6 results on '"Hopewell, Robert"'
Search Results
2. CSF tau368/total-tau ratio reflects cognitive performance and neocortical tau better compared to p-tau181 and p-tau217 in cognitively impaired individuals.
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Simrén, Joel, Brum, Wagner S., Ashton, Nicholas J., Benedet, Andrea L., Karikari, Thomas K., Kvartsberg, Hlin, Sjons, Emma, Lussier, Firoza Z., Chamoun, Mira, Stevenson, Jenna, Hopewell, Robert, Pallen, Vanessa, Ye, Keqiang, Pascoal, Tharick A., Zetterberg, Henrik, Rosa-Neto, Pedro, and Blennow, Kaj
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MILD cognitive impairment ,COGNITIVE ability ,TAU proteins ,SINGLE molecules ,NEUROFIBRILLARY tangles ,ALZHEIMER'S disease ,CLASSICAL swine fever ,PROGRESSIVE supranuclear palsy - Abstract
Introduction: Cerebrospinal fluid (CSF) tau biomarkers are reliable diagnostic markers for Alzheimer's disease (AD). However, their strong association with amyloid pathology may limit their reliability as specific markers of tau neurofibrillary tangles. A recent study showed evidence that a ratio of CSF C-terminally truncated tau (tau368, a tangle-enriched tau species), especially in ratio with total tau (t-tau), correlates strongly with tau PET tracer uptake. In this study, we set to evaluate the performance of the tau368/t-tau ratio in capturing tangle pathology, as indexed by a high-affinity tau PET tracer, as well as its association with severity of clinical symptoms. Methods: In total, 125 participants were evaluated cross-sectionally from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort (21 young, 60 cognitively unimpaired [CU] elderly [15 Aβ+], 10 Aβ+ with mild cognitive impairment [MCI], 14 AD dementia patients, and 20 Aβ− individuals with non-AD cognitive disorders). All participants underwent amyloid and tau PET scanning, with [
18 F]-AZD4694 and [18 F]-MK6240, respectively, and had CSF measurements of p-tau181, p-tau217, and t-tau. CSF concentrations of tau368 were quantified in all individuals with an in-house single molecule array assay. Results: CSF tau368 concentration was not significantly different across the diagnostic groups, although a modest increase was observed in all groups as compared with healthy young individuals (all P < 0.01). In contrast, the CSF tau368/t-tau ratio was the lowest in AD dementia, being significantly lower than in CU individuals (Aβ−, P < 0.001; Aβ+, P < 0.01), as well as compared to those with non-AD cognitive disorders (P < 0.001). Notably, in individuals with symptomatic AD, tau368/t-tau correlated more strongly with [18 F]-MK6240 PET SUVR as compared to the other CSF tau biomarkers, with increasing associations being seen in brain regions associated with more advanced disease (isocortical regions > limbic regions > transentorhinal regions). Importantly, linear regression models indicated that these associations were not confounded by Aβ PET SUVr. CSF tau368/t-tau also tended to continue to become more abnormal with higher tau burden, whereas the other biomarkers plateaued after the limbic stage. Finally, the tau368/t-tau ratio correlated more strongly with cognitive performance in individuals with symptomatic AD as compared to t-tau, p-tau217 and p-tau181. Conclusion: The tau368/t-tau ratio captures novel aspects of AD pathophysiology and disease severity in comparison to established CSF tau biomarkers, as it is more closely related to tau PET SUVR and cognitive performance in the symptomatic phase of the disease. [ABSTRACT FROM AUTHOR]- Published
- 2022
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3. [11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer's disease.
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Pascoal, Tharick A., Chamoun, Mira, Lax, Elad, Wey, Hsiao-Ying, Shin, Monica, Ng, Kok Pin, Kang, Min Su, Mathotaarachchi, Sulantha, Benedet, Andrea L., Therriault, Joseph, Lussier, Firoza Z., Schroeder, Frederick A., DuBois, Jonathan M., Hightower, Baileigh G., Gilbert, Tonya M., Zürcher, Nicole R., Wang, Changning, Hopewell, Robert, Chakravarty, Mallar, and Savard, Melissa
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ALZHEIMER'S disease ,TAU proteins ,POSITRON emission tomography ,HISTONES ,HISTONE deacetylase ,CEREBRAL atrophy ,PATIENT-ventilator dyssynchrony ,FORENSIC pathology - Abstract
Alzheimer's disease (AD) is characterized by the brain accumulation of amyloid-β and tau proteins. A growing body of literature suggests that epigenetic dysregulations play a role in the interplay of hallmark proteinopathies with neurodegeneration and cognitive impairment. Here, we aim to characterize an epigenetic dysregulation associated with the brain deposition of amyloid-β and tau proteins. Using positron emission tomography (PET) tracers selective for amyloid-β, tau, and class I histone deacetylase (HDAC I isoforms 1–3), we find that HDAC I levels are reduced in patients with AD. HDAC I PET reduction is associated with elevated amyloid-β PET and tau PET concentrations. Notably, HDAC I reduction mediates the deleterious effects of amyloid-β and tau on brain atrophy and cognitive impairment. HDAC I PET reduction is associated with 2-year longitudinal neurodegeneration and cognitive decline. We also find HDAC I reduction in the postmortem brain tissue of patients with AD and in a transgenic rat model expressing human amyloid-β plus tau pathology in the same brain regions identified in vivo using PET. These observations highlight HDAC I reduction as an element associated with AD pathophysiology. The link between amyloid and tau proteins with Alzheimer's disease progression remains unclear. Here, the authors propose HDACs I downregulation as an element linking the deleterious effects of brain proteinopathies with disease progression. [ABSTRACT FROM AUTHOR]
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- 2022
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4. 18F-MK-6240 PET for early and late detection of neurofibrillary tangles.
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Pascoal, Tharick A, Therriault, Joseph, Benedet, Andrea L, Savard, Melissa, Lussier, Firoza Z, Chamoun, Mira, Tissot, Cécile, Qureshi, Muhammad Naveed Iqbal, Kang, Min Su, Mathotaarachchi, Sulantha, Stevenson, Jenna, Hopewell, Robert, Massarweh, Gassan, Soucy, Jean-Paul, Gauthier, Serge, and Rosa-Neto, Pedro
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NEUROFIBRILLARY tangles ,FRONTOTEMPORAL lobar degeneration ,MILD cognitive impairment ,COGNITION disorders ,CEREBRAL amyloid angiopathy ,ALZHEIMER'S disease ,ALZHEIMER'S patients ,RESEARCH ,NEURONS ,CROSS-sectional method ,RESEARCH methodology ,ISOQUINOLINE ,RADIOISOTOPES ,EVALUATION research ,MEDICAL cooperation ,FLUORINE isotopes ,COMPARATIVE studies ,RESEARCH funding ,EARLY diagnosis - Abstract
Braak stages of tau neurofibrillary tangle accumulation have been incorporated in the criteria for the neuropathological diagnosis of Alzheimer's disease. It is expected that Braak staging using brain imaging can stratify living individuals according to their individual patterns of tau deposition, which may prove crucial for clinical trials and practice. However, previous studies using the first-generation tau PET agents have shown a low sensitivity to detect tau pathology in areas corresponding to early Braak histopathological stages (∼20% of cognitively unimpaired elderly with tau deposition in regions corresponding to Braak I-II), in contrast to ∼80-90% reported in post-mortem cohorts. Here, we tested whether the novel high affinity tau tangles tracer 18F-MK-6240 can better identify individuals in the early stages of tau accumulation. To this end, we studied 301 individuals (30 cognitively unimpaired young, 138 cognitively unimpaired elderly, 67 with mild cognitive impairment, 54 with Alzheimer's disease dementia, and 12 with frontotemporal dementia) with amyloid-β 18F-NAV4694, tau 18F-MK-6240, MRI, and clinical assessments. 18F-MK-6240 standardized uptake value ratio images were acquired at 90-110 min after the tracer injection. 18F-MK-6240 discriminated Alzheimer's disease dementia from mild cognitive impairment and frontotemporal dementia with high accuracy (∼85-100%). 18F-MK-6240 recapitulated topographical patterns consistent with the six hierarchical stages proposed by Braak in 98% of our population. Cognition and amyloid-β status explained most of the Braak stages variance (P < 0.0001, R2 = 0.75). No single region of interest standardized uptake value ratio accurately segregated individuals into the six topographic Braak stages. Sixty-eight per cent of the cognitively unimpaired elderly amyloid-β-positive and 37% of the cognitively unimpaired elderly amyloid-β-negative subjects displayed tau deposition, at least in the transentorhinal cortex (Braak I). Tau deposition solely in the transentorhinal cortex was associated with an elevated prevalence of amyloid-β, neurodegeneration, and cognitive impairment (P < 0.0001). 18F-MK-6240 deposition in regions corresponding to Braak IV-VI was associated with the highest prevalence of neurodegeneration, whereas in Braak V-VI regions with the highest prevalence of cognitive impairment. Our results suggest that the hierarchical six-stage Braak model using 18F-MK-6240 imaging provides an index of early and late tau accumulation as well as disease stage in preclinical and symptomatic individuals. Tau PET Braak staging using high affinity tracers has the potential to be incorporated in the diagnosis of living patients with Alzheimer's disease in the near future. [ABSTRACT FROM AUTHOR]
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- 2020
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5. A simplified radiosynthesis of [18F]MK‐6240 for tau PET imaging.
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Hopewell, Robert, Ross, Karen, Kostikov, Alexey, Pascoal, Tharick A., Alberti, Thais, Lacatus‐Samoila, Monica, Soucy, Jean‐Paul, Bennacef, Idriss, Kobayashi, Eliane, Kang, Min Su, Rosa‐Neto, Pedro, and Massarweh, Gassan
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POSITRON emission tomography , *RADIOACTIVE tracers , *NEUROFIBRILLARY tangles , *HIGH performance liquid chromatography , *ALZHEIMER'S disease - Abstract
[18F]MK‐6240 (6‐(fluoro)‐3‐(1H‐pyrrolo[2,3‐c]pyridin‐1‐yl)isoquinolin‐5‐amine) is a highly selective PET radiotracer for the in vivo imaging of neurofibrillary tangles (NFTs). [18F]MK‐6240 was synthesized in one step from its bis‐Boc protected precursor N‐[(tert‐butoxy)carbonyl]‐N‐(6‐nitro‐3‐[1H‐pyrrolo[2,3‐c]pyridin‐1‐yl]isoquinolin‐5‐yl) carbamate in DMSO using [18F] fluoride with TEA HCO3 with step‐wise heating up to 150°C, resulting in an isolated radiochemical yield of 9.8% ± 1.8% (n = 3) calculated from the end of bombardment (5.2% ± 1.0% calculated from the end of synthesis). This new synthetic approach eliminates the acidic deprotection of the bis‐Boc 18F‐labeled intermediate, which reduces the number of operations necessary for the synthesis as well as losses, which occur during deprotection and neutralization of the crude product mixture prior to the HPLC purification. The synthesis was performed automatically with a single‐use cassette on an IBA Synthera+ synthesis module. This synthesis method affords the radioligand with a reliable radiochemical yield, high radiochemical purity, and a high molar activity. [18F]MK‐6240 synthesized with this method has been regularly (n > 60) used in our ongoing human and animal PET imaging studies. [18F]MK‐6240, a highly selective positron emission tomography (PET) radiotracer for the in vivo imaging of neurofibrillary tangles, was prepared by a simple one‐step reaction and validated for use in humans. [ABSTRACT FROM AUTHOR]
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- 2019
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6. In vivo quantification of neurofibrillary tangles with [18F]MK-6240.
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Pascoal, Tharick A., Shin, Monica, Kang, Min Su, Chamoun, Mira, Chartrand, Daniel, Mathotaarachchi, Sulantha, Bennacef, Idriss, Therriault, Joseph, Ng, Kok Pin, Hopewell, Robert, Bouhachi, Reda, Hsiao, Hung-Hsin, Benedet, Andrea L., Soucy, Jean-Paul, Massarweh, Gassan, Gauthier, Serge, and Rosa-Neto, Pedro
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NEUROFIBRILLARY tangles ,ALZHEIMER'S disease diagnosis ,POSITRON emission tomography ,AUTORADIOGRAPHY ,MILD cognitive impairment ,PATIENTS - Abstract
Background: Imaging agents capable of quantifying the brain's tau aggregates will allow a more precise staging of Alzheimer's disease (AD). The aim of the present study was to examine the in vitro properties as well as the in vivo kinetics, using gold standard methods, of the novel positron emission tomography (PET) tau imaging agent [
18 F]MK-6240. Methods: In vitro properties of [18 F]MK-6240 were estimated with autoradiography in postmortem brain tissues of 14 subjects (seven AD patients and seven age-matched controls). In vivo quantification of [18 F]MK-6240 binding was performed in 16 subjects (four AD patients, three mild cognitive impairment patients, six healthy elderly individuals, and three healthy young individuals) who underwent 180-min dynamic scans; six subjects had arterial sampling for metabolite correction. Simplified approaches for [18 F]MK-6240 quantification were validated using full kinetic modeling with metabolite-corrected arterial input function. All participants also underwent amyloid-PET and structural magnetic resonance imaging. Results: In vitro [18 F]MK-6240 uptake was higher in AD patients than in age-matched controls in brain regions expected to contain tangles such as the hippocampus, whereas no difference was found in the cerebellar gray matter. In vivo, [18 F]MK-6240 displayed favorable kinetics with rapid brain delivery and washout. The cerebellar gray matter had low binding across individuals, showing potential for use as a reference region. A reversible two-tissue compartment model well described the time–activity curves across individuals and brain regions. Distribution volume ratios using the plasma input and standardized uptake value ratios (SUVRs) calculated after the binding approached equilibrium (90 min) were correlated and higher in mild cognitive impairment or AD dementia patients than in controls. Reliability analysis revealed robust SUVRs calculated from 90 to 110 min, while earlier time points provided inaccurate estimates. Conclusions: This evaluation shows an [18 F]MK-6240 distribution in concordance with postmortem studies and that simplified quantitative approaches such as the SUVR offer valid estimates of neurofibrillary tangle load 90 min post injection. [18 F]MK-6240 is a promising tau tracer with the potential to be applied in the disease diagnosis and assessment of therapeutic interventions. [ABSTRACT FROM AUTHOR]- Published
- 2018
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