-tissue compartment (1TC) model for 11C-UCB-J. Acquisition times of 70, 80 and 60 minutes for 18F-BCPP-EF, 11C-SA-4503, 11C-UCB-J, respectively, provided good estimates of regional VT 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.
Venkataraman A, Mansur A, Lewis Y, et al., Evaluation of mitochondrial and synaptic function in Alzheimer’s disease (AD): a [18F]BCPP-EF, [11C]SA4503 and [11C]UCB-J PET study, Journal of Cerebral Blood Flow and Metabolism, Vol: 39, Pages: 121-122, ISSN: 1559-7016
ObjectivesMitochondrial deficits leading to synaptic dysfunction have been hypothesised in the pathophysiology of neurodegenerative disease, with Aβ/tau impairing mitochondrial function in AD. To date a combined evaluation of human mitochondrial and synaptic function has not been performed directly in vivo. We describe the pilot results of MINDMAPS-AD, a study within the MINDMAPS1 programme aiming to evaluate mitochondrial and synaptic function in the brain of patients with MCI/AD. MINDMAPS-AD uses the novel radioligands [18F]BCPP-EF, [11C]SA4503 and [11C]UCB-J, to compare the regional density of mitochondrial complex I (MC1), the sigma 1 receptor (s1R) and synaptic vesicular protein 2A (SV2A) respectively.MethodsSix participants with a range of AD related pathologies, EMCI (n = 2), LMCI (n = 2), and AD (n = 2), were enrolled into the study. Participants fulfilled NIA-AA criteria and were amyloid-beta +ve confirmed by [18F]Florbetaben PET. All participants underwent three PET scans with [18F]BCPP-EF, [11C]SA4503 and [11C]UCB-J. Arterial blood samples were collected and a metabolite corrected arterial plasma input function was estimated to derive regional volumes of distribution (VT). These data were compared to six age/sex matched cognitively normal (CN) healthy subjects recruited for ongoing studies within the MINDMAPS programme. Regions of interest (ROIs) were defined on individual subject MR images using an anatomical atlas and included: frontal cortex, hippocampus, amygdala, anterior cingulate, posterior cingulate, thalamus, temporal cortex, parietal cortex, caudate, putamen, and occipital lobe. Regional target density was evaluated using the VT, as well as VT corrected for the plasma free fraction of the radioligand (fP; VT/fp), and the regional VT ratio versus the VT in the centrum semiovale, a white matter region expected to have low levels of the targets evaluated (DVR). Comparison of regional target density and
Martin Bastida A, Lao-Kaim N, Roussakis A, et al., 2019, Relationship between neuromelanin and dopamine terminals within the parkinson’s nigrostriatal system, Brain, Vol: 142, Pages: 2023-2036, ISSN: 1460-2156
Parkinson’s disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterising its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we utilised neuromelanin-sensitive magnetic resonance imaging and the highly specific dopamine transporter positron emission tomography radioligand, 11C-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson’s disease. Fifteen healthy controls also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal/ventral tiers and striatal nuclei into pre/post-commissural sub-regions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson’s disease subjects displayed reduced neuromelanin levels in the ventral (-30±28%) and dorsal tiers (-21±24%) as compared to the control group (F1,43 = 11.95, P = 0.001). Within the Parkinson’s disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier (F1,29 = 36.19, P < 0.001) and lower in the clinically-defined most affected side (F1,29 = 4.85, P = 0.036). Similarly, lower dopamine transporter density was observed in the ventral tier (F1,29 = 76.39, P < 0.001) and clinically-defined most affected side (F1,29 = 4.21, P = 0.049). Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-d
Saleem A, Helo Y, Searle G, et al., 2019, Imaging radiotherapy induced pulmonary fibrogenic changes with integrin-PET, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Pagano G, Wilson H, Mansur A, et al., 2019, Mitochondrial complex 1, sigma 1 receptor and synaptic vesicle protein 2A density in early de novo patients with Parkinson's disease: pilot PET data, 5th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 532-532, ISSN: 1351-5101
Pagano G, Wilson H, Yousaf T, et al., 2019, Comparison of PDE10A and DAT expression as markers of disease burden in early Parkinson's disease, 5th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 532-532, ISSN: 1351-5101
Lao-Kaim NP, Martin-Bastida A, Roussakis A-A, et al., 2019, Multimodal imaging of neuromelanin and dopamine transporters in Parkinson's disease reveals asymmetrical relationships within the nigrostriatal system, 5th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 99-99, ISSN: 1351-5101
Wilson H, Niccolini F, Dervenoulas G, et al., 2019, Evaluation of imidazoline 2 binding sites reflecting astroglia pathology in Huntington's disease: an in vivo [11C] BU99008 PET study, 5th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 317-318, ISSN: 1351-5101
Wilson H, Dervenoulas G, Pagano G, et al., 2019, Evaluation of Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson's disease: an in vivo [11C] BU99008 PET study, 5th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 1005-1005, ISSN: 1351-5101
Whittington A, Seibyl J, Hesterman J, et al., 2019, Tau(IQ) - a quantitative algorithm for tau PET imaging in clinical trials, 29th International Symposium on Cerebral Blood Flow, Metabolism and Function / 14th International Conference on Quantification of Brain Function with PET (BRAIN and BRAIN Pet), Publisher: SAGE PUBLICATIONS INC, Pages: 100-101, ISSN: 0271-678X
Venkataraman AV, Mansur A, Huiban M, et al., 2019, Evaluation of mitochondrial and synaptic function in Alzheimer's disease (AD): a [F-18]BCPP-EF, [C-11]SA4503 and [C-11]UCB-J PET study, 29th International Symposium on Cerebral Blood Flow, Metabolism and Function / 14th International Conference on Quantification of Brain Function with PET (BRAIN and BRAIN Pet), Publisher: SAGE PUBLICATIONS INC, Pages: 121-122, ISSN: 0271-678X
Erritzoe D, Godlewska BR, Rizzo G, et al., 2019, Reduced serotonin release in patients with major depression: a PET study with [11C]Cimbi-36 and d-amphetamine challenge, 29th International Symposium on Cerebral Blood Flow, Metabolism and Function / 14th International Conference on Quantification of Brain Function with PET (BRAIN and BRAIN Pet), Publisher: SAGE PUBLICATIONS INC, Pages: 548-549, ISSN: 0271-678X
Wilson H, Dervenoulas G, Pagano G, et al., 2019, Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study, Lancet Neurology, Vol: 18, Pages: 748-759, ISSN: 1474-4422
BACKGROUND: Because of the highly penetrant gene mutation and clinical features consistent with idiopathic Parkinson's disease, carriers of the autosomal dominant Ala53Thr (A53T; 209G→A) point mutation in the α-synuclein (SNCA) gene are an ideal population to study the premotor phase and evolution of Parkinson's pathology. Given the known neurochemical changes in the serotonergic system and their association with symptoms of Parkinson's disease, we hypothesised that carriers of the A53T SNCA mutation might show abnormalities in the serotonergic neurotransmitter system before the diagnosis of Parkinson's disease, and that this pathology might be associated with measures of Parkinson's burden. METHODS: In this cross-sectional study, we recruited carriers of the A53T SNCA mutation from specialist Movement Disorders clinics in Athens, Greece, and Salerno, Italy, and a cohort of healthy controls with no personal or family history of neurological or psychiatric disorders from London, UK (recruited via public advertisement) who were age matched to the A53T SNCA carriers. We also recruited one cohort of patients with idiopathic Parkinson's disease (cohort 1) from Movement Disorders clinics in London, UK, and retrieved data on a second cohort of such patients (cohort 2; n=40) who had been scanned with a different scanner. 7-day continuous recording of motor function was used to determine the Parkinson's disease status of the A53T carriers. To assess whether serotonergic abnormalities were present, we used [11C]DASB PET non-displaceable binding to quantify serotonin transporter density. We constructed brain topographic maps reflecting Braak stages 1-6 and used these as seed maps to calculate [11C]DASB non-displaceable binding potential in our cohort of A53T SNCA carriers. Additionally, all participants underwent a battery of clinical assessments to determine motor and non-motor symptoms and cognitive status, and [123I]FP-CIT single-photon emission CT (SPECT) to ass
McCluskey S, Haslop A, Coello C, et al., 2019, Imaging chemotherapy induced acute cardiotoxicity with 18F-labelled lipophilic cations, Journal of Nuclear Medicine, ISSN: 1535-5667
Many chemotherapy agents are toxic to the heart, such that increasing numbers of cancer survivors are now living with the potentially lethal cardiovascular consequences of their treatment. Earlier and more sensitive detection of chemotherapy-induced cardiotoxicity may allow improved treatment strategies and increase long-term survival. Lipophilic cation positron emission tomography (PET) tracers may be suitable for early detection of cardiotoxicity. This study aims to evaluate an 18F-labelled lipophilic phosphonium cation e.g. 18F-Mitophos, as a cardiac imaging agent, comparing it to leading PET and SPECT lipophilic cationic tracers before further assessing its potential for imaging cardiotoxicity in an acute doxorubicin (DOX) model.
Whittington A, Gunn RN, 2019, Amyloid load - a more sensitive biomarker for amyloid imaging, Journal of Nuclear Medicine, Vol: 60, Pages: 536-540, ISSN: 1535-5667
Amyloid-β (Aβ) plays a key role in the pathogenesis of Alzheimer's disease (AD) and it can be imaged in vivo using [18F]-AV45 positron emission tomography (PET). The mean cortical standardised uptake value ratio (SUVr) is a commonly used outcome measure for quantifying the global Aβ burden however the sensitivity is sub-optimal which can lead to low power in clinical trials. We introduce amyloid load, AβL as a novel biomarker to quantify the global Aβ burden along with an automated algorithm for its calculation (IQA). AβL is evaluated on cross-sectional and longitudinal data obtained from the Alzheimer's disease neuroimaging initiative (ADNI). The cross-sectional data consisted of 769 subjects across the disease spectrum (211 healthy controls (HC), 223 early mild cognitive impairment (EMCI), 204 late mild cognitive impairment (LMCI), 132 AD). The distributions of in the four different classifications were compared and the same analyses were applied to the mean cortical SUVr outcome measure. The effect sizes (hedges' g) between all classifications were higher for AβL than mean cortical SUVr with the mean difference in effect size being 56%. 147 of the EMCI patients had a two-year follow-up scan and the effect size between baseline and follow-up for was 0.49 compared to 0.35 for mean cortical SUVr demonstrating an equivalent increase in power for longitudinal data. These results provide evidence that AβL will be a valuable outcome measure in future Aβ imaging studies providing an substantial increase in power over currently employed SUVr methods.
Koychev I, Lawson J, Chessell T, et al., 2019, Deep and frequent phenotyping study protocol: an observational study in prodromal Alzheimer's disease., BMJ Open, Vol: 9, ISSN: 2044-6055
INTRODUCTION: Recent failures of potential novel therapeutics for Alzheimer's disease (AD) have prompted a drive towards clinical studies in prodromal or preclinical states. However, carrying out clinical trials in early disease stages is extremely challenging-a key reason being the unfeasibility of using classical outcome measures of dementia trials (eg, conversion to dementia) and the lack of validated surrogate measures so early in the disease process. The Deep and Frequent Phenotyping (DFP) study aims to resolve this issue by identifying a set of markers acting as indicators of disease progression in the prodromal phase of disease that could be used as indicative outcome measures in proof-of-concept trials. METHODS AND ANALYSIS: The DFP study is a repeated measures observational study where participants will be recruited through existing parent cohorts, research interested lists/databases, advertisements and memory clinics. Repeated measures of both established (cognition, positron emission tomography (PET) imaging or cerebrospinal fluid (CSF) markers of pathology, structural MRI markers of neurodegeneration) and experimental modalities (functional MRI, magnetoencephalography and/or electroencephalography, gait measurement, ophthalmological and continuous smartphone-based cognitive and other assessments together with experimental CSF, blood, tear and saliva biomarkers) will be performed. We will be recruiting male and female participants aged >60 years with prodromal AD, defined as absence of dementia but with evidence of cognitive impairment together with AD pathology as assessed using PET imaging or CSF biomarkers. Control participants without evidence of AD pathology will be included at a 1:4 ratio. ETHICS AND DISSEMINATION: The study gained favourable ethical opinion from the South Central-Oxford B NHS Research Ethics Committee (REC reference 17/SC/0315; approved on 18 August 2017; amendment 13 February 2018). Data will be shared with the scientific commu
Plavén-Sigray P, Schain M, Zanderigo F, et al., 2019, Accuracy and reliability of [11C]PBR28 specific binding estimated without the use of a reference region., Neuroimage, Vol: 188, Pages: 102-110
[11C]PBR28 is a positron emission tomography radioligand used to examine the expression of the 18 kDa translocator protein (TSPO). TSPO is located in glial cells and can function as a marker for immune activation. Since TSPO is expressed throughout the brain, no true reference region exists. For this reason, an arterial input function is required for accurate quantification of [11C]PBR28 binding and the most common outcome measure is the total distribution volume (VT). Notably, VT reflects both specific binding and non-displaceable binding. Therefore, estimates of specific binding, such as binding potential (e.g. BPND) and specific distribution volume (VS) should theoretically be more sensitive to underlying differences in TSPO expression. It is unknown, however, if unbiased and accurate estimates of these outcome measures are obtainable for [11C]PBR28. The Simultaneous Estimation (SIME) method uses time-activity-curves from multiple brain regions with the aim to obtain a brain-wide estimate of the non-displaceable distribution volume (VND), which can subsequently be used to improve the estimation of BPND and VS. In this study we evaluated the accuracy of SIME-derived VND, and the reliability of resulting estimates of specific binding for [11C]PBR28, using a combination of simulation experiments and in vivo studies in healthy humans. The simulation experiments, based on data from 54 unique [11C]PBR28 examinations, showed that VND values estimated using SIME were both precise and accurate. Data from a pharmacological competition challenge (n = 5) showed that SIME provided VND values that were on average 19% lower than those obtained using the Lassen plot, but similar to values obtained using the Likelihood-Estimation of Occupancy technique. Test-retest data (n = 11) showed that SIME-derived VS values exhibited good reliability and precision, while larger variability was observed in SIME-derived BPND values. The results support the use of SIME for quantifying specific
Wilson H, Pagano G, Niccolini F, et al., 2019, The role of phosphodiesterase 4 in excessive daytime sleepiness in Parkinson's disease, Parkinsonism and Related Disorders, ISSN: 1353-8020
INTRODUCTION: Preclinical studies suggest a link between cAMP/PKA signalling, phosphodiesterase 4 (PDE4) expression and excessive daytime sleepiness (EDS). Here, we investigated in vivo the association between PDE4 expression and EDS in Parkinson's disease (PD) patients using [11C]rolipram PET and MR imaging. METHODS: Eighteen participants, 12 PD and 6 healthy controls, underwent one [11C]rolipram PET and a multi-modal MRI scan. Probabilistic tractography was performed on subjects' diffusion data to functionally parcellate the striatum according with projections to limbic cortical areas. The severity of EDS was assessed using the Epworth Sleepiness Scale (ESS). To assess PDE4 expression in PD patients with EDS, the PD cohort was divided according to the presence (n = 5) or absence (n = 7) of EDS, defined using validated cut-off of score ≥10 on the ESS as score ≥10 on the ESS. RESULTS: PD patients with EDS showed significantly increased [11C]rolipram volume of distribution (VT) in the caudate (P = 0.029), hypothalamus (P = 0.013), hippocampus (P = 0.036) and limbic striatum (P = 0.030) compared to patients without EDS. Furthermore, higher ESS scores correlated with increased [11C]rolipram VT in the caudate (r = 0.77; P = 0.003), hypothalamus (r = 0.84; P = 0.001), hippocampus (r = 0.81; P = 0.001) and limbic subdivisions of the striatum (r = 0.80; P = 0.003). CONCLUSION: Our findings translate into humans preclinical data indicating that EDS is associated with elevated PDE4 in regions regulating sleep. The severity of EDS in PD was associated with elevated PDE4 expression; thus, suggesting a role of PDE4 in the pathophysiology of EDS in PD.
Kocagoncu E, Quinn A, Firouzian A, et al., 2019, Tau pathology in early Alzheimer's disease disrupts selective neurophysiological networks dynamics: Supplementary information, Publisher: Cold Spring Harbor Laboratory
<jats:p>The role of aggregation of misfolded Tau protein in the pathogenesis of Alzheimer's disease is the subject of rapid biomarker development and new therapeutic strategies to slow or prevent dementia. We tested the hypothesis that Tau pathology is associated with functional organization of widespread neurophysiological networks. We used electro-magnetoencephalography (E/MEG) in combination with [18F]AV1451 PET scanning to quantify Tau-dependent network disruption. Using a graph theoretical approach to MEG connectivity, we quantified nodal measures of functional segregation, centrality and efficiency of information transfer. We correlated these metrics against the nodes' uptake of [18F]AV1451. There were both regional- and frequency-specific effects of Tau levels on the efficiency of information transfer and network segregation in early AD. Tau correlated with temporal regional participation coefficient (in delta, theta, beta bands); and temporal lobar eigenvector centrality (in theta, alpha, beta bands), but greater eccentricity at higher frequencies (gamma). The results support the translational development of neurophysiological "signatures" as biomarkers of Alzheimer's disease, with potential to facilitate experimental medicines studies.</jats:p>
Niccolini F, Mencacci NE, Yousaf T, et al., 2018, PDE10A and ADCY5 mutations linked to molecular and microstructural basal ganglia pathology, MOVEMENT DISORDERS, Vol: 33, Pages: 1961-1965, ISSN: 0885-3185
Niccolini F, Wilson H, Hirschbichler S, et al., 2018, Disease-related patterns of in vivo pathology in corticobasal syndrome, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 45, Pages: 2413-2425, ISSN: 1619-7070
Purpose To assess disease-related patterns of in vivo pathology in 11 patients with Corticobasal Syndrome (CBS) compared to20 healthy controls and 33 mild cognitive impairment (MCI) patients due to Alzheimer’s disease.Methods We assessed tau aggregates with [18F]AV1451 PET, amyloid-β depositions with [18F]AV45 PET, and volumetricmicrostructural changes with MRI. We validated for [18F]AV1451 standardised uptake value ratio (SUVRs) against inputfunctions from arterial metabolites and found that SUVRs and arterial-derived distribution volume ratio (DVRs) provide equallyrobust measures of [18F]AV1451 binding.Results CBS patients showed increases in [18F]AV1451 SUVRs in parietal (P < 0.05) and frontal (P < 0.05) cortices in theaffected hemisphere compared to healthy controls and in precentral (P = 0.008) and postcentral (P = 0.034) gyrus in theaffected hemisphere compared to MCI patients. Our data were confirmed at the histopathological level in one CBS patientwho underwent brain biopsy and showed sparse tau pathology in the parietal cortex co-localizing with increased[18F]AV1451 signal. Cortical and subcortical [18F]AV45 uptake was within normal levels in CBS patients. In parietaland frontal cortices of the most affected hemisphere we found also grey matter loss (P < 0.05), increased mean diffusivity(P < 0.05) and decreased fractional anisotropy (P < 0.05) in CBS patients compared to healthy controls and MCI patients.Grey matter loss and white matter changes in the precentral gyrus of CBS patients were associated with worse motorsymptoms.Conclusions Our findings demonstrate disease-related patterns of in vivo tau and microstructural pathology in the absence ofamyloid-β, which distinguish CBS from non-affected individuals and MCI patients.
van der Aart J, Salinas C, Dimber R, et al., 2018, Quantification of human brain PDE4 occupancy by GSK356278: A [(11)C](R)-rolipram PET study, Journal of Cerebral Blood Flow and Metabolism, Vol: 38, Pages: 2033-2040, ISSN: 1559-7016
We characterized the relationship between the plasma concentration of the phospodiesterase (PDE)-4 inhibitor GSK356278 and occupancy of the PDE4 enzyme in the brain of healthy volunteers, using the positron emission tomography (PET) tracer [(11)C](R)-rolipram. To this end, PET scans were acquired in eight male volunteers before and at 3 and 8 h after a single 14 mg oral dose of GSK356278. A metabolite-corrected arterial input function was used in conjunction with the dynamic PET emission data to estimate volumes of distribution (VT) from a two-tissue compartment model. The administration of GSK356278 reduced [(11)C](R)-rolipram whole brain VT by 17% at 3 h post-dose (p = 0.01) and by 4% at 8 h post-dose. The mean plasma Cmax was 42.3 ng/ml, leading to a PDE4 occupancy of 48% at Tmax. The in vivo affinity of GSK356278 was estimated as EC50 = 46 ± 3.6 ng/ml. We present the first report of a direct estimation of PDE4 blockade in the living human brain. In vivo affinity of GSK356278 for the PDE4, estimated in this early phase study, was combined with GSK356278 safety and tolerability data to decide on a therapeutic dose for future clinical development.
Wadhwa P, Thielemans K, Efthimiou N, et al., 2018, Implementation of Image Reconstruction for GE SIGNA PET/MR PET Data in the STIR Library
© 2018 IEEE. Software for Tomographic Image Reconstruction (STIR: http://stir.sf.net) is an open source C++ library available for reconstruction of emission tomography data. This work aims at the incorporation of the GE SIGNA PET/MR scanner in STIR and enables PET image reconstruction with data corrections. The data extracted from the scanner after an acquisition includes a list of raw data files (emission, normalisation, geometric and well counter calibration (wcc) factors), magnetic resonance attenuation correction (MRAC) images and the scanner-based reconstructions. The listmode (LM) file stores a list of 'prompt' events and the singles per crystal per second. MRAC images from the scanner are used for attenuation correction. The modifications to STIR that allow accurate histogramming of this LM data in the same sinogram organisation as the scanner are also described. This allows reconstruction of acquisition data with all data corrections using STIR, and independent of any software supplied by the manufacturer. The implementations were validated by comparing the histogrammed data, data corrections and final reconstruction using the ordered subset expectation maximisation (OSEM) algorithm with the equivalents from the GE-toolbox, supplied by the manufacturer for the scanner. There is no difference in the histogrammed counts whereas an overall relative difference of 6.7 × 10-8% and from 0.01% to 0.86% is seen in the normalisation and randoms correction sinograms respectively. The STIR reconstructed images have similar resolution and quantification but have some residual differences due to wcc factors, decay and deadtime corrections, as well as the offset between PET and MR gantries that will be addressed in future work. This work will enable the use of all current and future STIR algorithms, including penalized image reconstruction, motion correction and direct parametric image estimation, on data from GE SIGNA PET/MR scanners.
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