271 results on '"Richardson, Jc"'
Search Results
2. TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels
- Author
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Hong, SJ, Dobricic, V, Ohlei, O, Bos, I, Vos, SJB, Prokopenko, D, Tijms, BM, Andreasson, U, Blennow, K, Vandenberghe, R, Gabel, S, Scheltens, P, Teunissen, CE, Engelborghs, S, Frisoni, G, Blin, O, Richardson, JC, Bordet, R, Lleo, A, Alcolea, D, Popp, J, Clark, C, Peyratout, G, Martinez-Lage, P, Tainta, M, Dobson, RJB, Legido-Quigley, C, Sleegers, K, Van Broeckhoven, C, Tanzi, RE, ten Kate, M, Wittig, M, Franke, A, Lill, CM, Barkhof, F, Lovestone, S, Streffer, J, Zetterberg, H, Visser, PJ, Bertram, L, and Neuroimaging Initiative
- Subjects
s disease ,wide association study ,chitinase‐ ,like protein 1 ,neurogranin ,neurofilament light ,3‐ ,biomarker ,genome‐ ,Alzheimer&apos ,cerebrospinal fluid - Abstract
Introduction Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Methods We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. Results We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. Discussion Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
- Published
- 2021
3. Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset
- Author
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Hong, SJ, Prokopenko, D, Dobricic, V, Kilpert, F, Bos, I, Vos, SJB, Tijms, BM, Andreasson, U, Blennow, K, Vandenberghe, R, Cleynen, I, Gabel, S, Schaeverbeke, J, Scheltens, P, Teunissen, CE, Niemantsverdriet, E, Engelborghs, S, Frisoni, G, Blin, O, Richardson, JC, Bordet, R, Molinuevo, JL, Rami, L, Kettunen, P, Wallin, A, Lleo, A, Sala, I, Popp, J, Peyratout, G, Martinez-Lage, P, Tainta, M, Dobson, RJB, Legido-Quigley, C, Sleegers, K, Van Broeckhoven, C, ten Kate, M, Barkhof, F, Zetterberg, H, Lovestone, S, Streffer, J, Wittig, M, Franke, A, Tanzi, RE, Visser, PJ, Bertram, L, and Alzheimers Dis Neuroimaging Initia
- Abstract
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (A beta) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to A beta 42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-A beta 38 and CSF-A beta 40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-A beta and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
- Published
- 2020
4. Inflammatory biomarkers in Alzheimer's disease plasma
- Author
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Leckey, C, Nevado-Holgado, AJ, Barkhof, F, Bertram, L, Blin, O, Bos, I, Dobricic, V, Engelborghs, S, Frisoni, G, Frolich, L, Gabel, S, Johannsen, P, Kettunen, P, Koszewska, I, Legido-Quigley, C, Lleo, A, Martinez-Lage, P, Mecocci, P, Meersmans, K, Molinuevo, JL, Peyratout, G, Popp, J, Richardson, J, Sala, I, Scheltens, P, Streffer, J, Soininen, H, Tainta-Cuezva, M, Teunissen, C, Tsolaki, M, Vandenberghe, R, Visser, PJ, Vos, S, Wahlund, LO, Wallin, A, Westwood, S, Zetterberg, H, Bullmore, ET, Bhatti, J, Chamberlain, SJ, Correia, MM, Crofts, AL, Dickinson, A, Foster, AC, Kitzbichler, MG, Knight, C, Lynall, ME, Maurice, C, O'Donnell, C, Pointon, LJ, Hyslop, PS, Turner, L, Vertes, P, Widmer, B, Williams, GB, Morgan, BP, Morgan, AR, O'Hagan, C, Touchard, S, Cavanagh, J, Deith, C, Farmer, S, McClean, J, McColl, A, McPherson, A, Scouller, P, Sutherland, M, Boddeke, HWGM, Richardson, JC, Khan, S, Murphy, P, Parker, CA, Patel, J, Jones, D, Boer, P, Kemp, J, Drevets, WC, Nye, JS, Wittenberg, G, Isaac, J, Bhattacharya, A, Carruthers, N, Kolb, H, Pariante, CM, Turkheimer, F, Barker, GJ, Byrom, H, Cash, D, Cattaneo, A, Gee, A, Hastings, C, Mariani, N, McLaughlin, A, Mondelli, V, Nettis, M, Nikkheslat, N, Randall, K, Sheridan, H, Simmons, C, Singh, N, Van Loo, V, Vicente-Rodriguez, M, Wood, TC, Worrell, C, Zajkowska, Z, Plath, N, Egebjerg, J, Eriksson, H, Gastambide, F, Adams, KH, Jeggo, R, Thomsen, C, Pederson, JT, Campbell, B, Moller, T, Nelson, B, Zorn, S, O'Connor, J, Attenburrow, MJ, Baird, A, Benjamin, J, Clare, S, Cowen, P, Huang, IS, Hurley, S, Jones, H, Lovestone, S, Mada, F, Nevado-Holgado, A, Oladejo, A, Ribe, E, Smith, K, Vyas, A, Hughes, Z, Balice-Gordon, R, Duerr, J, Piro, JR, Sporn, J, Perry, VH, Cleal, M, Fryatt, G, Gomez-Nicola, D, Mancuso, R, Reynolds, R, Harrison, NA, Cercignani, M, Clarke, CL, Hoskins, E, Kohn, C, Murray, R, Wilcock, L, Wlazly, D, NIMA Consortium, and NIMA-Wellcome Trust Consortium
- Subjects
Inflammation ,Plasma ,Complement ,Biomarker ,Alzheimer's disease - Abstract
Introduction: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a "Holy Grail" of AD research and intensively sought; however, there are no well-established plasma markers. Methods: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. Results: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOe4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). Discussion: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation. (C) 2019 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
- Published
- 2019
5. Where is my sink? Reconstruction of landscape development in 1 southwestern Africa since the Late Jurassic
- Author
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Richardson, JC, Hodgson, DM, Paton, D, Craven, B, Rawcliffe, A, Lang, A, and Somerville, I
- Abstract
Quantifying the rates and timing of landscape denudation provides a means to constrain sediment flux through time to offshore sedimentary basins. The Late Mesozoic evolution of drainage basins in southern Africa is poorly constrained despite the presence of several onshore and offshore sedimentary basins. A novel approach has been developed to calculate the volume of material eroded since the Late Jurassic at different time steps by constructing structural cross-sections and extrapolating thicknesses of eroded material. Using different assumptions, the calculated volumes of material eroded from southwestern Africa range from 2.52x10⁶ km³ (11.3 km of vertical thickness removed) to 8.87 x10⁵ km³ (4.0 km of vertical thickness removed). For the southward draining systems alone, the calculated removal of 7.81 x10⁵ – 2.60 x10⁵ km³ of material is far greater than the volumes of sediment recorded in offshore sedimentary basins (268 500 km³). Reconstruction of the drainage systems using geomorphic indicators and clast provenance of the Uitenhage Group, as well as extrapolated surface exposure ages, indicate the southern draining systems were active from the Late Jurassic with coeval activity in axial and transverse drainage systems. The calculated volumes are tied to published apatite fission track (AFT) dates to constrain the changes in exhumation rate through time (using multiple scenarios), which indicate a significant amount of Early Cretaceous exhumation (up to 1.26 x10⁶ km³, equivalent to 5.70km of vertical thickness). For the first time, this has permitted long-term landscape evolution to be used to support the interpretation that some of the ‘missing’ sediment was deposited in sedimentary basins on the Falkland Plateau as it moved past southern Africa during the Early Cretaceous. This implies that in this instance, the sinks are separated from their source areas by ~6000 km.
- Published
- 2017
6. Progressive Supranuclear Palsy: A Heterogeneous Degeneration Involving the Brain Stem, Basal Ganglia and Cerebellum With Vertical Gaze and Pseudobulbar Palsy, Nuchal Dystonia and Dementia
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Richardson Jc, Olszewski J, and Steele Jc
- Subjects
Male ,Cerebellum ,Histology ,Pseudobulbar Palsy ,Pyramidal Tracts ,Degeneration (medical) ,Basal Ganglia ,Progressive supranuclear palsy ,Diagnosis, Differential ,Arts and Humanities (miscellaneous) ,Cerebellar Diseases ,Basal ganglia ,Pathology ,Cerebellar Degeneration ,Humans ,Paralysis ,Corticobasal degeneration ,Medicine ,Dementia ,Aged ,Dystonia ,Brain Diseases ,Vertical supranuclear gaze palsy ,business.industry ,Mental Disorders ,Supranuclear ophthalmoplegia ,Middle Aged ,Pseudobulbar palsy ,medicine.disease ,Gaze ,Supranuclear gaze palsy ,medicine.anatomical_structure ,Neurology ,Ganglia ,Supranuclear Palsy, Progressive ,Neurology (clinical) ,Psychology ,business ,Motor neurone disease ,Neuroscience ,Brain Stem - Abstract
Introduction In this report we are describing a progressive brain disease featured by supranuclear ophthalmoplegia affecting chiefly vertical gaze, pseudobulbar palsy, dysarthria, dystonic rigidity of the neck and upper trunk, and other less constant cerebellar and pyramidal symptoms. Dementia has usually remained mild. This disease would appear to be predominantly a nerve cell degeneration centered chiefly in the brain stem. The fully developed clinical picture presented by this disease seems to follow a fairly definitive pattern and does not conform to the classical system degenerations such as motor neurone disease, paralysis agitans, cerebellar degeneration, Creuzfeldt-Jakob disease, or the presenile dementias. Yet it would seem unlikely that the disease shown by our cases is a new one, and similar earlier cases may well have been accepted as arteriosclerotic parkinsonism when that diagnosis was used in a very broad sense such as in Critchley's monograph of 1929. 1 There are some resemblances to
- Published
- 2014
7. Histamine Receptor 3 negatively regulates oligodendrocyte differentiation and remyelination
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de Castro, F, Chen, Y, Zhen, W, Guo, T, Zhao, Y, Liu, A, Rubio, JP, Krull, D, Richardson, JC, Lu, H, Wang, R, de Castro, F, Chen, Y, Zhen, W, Guo, T, Zhao, Y, Liu, A, Rubio, JP, Krull, D, Richardson, JC, Lu, H, and Wang, R
- Abstract
BACKGROUND: Agents promoting oligodendrocyte precursor cell differentiation have the potential to restore halted and/or delayed remyelination in patients with multiple sclerosis. However, few therapeutic targets have been identified. The objective of this study was to identify novel targets for promotion of remyelination and characterize their activity in vitro and in vivo. METHODS: A high-content screening assay with differentiation of primary rat oligodendrocyte precursor cells was used to screen GSK-proprietary annotated libraries for remyelination-promoting compounds. Compounds were further validated in vitro and in vivo models; clinical relevance of target was confirmed in human post-mortem brain sections from patients with MS. RESULTS: Of ~1000 compounds screened, 36 promoted oligodendrocyte precursor cell differentiation in a concentration-dependent manner; seven were histamine receptor-3 (H3R) antagonists. Inverse agonists of H3R but not neutral antagonists promoted oligodendrocyte precursor cell (OPC) differentiation. H3R was expressed throughout OPC differentiation; H3R expression was transiently upregulated on Days 3-5 and subsequently downregulated. H3R gene knockdown in OPCs increased the expression of differentiation markers and the number of mature oligodendrocytes. Overexpression of full-length H3R reduced differentiation marker expression and the number of mature cells. H3R inverse agonist GSK247246 reduced intracellular cyclic AMP (cAMP) and downstream cAMP response element-binding protein (CREB) phosphorylation in a dose-dependent manner. Histone deacetylase (HDAC-1) and Hes-5 were identified as key downstream targets of H3R during OPC differentiation. In the mouse cuprizone/rapamycin model of demyelination, systemic administration of brain-penetrable GSK247246 enhanced remyelination and subsequently protected axons. Finally, we detected high H3R expression in oligodendroglial cells from demyelination lesions in human samples of patients with MS
- Published
- 2017
8. P07 Media constructions of ‘arthritis’: a mixed Methods qualitative study
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Rowley, R, primary, Jinks, C, additional, and Richardson, JC, additional
- Published
- 2016
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9. Effects of acetylcholinesterase inhibitors and memantine on resting-state electroencephalographic rhythms in Alzheimer's disease patients
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Babiloni, C, Del Percio, C, Bordet, R, Bourriez, J, Bentivoglio, M, Payoux, P, Derambure, P, Dix, S, Infarinato, F, Lizio, R, Triggiani, Ai, Richardson, Jc, Rossini, Paolo Maria, Rossini, Paolo Maria (ORCID:0000-0003-2665-534X), Babiloni, C, Del Percio, C, Bordet, R, Bourriez, J, Bentivoglio, M, Payoux, P, Derambure, P, Dix, S, Infarinato, F, Lizio, R, Triggiani, Ai, Richardson, Jc, Rossini, Paolo Maria, and Rossini, Paolo Maria (ORCID:0000-0003-2665-534X)
- Abstract
Acetylcholinesterase inhibitors (AChEIs) are the most widely used symptomatic treatment for mild to severe Alzheimer's disease (AD) patients, while N-methyl-d-aspartic acid (NMDA) receptor antagonist memantine is licensed for use in moderate to severe AD patients. In this article, the effect of these compounds on resting state eyes-closed electroencephalographic (EEG) rhythms in AD patients is reviewed to form a knowledge platform for the European Innovative Medicine Initiative project "PharmaCog" (IMI Grant Agreement No. 115009) aimed at developing innovative translational models for drug testing in AD. Indeed, quite similar EEG experiments and the same kind of spectral data analysis can be performed in animal models of AD and in elderly individuals with prodromal or manifest AD. Several studies have shown that AChEIs affect both resting state EEG rhythms and cognitive functions in AD patients. After few weeks of successful treatment, delta (0-3 Hz) or theta (4-7 Hz) rhythms decrease, dominant alpha rhythms (8-10 Hz) increase, and cognitive functions slightly improve. Beneficial effects of these rhythms and cognitive functions were also found in AD responders to the long-term successful treatment (i.e. 6-12 months). In contrast, only one study has explored the long-term effects of memantine on EEG rhythms in AD patients, showing reduced theta rhythms. The present review enlightens the expected effects of AChEIs on resting state EEG rhythms in AD patients as promising EEG markers for the development of translational protocols both within the PharmaCog project and for wider use.
- Published
- 2013
10. Effects of pharmacological agents, sleep deprivation, hypoxia and transcranial magnetic stimulation on electroencephalographic rhythms in rodents: towards translational challenge models for drug discovery in Alzheimer's disease
- Author
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Babiloni, C, Infarinato, F, Aujard, F, Bastlund, Jf, Bentivoglio, M, Bertini, G, Del Percio, C, Fabene, Pf, Forloni, G, Herrero Ezquerro, Mt, Noè, Fm, Pifferi, F, Ros Bernal, F, Christensen, Dz, Dix, S, Richardson, Jc, Lamberty, Y, Drinkenburg, W, Rossini, Paolo Maria, Rossini, Paolo Maria (ORCID:0000-0003-2665-534X), Babiloni, C, Infarinato, F, Aujard, F, Bastlund, Jf, Bentivoglio, M, Bertini, G, Del Percio, C, Fabene, Pf, Forloni, G, Herrero Ezquerro, Mt, Noè, Fm, Pifferi, F, Ros Bernal, F, Christensen, Dz, Dix, S, Richardson, Jc, Lamberty, Y, Drinkenburg, W, Rossini, Paolo Maria, and Rossini, Paolo Maria (ORCID:0000-0003-2665-534X)
- Abstract
Different kinds of challenge can alter spontaneous ongoing electroencephalographic (EEG) rhythms in animal models, thus providing paradigms to evaluate treatment effects in drug discovery. The effects of challenges represented by pharmacological agents, hypoxia, sleep deprivation and transcranial magnetic stimulation (TMS) on EEG rhythms are here reviewed to build a knowledge platform for innovative translational models for drug discovery in Alzheimer's disease (AD). It has been reported that antagonists of cholinergic neurotransmission cause synchronisation of spontaneous ongoing EEG rhythms in terms of enhanced power of EEG low frequencies and decreased power of EEG high frequencies. Acetylcholinesterase inhibitors and serotonergic drugs may restore a normal pattern of EEG desynchronisation. Sleep deprivation and hypoxia challenges have also been reported to elicit abnormal synchronisation of spontaneous ongoing EEG rhythms in rodents. The feasibility and reproducibility of TMS have been demonstrated in rodents but information on a consistent modulation of EEG after TMS manipulation is very limited. Transgenic mice over-expressing human amyloid precursor protein complementary DNAs (cDNAs) harbouring the 'Swedish' mutation and PS-1 cDNAs harbouring the A264E mutation, which recapitulate some of the pathological features of AD, exhibit alterations of spontaneous ongoing EEG rhythms at several low and high frequencies. This does not appear, however, to be a consequence of beta-amyloid deposition in the brain. The present review provides a critical evaluation of changes of spontaneous ongoing EEG rhythms due to the experimental manipulations described above, in order to stimulate the promote more adherent models fitting dynamics in humans.
- Published
- 2013
11. Cortical sources of resting state EEG rhythms are sensitive to the progression of early stage Alzheimer's disease
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Laudio, Lizio, R, Del Percio, C, Marzano, N, Soricelli, A, Salvatore, E, Ferri, R, Cosentino, Fii, Tedeschi, G, Montella, P, Marino, S, De Salvo, S, Rodriguez, G, Nobili, F, Vernieri, F, Ursini, F, Mundi, C, Richardson, Jc, Frisoni, Giovanni, Rossini, Paolo Maria, Rossini, Paolo Maria (ORCID:0000-0003-2665-534X), Laudio, Lizio, R, Del Percio, C, Marzano, N, Soricelli, A, Salvatore, E, Ferri, R, Cosentino, Fii, Tedeschi, G, Montella, P, Marino, S, De Salvo, S, Rodriguez, G, Nobili, F, Vernieri, F, Ursini, F, Mundi, C, Richardson, Jc, Frisoni, Giovanni, Rossini, Paolo Maria, and Rossini, Paolo Maria (ORCID:0000-0003-2665-534X)
- Abstract
Cortical sources of resting state electroencephalographic (EEG) rhythms are abnormal in subjects with Alzheimer's disease (AD). Here we tested the hypothesis that these sources are also sensitive to the progression of early stage AD over the course of one year. The resting state eyes-closed EEG data were recorded in 88 mild AD patients at baseline (Mini Mental State Evaluation, MMSE I = 21.7 ± 0.2 standard error, SE) and at approximately one-year follow up (13.3 months ± 0.5 SE; MMSE II = 20 ± 0.4 SE). All patients received standard therapy with acetylcholinesterase inhibitors. EEG recordings were also performed in 35 normal elderly (Nold) subjects as controls. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), beta 2 (20-30 Hz), and gamma (30-40 Hz). Cortical EEG sources were estimated by low-resolution brain electromagnetic tomography (LORETA). Compared to the Nold subjects, the mild AD patients were characterized by a power increase of widespread delta sources and by a power decrease of posterior alpha sources. In the mild AD patients, the follow-up EEG recordings showed increased power of widespread delta sources as well as decreased power of widespread alpha and posterior beta 1 sources. These results suggest that the resting state EEG sources were sensitive, at least at group level, to the cognitive decline occurring in the mild AD group over a one-year period, and might represent cost-effective and non-invasive markers with which to enrich cohorts of AD patients that decline faster for clinical studies.
- Published
- 2013
12. Effects of acetylcholinesterase inhibitors and memantine on resting-state electroencephalographic rhythms in Alzheimer's disease patients
- Author
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Babiloni, C, Del Percio, C, Bordet, R, Bourriez, J, Bentivoglio, M, Payoux, P, Derambure, P, Dix, S, Infarinato, F, Lizio, R, Triggiani, Antonella, Richardson, Jc, Rossini, Paolo Maria, Rossini, Paolo Maria (ORCID:0000-0003-2665-534X), Babiloni, C, Del Percio, C, Bordet, R, Bourriez, J, Bentivoglio, M, Payoux, P, Derambure, P, Dix, S, Infarinato, F, Lizio, R, Triggiani, Antonella, Richardson, Jc, Rossini, Paolo Maria, and Rossini, Paolo Maria (ORCID:0000-0003-2665-534X)
- Abstract
Acetylcholinesterase inhibitors (AChEIs) are the most widely used symptomatic treatment for mild to severe Alzheimer's disease (AD) patients, while N-methyl-d-aspartic acid (NMDA) receptor antagonist memantine is licensed for use in moderate to severe AD patients. In this article, the effect of these compounds on resting state eyes-closed electroencephalographic (EEG) rhythms in AD patients is reviewed to form a knowledge platform for the European Innovative Medicine Initiative project "PharmaCog" (IMI Grant Agreement No. 115009) aimed at developing innovative translational models for drug testing in AD. Indeed, quite similar EEG experiments and the same kind of spectral data analysis can be performed in animal models of AD and in elderly individuals with prodromal or manifest AD. Several studies have shown that AChEIs affect both resting state EEG rhythms and cognitive functions in AD patients. After few weeks of successful treatment, delta (0-3Hz) or theta (4-7Hz) rhythms decrease, dominant alpha rhythms (8-10Hz) increase, and cognitive functions slightly improve. Beneficial effects of these rhythms and cognitive functions were also found in AD responders to the long-term successful treatment (i.e. 6-12months). In contrast, only one study has explored the long-term effects of memantine on EEG rhythms in AD patients, showing reduced theta rhythms. The present review enlightens the expected effects of AChEIs on resting state EEG rhythms in AD patients as promising EEG markers for the development of translational protocols both within the PharmaCog project and for wider use.
- Published
- 2012
13. General Practice in the Armed Forces: A Definition and Model
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Mears, KP, primary, Morgan-Jones, DJ, additional, Richardson, JC, additional, Simpson, R, additional, and Wall, C, additional
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- 2012
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14. Experiencing chronic widespread pain in a family context: giving and receiving practical and emotional support.
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Richardson JC, Ong BN, and Sim J
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CHRONIC pain , *FAMILY research , *SOCIAL networks , *CHRONICALLY ill , *HEALTH of caregivers , *CARE of people , *SOCIAL history - Abstract
The impact of pain and chronic illness on the family has been documented, but there is little information about living with chronic widespread pain in the context of the family. This article uses data from a qualitative study of the experience of living with chronic widespread pain to examine the experience and meaning of support for people with this condition in the context of their families. It focuses on the varying, dynamic and reciprocal nature of practical and emotional support in the family. Family members may provide support but are also receivers of support from the person with chronic widespread pain. The factors mediating the provision of this support are also explored, including the nature of the pain and the needs of the person with pain, and the roles, responsibilities and characteristics of other family members. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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15. Remaking the future: contemplating a life with chronic widespread pain.
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Richardson JC, Ong BN, and Sim J
- Abstract
OBJECTIVES: This paper reports findings from a larger study that aimed to explore how people with chronic widespread pain experience, understand and make meaning of their 'condition', and attempt to influence or exert control over their pain. This included an exploration of sufferers' understanding of the past and future as well as of their present situation. METHODS: A combination of data generation methods was used, including lifegrid interviews, diaries and diary interviews, with eight people with chronic widespread pain. Five family members also participated in interviews. Analytical methods were based on interpretative phenomenological analysis (IPA). RESULTS: With regard to their views about the future, participants could be categorized into those who were 'optimistic' ('things can only get better'), those who were pessimistic ('things will get worse'), and those who were overwhelmed with uncertainty about the future. Uncertainty was a dominant feature in all the accounts of the future. DISCUSSION: The pervading uncertainty of chronic widespread pain, in which there is no framework for the trajectory of the condition, affects perceptions of the future and makes planning for the future difficult. The findings also raise the question of how this makes chronic widespread pain different from other chronic conditions in terms of understanding of chronicity, time and future, and hence 'acceptance'. [ABSTRACT FROM AUTHOR]
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- 2006
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16. Principles of Diagnosis in Neurology
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Richardson Jc
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medicine.medical_specialty ,Neurology ,business.industry ,Medicine ,Medical physics ,Neurology (clinical) ,General Medicine ,business - Published
- 1977
17. Nuclear non-chromatin proteinaceous structures: their role in the organization and function of the interphase nucleus
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Richardson Jc and Agutter Ps
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Cell Nucleus ,Microscopy, Electron ,Nucleoproteins ,Interphase nucleus ,Nuclear Envelope ,Humans ,Proteins ,Cell Biology ,Biology ,Interphase ,Function (biology) ,Chromatin ,Cell biology - Published
- 1980
18. Clinical problems of motor system disease
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Richardson Jc
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Cognitive science ,Myoclonus ,Sociology of scientific knowledge ,Movement Disorders ,Prologue ,General Medicine ,Disease ,Neurology ,Hepatolenticular Degeneration ,Motor system ,Research studies ,Humans ,Neurology (clinical) ,Psychology ,Hypoxia - Abstract
SUMMARY:This prologue to a symposium of research studies on motor mechanisms is a general commentary by a clinical neurologist. The vast extent and intricacy of modern basic neurological scientific knowledge presents a rather bewildering challenge to reasonable clinical application. In some degree this is being handled by complex and diverse neurological subspecialization. It is recalled that many past advances in the knowledge of neurological disease were achieved by a series of alternating and supporting bedside and laboratory observations and studies.The varied disorders of movement and muscle tone which signal disordered motor mechanisms will continue to demand explanation and will keep the human model in a leading research position. Clinical and laboratory research leading to part discoveries of mechanisms of disease is sometimes productive of dramatic new means of therapy. The story of Wilson’s disease is briefly reviewed in that context. Some recent studies on hypoxic myoclonus are described with the evidence of a serotonin defect and useful related therapy.
- Published
- 1975
19. Primary intracerebral hemorrhage
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Einhorn Rw and Richardson Jc
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Intracerebral hemorrhage ,Coma ,medicine.medical_specialty ,Canada ,medicine.diagnostic_test ,business.industry ,Brain Neoplasms ,Autopsy ,medicine.disease ,Prognosis ,Cerebral Angiography ,Hypertension ,medicine ,Humans ,Surgery ,Neurology (clinical) ,Radiology ,medicine.symptom ,business ,Cerebral angiography ,Cerebral Hemorrhage - Published
- 1963
20. Nuclear non-chromatin proteinaceous structures: their role in the organization and function of the interphase nucleus
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Agutter, PS, primary and Richardson, JC, additional
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- 1980
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21. Experiencing and controlling time in everyday life with chronic widespread pain: a qualitative study.
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Richardson JC, Ong BN, and Sim J
- Abstract
Background: Chronic widespread pain (CWP) affects 10% of adults and often causes significant disability in everyday life. Research on time in chronic conditions has focused on biographical disruption and perceptions of past and future. However, more mundane aspects of time are also disrupted in a condition such as CWP, which is uncertain on a minute-to-minute, day-to-day basis, as well as in the longer term. The results presented here are part of a wider study, the aim of which was to explore how people with CWP experience and give meaning to their 'condition'. This article focuses on how mundane, repetitive and taken-for-granted aspects of everyday life are disrupted for people with CWP. Methods: Eight people aged 40-60 years living with CWP took part in multiple in-depth interviews, diaries and family interviews, exploring the meanings and interpretations of participants and individuals' experiences in a social context. Results: The findings illuminate the ways in which the experience of time is changed by CWP: carrying out the tasks of everyday life takes longer, routines are disrupted, and changes are needed in how time is managed. Some strategies for managing these tasks rely on ability to control one's time. However, this is not always possible and, for some, the experience of CWP becomes characterised by lack of such control. Conclusion: This study explored the concept of controllable time in the experience of CWP. Regaining control over time is an important element in coping with chronic pain, and helping patients to regain such control has potential as a target for health professionals involved in pain management. [ABSTRACT FROM AUTHOR]
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- 2008
22. Blood-based multivariate methylation risk score for cognitive impairment and dementia.
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Koetsier J, Cavill R, Reijnders R, Harvey J, Homann J, Kouhsar M, Deckers K, Köhler S, Eijssen LMT, van den Hove DLA, Demuth I, Düzel S, Smith RG, Smith AR, Burrage J, Walker EM, Shireby G, Hannon E, Dempster E, Frayling T, Mill J, Dobricic V, Johannsen P, Wittig M, Franke A, Vandenberghe R, Schaeverbeke J, Freund-Levi Y, Frölich L, Scheltens P, Teunissen CE, Frisoni G, Blin O, Richardson JC, Bordet R, Engelborghs S, de Roeck E, Martinez-Lage P, Tainta M, Lleó A, Sala I, Popp J, Peyratout G, Verhey F, Tsolaki M, Andreasson U, Blennow K, Zetterberg H, Streffer J, Vos SJB, Lovestone S, Visser PJ, Lill CM, Bertram L, Lunnon K, and Pishva E
- Abstract
Introduction: The established link between DNA methylation and pathophysiology of dementia, along with its potential role as a molecular mediator of lifestyle and environmental influences, positions blood-derived DNA methylation as a promising tool for early dementia risk detection., Methods: In conjunction with an extensive array of machine learning techniques, we employed whole blood genome-wide DNA methylation data as a surrogate for 14 modifiable and non-modifiable factors in the assessment of dementia risk in independent dementia cohorts., Results: We established a multivariate methylation risk score (MMRS) for identifying mild cognitive impairment cross-sectionally, independent of age and sex (P = 2.0 × 10
-3 ). This score significantly predicted the prospective development of cognitive impairments in independent studies of Alzheimer's disease (hazard ratio for Rey's Auditory Verbal Learning Test (RAVLT)-Learning = 2.47) and Parkinson's disease (hazard ratio for MCI/dementia- Published
- 2024
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23. Blood DNA methylomic signatures associated with CSF biomarkers of Alzheimer's disease in the EMIF-AD study.
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Smith RG, Pishva E, Kouhsar M, Imm J, Dobricic V, Johannsen P, Wittig M, Franke A, Vandenberghe R, Schaeverbeke J, Freund-Levi Y, Frölich L, Scheltens P, Teunissen CE, Frisoni G, Blin O, Richardson JC, Bordet R, Engelborghs S, de Roeck E, Martinez-Lage P, Altuna M, Tainta M, Lleó A, Sala I, Popp J, Peyratout G, Winchester L, Nevado-Holgado A, Verhey F, Tsolaki M, Andreasson U, Blennow K, Zetterberg H, Streffer J, Vos SJB, Lovestone S, Visser PJ, Bertram L, and Lunnon K
- Abstract
Introduction: We investigated blood DNA methylation patterns associated with 15 well-established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathophysiology, neuroinflammation, and neurodegeneration., Methods: We assessed DNA methylation in 885 blood samples from the European Medical Information Framework for Alzheimer's Disease (EMIF-AD) study using the EPIC array., Results: We identified Bonferroni-significant differential methylation associated with CSF YKL-40 (five loci) and neurofilament light chain (NfL; seven loci) levels, with two of the loci associated with CSF YKL-40 levels correlating with plasma YKL-40 levels. A co-localization analysis showed shared genetic variants underlying YKL-40 DNA methylation and CSF protein levels, with evidence that DNA methylation mediates the association between genotype and protein levels. Weighted gene correlation network analysis identified two modules of co-methylated loci correlated with several amyloid measures and enriched in pathways associated with lipoproteins and development., Discussion: We conducted the most comprehensive epigenome-wide association study (EWAS) of AD-relevant CSF biomarkers to date. Future work should explore the relationship between YKL-40 genotype, DNA methylation, and protein levels in the brain., Highlights: Blood DNA methylation was assessed in the EMIF-AD MBD study. Epigenome-wide association studies (EWASs) were performed for 15 Alzheimer's disease (AD)-relevant cerebrospinal fluid (CSF) biomarker measures. Five Bonferroni-significant loci were associated with YKL-40 levels and seven with neurofilament light chain (NfL). DNA methylation in YKL-40 co-localized with previously reported genetic variation. DNA methylation potentially mediates the effect of single-nucleotide polymorphisms (SNPs) in YKL-40 on CSF protein levels., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
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- 2024
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24. Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability.
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Sampedro-Castañeda M, Baltussen LL, Lopes AT, Qiu Y, Sirvio L, Mihaylov SR, Claxton S, Richardson JC, Lignani G, and Ultanir SK
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- Animals, Child, Humans, Mice, Calcium Channels genetics, Protein Serine-Threonine Kinases genetics, Epilepsy genetics, Epileptic Syndromes genetics, Spasms, Infantile genetics
- Abstract
Developmental and epileptic encephalopathies (DEEs) are a group of rare childhood disorders characterized by severe epilepsy and cognitive deficits. Numerous DEE genes have been discovered thanks to advances in genomic diagnosis, yet putative molecular links between these disorders are unknown. CDKL5 deficiency disorder (CDD, DEE2), one of the most common genetic epilepsies, is caused by loss-of-function mutations in the brain-enriched kinase CDKL5. To elucidate CDKL5 function, we looked for CDKL5 substrates using a SILAC-based phosphoproteomic screen. We identified the voltage-gated Ca
2+ channel Cav2.3 (encoded by CACNA1E) as a physiological target of CDKL5 in mice and humans. Recombinant channel electrophysiology and interdisciplinary characterization of Cav2.3 phosphomutant mice revealed that loss of Cav2.3 phosphorylation leads to channel gain-of-function via slower inactivation and enhanced cholinergic stimulation, resulting in increased neuronal excitability. Our results thus show that CDD is partly a channelopathy. The properties of unphosphorylated Cav2.3 closely resemble those described for CACNA1E gain-of-function mutations causing DEE69, a disorder sharing clinical features with CDD. We show that these two single-gene diseases are mechanistically related and could be ameliorated with Cav2.3 inhibitors., (© 2023. The Author(s).)- Published
- 2023
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25. Multivariate GWAS of Alzheimer's disease CSF biomarker profiles implies GRIN2D in synaptic functioning.
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Neumann A, Ohlei O, Küçükali F, Bos IJ, Timsina J, Vos S, Prokopenko D, Tijms BM, Andreasson U, Blennow K, Vandenberghe R, Scheltens P, Teunissen CE, Engelborghs S, Frisoni GB, Blin O, Richardson JC, Bordet R, Lleó A, Alcolea D, Popp J, Marsh TW, Gorijala P, Clark C, Peyratout G, Martinez-Lage P, Tainta M, Dobson RJB, Legido-Quigley C, Van Broeckhoven C, Tanzi RE, Ten Kate M, Lill CM, Barkhof F, Cruchaga C, Lovestone S, Streffer J, Zetterberg H, Visser PJ, Sleegers K, and Bertram L
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- Humans, Female, Male, Genome-Wide Association Study, tau Proteins genetics, Biomarkers, Inflammation, Apolipoproteins E genetics, Membrane Proteins genetics, Nerve Tissue Proteins genetics, Receptors, N-Methyl-D-Aspartate genetics, Alzheimer Disease genetics, Alzheimer Disease pathology
- Abstract
Background: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences., Methods: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects., Results: Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers., Conclusions: These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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26. Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits.
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Küçükali F, Neumann A, Van Dongen J, De Pooter T, Joris G, De Rijk P, Ohlei O, Dobricic V, Bos I, Vos SJB, Engelborghs S, De Roeck E, Vandenberghe R, Gabel S, Meersmans K, Tsolaki M, Verhey F, Martinez-Lage P, Tainta M, Frisoni G, Blin O, Richardson JC, Bordet R, Scheltens P, Popp J, Peyratout G, Johannsen P, Frölich L, Freund-Levi Y, Streffer J, Lovestone S, Legido-Quigley C, Kate MT, Barkhof F, Zetterberg H, Bertram L, Strazisar M, Visser PJ, Van Broeckhoven C, and Sleegers K
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- Humans, Exome genetics, Genetic Association Studies, Phenotype, Biomarkers, Alzheimer Disease genetics, Alzheimer Disease diagnosis
- Abstract
Introduction: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes., Methods: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808)., Results: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively., Discussion: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
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- 2023
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27. The Process of Developing a Digital Repository for Online Teaching Using Design-Based Research.
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Richardson JC, Castellanos Reyes D, Janakiraman S, and Duha MSU
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The P urdue R epository for Online T eaching a nd L earning (PoRTAL) was developed as an Open Educational Resource (OER) for graduate students and faculty in higher education settings to enhance their online teaching skills and strategies. The PoRTAL team used a design-based research approach (DBR; Wang & Hannafin, Educational Technology Research and Development, 53 (4), 5-23, 2005). In this study context, we used Van Tiem et al.'s (2012) model to identify problems faced by instructors who struggled with or were new to online teaching from a Human Performance Technology (HPT) standpoint. To address the identified needs, we created resources for online teaching and embedded our research within practical activities to further study our design process. Our efforts resulted in an HPT-OER Model for Designing Digital Repositories. The purpose of this paper is to share the DBR process that we used to develop an OER repository within an HPT model., Competing Interests: Conflicts of InterestThe authors have no relevant financial or non-financial interests to disclose., (© Association for Educational Communications & Technology 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)
- Published
- 2023
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28. Rapid, label-free antibiotic susceptibility determined directly from positive blood culture.
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Filbrun AB, Richardson JC, Khanal PC, Tzeng YL, and Dickson RM
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- Anti-Bacterial Agents pharmacology, Bacteria, Escherichia coli, Humans, Microbial Sensitivity Tests, Staphylococcus aureus, Blood Culture, Sepsis
- Abstract
Bacterial bloodstream infections are a significant cause of global morbidity and mortality. Constrained by low bacterial burdens of 1-100 colony-forming-units per ml blood (CFU/ml), clinical diagnosis relies on lengthy culture amplification and isolation steps prior to identification and antibiotic susceptibility testing (AST). The resulting >60-h time to actionable treatment not only negatively impacts patient outcomes, but also increases the misuse and overuse of broad-spectrum antibiotics that accelerates the rise in multidrug resistant infections. Consequently, the development of novel technologies capable of rapidly recovering bacteria from blood-derived samples is crucial to human health. To address this need, we report a novel bacterial recovery technology from positive blood cultures that couples selective hemolysis with centrifugation through a sucrose cushion to perform rapid, background-free cytometric ASTs without long subculturing steps. Demonstrated on the most common bloodstream infection-causing bacteria: Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, near-pure bacteria are rapidly recovered (≤15 min) with minimal user intervention. Susceptibilities of recovered bacteria are readily performed via high throughput flow cytometry with excellent agreement with much slower, standard microbroth dilution assays. Altogether, this novel direct-from-positive blood culture AST technology enables susceptibility determinations within as little as 5 h, post blood culture positivity., (© 2022 International Society for Advancement of Cytometry.)
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- 2022
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29. Genome-Wide Association Study of Alzheimer's Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery Dataset.
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Homann J, Osburg T, Ohlei O, Dobricic V, Deecke L, Bos I, Vandenberghe R, Gabel S, Scheltens P, Teunissen CE, Engelborghs S, Frisoni G, Blin O, Richardson JC, Bordet R, Lleó A, Alcolea D, Popp J, Clark C, Peyratout G, Martinez-Lage P, Tainta M, Dobson RJB, Legido-Quigley C, Sleegers K, Van Broeckhoven C, Wittig M, Franke A, Lill CM, Blennow K, Zetterberg H, Lovestone S, Streffer J, Ten Kate M, Vos SJB, Barkhof F, Visser PJ, and Bertram L
- Abstract
Alzheimer's disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline., Competing Interests: HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and was a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which was a part of the GU Ventures Incubator Program. FB is supported by the NIHR biomedical research centre at UCLH. JP received consultation honoraria from Nestle Institute of Health Sciences, Ono Pharma, OM Pharma, and Fujirebio, unrelated to the submitted work. CT has a collaboration contract with ADx Neurosciences, Quanterix and Eli Lilly, performed contract research or received grants from AC-Immune, Axon Neurosciences, Biogen, Brainstorm Therapeutics, Celgene, EIP Pharma, Eisai, PeopleBio, Roche, Toyama, Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer Research and Therapy, Neurology: Neuroimmunology and Neuroinflammation, and was editor of a Neuromethods book Springer. CT also holds a speaker’s contract with Roche, Inc. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and was a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which was a part of the GU Ventures Incubator Program, outside the work presented in this paper. SL is currently an employee at Janssen Medical UK. JS was an employee of Janssen R&D, LLC., and is currently an employee and chief medical officer of AC Immune SA. JR was an employee of Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK., (Copyright © 2022 Homann, Osburg, Ohlei, Dobricic, Deecke, Bos, Vandenberghe, Gabel, Scheltens, Teunissen, Engelborghs, Frisoni, Blin, Richardson, Bordet, Lleó, Alcolea, Popp, Clark, Peyratout, Martinez-Lage, Tainta, Dobson, Legido-Quigley, Sleegers, Van Broeckhoven, Wittig, Franke, Lill, Blennow, Zetterberg, Lovestone, Streffer, ten Kate, Vos, Barkhof, Visser and Bertram.)
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- 2022
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30. Role of functional echocardiographic parameters in the diagnosis of bronchopulmonary dysplasia-associated pulmonary hypertension.
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Dasgupta S, Richardson JC, Aly AM, and Jain SK
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- Cardiac Catheterization, Child, Echocardiography, Humans, Infant, Newborn, Bronchopulmonary Dysplasia complications, Bronchopulmonary Dysplasia diagnostic imaging, Hypertension, Pulmonary diagnostic imaging, Hypertension, Pulmonary etiology
- Abstract
Echocardiogram (echo) is a commonly used noninvasive modality for the diagnosis of bronchopulmonary dysplasia associated pulmonary hypertension (BPD-PH). Though not considered the gold standard for the diagnosis of BPD-PH, it is an extremely valuable tool in the neonatal and pediatric population, especially when cardiac catheterization is not feasible. In addition to the traditional echo parameters that are used to assess the presence of BPD-PH, much attention has been recently placed on newer bedside echo measures, the so-called functional echo parameters, to aid and assist in the diagnosis. This review article provides a brief introduction to BPD-PH, describes the pitfalls of traditional echo parameters and details the newer echo modalities currently available for the diagnosis of neonatal PH., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2022
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31. A Monte Carlo study of different LET definitions and calculation parameters for proton beam therapy.
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Smith EAK, Winterhalter C, Underwood TSA, Aitkenhead AH, Richardson JC, Merchant MJ, Kirkby NF, Kirby KJ, and Mackay RI
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- Humans, Monte Carlo Method, Protons, Relative Biological Effectiveness, Linear Energy Transfer, Proton Therapy methods
- Abstract
The strong in vitro evidence that proton Relative Biological Effectiveness (RBE) varies with Linear Energy Transfer (LET) has led to an interest in applying LET within treatment planning. However, there is a lack of consensus on LET definition, Monte Carlo (MC) parameters or clinical methodology. This work aims to investigate how common variations of LET definition may affect potential clinical applications. MC simulations (GATE/GEANT4) were used to calculate absorbed dose and different types of LET for a simple Spread Out Bragg Peak (SOBP) and for four clinical PBT plans covering a range of tumour sites. Variations in the following LET calculation methods were considered: (i) averaging (dose-averaged LET (LET
d ) & track-averaged LET); (ii) scoring (LETd to water, to medium and to mass density); (iii) particle inclusion (LETd to all protons, to primary protons and to particles); (iv) MC settings (hit type and Maximum Step Size (MSS)). LET distributions were compared using: qualitative comparison, LET Volume Histograms (LVHs), single value criteria (maximum and mean values) and optimised LET-weighted dose models. Substantial differences were found between LET values in averaging, scoring and particle type. These differences depended on the methodology, but for one patient a difference of ∼100% was observed between the maximum LETd for all particles and maximum LETd for all protons within the brainstem in the high isodose region (4 keV μ m-1 and 8 keV μ m-1 respectively). An RBE model using LETd including heavier ions was found to predict substantially different LET-weighted dose compared to those using other LET definitions. In conclusion, the selection of LET definition may affect the results of clinical metrics considered in treatment planning and the results of an RBE model. The authors' advocate for the scoring of dose-averaged LET to water for primary and secondary protons using a random hit type and automated MSS., (Creative Commons Attribution license.)- Published
- 2021
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32. TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels.
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Hong S, Dobricic V, Ohlei O, Bos I, Vos SJB, Prokopenko D, Tijms BM, Andreasson U, Blennow K, Vandenberghe R, Gabel S, Scheltens P, Teunissen CE, Engelborghs S, Frisoni G, Blin O, Richardson JC, Bordet R, Lleó A, Alcolea D, Popp J, Clark C, Peyratout G, Martinez-Lage P, Tainta M, Dobson RJB, Legido-Quigley C, Sleegers K, Van Broeckhoven C, Tanzi RE, Ten Kate M, Wittig M, Franke A, Lill CM, Barkhof F, Lovestone S, Streffer J, Zetterberg H, Visser PJ, and Bertram L
- Subjects
- Aged, Chitinase-3-Like Protein 1 genetics, Female, Humans, Male, Neurofilament Proteins genetics, Neurogranin cerebrospinal fluid, Alzheimer Disease genetics, Biomarkers cerebrospinal fluid, Genome-Wide Association Study, Membrane Proteins genetics, Nerve Tissue Proteins genetics
- Abstract
Introduction: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively., Methods: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates., Results: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1., Discussion: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
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- 2021
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33. Replication study of plasma proteins relating to Alzheimer's pathology.
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Shi L, Winchester LM, Westwood S, Baird AL, Anand SN, Buckley NJ, Hye A, Ashton NJ, Bos I, Vos SJB, Kate MT, Scheltens P, Teunissen CE, Vandenberghe R, Gabel S, Meersmans K, Engelborghs S, De Roeck EE, Sleegers K, Frisoni GB, Blin O, Richardson JC, Bordet R, Molinuevo JL, Rami L, Wallin A, Kettunen P, Tsolaki M, Verhey F, Lléo A, Sala I, Popp J, Peyratout G, Martinez-Lage P, Tainta M, Johannsen P, Freund-Levi Y, Frölich L, Dobricic V, Legido-Quigley C, Barkhof F, Andreasson U, Blennow K, Zetterberg H, Streffer J, Lill CM, Bertram L, Visser PJ, Kolb HC, Narayan VA, Lovestone S, and Nevado-Holgado AJ
- Subjects
- Aged, Apolipoprotein E4 blood, Apolipoprotein E4 genetics, Cognitive Dysfunction blood, Cognitive Dysfunction pathology, Europe, Female, Humans, Male, Middle Aged, Alzheimer Disease blood, Alzheimer Disease pathology, Amyloid beta-Peptides blood, Biomarkers blood, Blood Proteins, Proteomics, tau Proteins blood
- Abstract
Introduction: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis., Methods: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively., Results: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis., Discussion: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis., (© 2021 the Alzheimer's Association.)
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- 2021
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34. 'It's just a great muddle when it comes to food': a qualitative exploration of patient decision-making around diet and gout.
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Liddle J, Richardson JC, Hider SL, Mallen CD, Watson L, Chandratre P, and Roddy E
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Objective: Our aim was to understand whether, why and how patients choose to modify their diets after developing gout., Methods: We conducted an inductive thematic secondary analysis of qualitative data from 43 interviews and four focus groups with UK participants with gout ( n = 61)., Results: Participants commonly initiated dietary changes as part of a self-management strategy for gout. Reasons for making such dietary changes included: desperation; a desire for control; and belief that it would be possible to achieve successful management through diet alone; but not weight loss. Participants who did not make changes or who reverted to previous dietary patterns did so because: they believed urate-lowering therapy was successfully managing their gout; medication allowed normal eating; they did not find 'proof' that diet would be an effective treatment; or the dietary advice they found was unrealistic, unmanageable or irrelevant. Dietary modification was patient led, but patients would have preferred the support of a health-care professional. Beliefs that diet could potentially explain and modify the timing of flares gave patients a sense of control over the condition. However, the belief that gout could be controlled through dietary modification appeared to be a barrier to acceptance of management with urate-lowering therapy., Conclusions: Perceptions about gout and diet play a large role in the way patients make decisions about how to manage gout in their everyday lives. Addressing the reasons why patients explore dietary solutions, promoting the value of urate-lowering therapy and weight loss and drawing on strong evidence to communicate clearly will be crucial in improving long-term clinical management and patient experience., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
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- 2021
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35. Accuracy and reproducibility of automated white matter hyperintensities segmentation with lesion segmentation tool: A European multi-site 3T study.
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Ribaldi F, Altomare D, Jovicich J, Ferrari C, Picco A, Pizzini FB, Soricelli A, Mega A, Ferretti A, Drevelegas A, Bosch B, Müller BW, Marra C, Cavaliere C, Bartrés-Faz D, Nobili F, Alessandrini F, Barkhof F, Gros-Dagnac H, Ranjeva JP, Wiltfang J, Kuijer J, Sein J, Hoffmann KT, Roccatagliata L, Parnetti L, Tsolaki M, Constantinidis M, Aiello M, Salvatore M, Montalti M, Caulo M, Didic M, Bargallo N, Blin O, Rossini PM, Schonknecht P, Floridi P, Payoux P, Visser PJ, Bordet R, Lopes R, Tarducci R, Bombois S, Hensch T, Fiedler U, Richardson JC, Frisoni GB, and Marizzoni M
- Subjects
- Adult, Aging, Algorithms, Automation, Cross-Sectional Studies, Female, Humans, Male, Reproducibility of Results, White Matter pathology, Image Processing, Computer-Assisted methods, Magnetic Resonance Imaging, White Matter diagnostic imaging
- Abstract
Brain vascular damage accumulate in aging and often manifest as white matter hyperintensities (WMHs) on MRI. Despite increased interest in automated methods to segment WMHs, a gold standard has not been achieved and their longitudinal reproducibility has been poorly investigated. The aim of present work is to evaluate accuracy and reproducibility of two freely available segmentation algorithms. A harmonized MRI protocol was implemented in 3T-scanners across 13 European sites, each scanning five volunteers twice (test-retest) using 2D-FLAIR. Automated segmentation was performed using Lesion segmentation tool algorithms (LST): the Lesion growth algorithm (LGA) in SPM8 and 12 and the Lesion prediction algorithm (LPA). To assess reproducibility, we applied the LST longitudinal pipeline to the LGA and LPA outputs for both the test and retest scans. We evaluated volumetric and spatial accuracy comparing LGA and LPA with manual tracing, and for reproducibility the test versus retest. Median volume difference between automated WMH and manual segmentations (mL) was -0.22[IQR = 0.50] for LGA-SPM8, -0.12[0.57] for LGA-SPM12, -0.09[0.53] for LPA, while the spatial accuracy (Dice Coefficient) was 0.29[0.31], 0.33[0.26] and 0.41[0.23], respectively. The reproducibility analysis showed a median reproducibility error of 20%[IQR = 41] for LGA-SPM8, 14% [31] for LGA-SPM12 and 10% [27] with the LPA cross-sectional pipeline. Applying the LST longitudinal pipeline, the reproducibility errors were considerably reduced (LGA: 0%[IQR = 0], p < 0.001; LPA: 0% [3], p < 0.001) compared to those derived using the cross-sectional algorithms. The DC using the longitudinal pipeline was excellent (median = 1) for LGA [IQR = 0] and LPA [0.02]. LST algorithms showed moderate accuracy and good reproducibility. Therefore, it can be used as a reliable cross-sectional and longitudinal tool in multi-site studies., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2021
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36. Convergent and Discriminant Validity of Default Mode Network and Limbic Network Perfusion in Amnestic Mild Cognitive Impairment Patients.
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Quattrini G, Marizzoni M, Pizzini FB, Galazzo IB, Aiello M, Didic M, Soricelli A, Albani D, Romano M, Blin O, Forloni G, Golay X, Jovicich J, Nathan PJ, Richardson JC, Salvatore M, Frisoni GB, and Pievani M
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- Aged, Alzheimer Disease physiopathology, Biomarkers cerebrospinal fluid, Cerebrovascular Circulation, Female, Hippocampus physiopathology, Humans, Magnetic Resonance Imaging, Male, Amnesia physiopathology, Cognitive Dysfunction physiopathology, Default Mode Network, Limbic System, Perfusion
- Abstract
Background: Previous studies reported default mode network (DMN) and limbic network (LIN) brain perfusion deficits in patients with amnestic mild cognitive impairment (aMCI), frequently a prodromal stage of Alzheimer's disease (AD). However, the validity of these measures as AD markers has not yet been tested using MRI arterial spin labeling (ASL)., Objective: To investigate the convergent and discriminant validity of DMN and LIN perfusion in aMCI., Methods: We collected core AD markers (amyloid-β 42 [Aβ42], phosphorylated tau 181 levels in cerebrospinal fluid [CSF]), neurodegenerative (hippocampal volumes and CSF total tau), vascular (white matter hyperintensities), genetic (apolipoprotein E [APOE] status), and cognitive features (memory functioning on Paired Associate Learning test [PAL]) in 14 aMCI patients. Cerebral blood flow (CBF) was extracted from DMN and LIN using ASL and correlated with AD features to assess convergent validity. Discriminant validity was assessed carrying out the same analysis with AD-unrelated features, i.e., somatomotor and visual networks' perfusion, cerebellar volume, and processing speed., Results: Perfusion was reduced in the DMN (F = 5.486, p = 0.039) and LIN (F = 12.678, p = 0.004) in APOE ɛ4 carriers compared to non-carriers. LIN perfusion correlated with CSF Aβ42 levels (r = 0.678, p = 0.022) and memory impairment (PAL, number of errors, r = -0.779, p = 0.002). No significant correlation was detected with tau, neurodegeneration, and vascular features, nor with AD-unrelated features., Conclusion: Our results support the validity of DMN and LIN ASL perfusion as AD markers in aMCI, indicating a significant correlation between CBF and amyloidosis, APOE ɛ4, and memory impairment.
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- 2021
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37. Chronic BACE-1 Inhibitor Administration in TASTPM Mice (APP KM670/671NL and PSEN1 M146V Mutation): An EEG Study.
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Lopez S, Del Percio C, Forloni G, Frasca A, Drinkenburg WH, Lizio R, Noce G, Ferri R, Soricelli A, Stocchi F, Vacca L, Bordet R, Richardson JC, and Babiloni C
- Subjects
- Amyloid Precursor Protein Secretases metabolism, Animals, Aspartic Acid Endopeptidases metabolism, Electrodes, Electromyography, Mice, Inbred C57BL, Mice, Transgenic, Signal Processing, Computer-Assisted, Amyloid Precursor Protein Secretases antagonists & inhibitors, Amyloid beta-Protein Precursor genetics, Aspartic Acid Endopeptidases antagonists & inhibitors, Electroencephalography, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors pharmacology, Mutation genetics, Presenilin-1 genetics
- Abstract
Objective: In this exploratory study, we tested whether electroencephalographic (EEG) rhythms may reflect the effects of a chronic administration (4 weeks) of an anti-amyloid β-site amyloid precursor protein (APP) cleaving enzyme 1 inhibitor (BACE-1; ER-901356; Eisai Co., Ltd., Tokyo, Japan) in TASTPM (double mutation in APP KM670/671NL and PSEN1 M146V) producing Alzheimer's disease (AD) amyloid neuropathology as compared to wild type (WT) mice., Methods: Ongoing EEG rhythms were recorded from a bipolar frontoparietal and two monopolar frontomedial (prelimbic) and hippocampal channels in 11 WT Vehicle, 10 WT BACE-1, 10 TASTPM Vehicle, and 11 TASTPM BACE-1 mice (males; aged 8/9 months old at the beginning of treatment). Normalized EEG power (density) was compared between the first day (Day 0) and after 4 weeks (Week 4) of the BACE-1 inhibitor (10 mg/Kg) or vehicle administration in the 4 mouse groups. Frequency and magnitude of individual EEG delta and theta frequency peaks (IDF and ITF) were considered during animal conditions of behaviorally passive and active wakefulness. Cognitive status was not tested., Results: Compared with the WT group, the TASTPM group generally showed a significantly lower reactivity in frontoparietal ITF power during the active over the passive condition ( p < 0.05). Notably, there was no other statistically significant effect (e.g., additional electrodes, recording time, and BACE-1 inhibitor)., Conclusions: The above EEG biomarkers reflected differences between the WT and TASTPM groups, but no BACE-1 inhibitor effect. The results suggest an enhanced experimental design with the use of younger mice, longer drug administrations, an effective control drug, and neuropathological amyloid markers., Competing Interests: The authors declare no conflict of interest.
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- 2020
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38. Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset.
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Hong S, Prokopenko D, Dobricic V, Kilpert F, Bos I, Vos SJB, Tijms BM, Andreasson U, Blennow K, Vandenberghe R, Cleynen I, Gabel S, Schaeverbeke J, Scheltens P, Teunissen CE, Niemantsverdriet E, Engelborghs S, Frisoni G, Blin O, Richardson JC, Bordet R, Molinuevo JL, Rami L, Kettunen P, Wallin A, Lleó A, Sala I, Popp J, Peyratout G, Martinez-Lage P, Tainta M, Dobson RJB, Legido-Quigley C, Sleegers K, Van Broeckhoven C, Ten Kate M, Barkhof F, Zetterberg H, Lovestone S, Streffer J, Wittig M, Franke A, Tanzi RE, Visser PJ, and Bertram L
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- Aged, Amyloid beta-Peptides genetics, Biomarkers, Female, Genome-Wide Association Study, Humans, Male, Peptide Fragments, tau Proteins genetics, Alzheimer Disease genetics
- Abstract
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aβ) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aβ42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aβ38 and CSF-Aβ40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aβ and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.
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- 2020
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39. Modular slowing of resting-state dynamic functional connectivity as a marker of cognitive dysfunction induced by sleep deprivation.
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Lombardo D, Cassé-Perrot C, Ranjeva JP, Le Troter A, Guye M, Wirsich J, Payoux P, Bartrés-Faz D, Bordet R, Richardson JC, Felician O, Jirsa V, Blin O, Didic M, and Battaglia D
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- Adult, Brain diagnostic imaging, Cognitive Dysfunction diagnostic imaging, Cognitive Dysfunction etiology, Humans, Male, Nerve Net diagnostic imaging, Sleep Deprivation diagnostic imaging, Time Factors, Attention physiology, Brain physiopathology, Cognitive Dysfunction physiopathology, Connectome, Memory, Short-Term physiology, Nerve Net physiopathology, Psychomotor Performance physiology, Sleep Deprivation physiopathology, Visual Perception physiology
- Abstract
Dynamic Functional Connectivity (dFC) in the resting state (rs) is considered as a correlate of cognitive processing. Describing dFC as a flow across morphing connectivity configurations, our notion of dFC speed quantifies the rate at which FC networks evolve in time. Here we probe the hypothesis that variations of rs dFC speed and cognitive performance are selectively interrelated within specific functional subnetworks. In particular, we focus on Sleep Deprivation (SD) as a reversible model of cognitive dysfunction. We found that whole-brain level (global) dFC speed significantly slows down after 24h of SD. However, the reduction in global dFC speed does not correlate with variations of cognitive performance in individual tasks, which are subtle and highly heterogeneous. On the contrary, we found strong correlations between performance variations in individual tasks -including Rapid Visual Processing (RVP, assessing sustained visual attention)- and dFC speed quantified at the level of functional sub-networks of interest. Providing a compromise between classic static FC (no time) and global dFC (no space), modular dFC speed analyses allow quantifying a different speed of dFC reconfiguration independently for sub-networks overseeing different tasks. Importantly, we found that RVP performance robustly correlates with the modular dFC speed of a characteristic frontoparietal module., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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40. Automated Monte-Carlo re-calculation of proton therapy plans using Geant4/Gate: implementation and comparison to plan-specific quality assurance measurements.
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Aitkenhead AH, Sitch P, Richardson JC, Winterhalter C, Patel I, and Mackay RI
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- Algorithms, Calibration, England, Humans, Monte Carlo Method, Radiotherapy Dosage, Reproducibility of Results, Proton Therapy methods, Quality Assurance, Health Care, Radiotherapy Planning, Computer-Assisted
- Abstract
Objectives: Software re-calculation of proton pencil beam scanning plans provides a method of verifying treatment planning system (TPS) dose calculations prior to patient treatment. This study describes the implementation of AutoMC, a Geant4 v10.3.3/Gate v8.1 (Gate-RTion v1.0)-based Monte-Carlo (MC) system for automated plan re-calculation, and presents verification results for 153 patients (730 fields) planned within year one of the proton service at The Christie NHS Foundation Trust., Methods: A MC beam model for a Varian ProBeam delivery system with four range-shifter options (none, 2 cm, 3 cm, 5 cm) was derived from beam commissioning data and implemented in AutoMC. MC and TPS (Varian Eclipse v13.7) calculations of 730 fields in solid-water were compared to physical plan-specific quality assurance (PSQA) measurements acquired using a PTW Octavius 1500XDR array and PTW 31021 Semiflex 3D ion chamber., Results: TPS and MC showed good agreement with array measurements, evaluated using γ analyses at 3%, 3 mm with a 10% lower dose threshold:>94% of fields calculated by the TPS and >99% of fields calculated by MC had γ ≤ 1 for>95% of measurement points within the plane. TPS and MC also showed good agreement with chamber measurements of absolute dose, with systematic differences of <1.5% for all range-shifter options., Conclusions: Reliable independent verification of the TPS dose calculation is a valuable complement to physical PSQA and may facilitate reduction of the physical PSQA workload alongside a thorough delivery system quality assurance programme., Advances in Knowledge: A Gate/Geant4-based MC system is thoroughly validated against an extensive physical PSQA dataset for 730 clinical fields, showing that clinical implementation of MC for PSQA is feasible.
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- 2020
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41. Amygdalar nuclei and hippocampal subfields on MRI: Test-retest reliability of automated volumetry across different MRI sites and vendors.
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Quattrini G, Pievani M, Jovicich J, Aiello M, Bargalló N, Barkhof F, Bartres-Faz D, Beltramello A, Pizzini FB, Blin O, Bordet R, Caulo M, Constantinides M, Didic M, Drevelegas A, Ferretti A, Fiedler U, Floridi P, Gros-Dagnac H, Hensch T, Hoffmann KT, Kuijer JP, Lopes R, Marra C, Müller BW, Nobili F, Parnetti L, Payoux P, Picco A, Ranjeva JP, Roccatagliata L, Rossini PM, Salvatore M, Schonknecht P, Schott BH, Sein J, Soricelli A, Tarducci R, Tsolaki M, Visser PJ, Wiltfang J, Richardson JC, Frisoni GB, and Marizzoni M
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- Adult, Aged, Female, Humans, Image Processing, Computer-Assisted methods, Magnetic Resonance Imaging methods, Magnetic Resonance Imaging standards, Male, Middle Aged, Neuroimaging methods, Reproducibility of Results, Amygdala anatomy & histology, Hippocampus anatomy & histology, Image Processing, Computer-Assisted standards, Neuroimaging standards, Software
- Abstract
Background: The amygdala and the hippocampus are two limbic structures that play a critical role in cognition and behavior, however their manual segmentation and that of their smaller nuclei/subfields in multicenter datasets is time consuming and difficult due to the low contrast of standard MRI. Here, we assessed the reliability of the automated segmentation of amygdalar nuclei and hippocampal subfields across sites and vendors using FreeSurfer in two independent cohorts of older and younger healthy adults., Methods: Sixty-five healthy older (cohort 1) and 68 younger subjects (cohort 2), from the PharmaCog and CoRR consortia, underwent repeated 3D-T1 MRI (interval 1-90 days). Segmentation was performed using FreeSurfer v6.0. Reliability was assessed using volume reproducibility error (ε) and spatial overlapping coefficient (DICE) between test and retest session., Results: Significant MRI site and vendor effects (p < .05) were found in a few subfields/nuclei for the ε, while extensive effects were found for the DICE score of most subfields/nuclei. Reliability was strongly influenced by volume, as ε correlated negatively and DICE correlated positively with volume size of structures (absolute value of Spearman's r correlations >0.43, p < 1.39E-36). In particular, volumes larger than 200 mm
3 (for amygdalar nuclei) and 300 mm3 (for hippocampal subfields, except for molecular layer) had the best test-retest reproducibility (ε < 5% and DICE > 0.80)., Conclusion: Our results support the use of volumetric measures of larger amygdalar nuclei and hippocampal subfields in multisite MRI studies. These measures could be useful for disease tracking and assessment of efficacy in drug trials., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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42. An Alzheimer Disease Challenge Model: 24-Hour Sleep Deprivation in Healthy Volunteers, Impact on Working Memory, and Reversal Effect of Pharmacological Intervention: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.
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Chan Kwong A, Cassé-Perrot C, Costes-Salon MC, Jouve E, Lanteaume L, Audebert C, Rouby F, Lefebvre MN, Ranjeva JP, Beck A, Deplanque D, Ponchel A, Vervueren C, Truillet R, Babilon C, Auffret A, Richardson JC, Payoux P, Bartrés-Faz D, Blin O, Bordet R, and Micallef J
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- Adult, Alzheimer Disease psychology, Cross-Over Studies, Donepezil therapeutic use, Double-Blind Method, Humans, Male, Modafinil therapeutic use, Models, Psychological, Neuropsychological Tests, Nootropic Agents therapeutic use, Reaction Time drug effects, Alzheimer Disease drug therapy, Cognitive Dysfunction drug therapy, Healthy Volunteers psychology, Memantine therapeutic use, Memory, Short-Term drug effects, Sleep Deprivation psychology
- Abstract
Purpose/background: Alzheimer disease (AD) is a public health issue because of the low number of symptomatic drugs and the difficulty to diagnose it at the prodromal stage. The need to develop new treatments and to validate sensitive tests for early diagnosis could be met by developing a challenge model reproducing cognitive impairments of AD. Therefore, we implemented a 24-hour sleep deprivation (SD) design on healthy volunteers in a randomized, double-blind, placebo-controlled, crossover study on 36 healthy volunteers., Methods/procedure: To validate the SD model, cognitive tests were chosen to assess a transient worsening of cognitive functions after SD and a restoration under modafinil as positive control (one dose of 200 mg). Then, the same evaluations were replicated after 15 days of donepezil (5 mg/d) or memantine (10 mg/d). The working memory (WM) function was assessed by the N-back task and the rapid visual processing (RVP) task., Findings/results: The accuracy of the N-back task and the reaction time of the RVP revealed the alteration of the WM with SD and its restoration with modafinil (changes in score after SD compared with baseline before SD), respectively, in the placebo group and in the modafinil group (-0.2% and +1.0% of satisfactory answers, P = 0.022; +21.3 and +1.9 milliseconds of reaction time, P = 0.025). Alzheimer disease drugs also tended to reverse this deterioration: the accuracy of the N-back task was more stable through SD (compared with -3.0% in the placebo group, respectively, in the memantine group and in the donepezil group: -1.4% and -1.6%, P = 0.027 and P = 0.092) and RVP reaction time was less impacted (compared with +41.3 milliseconds in the placebo group, respectively, in the memantine group and in the donepezil group: +16.1 and +29.3 milliseconds, P = 0.034 and P = 0.459)., Implications/conclusions: Our SD challenge model actually led to a worsening of WM that was moderated by both modafinil and AD drugs. To use this approach, the cognitive battery, the vulnerability of the subjects to SD, and the expected drug effect should be carefully considered.
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- 2020
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43. CSF cutoffs for MCI due to AD depend on APOEε4 carrier status.
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Marizzoni M, Ferrari C, Babiloni C, Albani D, Barkhof F, Cavaliere L, Didic M, Forloni G, Fusco F, Galluzzi S, Hensch T, Jovicich J, Marra C, Molinuevo JL, Nobili F, Parnetti L, Payoux P, Ranjeva JP, Ribaldi F, Rolandi E, Rossini PM, Salvatore M, Soricelli A, Tsolaki M, Visser PJ, Wiltfang J, Richardson JC, Bordet R, Blin O, and Frisoni GB
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease complications, Cognitive Dysfunction etiology, Cohort Studies, Female, Humans, Male, Alzheimer Disease diagnosis, Alzheimer Disease genetics, Amyloid beta-Peptides cerebrospinal fluid, Apolipoproteins E genetics, Biomarkers cerebrospinal fluid, Cognitive Dysfunction diagnosis, Cognitive Dysfunction genetics, Heterozygote, Peptide Fragments cerebrospinal fluid, tau Proteins cerebrospinal fluid
- Abstract
Amyloid and tau pathological accumulation should be considered for Alzheimer's disease (AD) definition and before subjects' enrollment in disease-modifying trials. Although age, APOEε4, and sex influence cerebrospinal fluid (CSF) biomarker levels, none of these variables are considered by current normality/abnormality cutoffs. Using baseline CSF data from 2 independent cohorts (PharmaCOG/European Alzheimer's Disease Neuroimaging Initiative and Alzheimer's Disease Neuroimaging Initiative), we investigated the effect of age, APOEε4 status, and sex on CSF Aβ42/P-tau distribution and cutoff extraction by applying mixture models with covariates. The Aβ42/P-tau distribution revealed the presence of 3 subgroups (AD-like, intermediate, control-like) and 2 cutoffs. The identification of the intermediate subgroup and of the higher cutoff was APOEε4 dependent in both cohorts. APOE-specific classification (higher cutoff for APOEε4+, lower cutoff for APOEε4-) showed higher diagnostic accuracy in identifying MCI due to AD compared to single Aβ42 and Aβ42/P-tau cutoffs. APOEε4 influences amyloid and tau CSF markers and AD progression in MCI patients supporting i) the use of APOE-specific cutoffs to identify MCI due to AD and ii) the utility of considering APOE genotype for early AD diagnosis., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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44. Ongoing Electroencephalographic Rhythms Related to Exploratory Movements in Transgenic TASTPM Mice.
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Del Percio C, Drinkenburg W, Lopez S, Pascarelli MT, Lizio R, Noce G, Ferri R, Bastlund JF, Laursen B, Christensen DZ, Pedersen JT, Forloni G, Frasca A, Noè FM, Fabene PF, Bertini G, Colavito V, Bentivoglio M, Kelley J, Dix S, Infarinato F, Soricelli A, Stocchi F, Richardson JC, and Babiloni C
- Subjects
- Amyloid beta-Protein Precursor genetics, Amyloidosis, Animals, Brain metabolism, Cognitive Dysfunction, Mice, Mice, Transgenic, Movement, Reproducibility of Results, Wakefulness, Alzheimer Disease genetics, Electroencephalography methods
- Abstract
Background: The European PharmaCog study (http://www.pharmacog.org) has reported a reduction in delta (1-6 Hz) electroencephalographic (EEG) power (density) during cage exploration (active condition) compared with quiet wakefulness (passive condition) in PDAPP mice (hAPP Indiana V717F mutation) modeling Alzheimer's disease (AD) amyloidosis and cognitive deficits., Objective: Here, we tested the reproducibility of that evidence in TASTPM mice (double mutation in APP KM670/671NL and PSEN1 M146V), which develop brain amyloidosis and cognitive deficits over aging. The reliability of that evidence was examined in four research centers of the PharmaCog study., Methods: Ongoing EEG rhythms were recorded from a frontoparietal bipolar channel in 29 TASTPM and 58 matched "wild type" C57 mice (range of age: 12-24 months). Normalized EEG power was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during the passive and active conditions., Results: Compared with the "wild type" group, the TASTPM group showed a significantly lower reduction in IDF power during the active over the passive condition (p < 0.05). This effect was observed in 3 out of 4 EEG recording units., Conclusion: TASTPM mice were characterized by "poor reactivity" of delta EEG rhythms during the cage exploration in line with previous evidence in PDAPP mice. The reliability of that result across the centers was moderate, thus unveiling pros and cons of multicenter preclinical EEG trials in TASTPM mice useful for planning future studies.
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- 2020
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45. Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology.
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Shi L, Winchester LM, Liu BY, Killick R, Ribe EM, Westwood S, Baird AL, Buckley NJ, Hong S, Dobricic V, Kilpert F, Franke A, Kiddle S, Sattlecker M, Dobson R, Cuadrado A, Hye A, Ashton NJ, Morgan AR, Bos I, Vos SJB, Ten Kate M, Scheltens P, Vandenberghe R, Gabel S, Meersmans K, Engelborghs S, De Roeck EE, Sleegers K, Frisoni GB, Blin O, Richardson JC, Bordet R, Molinuevo JL, Rami L, Wallin A, Kettunen P, Tsolaki M, Verhey F, Lleó A, Alcolea D, Popp J, Peyratout G, Martinez-Lage P, Tainta M, Johannsen P, Teunissen CE, Freund-Levi Y, Frölich L, Legido-Quigley C, Barkhof F, Blennow K, Rasmussen KL, Nordestgaard BG, Frikke-Schmidt R, Nielsen SF, Soininen H, Vellas B, Kloszewska I, Mecocci P, Zetterberg H, Morgan BP, Streffer J, Visser PJ, Bertram L, Nevado-Holgado AJ, and Lovestone S
- Subjects
- Aged, Alzheimer Disease genetics, Biomarkers blood, Female, Gene Expression, HEK293 Cells, Humans, Intercellular Signaling Peptides and Proteins biosynthesis, Intercellular Signaling Peptides and Proteins genetics, Male, Middle Aged, Alzheimer Disease blood, Alzheimer Disease pathology, Intercellular Signaling Peptides and Proteins blood
- Abstract
Background: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown., Objective: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes., Methods: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677)., Results: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts., Conclusions: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.
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- 2020
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46. Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer's Disease Multimodal Biomarker Discovery Cohort.
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Westwood S, Baird AL, Anand SN, Nevado-Holgado AJ, Kormilitzin A, Shi L, Hye A, Ashton NJ, Morgan AR, Bos I, Vos SJB, Baker S, Buckley NJ, Ten Kate M, Scheltens P, Teunissen CE, Vandenberghe R, Gabel S, Meersmans K, Engelborghs S, De Roeck EE, Sleegers K, Frisoni GB, Blin O, Richardson JC, Bordet R, Molinuevo JL, Rami L, Wallin A, Kettunen P, Tsolaki M, Verhey F, Lléo A, Sala I, Popp J, Peyratout G, Martinez-Lage P, Tainta M, Johannsen P, Freund-Levi Y, Frölich L, Dobricic V, Legido-Quigley C, Bertram L, Barkhof F, Zetterberg H, Morgan BP, Streffer J, Visser PJ, and Lovestone S
- Subjects
- Aged, Alzheimer Disease diagnostic imaging, Apolipoprotein E4 genetics, Body Burden, Cerebral Amyloid Angiopathy diagnostic imaging, Cognitive Dysfunction blood, Cognitive Dysfunction diagnostic imaging, Cohort Studies, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Positron-Emission Tomography, ROC Curve, tau Proteins cerebrospinal fluid, Alzheimer Disease blood, Biomarkers blood, Blood Proteins analysis, Cerebral Amyloid Angiopathy blood, Proteomics
- Abstract
We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer's disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ɛ4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.
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- 2020
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47. In Silico Models of DNA Damage and Repair in Proton Treatment Planning: A Proof of Concept.
- Author
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Smith EAK, Henthorn NT, Warmenhoven JW, Ingram SP, Aitkenhead AH, Richardson JC, Sitch P, Chadwick AL, Underwood TSA, Merchant MJ, Burnet NG, Kirkby NF, Kirkby KJ, and Mackay RI
- Subjects
- Adult, Algorithms, DNA Damage physiology, DNA Repair physiology, Female, Humans, Linear Energy Transfer genetics, Linear Energy Transfer physiology, Monte Carlo Method, Young Adult, DNA Damage genetics, DNA Repair genetics
- Abstract
There is strong in vitro cell survival evidence that the relative biological effectiveness (RBE) of protons is variable, with dependence on factors such as linear energy transfer (LET) and dose. This is coupled with the growing in vivo evidence, from post-treatment image change analysis, of a variable RBE. Despite this, a constant RBE of 1.1 is still applied as a standard in proton therapy. However, there is a building clinical interest in incorporating a variable RBE. Recently, correlations summarising Monte Carlo-based mechanistic models of DNA damage and repair with absorbed dose and LET have been published as the Manchester mechanistic (MM) model. These correlations offer an alternative path to variable RBE compared to the more standard phenomenological models. In this proof of concept work, these correlations have been extended to acquire RBE-weighted dose distributions and calculated, along with other RBE models, on a treatment plan. The phenomenological and mechanistic models for RBE have been shown to produce comparable results with some differences in magnitude and relative distribution. The mechanistic model found a large RBE for misrepair, which phenomenological models are unable to do. The potential of the MM model to predict multiple endpoints presents a clear advantage over phenomenological models.
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- 2019
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48. Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay.
- Author
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Shi L, Westwood S, Baird AL, Winchester L, Dobricic V, Kilpert F, Hong S, Franke A, Hye A, Ashton NJ, Morgan AR, Bos I, Vos SJB, Buckley NJ, Kate MT, Scheltens P, Vandenberghe R, Gabel S, Meersmans K, Engelborghs S, De Roeck EE, Sleegers K, Frisoni GB, Blin O, Richardson JC, Bordet R, Molinuevo JL, Rami L, Wallin A, Kettunen P, Tsolaki M, Verhey F, Lleó A, Alcolea D, Popp J, Peyratout G, Martinez-Lage P, Tainta M, Johannsen P, Teunissen CE, Freund-Levi Y, Frölich L, Legido-Quigley C, Barkhof F, Blennow K, Zetterberg H, Baker S, Morgan BP, Streffer J, Visser PJ, Bertram L, Lovestone S, and Nevado-Holgado AJ
- Subjects
- Age Factors, Aged, Apolipoprotein E4 genetics, Apolipoprotein E4 metabolism, Europe, Female, Humans, Male, Middle Aged, Alzheimer Disease genetics, Alzheimer Disease metabolism, Amyloid metabolism, Biomarkers blood, Brain metabolism, Proteomics
- Abstract
Introduction: Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins., Methods: 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid., Results: A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization., Discussion: The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2019
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49. miR-146a and miR-181a are involved in the progression of mild cognitive impairment to Alzheimer's disease.
- Author
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Ansari A, Maffioletti E, Milanesi E, Marizzoni M, Frisoni GB, Blin O, Richardson JC, Bordet R, Forloni G, Gennarelli M, and Bocchio-Chiavetto L
- Subjects
- Aged, Aged, 80 and over, Alzheimer Disease diagnostic imaging, Biomarkers blood, Cognitive Dysfunction diagnostic imaging, Cohort Studies, Female, Humans, Male, Middle Aged, Alzheimer Disease blood, Cognitive Dysfunction blood, Disease Progression, MicroRNAs blood
- Abstract
The identification of mechanisms associated with Alzheimer's disease (AD) development in mild cognitive impairment (MCI) would be of great usefulness to clarify AD pathogenesis and to develop preventive and therapeutic strategies. In this study, blood levels of the candidate microRNAs (small noncoding RNAs that play a pivotal role in gene expression) miR-146a, miR-181a, miR-181b, miR-24-3p, miR-186a, miR-101, miR-339, miR-590, and miR-22 have been investigated for association to AD conversion within 2 years in a group of 45 patients with MCI. Baseline miR-146a (p = 0.036) and miR-181a (p = 0.026) showed a significant upregulation in patients with MCI who later converted to AD. These alterations were related to AD hallmarks: a significant negative correlation was found with amyloid beta cerebrospinal fluid concentration for miR-146a (p = 0.006) and miR-181a (p = 0.001). Moreover, higher levels of miR-146a were associated to apolipoprotein E ε4 allele presence, smaller volume of the hippocampus (p = 0.045) and of the CA1 (p = 0.013) and the subiculum (p = 0.027) subfields. Increased levels of miR-146a (p = 0.031) and miR-181a (p = 0.002) were also linked with diffusivity alterations in the cingulum. These data support a role for miR-146a and miR-181a in the mechanisms of AD progression., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2019
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50. Sleep deprivation and Modafinil affect cortical sources of resting state electroencephalographic rhythms in healthy young adults.
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Del Percio C, Derambure P, Noce G, Lizio R, Bartrés-Faz D, Blin O, Payoux P, Deplanque D, Méligne D, Chauveau N, Bourriez JL, Casse-Perrot C, Lanteaume L, Thalamas C, Dukart J, Ferri R, Pascarelli MT, Richardson JC, Bordet R, and Babiloni C
- Subjects
- Adult, Alpha Rhythm drug effects, Alpha Rhythm physiology, Beta Rhythm drug effects, Beta Rhythm physiology, Brain Waves physiology, Cerebral Cortex diagnostic imaging, Cerebral Cortex physiology, Cross-Over Studies, Delta Rhythm drug effects, Delta Rhythm physiology, Electroencephalography methods, Functional Laterality, Gamma Rhythm drug effects, Gamma Rhythm physiology, Healthy Volunteers, Humans, Male, Sample Size, Theta Rhythm drug effects, Theta Rhythm physiology, Wakefulness drug effects, Wakefulness physiology, Brain Waves drug effects, Cerebral Cortex drug effects, Modafinil pharmacology, Rest physiology, Sleep Deprivation physiopathology, Wakefulness-Promoting Agents pharmacology
- Abstract
Objective: It has been reported that sleep deprivation affects the neurophysiological mechanisms underpinning the vigilance. Here, we tested the following hypotheses in the PharmaCog project (www.pharmacog.org): (i) sleep deprivation may alter posterior cortical delta and alpha sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms in healthy young adults; (ii) after the sleep deprivation, a vigilance enhancer may recover those rsEEG source markers., Methods: rsEEG data were recorded in 36 healthy young adults before (Pre-sleep deprivation) and after (Post-sleep deprivation) one night of sleep deprivation. In the Post-sleep deprivation, these data were collected after a single dose of PLACEBO or MODAFINIL. rsEEG cortical sources were estimated by eLORETA freeware., Results: In the PLACEBO condition, the sleep deprivation induced an increase and a decrease in posterior delta (2-4 Hz) and alpha (8-13 Hz) source activities, respectively. In the MODAFINIL condition, the vigilance enhancer partially recovered those source activities., Conclusions: The present results suggest that posterior delta and alpha source activities may be both related to the regulation of human brain arousal and vigilance in quiet wakefulness., Significance: Future research in healthy young adults may use this methodology to preselect new symptomatic drug candidates designed to normalize brain arousal and vigilance in seniors with dementia., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)
- Published
- 2019
- Full Text
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