Publications
230 results found
Dani M, Wood M, Mizoguchi R, et al., 2019, Tau Aggregation Correlates with Amyloid Deposition in Both Mild Cognitive Impairment and Alzheimer's Disease Subjects, JOURNAL OF ALZHEIMERS DISEASE, Vol: 70, Pages: 453-463, ISSN: 1387-2877
Roussakis A-A, Mohamed MA, Myers J, et al., 2019, Astrogliosis in Parkinson's disease dementia: a preliminary report with brain, 5th Congress of the European-Academy-of-Neurology (EAN)
Wang YT, Edison P, 2019, Tau imaging in neurodegenerative diseases using positron emission tomography, Current Neurology and Neuroscience Reports, Vol: 19, ISSN: 1528-4042
Purpose of ReviewAbnormal accumulation of tau protein is the main hallmark of tauopathies and is closely associated with neurodegeneration and cognitive impairment, whereas the advance in PET imaging provides a non-invasive detection of tau inclusions in the brain. In this review, we discuss the potential of PET imaging as a biomarker in tauopathies, the latest development of novel tau tracers with new clinical information that has been disclosed, and the opportunities for improving diagnosis and designing clinical trials in the future.Recent FindingsIn recent years, several first-generation tau PET tracers including [11C]PBB3, [18F]THK-5117, [18F]THK-5351 and [18F]AV-1451 have been developed and succeeded in imaging neurofibrillary pathology in vivo. Due to the common off-target binding and subcortical white matter uptake seen in the first-generation tracers, several research institutes and pharmaceutical companies have been working on developing second-generation tau PET tracers which exhibit higher binding affinity and selectivity.SummaryTau PET imaging is promising to serve as a biomarker to support differential diagnosis and monitor disease progression in many neurodegenerative diseases.
Femminella GD, Frangou E, Love SB, et al., 2019, Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study), Trials, Vol: 20, ISSN: 1745-6215
BACKGROUND: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer's disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12 months of treatment with liraglutide in participants with Alzheimer's disease compared to those who are receiving placebo. METHODS/DESIGN: ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer's dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer's Disease Assessment Scale-Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer's Disease Cooperative Study-Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores u
Femminella G, Dani M, Wood M, et al., 2019, Microglial activation in early Alzheimer trajectory is associated with higher grey matter volume, Neurology, Vol: 92, Pages: e1331-e1343, ISSN: 1526-632X
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 grey matter volume and hippocampal volume in MCI patients.Methods: In this study, fifty-five participants (37 early stages MCI and 18 controls) underwent [11C]PBR28 PET, a marker of microglial activation; volumetric MRI to evaluate grey matter and hippocampal volumes as well as clinical and neuropsychometric evaluation. [11C]PBR28 VT(volume of distribution) was calculated using arterial input function and Logan Graphical analysis. Grey matter volume and hippocampal volumes were calculated from MRI for each subject. Statistical parametric mapping software was used to perform voxel-wise correlations and biological parametric mapping analysis. Amyloid status was assessed using [18F]Flutemetamol PET.Results: Higher [11C]PBR28 VT in different cortical areas correlated with higher grey matter volume in both amyloid positive and negative MCI. Additionally, higher hippocampal volume correlated with higher cortical [11C]PBR28 Logan VT.Conclusions: In this in vivo study, we have demonstrated that microglial activation quantified using [11C]PBR28 PET was associated with higher grey matter volume and higher hippocampal volume in MCI patients. This may suggest that microglial activation may not always be associatedwith neuronal damage, and indeed it may have beneficial effect in early stages of Alzheimer’s trajectory. While further longitudinal studies are necessary, these findings have significant implications on therapeutic strategies targeting microglial activation.
Li X, Wang H, Long J, et al., 2018, Systematic analysis and biomarker study for Alzheimer’s disease, Scientific Reports
Edison P, Dani M, wood M, et al., 2018, Microglial activation correlates in vivo with both tau and amyloid in Alzheimer’s disease, Brain, Vol: 141, Pages: 2740-2754, ISSN: 1460-2156
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
Sastre M, Edison P, Donat C, 2018, In vivo imaging of Glial activation in Alzheimer's disease, Frontiers in Neurology, Vol: 9, ISSN: 1664-2295
Alzheimer's disease (AD) is characterized by memory loss and decline of cognitive function, associated with progressive neurodegeneration. While neuropathological processes like amyloid plaques and tau neurofibrillary tangles have been linked to neuronal death in AD, the precise role of glial activation on disease progression is still debated. It was suggested that neuroinflammation could occur well ahead of amyloid deposition and may be responsible for clearing amyloid, having a neuroprotective effect; however, later in the disease, glial activation could become deleterious, contributing to neuronal toxicity. Recent genetic and preclinical studies suggest that the different activation states of microglia and astrocytes are complex, not as polarized as previously thought, and that the heterogeneity in their phenotype can switch during disease progression. In the last few years, novel imaging techniques e.g., new radiotracers for assessing glia activation using positron emission tomography and advanced magnetic resonance imaging technologies have emerged, allowing the correlation of neuro-inflammatory markers with cognitive decline, brain function and brain pathology in vivo. Here we review all new imaging technology in AD patients and animal models that has the potential to serve for early diagnosis of the disease, to monitor disease progression and to test the efficacy and the most effective time window for potential anti-inflammatory treatments.
Calsolaro V, Mayers J, Fan Z, et al., 2018, Evaluation of novel astrocyte marker [11C]BU99008 PET in Alzheimer’s disease: a Dementia Platform U.K. experimental medicine study, Alzheimer's and Dementia, Vol: 14, Pages: P842-P843, ISSN: 1552-5260
Calsolaro V, Fan Z, Veronese M, et al., 2018, Novel third generation microglial marker flutriciclamide ([18F]GE180) in Alzheimer’s disease and mild cognitive impairment, Alzheimer's and Dementia, Vol: 14, Pages: P506-P506, ISSN: 1552-5260
Fan Z, Calsolaro V, Mayers J, et al., 2018, Relationship between astrocyte activation using [11C]BU99008 PET, glucose metabolism and amyloid in Alzheimer’s disease: a Dementia Platform UK experimental medicine study, Alzheimer's and Dementia, Vol: 14, Pages: P1640-P1640, ISSN: 1552-5260
Fan Z, Dani M, Hinz R, et al., 2018, Voxel-level interaction between NFT and amyloid influences/predicts the decline rate of cognition in patients with mild cognitive impairment, Alzheimer's and Dementia, Vol: 14, Pages: P1636-P1637, ISSN: 1552-5260
Femminella G, Fan Z, Frangou E, et al., 2018, Peripheral insulin resistance does not correlate with cerebral glucose metabolic rate in non-diabetic Alzheimer’s patients, Alzheimer's and Dementia, Vol: 14, Pages: P1157-P1158, ISSN: 1552-5260
Femminella G, Talib S, Harold D, et al., 2018, The differential influence of immune, endocytotic and lipid metabolism genes on amyloid deposition and neurodegeneration in Alzheimer’s disease, Alzheimer's and Dementia, Vol: 14, Pages: P659-P659, ISSN: 1552-5260
Femminella GD, Taylor-Davies G, Scott J, et al., 2018, Do Cardiometabolic Risk Factors Influence Amyloid, Tau, and Neuronal Function in APOE4 Carriers and Non-Carriers in Alzheimer's Disease Trajectory?, JOURNAL OF ALZHEIMERS DISEASE, Vol: 64, Pages: 981-993, ISSN: 1387-2877
Fan Z, Dani M, Femminella GD, et al., 2018, Parametric mapping using spectral analysis for11C-PBR28 PET reveals neuroinflammation in mild cognitive impairment subjects, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 45, Pages: 1432-1441, ISSN: 1619-7070
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 quantify11C-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 underwent11C-PBR28 PET scans with arterial cannulation. Spectral analysis with an arterial plasma input function was used to generate11C-PBR28 parametric maps. These maps were then compared with regional11C-PBR28 VT(volume of distribution) using a two-tissue compartment model and Logan graphic analysis. Amyloid load was also assessed with18F-Flutemetamol PET. RESULTS: With SA, three component peaks were identified in addition to blood volume. The11C-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 of11C-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 in11C-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 of11C-PBR28 uptake, and is able to detect microglial activation in amyloid-positive MCI subjects. IRF parametric maps of11C-PBR28 uptake allow voxel-wise single-subject analysis and could be used to evaluate microglial activation in individual subjects.
Edison P, Brooks D, 2018, Role of neuroinflammation in Alzheimer’s trajectory and in vivo quantification using PET, Journal of Alzheimers Disease, Vol: 64, Pages: S339-S351, ISSN: 1387-2877
Recent evidence suggests that neuroinflammation and immunity play a significant role in Alzheimer’s disease and other neurodegenerative diseases. It has also been observed that, independent of the presence of aggregated proteins, neuroinflammation could be present in different neurodegenerative diseases. It has also been suggested that neuroinflammation could occur well ahead of amyloid deposition in AD. Recent genetic studies and other preclinical studies specifically point to a role of neuroinflammation and, in this review, we evaluate the evidence of neuroinflammation in the Alzheimer’s disease trajectory and the different imaging modalities by which we could monitor neuroinflammation in vivo in humans.
Donat CK, Mirzaei N, Tang S-P, et al., 2018, Erratum to: Imaging of Microglial Activation in Alzheimer's Disease by [11C]PBR28 PET., Methods Mol Biol, Vol: 1750, Pages: E1-E1
Donat C, Mirzaei N, Tang S-P, et al., 2018, Imaging of Microglial Activation in Alzheimer's Disease by [11C]PBR28 PET, Biomarkers for Alzheimer's disease drug development, Editors: Perneczky, Publisher: Humana Press, Pages: 323-339
Donat CK, Mirzaei N, Tang S-P, et al., 2018, Imaging of Microglial Activation in Alzheimer's Disease by [11C]PBR28 PET., Methods Mol Biol, Vol: 1750, Pages: 323-339
Deficits in neuronal function and synaptic plasticity in Alzheimer's disease (AD) are believed to be linked to microglial activation. A hallmark of reactive microglia is the upregulation of mitochondrial translocator protein (TSPO) expression. Positron emission tomography (PET) is a nuclear imaging technique that measures the distribution of trace doses of radiolabeled compounds in the body over time. PET imaging using the 2nd generation TSPO tracer [11C]PBR28 provides an opportunity for accurate visualization and quantification of changes in microglial density in transgenic mouse models of Alzheimer's disease (AD). Here, we describe the methodology for the in vivo use of [11C]PBR28 in AD patients and the 5XFAD transgenic mouse model of AD and compare the results against healthy individuals and wild-type controls. To confirm the results, autoradiography with [3H]PBR28 and immunochemistry was carried out in the same mouse brains. Our data shows that [11C]PBR28 is suitable as a tool for in vivo monitoring of microglial activation and may be useful to assess treatment response in future studies.
Edison P, 2018, Tau imaging in preclinical Alzheimer’s disease, Biomarkers for Alzheimer’s Disease Drug Development, Editors: Perneczky, Pages: 189-197
Edison P, Brooks DJ, 2018, Role of Neuroinflammation in the Trajectory of Alzheimer's Disease and <i>in vivo</i> Quantification Using PET, ALZHEIMER'S DISEASE: NEW BEGINNINGS, Editors: Perry, Avila, Moreira, Sorensen, Tabaton, Publisher: IOS PRESS, Pages: 337-349, ISBN: 978-1-61499-875-4
Calsolaro V, Femminella G, Fan Z, et al., 2017, Evaluation of caspase-3 activation in an Alzheimer’s disease population using [18F]ICMT-11 PET/CT, Alzheimer's and Dementia, Vol: 13, Pages: P1353-P1354, ISSN: 1552-5260
Edison P, Mayers J, Calsolaro V, et al., 2017, Dementia Platform U.K. Experimental medicine: human in vivo astroglial activation in early Alzheimer’s disease, Alzheimer's and Dementia, Vol: 13, Pages: P1073-P1074, ISSN: 1552-5260
Femminella G, Taylor-Davies G, Scott J, et al., 2017, Cardiometabolic risk predicts biomarker progression in Alzheimer’s disease trajectory, Alzheimer's and Dementia, Vol: 13, Pages: P1227-P1227, ISSN: 1552-5260
Calsolaro V, Fan Z, Femminella G, et al., 2017, Microglial activation in Alzheimer’s disease detected by novel third generation translocator protein tracer flutriciclamide ([18F]GE180), Alzheimer's and Dementia, Vol: 13, Pages: P922-P922, ISSN: 1552-5260
Dani M, Fan Z, Wood M, et al., 2017, Amyloid deposition, tau aggregation and microglial activation correlate with vascular burden in vivo in Alzheimer's disease, Alzheimer's and Dementia, Vol: 13, Pages: P681-P682, ISSN: 1552-5260
Femminella G, Dani M, Wood M, et al., 2017, Microglial activation is associated with higher grey matter density and hippocampal volume in MCi subjects, Alzheimer's and Dementia, Vol: 13, Pages: P921-P921, ISSN: 1552-5260
Fan Z, Dani M, Femminella G, et al., 2017, Regional kinetic modelling application for TSPO PET tracer [11C]PBR28, Alzheimer's and Dementia, Vol: 13, Pages: P289-P289, ISSN: 1552-5260
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