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Authors: Cocks, Graham | Wilde, Jonathan I. | Graham, Simon J | Bousgouni, Vicky | Virley, David | Lovestone, Simon | Richardson, Jill

Article Type: Research Article

Abstract: In a recent clinical study, the thiazolidinedione (TZD) pioglitazone (Actos™ was reported to preserve cognitive function in patients with mild to moderate Alzheimer's disease and type II diabetes mellitus. TZDs are agonists of the nuclear hormone receptor peroxisome proliferator-activated receptor-γ (PPARγ), are peripheral insulin sensitizers, and have recently been reported to increase mitochondrial biogenesis in the central nervous system and dendritic spine density. We report a transcriptional profile of the TZD pioglitazone and the non-TZD PPARγ agonist GW347845 in primary cortical culture. We observed that pioglitazone, but not GW347845, increased cholesterol biosynthetic and lipogenic gene expression after 6 h, and …the expression of the cholesterol efflux transporters Abca1 and Abcg1 after 24 h. Co-treatment of pioglitazone with the PPARγ antagonist GW9662 did not significantly reduce these effects, suggesting a PPARγ-independent mechanism. These findings suggest a novel effect of TZDs in neurons that may be of relevance as a novel approach against Alzheimer's disease. Show more

Keywords: ABCA1, Alzheimer's disease, cholesterol biosynthesis, thiazolidinediones

DOI: 10.3233/JAD-2010-1266

Citation: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 631-646, 2010

Authors: Waldron, Ann-Marie | wyffels, Leonie | Verhaeghe, Jeroen | Richardson, Jill C. | Schmidt, Mark | Stroobants, Sigrid | Langlois, Xavier | Staelens, Steven

Article Type: Research Article

Abstract: We aimed to monitor the timing of amyloid-β deposition in relation to changes in brain function using in vivo imaging with [18 F]-AV45 and [18 F]-FDG in a mouse model of Alzheimer’s disease. TASTPM transgenic mice and wild-type controls were scanned longitudinally with [18 F]-AV45 and [18 F]-FDG before (3 months of age) and at multiple time points after the onset of amyloid deposition (6, 9, 12, and 15 months of age). As expected with increasing amyloidosis, TASTPM mice demonstrated progressive age-dependent increases in [18 F]-AV45 uptake that were significantly higher than for WT from 9 months onwards and correlated …to ex vivo measures of amyloid burden. The metabolism of [18 F]-AV45 produces several brain penetrant radiometabolites and normalization to a reference region helps to negate this non-specific binding and improve the sensitivity of [18 F]-AV45. The observed trajectory of [18 F]-FDG alterations deviated from our proposed hypothesis of gradual decreases with worsening amyloidosis. While [18 F]-FDG uptake in TASTPM mice was significantly lower than that of WT at 9 months, reduced [18 F]-FDG was not associated with aging in TASTPM mice. Moreover, [18 F]-FDG uptake did not correlate to measures of ex vivo amyloid burden. Our findings suggest that while amyloid-β is sufficient to induce hypometabolism, these pathologies are not linked in a dose-dependent manner in TASTPM mice. Show more

Keywords: Alzheimer’s disease, [18F]-AV45, [18F]-FDG, longitudinal, small animal imaging, transgenic mice

DOI: 10.3233/JAD-160760

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1537-1548, 2017

Authors: Balducci, Claudia | Paladini, Alessandra | Micotti, Edoardo | Tolomeo, Daniele | La Vitola, Pietro | Grigoli, Emanuele | Richardson, Jill C. | Forloni, Gianluigi

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common form of dementia characterized by synaptic dysfunction, memory loss, neuroinflammation, and neuronal cell death. Amyloid-β (Aβ), recognized as the main culprit of AD, aggregates and accumulates in the extracellular compartment as neuritic plaques, after deregulation of its production or clearance. Apolipoprotein E (ApoE) plays a major role in Aβ clearance and its expression is transcriptionally regulated by the liver X receptor and retinoid X receptors (RXRs) system. Bexarotene (BEXA), an RXR agonist that increases ApoE expression and microglia phagocytosis has been proposed as a promising therapy for AD, resolving both the amyloid pathology …and memory loss. Despite the first compelling report, however, multiple failures have been documented, raising concern about whether BEXA could in fact become a novel disease-modifying strategy for AD. To help clarify this, we investigated the effect of BEXA in vivo at multiple levels in TASTPM transgenic mice. Seven-day oral administration of BEXA to these mice did not achieve any significant memory improvement, plaque reduction, or enhancement of microglial cell activation. No differences were found when specifically investigating the microglial phagocytic state in vivo . In addition, a brain structural analysis with magnetic resonance did not detect any BEXA-mediated change in the volume reduction of the main affected brain areas in our mice. These results suggest that BEXA has no beneficial effects on the multi-factorial pathologic phenotype of AD mice. Show more

Keywords: Alzheimer’s disease, amyloid-β, apolipoprotein E, bexarotene, magnetic resonance imaging, memory, TASTPM mice, therapy

DOI: 10.3233/JAD-150029

Citation: Journal of Alzheimer's Disease, vol. 46, no. 2, pp. 471-482, 2015

Authors: Strum, Jay C. | Shehee, Ron | Virley, David | Richardson, Jill | Mattie, Michael | Selley, Paula | Ghosh, Sujoy | Nock, Christina | Saunders, Ann | Roses, Allen

Article Type: Research Article

Abstract: Rosiglitazone was found to simulate mitochondrial biogenesis in mouse brain in an apolipoprotein (Apo) E isozyme-independent manner. Rosiglitazone induced both mitochondrial DNA (mtDNA) and estrogen-stimulated related receptor alpha (ESRRA) mRNA, a key regulator of mitochondrial biogenesis. Transcriptomics and proteomics analysis suggested the mitochondria produced in the presence of human ApoE3 and E4 were not as metabolically efficient as those in the wild type or ApoE knockout mice. Thus, we propose that PPARγ agonism induces neuronal mitochondrial biogenesis and improves glucose utilization leading to improved cellular function and provides mechanistic support for the improvement in cognition observed in treatment of Alzheimer's …patients with rosiglitazone. Show more

Keywords: Mitochodrial biogenesis, PPARγ Alzheimer's Disease, rosiglitazone, real time PCR

DOI: 10.3233/JAD-2007-11108

Citation: Journal of Alzheimer's Disease, vol. 11, no. 1, pp. 45-51, 2007

Authors: Cogswell, John P. | Ward, James | Taylor, Ian A. | Waters, Michelle | Shi, Yunling | Cannon, Brian | Kelnar, Kevin | Kemppainen, Jon | Brown, David | Chen, Caifu | Prinjha, Rab K. | Richardson, Jill C. | Saunders, Ann M. | Roses, Allen D. | Richards, Cynthia A.

Article Type: Research Article

Abstract: MicroRNAs have essential functional roles in brain development and neuronal specification but their roles in neurodegenerative diseases such as Alzheimer's disease (AD) is unknown. Using a sensitive qRT-PCR platform we identified regional and stage-specific deregulation of miRNA expression in AD patient brains. We used experimental validation in addition to literature to reveal how the deregulated brain microRNAs are biomarkers for known and novel pathways in AD pathogenesis related to amyloid processing, neurogenesis, insulin resistance, and innate immunity. We additionally recovered miRNAs from cerebrospinal fluid and discovered AD-specific miRNA changes consistent with their role as potential biomarkers of disease.

Keywords: Alzheimer's disease, inflammation, insulin signaling, microRNA, neurogenesis

DOI: 10.3233/JAD-2008-14103

Citation: Journal of Alzheimer's Disease, vol. 14, no. 1, pp. 27-41, 2008

Authors: Marizzoni, Moira | Ferrari, Clarissa | Jovicich, Jorge | Albani, Diego | Babiloni, Claudio | Cavaliere, Libera | Didic, Mira | Forloni, Gianluigi | Galluzzi, Samantha | Hoffmann, Karl-Titus | Molinuevo, José Luis | Nobili, Flavio | Parnetti, Lucilla | Payoux, Pierre | Ribaldi, Federica | Rossini, Paolo Maria | Schönknecht, Peter | Salvatore, Marco | Soricelli, Andrea | Hensch, Tilman | Tsolaki, Magda | Visser, Pieter Jelle | Wiltfang, Jens | Richardson, Jill C. | Bordet, Régis | Blin, Olivier | Frisoni, Giovanni B. | The PharmaCog Consortium

Article Type: Research Article

Abstract: Background: Early Alzheimer’s disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients. Objective: To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression. Methods: APOE ɛ 4 specific CSF Aβ42 /P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42 /P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with …Aβ42 /P-tau status, time, and Aβ42 /P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers. Results: Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients who declined faster (interaction, p = 0.003). Lateral ventricle volume and medial temporal lobe measures were the biomarkers most sensitive to disease progression (interaction, p ≤0.042). Enrichment through ventricular volume reduced the sample size that a clinical trial would require from 13 to 76%, depending on structural outcome variable. The biomarker needing the lowest sample size was the hippocampal subfield GC-ML-DG (granule cells of molecular layer of the dentate gyrus) (n = 82 per arm to demonstrate a 20% atrophy reduction). Conclusion: MRI structural biomarkers can enrich prodromal AD with fast progressors and significantly decrease group size in clinical trials of disease modifying drugs. Show more

Keywords: Alzheimer’s disease, biomarkers, clinical trial, magnetic resonance imaging, mild cognitive impairment, precision medicine

DOI: 10.3233/JAD-180152

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 3-14, 2019

Authors: Quattrini, Giulia | Marizzoni, Moira | Pizzini, Francesca B. | Galazzo, Ilaria Boscolo | Aiello, Marco | Didic, Mira | Soricelli, Andrea | Albani, Diego | Romano, Melissa | Blin, Olivier | Forloni, Gianluigi | Golay, Xavier | Jovicich, Jorge | Nathan, Pradeep J. | Richardson, Jill C. | Salvatore, Marco | Frisoni, Giovanni B. | Pievani, Michela | on behalf of the PharmaCog Consortium

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, arterial spin labeling, brain perfusion, default mode network, limbic network, mild cognitive impairment

DOI: 10.3233/JAD-210531

Citation: Journal of Alzheimer's Disease, vol. 82, no. 4, pp. 1797-1808, 2021

Authors: Del Percio, Claudio | Drinkenburg, Wilhelmus | Lopez, Susanna | Pascarelli, Maria Teresa | Lizio, Roberta | Noce, Giuseppe | Ferri, Raffaele | Bastlund, Jesper Frank | Laursen, Bettina | Christensen, Ditte Zerlang | Pedersen, Jan T. | Forloni, Gianluigi | Frasca, Angelisa | Noè, Francesco M. | Fabene, Paolo Francesco | Bertini, Giuseppe | Colavito, Valeria | Bentivoglio, Marina | Kelley, Jonathan | Dix, Sophie | Infarinato, Francesco | Soricelli, Andrea | Stocchi, Fabrizio | Richardson, Jill C. | Babiloni, Claudio | on behalf of PharmaCog Consortium

Article Type: Research Article

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. Show more

Keywords: Active and passive state in wakefulness, Alzheimer’s disease, electroencephalography, TASTPM mice, wild type mice

DOI: 10.3233/JAD-190351

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 291-308, 2020

Authors: Babiloni, Claudio | Lizio, Roberta | Del Percio, Claudio | Marzano, Nicola | Soricelli, Andrea | Salvatore, Elena | Ferri, Raffaele | Cosentino, Filomena I.I. | Tedeschi, Gioacchino | Montella, Patrizia | Marino, Silvia | De Salvo, Simona | Rodriguez, Guido | Nobili, Flavio | Vernieri, Fabrizio | Ursini, Francesca | Mundi, Ciro | Richardson, Jill C. | Frisoni, Giovanni B | Rossini, Paolo M.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, disease progression, electroencephalography, low resolution brain electromagnetic tomography (LORETA)

DOI: 10.3233/JAD-121750

Citation: Journal of Alzheimer's Disease, vol. 34, no. 4, pp. 1015-1035, 2013

Authors: Marizzoni, Moira | Ferrari, Clarissa | Macis, Ambra | Jovicich, Jorge | Albani, Diego | Babiloni, Claudio | Cavaliere, Libera | Didic, Mira | Forloni, Gianluigi | Galluzzi, Samantha | Hoffmann, Karl-Titus | Molinuevo, José Luis | Nobili, Flavio | Parnetti, Lucilla | Payoux, Pierre | Pizzini, Francesca | Rossini, Paolo Maria | Salvatore, Marco | Schönknecht, Peter | Soricelli, Andrea | Del Percio, Claudio | Hensch, Tilman | Hegerl, Ulrich | Tsolaki, Magda | Visser, Pieter Jelle | Wiltfang, Jens | Richardson, Jill C. | Bordet, Régis | Blin, Olivier | Frisoni, Giovanni B. | The PharmaCog Consortium

Article Type: Research Article

Abstract: Background: Assessment of human brain atrophy in temporal regions using magnetic resonance imaging (MRI), resting state functional MRI connectivity in the left parietal cortex, and limbic electroencephalographic (rsEEG) rhythms as well as plasma amyloid peptide 42 (Aβ42 ) has shown that each is a promising biomarker of disease progression in amnestic mild cognitive impairment (aMCI) patients with prodromal Alzheimer’s disease (AD). However, the value of their combined use is unknown. Objective: To evaluate the association with cognitive decline and the effect on sample size calculation when using a biomarker composite matrix in prodromal AD clinical trials. Methods: Multicenter longitudinal study …with follow-up of 2 years or until development of incident dementia. APOE ɛ 4-specific cerebrospinal fluid (CSF) Aβ42 /P-tau cut-offs were used to identify aMCI with prodromal AD. Linear mixed models were performed 1) with repeated matrix values and time as factors to explain the longitudinal changes in ADAS-cog13, 2) with CSF Aβ42 /P-tau status, time, and CSF Aβ42 /P-tau status×time interaction as factors to explain the longitudinal changes in matrix measures, and 3) to compute sample size estimation for a trial implemented with the selected matrices. Results: The best composite matrix included the MRI volumes of hippocampal dentate gyrus and lateral ventricle. This matrix showed the best sensitivity to track disease progression and required a sample size 31% lower than that of the best individual biomarker (i.e., volume of hippocampal dentate gyrus). Conclusion: Optimal matrices improved the statistical power to track disease development and to measure clinical progression in the short-term period. This might contribute to optimize the design of future clinical trials in MCI. Show more

Keywords: Alzheimer’s disease, biomarker matrices, clinical trial, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-181016

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 49-58, 2019