Publications
230 results found
Dani M, Wood M, Mizoguchi R, et al., 2017, Different modelling approaches for tau tracer 18F-AV1451 in mild cognitive impairment and Alzheimer's disease, Alzheimer's and Dementia, Vol: 13, Pages: P291-P292, ISSN: 1552-5260
Dani M, Brooks DJ, Edison P, 2017, Suspected non Alzheimer's pathology - Is it non-Alzheimer's or non-amyloid?, AGEING RESEARCH REVIEWS, Vol: 36, Pages: 20-31, ISSN: 1568-1637
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- Citations: 28
Femminella GD, Bencivenga L, Petraglia L, et al., 2017, Antidiabetic Drugs in Alzheimer's Disease: Mechanisms of Action and Future Perspectives, Journal of Diabetes Research, Vol: 2017, ISSN: 2314-6745
Diabetes mellitus (DM) and Alzheimer’s disease (AD) are two highly prevalent conditions in the elderly population and majorpublic health burden. In the past decades, a pathophysiological link between DM and AD has emerged and central nervoussystem insulin resistance might play a significant role as a common mechanism; however, other factors such as inflammationand oxidative stress seem to contribute to the shared pathophysiological link. Both preclinical and clinical studies have evaluatedthe possible neuroprotective mechanisms of different classes of antidiabetic medications in AD, with some promising results.Here, we review the evidence on the mechanisms of action of antidiabetic drugs and their potential use in AD.
Parbo P, Ismail R, Hansen KV, et al., 2017, Brain inflammation accompanies amyloid in the majority of mild cognitive impairment cases due to Alzheimer's disease, BRAIN, Vol: 140, Pages: 2002-2011, ISSN: 0006-8950
Fan Z, Brooks DJ, Okello A, et al., 2017, An early and late peak in microglial activation in Alzheimer's disease trajectory, Brain, Vol: 140, Pages: 792-803, ISSN: 0006-8950
search inputSearchAn early and late peak in microglial activation in Alzheimer’s disease trajectoryZhen Fan, David J. Brooks, Aren Okello, Paul EdisonBrain, Volume 140, Issue 3, March 2017, Pages 792–803, https://doi.org/10.1093/brain/aww349Published:24 January 2017Article historyReceived:20 June 2016Revision received:31 October 2016Accepted:18 November 2016Published:24 January 2017 pdfPDF Split View Cite Permissions Icon Permissions ShareAbstractAmyloid-β deposition, neuroinflammation and tau tangle formation all play a significant role in Alzheimer’s disease. We hypothesized that there is microglial activation early on in Alzheimer’s disease trajectory, where in the initial phase, microglia may be trying to repair the damage, while later on in the disease these microglia could be ineffective and produce proinflammatory cytokines leading to progressive neuronal damage. In this longitudinal study, we have evaluated the temporal profile of microglial activation and its relationship between fibrillar amyloid load at baseline and follow-up in subjects with mild cognitive impairment, and this was compared with subjects with Alzheimer’s disease. Thirty subjects (eight mild cognitive impairment, eight Alzheimer’s disease and 14 controls) aged between 54 and 77 years underwent 11C-(R)PK11195, 11C-PIB positron emission tomography and magnetic resonance imaging scans. Patients were followed-up after 14 ± 4 months. Region of interest and Statistical Parametric Mapping analysis were used to determine longitudinal alterations. Single subject analysis was performed to evaluate the individualized pathological changes over time. Correlations between levels of microglial activation and amyloid deposition at a voxel level were assessed using Biological Parametric Mapping. We demonstrated that both baseline and follow-up microglial activation in the mild cognitive impairment cohort compared to controls were increased by 4
Calsolaro V, Ashraf A, Fan Z, et al., 2016, Increased [11C](R)PK11195-PET and attenuated cerebral glucose metabolism: a common theme in neurodegenerative diseases?, Alzheimer's and Dementia, Vol: 12, Pages: P1085-P1085, ISSN: 1552-5260
Femminella G, Dani M, Fan Z, et al., 2016, Does neuroinflammation predate amyloid formation in subjects at risk for Alzheimer’s disease?, Alzheimer's and Dementia, Vol: 12, Pages: P283-P283, ISSN: 1552-5260
Fan Z, Brooks D, Okello A, et al., 2016, An early and late peak in microglial activation in Alzheimer’s disease trajectory: a longitudinal PET study, Alzheimer's and Dementia, Vol: 12, Pages: P527-P528, ISSN: 1552-5260
Fan Z, Edison P, Atkinson R, et al., 2016, Flutriciclamide ([18F]GE180) PET: first in human PET study of novel in vivo marker of human translator protein, Alzheimer's and Dementia, Vol: 12, Pages: P397-P397, ISSN: 1552-5260
Edison P, 2016, 1. Does microglial activation predate amyloid formation in Alzheimer’s disease trajectory?, Alzheimer’s Association International Conference
Calsolaro V, Edison P, 2016, Alterations in glucose metabolism in Alzheimer's disease, Recent Patents on Endocrine, Metabolic and Immune Drug Discovery, Vol: 10, ISSN: 1872-2148
BACKGROUND: Alzheimer's disease (AD) is the most frequent type of dementia in people over 65 years of age; type 2 diabetes mellitus is a metabolic condition affecting 382 million of adults worldwide. Glucose is the main substrate for energy for the brain, which consumes 25% of the body's glucose. Glucose metabolism, evaluated using Positron Emission Tomography (PET) scanning using 18F-fluorodeoxyglucose ([18F]-FDG) is commonly used for diagnosis and follow up in AD. Epidemiological and pathophysiological studies showed a link between AD and diabetes, particularly regarding the insulin resistance. OBJECTIVE: In this paper, we discuss how [18F]FDG is a marker of glucose metabolism, how insulin resistance is related to diabetes, the link between diabetes and AD, and how novel treatments for diabetes could be beneficial in the treatment of Alzheimer's disease. We also review few recent patents in the field, suggesting both diagnostic and therapeutic potential approaches. METHODS: The electronic searches were performed in MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases. We also manually searched abstract books and reviewed available recent patetns on specific websites. RESULTS: The impaired glucose metabolism in the brain of subject with AD is a widely recognised early feature of the disease; in vivo evaluation with PET is a useful diagnostic tool. The link between diabetes and neurodegeneration is widely recognized and offer a target for novel therapeutic strategies. CONCLUSIONS: Early diagnosis and early therapeutic intervention are needed to approach this devastating disease. Important studies targeting different aspect of the disease are currently ongoing.
Fan Z, Calsolaro V, Atkinson R, et al., 2016, Flutriciclamide (18F-GE180) PET: first in human PET study of novel 3rd generation in vivo marker of human translator protein., Journal of Nuclear Medicine, Vol: 57, Pages: 1753-1759, ISSN: 1535-5667
Neuroinflammation is associated with neurodegenerative disease. PET (positron emission tomography) radioligands targeting the 18 kDa translocator protein (TSPO) has been used as in vivo markers of neuroinflammation, but there is an urgent need for novel probes with improved signal-to-noise ratio. Flutriciclamide ((18)F-GE180) is a recently developed third generation TSPO ligand. In this first study, we evaluated the optimum scan duration and kinetic modelling strategies for (18)F-GE180 PET in (older) healthy controls (HC). METHODS: Ten HC, six TSPO high affinity binders (HABs) and four mixed affinity binders (MABs), were recruited. All subjects had detailed neuropsychological tests, MRI and a 210 min (18)F-GE180 dynamic PET/CT scan using metabolite corrected arterial plasma input function. We evaluated five different kinetic models: irreversible and reversible two-tissue compartment models, a reversible one-tissue model and two models with an extra irreversible vascular compartment. The optimum scan length was investigated based on 210 min scan data. The feasibility of generating parametric maps was also investigated using graphical analysis. RESULTS: (18)F-GE180 concentration was higher in plasma than in whole blood during the entire scan duration. Using the kinetic model, the volume of distribution (VT) was 0.17 in HABs and 0.12 in MABs. The model that best represented brain (18)F-GE180 kinetics across regions was the reversible two-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 VT highly consistent with VT in kinetic model, which could be used for voxel-wise analysis. CONCLUSION: We report for the first time the kinetic properties of the novel third generation TSPO PET ligand, (18)F-GE180, in humans: 2TCM4k is the optimal method to quantify the brain uptake, 90 min is the optimal scan length and Logan approach could be used to genera
Calsolaro V, Edison P, 2016, Neuroinflammation in Alzheimer's disease: Current evidence and future directions, Alzheimers & Dementia, Vol: 12, Pages: 719-732, ISSN: 1552-5279
Several attempts have been made to treat Alzheimer's disease (AD) using anti-amyloid strategies with disappointing results. It is clear that the “amyloid cascade hypothesis” alone cannot fully explain the neuronal damage in AD, as evidenced both by autopsy and imaging studies. Neuroinflammation plays a significant role in neurodegenerative diseases, whereas the debate is ongoing about its precise role, whether it is protective or harmful. In this review, we focus on the potential mechanism of glial activation and how local and systemic factors influence disease progression. We focus on neuroinflammation in AD, especially in the earliest stages, a vicious cycle of glial priming, release of pro-inflammatory factors, and neuronal damage. We review the evidence from imaging studies, regarding the temporal relationship between amyloid deposition and neuroinflammation, the influence of systemic inflammation on glial activation, both in acute and chronic stimulation and the relevance of inflammation as a diagnostic and therapeutic target.
Femminella GD, Ninan S, Atkinson R, et al., 2016, Does Microglial Activation Influence Hippocampal Volume and Neuronal Function in Alzheimer's Disease and Parkinson's Disease Dementia?, Journal of Alzheimers Disease, Vol: 51, Pages: 1275-1289, ISSN: 1875-8908
Background:The influence of neuroinflammation on neuronal function and hippocampal atrophy in Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD) is still unclear.Objectives:Here we investigated whether microglial activation measured by [11C]PK11195 PET is associated with neuronal function measured by cerebral glucose metabolic rate (rCMRGlc) using FDG-PET and hippocampal volume measurements.Methods:We enrolled 25 subjects (9 PDD, 8 AD, and 8 controls) who underwent PET scans with [11C](R)PK11195, [18F]FDG, and volumetric MRI scanning.Results:SPM correlation analysis in AD and PDD showed a negative correlation between hippocampal volume and microglial activation within hippocampus or parahippocampus and with cortical and subcortical areas of projections from hippocampus, while there was a positive correlation between rCMRGlc in cortical and subcortical areas of projections from hippocampus and hippocampal volume. Hippocampal volume was significantly reduced in AD compared to controls but not in PDD.Conclusions:These findings indicate that microglial activation inversely correlated with hippocampal volume and hippocampal rCMRGlc in neurodegenerative diseases with dementia, providing further evidence for the central role of microglial activation in neurodegenerative diseases.
Scott GPT, Ramlackhansingh A, Edison P, et al., 2016, Amyloid pathology and axonal injury after brain trauma, Neurology, Vol: 86, Pages: 821-828, ISSN: 0028-3878
Objective: To image amyloid-β (Aβ) plaque burden in long-term survivors of traumatic brain injury (TBI), test whether traumatic axonal injury and Aβ are correlated, and compare the spatial distribution of Aβ to Alzheimer’s disease.Methods: Patients 11 months to 17 years after moderate-severe TBI had 11C-Pittsburgh compound-B (PIB) PET, structural and diffusion MRI and neuropsychological examination. Healthy aged controls and AD patients had PET and structural MRI. Binding potential (BPND) images of 11C-PIB, which index Aβ plaque density, were computed using an automatic reference region extraction procedure. Voxelwise and regional differences in BPND were assessed. In TBI, a measure of white matter integrity, fractional anisotropy (FA), was estimated and correlated with 11C-PIB BPND.Results: 28 participants (9 TBI, 9 controls, 10 AD) were assessed. Increased 11C-PIB BPND was found in TBI versus controls in the posterior cingulate cortex (PCC) and cerebellum. Binding in the PCC increased with decreasing FA of associated white matter tracts, and increased with time since injury. Compared to AD, binding after TBI was lower in neocortical regions, but increased in the cerebellum. Conclusions: Increased Aβ burden was observed in TBI. The distribution overlaps with, but is distinct from, that of AD. This suggests a mechanistic link between TBI and the development of neuropathological features of dementia, which may relate to axonal damage produced by the injury.
Edison P, Calsolaro V, 2015, Novel GLP-1 (Glucagon-Like Peptide-1) Analogues and Insulin in the Treatment for Alzheimer’s Disease and Other Neurodegenerative Diseases, CNS Drugs, ISSN: 1172-7047
Dani M, Brooks DJ, Edison P, 2015, Tau imaging in neurodegenerative diseases, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 43, Pages: 1139-1150, ISSN: 1619-7089
Fan Z, Okello AA, Brooks DJ, et al., 2015, Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer’s disease, Brain, Vol: 138, Pages: 3685-3698, ISSN: 1460-2156
Amyloid deposition, tangle formation, neuroinflammation and neuronal dysfunction are pathological processes involved in Alzheimer’s disease. However, the relative role of these processes in driving disease progression is still unclear. The aim of this positron emission tomography study was to: (i) investigate longitudinal changes of microglial activation, amyloid and glucose metabolism; and (ii) assess the temporospatial relationship between these three processes in Alzheimer’s disease. A group of eight patients with a diagnosis of Alzheimer’s disease (66 ± 4.8 years) and 14 healthy controls (65 ± 5.5 years) underwent T1 and T2 magnetic resonance imaging, along with 11C-(R)-PK11195, 11C-Pittsburgh compound B and 18F-fluorodeoxyglucose positron emission tomography scans for microglial activation, amyloid deposition and glucose metabolism. All patients were followed-up with repeated magnetic resonance imaging and three positron emission tomography scans after 16 months. Parametric maps were interrogated using region of interest analysis, Statistical Parametric Mapping, and between-group correlation analysis at voxel-level using Biological Parametric Mapping. At baseline, patients with Alzheimer’s disease showed significantly increased microglial activation compared to the control subjects. During follow-up, for the first time, we found that while there is a progressive reduction of glucose metabolism, there was a longitudinal increase of microglial activation in the majority of the patients with Alzheimer’s disease. Voxel-wise correlation analysis revealed that microglial activation in patients with Alzheimer’s disease was positively correlated with amyloid deposition and inversely correlated with regional cerebral metabolic rate at voxel level over time. Even though one of the limitations of this study is the lack of longitudinal follow-up of healthy control subjects, this study demonstrates that there is persistent n
Varley J, Brooks DJ, Edison P, 2015, Imaging neuroinflammation in Alzheimer's disease and other dementias: Recent advances and future directions, ALZHEIMERS & DEMENTIA, Vol: 11, Pages: 1110-1120, ISSN: 1552-5260
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- Citations: 59
Dani M, Edison P, Brooks DJ, 2015, Imaging biomarkers in tauopathies, Parkinsonism & Related Disorders, Vol: 22, Pages: S26-S28, ISSN: 1353-8020
Abnormally aggregated tau protein is central to the pathophysiology of Alzheimer's disease, frontotemporal dementia variants, progressive supranuclear palsy, corticobasal degeneration and chronic traumatic encephalopathy. The post-mortem cortical density of hyperphosphorylated tau tangles correlates with pre-morbid cognitive dysfunction and neuron loss. Selective PET ligands including [18F]THK5117, [18F]THK5351, [18F]AV1451 (T807) and [11C]PBB3 now provide in vivo imaging information about the timing and distribution of tau in the early phases of neurodegenerative diseases. They are potential imaging biomarkers for both supporting diagnosis and tracking disease progression. Here, we discuss the challenges posed in developing selective tau ligands as biomarkers, their state of development and the new clinical information that has been revealed.
Edison P, 2015, 2. Does microglial activation influence hippocampal volume and neuronal function in Alzheimer’s and Parkinson’s disease?, Alzheimer’s Association International Conference
Fan Z, Aman Y, Ahmed I, et al., 2015, Influence of microglial activation on neuronal function in Alzheimer's and Parkinson's disease dementia, Alzheimers & Dementia, Vol: 11, Pages: 608-621, ISSN: 1552-5260
BackgroundAlzheimer's disease (AD) and Parkinson's disease (PD) are the two common neurodegenerative diseases characterized by progressive neuronal dysfunction in the presence of pathological microglial activation.Methods10 AD, 10 mild cognitive impairment (MCI), 11 PD dementia (PDD), and 16 controls underwent magnetic resonance imaging, [11C](R)PK11195 (1‐[2‐chlorophenyl]‐N‐methyl‐N‐[1‐methyl‐propyl]‐3‐isoquinoline carboxamide), [11C]PIB (11C‐Pittsburgh compound B), [18F]FDG‐PET (18F‐2‐fluoro‐2‐deoxyglucose positron emission tomography) scans. Parametric images were interrogated using region of interest (ROI), biological parametric mapping (BPM) and statistical parametric mapping analysis, and neuropsychometric tests.ResultsUsing BPM analysis, AD, MCI, and PDD subjects demonstrated significant correlation between increased microglial activation and reduced glucose metabolism (rCMRGlc). AD and MCI subjects also showed significant positive correlation between amyloid and microglial activation. Levels of cortical microglial activation were negatively correlated with Mini‐Mental State Examination in both AD and PDD.ConclusionThe significant inverse correlations between cortical levels of microglial activation and rCMRGlc in AD and PDD suggest cortical neuroinflammation may drive neuronal dysfunction in these dementias.
Femminella GD, Edison P, 2015, Adrenergic system in Alzheimer's disease, GIORNALE DI GERONTOLOGIA, Vol: 63, Pages: 121-127, ISSN: 0017-0305
Fan Z, Harold D, Pasqualetti G, et al., 2015, Can Studies of Neuroinflammation in a TSPO Genetic Subgroup (HAB or MAB) Be Applied to the Entire AD Cohort?, JOURNAL OF NUCLEAR MEDICINE, Vol: 56, Pages: 707-713, ISSN: 0161-5505
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- Citations: 26
Pasqualetti G, Brooks DJ, Edison P, 2015, The Role of Neuroinflammation in Dementias, CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS, Vol: 15, ISSN: 1528-4042
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- Citations: 94
Femminella GD, Kenny LM, Sinha A, et al., 2015, Carcinoid-associated Encephalopathy, JOURNAL OF CLINICAL GASTROENTEROLOGY, Vol: 49, Pages: 353-354, ISSN: 0192-0790
Ashraf A, Fan Z, Brooks DJ, et al., 2015, Cortical hypermetabolism in MCI subjects: a compensatory mechanism?, EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, Vol: 42, Pages: 447-458, ISSN: 1619-7070
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- Citations: 85
Varley J, Brooks DJ, Edison P, 2014, Imaging neuroinflammation in Alzheimer's and other dementias: recent advances and future directions. Alzheimers & Dementia. (in press).
Ashraf A, Fan Z, Brooks DJ, et al., 2014, Cortical hypermetabolism in MCI subjects: a compensatory mechanism? Eur J Nucl Med Mol Imaging (in press)., Eur J Nucl Med Mol Imaging
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