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1. Comparison of plasma soluble and extracellular vesicles-associated biomarkers in Alzheimer’s disease patients and cognitively normal individuals

Author

Emilien Boyer, Louise Deltenre, Marion Dourte, Lise Colmant, Esther Paître, Kristel Sleegers, Nuria Suelves, Bernard Hanseeuw, and Pascal Kienlen-Campard

Subjects
Alzheimer’s disease, Blood biomarkers, Extracellular vesicles, Aβ42/40 ratio, Tau, Neurally-derived EVs, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Amyloid-β (Aβ) and tau are brain hallmarks of Alzheimer’s disease (AD), also present in blood as soluble biomarkers or encapsulated in extracellular vesicles (EVs). Our goal was to assess how soluble plasma biomarkers of AD pathology correlate with the number and content of EVs. Methods Single-molecule enzyme-linked assays were used to quantify Aβ42/40 and tau in plasma samples and neurally-derived EVs (NDEVs) from a cohort of APOE ε4– (n = 168) and APOE ε4+ (n = 68) cognitively normal individuals and AD patients (n = 55). The ratio of CD56 (Neuronal cell-adhesion molecule) to CD81 signal measured by ELISA-DELFIA was used for the relative quantification of NDEVs in plasma samples. Results The soluble plasma Aβ42/40 ratio is decreased in AD patients compared to cognitively normal individuals. The amount and content (Aβ40, Aβ42, tau) of plasma NDEVs were similar between groups. Plasma NDEVs quantity remain consistent with aging and between AD and CN individuals. However, the quantity of soluble biomarkers was negatively correlated to NDEVs number in cognitively normal individuals, while in AD patients, this correlation is lost, suggesting a shift in the mechanism underpinning the production and the release of these biomarkers in pathological conditions. Conclusion Soluble plasma Aβ42/40 ratio is the most robust biomarker to discriminate between AD patients and CN individuals, as it normalizes for the number of NDEVs. Analysis of NDEVs and their content pointed toward peculiar mechanisms of Aβ release in AD. Further research on independent cohorts can confirm our findings and assess whether plasma Aβ and tau need correction by NDEVs for better AD risk identification in CN populations.

Published
2024
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2. Brain age as a biomarker for pathological versus healthy ageing – a REMEMBER study

Author

Mandy M.J. Wittens, Stijn Denissen, Diana M. Sima, Erik Fransen, Ellis Niemantsverdriet, Christine Bastin, Florence Benoit, Bruno Bergmans, Jean-Christophe Bier, Peter Paul de Deyn, Olivier Deryck, Bernard Hanseeuw, Adrian Ivanoiu, Gaëtane Picard, Annemie Ribbens, Eric Salmon, Kurt Segers, Anne Sieben, Hanne Struyfs, Evert Thiery, Jos Tournoy, Anne-Marie van Binst, Jan Versijpt, Dirk Smeets, Maria Bjerke, Guy Nagels, and Sebastiaan Engelborghs

Subjects
Alzheimer’s disease, Magnetic resonance imaging, Biomarker, Brain predicted age difference, Brain age, Automated volumetry, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Objectives This study aimed to evaluate the potential clinical value of a new brain age prediction model as a single interpretable variable representing the condition of our brain. Among many clinical use cases, brain age could be a novel outcome measure to assess the preventive effect of life-style interventions. Methods The REMEMBER study population (N = 742) consisted of cognitively healthy (HC,N = 91), subjective cognitive decline (SCD,N = 65), mild cognitive impairment (MCI,N = 319) and AD dementia (ADD,N = 267) subjects. Automated brain volumetry of global, cortical, and subcortical brain structures computed by the CE-labeled and FDA-cleared software icobrain dm (dementia) was retrospectively extracted from T1-weighted MRI sequences that were acquired during clinical routine at participating memory clinics from the Belgian Dementia Council. The volumetric features, along with sex, were combined into a weighted sum using a linear model, and were used to predict ‘brain age’ and ‘brain predicted age difference’ (BPAD = brain age–chronological age) for every subject. Results MCI and ADD patients showed an increased brain age compared to their chronological age. Overall, brain age outperformed BPAD and chronological age in terms of classification accuracy across the AD spectrum. There was a weak-to-moderate correlation between total MMSE score and both brain age (r = -0.38,p

Published
2024
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3. Risk of conversion to mild cognitive impairment or dementia among subjects with amyloid and tau pathology: a systematic review and meta-analysis

Author

Zsolt Huszár, Marie Anne Engh, Márk Pavlekovics, Tomoya Sato, Yalea Steenkamp, Bernard Hanseeuw, Tamás Terebessy, Zsolt Molnár, Péter Hegyi, and Gábor Csukly

Subjects
Beta-amyloid, Phosphorylated tau, Dementia, Mild cognitive impairment, Alzheimer’s disease, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Measurement of beta-amyloid (Aβ) and phosphorylated tau (p-tau) levels offers the potential for early detection of neurocognitive impairment. Still, the probability of developing a clinical syndrome in the presence of these protein changes (A+ and T+) remains unclear. By performing a systematic review and meta-analysis, we investigated the risk of mild cognitive impairment (MCI) or dementia in the non-demented population with A+ and A- alone and in combination with T+ and T- as confirmed by PET or cerebrospinal fluid examination. Methods A systematic search of prospective and retrospective studies investigating the association of Aβ and p-tau with cognitive decline was performed in three databases (MEDLINE via PubMed, EMBASE, and CENTRAL) on January 9, 2024. The risk of bias was assessed using the Cochrane QUIPS tool. Odds ratios (OR) and Hazard Ratios (HR) were pooled using a random-effects model. The effect of neurodegeneration was not studied due to its non-specific nature. Results A total of 18,162 records were found, and at the end of the selection process, data from 36 cohorts were pooled (n= 7,793). Compared to the unexposed group, the odds ratio (OR) for conversion to dementia in A+ MCI patients was 5.18 [95% CI 3.93; 6.81]. In A+ CU subjects, the OR for conversion to MCI or dementia was 5.79 [95% CI 2.88; 11.64]. Cerebrospinal fluid Aβ42 or Aβ42/40 analysis and amyloid PET imaging showed consistent results. The OR for conversion in A+T+ MCI subjects (11.60 [95% CI 7.96; 16.91]) was significantly higher than in A+T- subjects (2.73 [95% CI 1.65; 4.52]). The OR for A-T+ MCI subjects was non-significant (1.47 [95% CI 0.55; 3.92]). CU subjects with A+T+ status had a significantly higher OR for conversion (13.46 [95% CI 3.69; 49.11]) than A+T- subjects (2.04 [95% CI 0.70; 5.97]). Meta-regression showed that the ORs for Aβ exposure decreased with age in MCI. (beta = -0.04 [95% CI -0.03 to -0.083]). Conclusions Identifying Aβ-positive individuals, irrespective of the measurement technique employed (CSF or PET), enables the detection of the most at-risk population before disease onset, or at least at a mild stage. The inclusion of tau status in addition to Aβ, especially in A+T+ cases, further refines the risk assessment. Notably, the higher odds ratio associated with Aβ decreases with age. Trial registration The study was registered in PROSPERO (ID: CRD42021288100).

Published
2024
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4. Recruitment of pre-dementia participants: main enrollment barriers in a longitudinal amyloid-PET study

Author

Ilse Bader, Ilona Bader, Isadora Lopes Alves, David Vállez García, Bruno Vellas, Bruno Dubois, Mercè Boada, Marta Marquié, Daniele Altomare, Philip Scheltens, Rik Vandenberghe, Bernard Hanseeuw, Michael Schöll, Giovanni B. Frisoni, Frank Jessen, Agneta Nordberg, Miia Kivipelto, Craig W. Ritchie, Oriol Grau-Rivera, José Luis Molinuevo, Lisa Ford, Andrew Stephens, Rossella Gismondi, Juan Domingo Gispert, Gill Farrar, Frederik Barkhof, Pieter Jelle Visser, Lyduine E. Collij, and on behalf of the AMYPAD consortium

Subjects
Alzheimer’s disease, Preclinical, Recruitment, Enrollment barriers, Amyloid PET, Clinical trial, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background The mismatch between the limited availability versus the high demand of participants who are in the pre-dementia phase of Alzheimer’s disease (AD) is a bottleneck for clinical studies in AD. Nevertheless, potential enrollment barriers in the pre-dementia population are relatively under-reported. In a large European longitudinal biomarker study (the AMYPAD-PNHS), we investigated main enrollment barriers in individuals with no or mild symptoms recruited from research and clinical parent cohorts (PCs) of ongoing observational studies. Methods Logistic regression was used to predict study refusal based on sex, age, education, global cognition (MMSE), family history of dementia, and number of prior study visits. Study refusal rates and categorized enrollment barriers were compared between PCs using chi-squared tests. Results 535/1856 (28.8%) of the participants recruited from ongoing studies declined participation in the AMYPAD-PNHS. Only for participants recruited from clinical PCs (n = 243), a higher MMSE-score (β = − 0.22, OR = 0.80, p

Published
2023
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5. Cortical microstructural changes predict tau accumulation and episodic memory decline in older adults harboring amyloid

Author

Geoffroy Gagliardi, Elena Rodriguez-Vieitez, Victor Montal, Jorge Sepulcre, Ibai Diez, Cristina Lois, Bernard Hanseeuw, Aaron P. Schultz, Michael J. Properzi, Kathryn V. Papp, Gad A. Marshall, Juan Fortea, Keith A. Johnson, Reisa A. Sperling, and Patrizia Vannini

Subjects
Medicine
Abstract

Abstract Introduction Non-invasive diffusion-weighted imaging (DWI) to assess brain microstructural changes via cortical mean diffusivity (cMD) has been shown to be cross-sectionally associated with tau in cognitively normal older adults, suggesting that it might be an early marker of neuronal injury. Here, we investigated how regional cortical microstructural changes measured by cMD are related to the longitudinal accumulation of regional tau as well as to episodic memory decline in cognitively normal individuals harboring amyloid pathology. Methods 122 cognitively normal participants from the Harvard Aging Brain Study underwent DWI, T1w-MRI, amyloid and tau PET imaging, and Logical Memory Delayed Recall (LMDR) assessments. We assessed whether the interaction of baseline amyloid status and cMD (in entorhinal and inferior-temporal cortices) was associated with longitudinal regional tau accumulation and with longitudinal LMDR using separate linear mixed-effects models. Results We find a significant interaction effect of the amyloid status and baseline cMD in predicting longitudinal tau in the entorhinal cortex (p = 0.044) but not the inferior temporal lobe, such that greater baseline cMD values predicts the accumulation of entorhinal tau in amyloid-positive participants. Moreover, we find a significant interaction effect of the amyloid status and baseline cMD in the entorhinal cortex (but not inferior temporal cMD) in predicting longitudinal LMDR (p

Published
2023
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6. Association between ATN profiles and mortality in a clinical cohort of patients with cognitive disorders

Author

Mélina Régy, Aline Dugravot, Séverine Sabia, Elodie Bouaziz-Amar, Claire Paquet, Bernard Hanseeuw, Archana Singh-Manoux, and Julien Dumurgier

Subjects
Alzheimer’s disease, ATN classification, Mortality, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Alzheimer’s disease (AD) is the 5th leading cause of death in people 65 years and older. The ATN classification reflects a biological definition of AD pathology with markers of Aβ deposition (A), pathologic tau (T), and neurodegeneration (N). Little is known about the relationship between ATN status and the risk of mortality, leading us to examine this association in a relatively large population of patients seen at a memory clinic for cognitive disorders. Methods Data were drawn from the BioCogBank Study, including patients seen for cognitive disorders in Lariboisiere Hospital (Paris, France), followed up to 15 years. All participants underwent a lumbar puncture for an assessment of the levels of CSF tau (tau), phosphorylated tau (p-tau181), and β-amyloid 42 peptide (Aβ42). Vital status on July 1, 2020, was recorded for each participant using the national mortality register. Individuals were categorized according to their ATN profiles based on CSF Aβ42 or Aβ42/40 ratio, p-tau181, and tau. Kaplan–Meier and multivariate Cox analyses were performed with A-T-N − participants as the reference using a short (5 years) and long follow-up (15 years). Results Of the 1353 patients in the study (mean age: 68 years old, 53% of women, mean MMSE score: 22.6), 262 died during the follow-up. At 5 years of follow-up, A-T-N + individuals had the highest risk of mortality in Kaplan–Meier and adjusted Cox analyses [HR (95% CI) = 2.93 (1.31–6.56)]. At 15 years of follow-up, patients in the AD spectrum had a higher mortality risk with a gradient effect for biomarker positivity: A-T + [HR = 1.63 (1.04–2.55)], A + T − [HR = 2.17 (1.44–3.26)], and A + T + individuals [HR = 2.38 (1.66–3.39)], compared to A-T-N − patients. Adjustments on potential confounders had little impact on these associations. Conclusion This study shows ATN profiles to be associated with mortality in a relatively large patient cohort based on a memory clinic. Patients with isolated evidence of neurodegeneration had a higher mortality rate in the short follow-up, and patients with the AD profile had the highest mortality rate in the long follow-up.

Published
2023
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7. Definition of a Threshold for the Plasma Aβ42/Aβ40 Ratio Measured by Single-Molecule Array to Predict the Amyloid Status of Individuals without Dementia

Author

Lise Colmant, Emilien Boyer, Thomas Gerard, Kristel Sleegers, Renaud Lhommel, Adrian Ivanoiu, Philippe Lefèvre, Pascal Kienlen-Campard, and Bernard Hanseeuw

Subjects
Alzheimer’s disease, plasma amyloid, SIMOA, plasma Aβ42/Aβ40 ratio, amyloid prediction, biomarkers, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Alzheimer’s disease (AD) is characterized by amyloid beta (Aβ) plaques and hyperphosphorylated tau in the brain. Aβ plaques precede cognitive impairments and can be detected through amyloid-positron emission tomography (PET) or in cerebrospinal fluid (CSF). Assessing the plasma Aβ42/Aβ40 ratio seems promising for non-invasive and cost-effective detection of brain Aβ accumulation. This approach involves some challenges, including the accuracy of blood-based biomarker measurements and the establishment of clear, standardized thresholds to categorize the risk of developing brain amyloid pathology. Plasma Aβ42/Aβ40 ratio was measured in 277 volunteers without dementia, 70 AD patients and 18 non-AD patients using single-molecule array. Patients (n = 88) and some volunteers (n = 66) were subject to evaluation of amyloid status by CSF Aβ quantification or PET analysis. Thresholds of plasma Aβ42/Aβ40 ratio were determined based on a Gaussian mixture model, a decision tree, and the Youden’s index. The 0.0472 threshold, the one with the highest sensitivity, was retained for general population without dementia screening, and the 0.0450 threshold was retained for research and clinical trials recruitment, aiming to minimize the need for CSF or PET analyses to identify amyloid-positive individuals. These findings offer a promising step towards a cost-effective method for identifying individuals at risk of developing AD.

Published
2024
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8. The amyloid imaging for the prevention of Alzheimer's disease consortium: A European collaboration with global impact

Author

Lyduine E. Collij, Gill Farrar, David Valléz García, Ilona Bader, Mahnaz Shekari, Luigi Lorenzini, Hugh Pemberton, Daniele Altomare, Sandra Pla, Mery Loor, Pawel Markiewicz, Maqsood Yaqub, Christopher Buckley, Giovanni B. Frisoni, Agneta Nordberg, Pierre Payoux, Andrew Stephens, Rossella Gismondi, Pieter Jelle Visser, Lisa Ford, Mark Schmidt, Cindy Birck, Jean Georges, Anja Mett, Zuzana Walker, Mercé Boada, Alexander Drzezga, Rik Vandenberghe, Bernard Hanseeuw, Frank Jessen, Michael Schöll, Craig Ritchie, Isadora Lopes Alves, Juan Domingo Gispert, and Frederik Barkhof

Subjects
amyloid, positron emission tomography (PET), consortium, Alzheimer's disease, diagnosis, prognosis, Neurology. Diseases of the nervous system, RC346-429
Abstract

BackgroundAmyloid-β (Aβ) accumulation is considered the earliest pathological change in Alzheimer's disease (AD). The Amyloid Imaging to Prevent Alzheimer's Disease (AMYPAD) consortium is a collaborative European framework across European Federation of Pharmaceutical Industries Associations (EFPIA), academic, and ‘Small and Medium-sized enterprises’ (SME) partners aiming to provide evidence on the clinical utility and cost-effectiveness of Positron Emission Tomography (PET) imaging in diagnostic work-up of AD and to support clinical trial design by developing optimal quantitative methodology in an early AD population.The AMYPAD studiesIn the Diagnostic and Patient Management Study (DPMS), 844 participants from eight centres across three clinical subgroups (245 subjective cognitive decline, 342 mild cognitive impairment, and 258 dementia) were included. The Prognostic and Natural History Study (PNHS) recruited pre-dementia subjects across 11 European parent cohorts (PCs). Approximately 1600 unique subjects with historical and prospective data were collected within this study. PET acquisition with [18F]flutemetamol or [18F]florbetaben radiotracers was performed and quantified using the Centiloid (CL) method.ResultsAMYPAD has significantly contributed to the AD field by furthering our understanding of amyloid deposition in the brain and the optimal methodology to measure this process. Main contributions so far include the validation of the dual-time window acquisition protocol to derive the fully quantitative non-displaceable binding potential (BPND), assess the value of this metric in the context of clinical trials, improve PET-sensitivity to emerging Aβ burden and utilize its available regional information, establish the quantitative accuracy of the Centiloid method across tracers and support implementation of quantitative amyloid-PET measures in the clinical routine.Future stepsThe AMYPAD consortium has succeeded in recruiting and following a large number of prospective subjects and setting up a collaborative framework to integrate data across European PCs. Efforts are currently ongoing in collaboration with ARIDHIA and ADDI to harmonize, integrate, and curate all available clinical data from the PNHS PCs, which will become openly accessible to the wider scientific community.

Published
2023
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9. CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia

Author

Chritica Lodder, Isabelle Scheyltjens, Ilie Cosmin Stancu, Pablo Botella Lucena, Manuel Gutiérrez de Ravé, Sarah Vanherle, Tim Vanmierlo, Niels Cremers, Hannah Vanrusselt, Bert Brône, Bernard Hanseeuw, Jean-Noël Octave, Astrid Bottelbergs, Kiavash Movahedi, and Ilse Dewachter

Subjects
Alzheimer’s disease, Amyloid pathology, Tau pathology, Neurodegeneration, ATN-continuum, Microgliosis, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Alzheimer's disease (AD) is characterized by a sequential progression of amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), constituting ATN pathology. While microglia are considered key contributors to AD pathogenesis, their contribution in the combined presence of ATN pathologies remains incompletely understood. As sensors of the brain microenvironment, microglial phenotypes and contributions are importantly defined by the pathologies in the brain, indicating the need for their analysis in preclinical models that recapitulate combined ATN pathologies, besides their role in A and T models only. Here, we report a new tau-seed model in which amyloid pathology facilitates bilateral tau propagation associated with brain atrophy, thereby recapitulating robust ATN pathology. Single-cell RNA sequencing revealed that ATN pathology exacerbated microglial activation towards disease-associated microglia states, with a significant upregulation of Apoe as compared to amyloid-only models (A). Importantly, Colony-Stimulating Factor 1 Receptor inhibition preferentially eliminated non-plaque-associated versus plaque associated microglia. The preferential depletion of non-plaque-associated microglia significantly attenuated tau pathology and neuronal atrophy, indicating their detrimental role during ATN progression. Together, our data reveal the intricacies of microglial activation and their contributions to pathology in a model that recapitulates the combined ATN pathologies of AD. Our data may provide a basis for microglia-targeting therapies selectively targeting detrimental microglial populations, while conserving protective populations.

Published
2021
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10. Pathological correlates of impaired self-awareness of memory function in Alzheimer’s disease

Author

Geoffroy Gagliardi, Madeline Kuppe, Cristina Lois, Bernard Hanseeuw, Patrizia Vannini, and for the Alzheimer’s Disease Neuroimaging Initiative

Subjects
Alzheimer’s disease, Awareness, Cognition, Tau, Amyloid, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Introduction Impaired self-awareness of memory function, a.k.a. anosognosia, is a common symptom in Alzheimer’s disease (AD); however, its pathological correlates remain unclear. Here, we investigated the impact of amyloid and tau on memory self-awareness. Methods Two hundred thirty-six clinically normal (N) and 102 impaired (I) participants from the ADNI cohort were included. Amyloid (global) and tau burden (in entorhinal and inferior temporal cortices) were assessed using positron emission tomography (PET). Self-awareness of memory was assessed using discrepancy indexes of subjective participant-informant ratings, as well as participant-objective scores of memory performance. Subjective and objective values were derived from the Everyday Cognition memory questionnaire and Logical Memory (delayed recall). Results Lower awareness (both methods) of memory function was associated with higher levels of pathology in the I group as compared to N. There was a significant effect of tauopathy, but not amyloidosis, on individual complaint, such that higher levels of tau associated with lower awareness. Discussion Impaired self-awareness appears progressively in the evolution of the disease related to AD biomarkers. Discordant subjective and objective measures may be important for clinical consideration.

Published
2021
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11. Association of APOE ε4 with cerebral gray matter volumes in non-demented older adults: The MEMENTO cohort study

Author

Mélina Régy, Aline Dugravot, Séverine Sabia, Aurore Fayosse, Jean-Francois Mangin, Marie Chupin, Clara Fischer, Vincent Bouteloup, Carole Dufouil, Geneviève Chêne, Claire Paquet, Bernard Hanseeuw, Archana Singh-Manoux, and Julien Dumurgier

Subjects
APOE genotype, MRI, Longitudinal analysis, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Data on 2,045 non-demented individuals with memory complaints were drawn from the Memento cohort study to examine the association between Apolipoprotein E ε4 allele (APOE4) and regional brain gray matter volumes. Linear regression was used to examine the association of APOE4 and measures of regional gray matter volumes in cross-sectional analysis and change therein using longitudinal analyses based on two brain MRI performed at baseline and at two-year follow-up. Overall, in analyses adjusted for age, sex, and intracranial volume, the presence of APOE4 was associated with lower total gray matter volume at baseline and with a higher atrophy rate over the follow-up. The hippocampus and entorhinal cortex were the two gray matter regions most associated with APOE4. Further adjustment for cardiovascular risk factors had little impact on these associations. There was an interaction between age, APOE4 status and total brain volume atrophy rate, with evidence of an earlier age at onset of atrophy in hippocampal volume in APOE4 carriers compared to non-carriers. Those results are in accordance with the role of medial temporal structures in the greater risk of dementia observed in people carrying the APOE4 allele.

Published
2022
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12. Excessive Worrying as a Central Feature of Anxiety during the First COVID-19 Lockdown-Phase in Belgium: Insights from a Network Approach

Author

Alexandre Heeren, Bernard Hanseeuw, Louise-Amélie Cougnon, and Grégoire Lits

Subjects
covid-19, anxiety, worry, gad, network approach to psychopathology, directed acyclic graph, gaussian graphical model, psychopathology, pandemic, lockdown, Psychology, BF1-990
Abstract

Since the WHO declared the COVID-19 pandemic on March 11, 2020, the novel coronavirus, SARS-CoV-2, has profoundly impacted public health and the economy worldwide. But there are not the only ones to be hit. The COVID-19 pandemic has also substantially altered mental health, with anxiety symptoms being one of the most frequently reported problems. Especially, the number of people reporting anxiety symptoms increased significantly during the first lockdown-phase compared to similar data collected before the pandemic. Yet, most of these studies relied on a unitary approach to anxiety, wherein its different constitutive features (i.e., symptoms) were tallied into one sum-score, thus ignoring any possibility of interactions between them. Therefore, in this study, we seek to map the associations between the core features of anxiety during the first weeks of the first Belgian COVID-19 lockdown-phase ('n' = 2,829). To do so, we implemented, in a preregistered fashion, two distinct computational network approaches: a Gaussian graphical model and a Bayesian network modelling approach to estimate a directed acyclic graph. Despite their varying assumptions, constraints, and computational methods to determine nodes (i.e., the variables) and edges (i.e., the relations between them), both approaches pointed to excessive worrying as a node playing an especially influential role in the network system of the anxiety features. Altogether, our findings offer novel data-driven clues for the ongoing field’s larger quest to examine, and eventually alleviate, the mental health consequences of the COVID-19 pandemic.

Published
2021
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13. Spouse-Appraised Memory Functioning Predicts Memory Decline Better Than Subjective Memory Complaints in Community Dwelling Older Adults at Genetic Risk for Alzheimer's Disease

Author

Youssef Bellaali, John L. Woodard, Bernard Hanseeuw, and Adrian Ivanoiu

Subjects
lack of awareness, subjective memory complaints, preclinical Alzheimer disease, memory impairments, relative's account, Apolipoprotein E, Psychiatry, RC435-571
Abstract

Objective: Alzheimer's disease (AD) begins with subtle memory decline, years before dementia onset. The presence of subjective memory complaints (SMC) has been proposed as a marker of preclinical AD. However, recent evidence has demonstrated early and progressive loss of awareness of memory difficulties in non-demented older adults harboring AD pathology. We investigated the respective contributions of SMC and spouse-appraised memory functioning (SAM) to predict memory decline in a large cohort of community dwelling older adults.Methods: The Wisconsin Longitudinal Study collected cognitive data from a community-based cohort of 3,583 participants in both 2005 and 2011. The participant and the participant's spouse were each asked to rate the participant's memory functioning using a Likert scale. We predicted change in objective episodic memory with models including baseline SMC, baseline SAM, or both SMC and SAM. We also evaluated an awareness index (SMC minus SAM). We then tested the interaction between Apolipoprotein E (APOE ε4) carrier status and SMC/SAM to evaluate whether the effects were driven by individuals at-risk for AD pathology.Results: In separate models, SMC (−0.081 ± 0.036, p = 0.025) and SAM (−0.084 ± 0.278, p = 0.003) were both associated with memory decline over ~6 years. However, the AI was not significantly associated with memory decline (0.031 ± 0.024, p = 0.19). When both predictors were included in the same model, SAM (−0.074 ± 0.03, p = 0.0092) was associated with memory decline, while SMC was not significant (−0.061 ± 0.04, p = 0.99). The association between SAM and memory decline was stronger in the APOE ε4 carriers than in the non-carriers (APOE-by-SAM interaction: F = 6.07; p = 0.002), and follow up analyses revealed that SAM was particularly predictive of decline only for APOE ε4 carriers. The association between SMC and memory decline was independent of APOE ε4 carrier status (APOE-by-SMC interaction: F = 2.29; p = 0.13).Conclusions: Spouse-appraised memory functioning was more predictive of memory decline than SMC or an awareness index, particularly in APOE ε4 carriers, who are at increased risk for AD pathology.

Published
2021
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14. Frontotemporal Lobar Degeneration Case with an N-Terminal TUBA4A Mutation Exhibits Reduced TUBA4A Levels in the Brain and TDP-43 Pathology

Author

Evelien Van Schoor, Mathieu Vandenbulcke, Valérie Bercier, Rik Vandenberghe, Julie van der Zee, Christine Van Broeckhoven, Markus Otto, Bernard Hanseeuw, Philip Van Damme, Ludo Van Den Bosch, and Dietmar Rudolf Thal

Subjects
frontotemporal dementia, TUBA4A, transactive response DNA-binding protein 43 kD, Microbiology, QR1-502
Abstract

Recently, disease-associated variants of the TUBA4A gene were identified in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we present the neuropathological report of a patient with the semantic variant of primary progressive aphasia with a family history of Parkinsonism, harboring a novel frameshift mutation c.187del (p.Arg64Glyfs*90) in TUBA4A. Immunohistochemistry showed abundant TAR DNA-binding protein 43 kDa (TDP-43) dystrophic neurite pathology in the frontal and temporal cortex and the dentate gyrus of the hippocampus, consistent with frontotemporal lobar degeneration (FTLD). The observed pathology pattern fitted best with that of FTLD-TDP Type C. qPCR showed the presence of mutant TUBA4A mRNA. However, no truncated TUBA4A was detected at the protein level. A decrease in total TUBA4A mRNA and protein levels suggests loss-of-function as a potential pathogenic mechanism. This report strengthens the idea that N-terminal TUBA4A mutations are associated with FTLD-TDP. These N-terminal mutations possibly exert their pathogenic effects through haploinsufficiency, contrary to C-terminal TUBA4A mutations which are thought to disturb the microtubule network via a dominant-negative mechanism.

Published
2022
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15. Interactive versus additive relationships between regional cortical thinning and amyloid burden in predicting clinical decline in mild AD and MCI individuals

Author

Federico d'Oleire Uquillas, Heidi I.L. Jacobs, Bernard Hanseeuw, Gad A. Marshall, Michael Properzi, Aaron P. Schultz, Molly R. LaPoint, Keith A. Johnson, Reisa A. Sperling, and Patrizia Vannini

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

The biological mechanisms that link Beta-amyloid (Aβ) plaque deposition, neurodegeneration, and clinical decline in Alzheimer's disease (AD) dementia, have not been completely elucidated. Here we studied whether amyloid accumulation and neurodegeneration, independently or interactively, predict clinical decline over time in a group of memory impaired older individuals [diagnosed with either amnestic mild cognitive impairment (MCI), or mild AD dementia]. We found that baseline Aβ-associated cortical thinning across clusters encompassing lateral and medial temporal and parietal cortices was related to higher baseline Clinical Dementia Rating Sum-of-Boxes (CDR-SB). Baseline Aβ-associated cortical thinning also predicted CDR-SB over time. Notably, the association between CDR-SB change and cortical thickness values from the right lateral temporo-parietal cortex and right precuneus was driven by individuals with high Aβ burden. In contrast, the association between cortical thickness in the medial temporal lobe (MTL) and clinical decline was similar for individuals with high or low Aβ burden. Furthermore, amyloid pathology was a stronger predictor for clinical decline than MTL thickness. While this study validates previous findings relating AD biomarkers of neurodegeneration to clinical impairment, here we show that regions outside the MTL may be more vulnerable and specific to AD dementia. Additionally, excluding mild AD individuals revealed that these relationships remained, suggesting that lower cortical thickness values in specific regions, vulnerable to amyloid pathology, predict clinical decline already at the prodromal stage. Keywords: Alzheimer's disease, Beta-amyloid, Clinical decline, Cortical thickness, Medial temporal lobe, Mild cognitive impairment

Published
2018
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16. Anosognosia for memory deficits in mild cognitive impairment: Insight into the neural mechanism using functional and molecular imaging

Author

Patrizia Vannini, Bernard Hanseeuw, Catherine E. Munro, Rebecca E. Amariglio, Gad A. Marshall, Dorene M. Rentz, Alvaro Pascual-Leone, Keith A. Johnson, and Reisa A. Sperling

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

Anosognosia, or loss of insight of memory deficits, is a common and striking symptom in Alzheimer's disease (AD). Previous findings in AD dementia patients suggest that anosognosia is due to both functional metabolic changes within cortical midline structures involved in self-referential processes, as well as functional disconnection between these regions. The present study aims to extend these findings by investigating the neural correlates of anosognosia in the prodromal stage of AD. Here, we used regional brain metabolism (resting state 18-F fluorodeoxyglucose positron emission tomography (FDG-PET)) to unravel the metabolic correlates of anosognosia in subjects with amnestic mild cognitive impairment (aMCI) and subsequently resting state functional magnetic resonance imaging (rs-fMRI) to investigate the intrinsic connectivity disruption between brain regions. Thirty-one subjects (mean age: 74.1; Clinical Dementia Rating (CDR) global score: 0.5) with aMCI, and 251 cognitively normal (CN) older adults (mean age: 73.3; CDR: 0) were included as a reference group for behavioral and FDG data. An anosognosia index was obtained by calculating a discrepancy score between subjective and objective memory scores. All subjects underwent FDG-PET for glucose metabolism measurement, and aMCI subjects underwent additional rs-fMRI for intrinsic connectivity measurement. Voxel-wise correlations between anosognosia and neuroimaging data were conducted in the aMCI subjects. Subjects with aMCI had significantly decreased memory awareness as compared to the CN older adults. Greater anosognosia in aMCI subjects was associated with reduced glucose metabolism in the posterior cingulate (PCC) cortices and hippocampus. Intrinsic connectivity analyses revealed a significant association between anosognosia and attenuated functional connectivity between the PCC seed region and orbitofrontal cortex (OFC) as well as bilateral inferior parietal lobes (IPL). These findings provide further evidence that implicates cortical midline structures and hippocampus in the awareness of memory deficits. Investigating neuroimaging changes that co-vary with memory awareness may improve our ability to identify the cause of anosognosia and ultimately increase our chances for its treatment. Keywords: Alzheimer's disease, Anosognosia, Awareness, Mild cognitive impairment, Magnetic resonance imaging, Positron emission tomography

Published
2017
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17. Decreased meta-memory is associated with early tauopathy in cognitively unimpaired older adults

Author

Patrizia Vannini, Federico d'Oleire Uquillas, Heidi I.L. Jacobs, Jorge Sepulcre, Jennifer Gatchel, Rebecca E. Amariglio, Bernard Hanseeuw, Kathryn V. Papp, Trey Hedden, Dorene M. Rentz, Alvaro Pascual-Leone, Keith A. Johnson, and Reisa. A. Sperling

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

The ability to accurately judge memory efficiency (meta-memory monitoring) for newly learned (episodic) information, is decreased in older adults and even worse in Alzheimer's disease (AD), whereas no differences have been found for semantic meta-memory. The pathological substrates of this phenomenon are poorly understood. Here, we examine the association between meta-memory monitoring for episodic and semantic information to the two major proteinopathies in AD: amyloid (Aβ) and tau pathology in a group of cognitively unimpaired older adults. All participants underwent multi-tracer PET and meta-memory monitoring was assessed using a feeling-of-knowing (FOK) task for non-famous (episodic) and famous (semantic) face-name pairs. Whole brain voxel-wise correlations between meta-memory and PET data were conducted (controlling for memory), as well as confirmatory region-of-interest analyses. Participants had reduced episodic FOK compared to semantic FOK. Decreased episodic FOK was related to tauopathy in the medial temporal lobe regions, including the entorhinal cortex and temporal pole, whereas decreased semantic FOK was related to increased tau in regions associated with the semantic knowledge network. No association was found with Aβ-pathology. Alterations in the ability to accurately judge memory efficiency (in the absence of memory decline) may be a sensitive clinical indicator of AD pathophysiology in the pre-symptomatic phase. Keywords: Alzheimer's disease, Amyloid, Feeling-of-knowing, Meta-memory, Tau

Published
2019
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18. Performance on the RI-48 Cued Recall Test Best Predicts Conversion to Dementia at the 5- and 10-Year Follow-Ups

Author

Bernard Hanseeuw and Adrian Ivanoiu

Subjects
Alzheimerߣs disease, Encoding specificity, Follow-up study, Mild cognitive impairment, RI-48 cued recall test, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Background: TheRI-48 cued recall test was devised to discriminate between healthy elderly and patients with mild cognitive impairment who are at risk of developing Alzheimer’s disease (AD). However, no long-term follow-up studies have been conducted using this test. Methods: We analyzed the predictive power of the RI-48 test for determining the patients who will convert to AD dementia within the decade after testing. During 10 years, we followed up 40 non-demented patients who attended our Memory Clinic and underwent complete neuropsychological evaluation including the RI-48. Results: Of the 40 patients, 21 developed dementia (converters, CO) and 19 remained stable patients (SP). Of the tests performed at inclusion, only the RI-48 (p Conclusion: The RI-48 had the best overall diagnostic accuracy at 5- and at 10-year follow-ups.

Published
2011
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21. The Amyloid Imaging for the Prevention of Alzheimer's Disease Consortium: A European collaboration with a global impact

Author

Lyduine Collij, Gill Farrar, David Valléz García, Ilona Bader, Mahnaz Shekari, Luigi Lorenzini, Hugh Pemberton, Daniele Altomare, Sandra Pla, Mery Loor, Pawel Markiewicz, Maqsood Yaqub, Christopher Buckley, Giovanni B. Frisoni, Agneta Nordberg, Pierre Payoux, Andrew Stephens, Rossella Gismondi, Pieter Jelle Visser, Lisa Ford, Mark Schmidt, Cindy Birck, Jean Georges, Anja Mett, Zuzana Walker, Mercé Boada, Alexander Drzezga, Rik Vandenberghe, Bernard Hanseeuw, Frank Jessen, Michael Schöll, Craig Ritchie, Isadora Lopes Alves, Juan Domingo Gispert, Frederik Barkhof, and on behalf of the AMYPAD consortium

Subjects
diagnosis, amyloid, consortium, positron emission tomography (PET), prognosis, Alzheimer's disease
Abstract

Background: Amyloid-β (Aβ) accumulation is considered the earliest pathological change in Alzheimer’s disease (AD). The Amyloid Imaging to Prevent Alzheimer’s Disease (AMYPAD) consortium is a collaborative European framework across European Federation of Pharmaceutical Industries Associations (EFPIA), academic, and ‘Small and Medium-sized enterprises’ (SME) partners aiming to provide evidence on the clinical utility and cost-effectiveness of Positron Emission Tomography (PET) imaging in diagnostic work-up of AD and to support clinical trial design by developing optimal quantitative methodology in an early AD population. The AMYPAD studies: In the Diagnostic and Patient Management Study (DPMS), 844 participants from eight centres across three clinical subgroups (245 subjective cognitive decline, 342 mild cognitive impairment, and 258 dementia) were included. The Prognostic and Natural History Study (PNHS) recruited pre-dementia subjects across 11 European parent cohorts (PCs). Approximately 1600 unique subjects with historical and prospective data were collected within this study. PET acquisition with [18F]flutemetamol or [18F]florbetaben radiotracers was performed and quantified using the Centiloid (CL) method. Results: AMYPAD has significantly contributed to the AD field by furthering our understanding of amyloid deposition in the brain and the optimal methodology to measure this process. Main contributions so far include the validation of the dual-time window acquisition protocol to derive the fully quantitative non-displaceable binding potential (BPND), assess the value of this metric in the context of clinical trials, improve PET-sensitivity to emerging Aβ burden and utilize its available regional information, establish the quantitative accuracy of the Centiloid method across tracers and support implementation of quantitative amyloid-PET measures in the clinical routine. Future steps: The AMYPAD consortium has succeeded in recruiting and following a large number of prospective subjects and setting up a collaborative framework to integrate data across European PCs. Efforts are currently ongoing in collaboration with ARIDHIA and ADDI to harmonize, integrate, and curate all available clinical data from the PNHS PCs, which will become openly accessible to the wider scientific community.

Published
2023

22. Specific post-translational modifications of the soluble tau protein distinguish between Alzheimer’s disease, 4R-, and 3R-tauopathies

Author

Nathalie Kyalu Ngoie Zola, Clémence Balty, Sébastien Pyr dit Ruys, Axelle Vanparys, Nicolas Huyghe, Gaëtan Herinckx, Manuel Johanns, Emilien Boyer, Pascal Kienlen-Campard, Mark Rider, Didier Vertommen, and Bernard Hanseeuw

Abstract

The tau protein aggregates in several neurodegenerative disorders, referred to as tauopathies. The type of tau isoforms (4R/3R) observed in brain aggregates is used to classify tauopathies. However, distinguishing tauopathies in cerebrospinal fluid remains challenging. Here, we demonstrated that the difference in tau isoforms between tauopathies is only observed in aggregates, not in soluble brain extracts. We therefore used untargeted mass spectrometry to characterize all post-translational modifications of both the aggregated and the soluble tau protein obtained from human brain tissue of patients with Alzheimer’s disease, cortico-basal degeneration, Pick’s disease, and fronto-temporal lobe degeneration. We found specific soluble signatures predictive of each tauopathy and its peculiar type of aggregated tau isoforms. These findings provide potential targets for developing cerebrospinal fluid assays able to distinguish between tauopathies in vivo. The comparison between soluble and aggregated tau features indicates potential mechanisms of tau aggregation, providing novel therapeutic leads for these diseases.

Published
2022

23. Longitudinal hippocampal atrophy is associated with cognitive decline independently of amyloid and tau in neocortex

Author

Bernard Hanseeuw, Heidi I.L. Jacobs, Aaron P Schultz, Rachel F. Buckley, Michael J Properzi, Alex Becker, Michelle E. Farrell, Justin S Sanchez, Kathryn V. Papp, Hyun‐Sik Yang, Jasmeer P. Chhatwal, Julie C Price, Georges El Fakhri, Dorene M. Rentz, Reisa A. Sperling, and Keith A. Johnson

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022

24. Lower in‐vivo locus coeruleus integrity is associated with lower cortical thickness in older individuals with elevated Alzheimer’s pathology

Author

Nina Engels, Stephanie Hsieh, Christoph Schneider, Prokopis C. Prokopiou, Aaron P. Schultz, Joost M. Riphagen, Elouise A. Koops, Bernard Hanseeuw, Dorene M. Rentz, Reisa A. Sperling, Keith A. Johnson, and Heidi I.L. Jacobs

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022

25. The role of cortical microstructural changes on longitudinal accumulation of tau and cognitive decline in at risk older adults

Author

Geoffroy Pierre Gagliardi, Elena Rodriguez‐Vieitez, Victor Montal, Jorge Sepulcre, Ibai Palacio Diez, Cristina Lois, Bernard Hanseeuw, Aaron P. Schultz, Michael J Properzi, Kathryn V. Papp, Gad A Marshall, Juan Fortea, Keith A. Johnson, Reisa A. Sperling, and Patrizia Vannini

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022

26. Developing early vulnerable area aggregates for PET detection of beta‐amyloid based on young and middle‐aged adults from the Framingham Heart Study

Author

Emma G. Thibault, Michelle E. Farrell, Alexa S Beiser, Alex Becker, Claudia L Satizabal, Heidi I.L. Jacobs, Charles S. DeCarli, Bernard Hanseeuw, Ronald J Killiany, Reisa A. Sperling, Sudha Seshadri, and Keith A. Johnson

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022

27. A longitudinal analysis of depressive symptoms in relation to repeated measurements of regional tau

Author

Catherine E Munro, Rachel F. Buckley, Patrizia Vannini, Bernard Hanseeuw, Yakeel T. Quiroz, Michelle E. Farrell, Dorene M. Rentz, Deborah Blacker, Reisa A. Sperling, Keith A. Johnson, Rebecca E. Amariglio, Gad A Marshall, and Jennifer R Gatchel

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2022

28. Mechanism of Cellular Formation and In Vivo Seeding Effects of Hexameric β-Amyloid Assemblies

Author

Loïc Quinton, Ludovic D'Auria, Vincent Van Pesch, Nuria Suelves, Céline Vrancx, Bernard Hanseeuw, Pascal Kienlen-Campard, Devkee M. Vadukul, Florian Perrin, and Sabrina Contino

Subjects
Aβ oligomers, GAMMA-SECRETASE, A-BETA-40, Seeding, Peptide, Plaque, Amyloid, Hexameric A beta, NEURON LOSS, Mice, SYNAPTIC PLASTICITY, Senile plaques, chemistry.chemical_classification, Neurons, A beta oligomers, Presenilins, Brain, Alzheimer's disease, ALZHEIMERS-DISEASE, Neurology, Cellular model, Life Sciences & Biomedicine, Alzheimer’s disease, Genetically modified mouse, PRESENILIN-1, FAD model, Neuroscience (miscellaneous), Context (language use), Mice, Transgenic, CHO Cells, PROTEIN A-BETA, Presenilin, Article, Cellular and Molecular Neuroscience, Cricetulus, In vivo, Alzheimer Disease, Cell Line, Tumor, Animals, Humans, Hexameric Aβ, Science & Technology, Amyloid beta-Peptides, Neurosciences, AGGREGATION, Fibroblasts, TRANSMEMBRANE DOMAIN, In vitro, PATHOLOGY, chemistry, Biophysics, Neurosciences & Neurology
Abstract

The β-amyloid peptide (Aβ) is the main constituent of senile plaques, a typical hallmark of Alzheimer’s disease (AD). Monomeric Aβ is generated through sequential processing of the amyloid precursor protein (APP), with a final step involving γ-secretase activity. In AD, Aβ monomers assemble in oligomers and ultimately fibrils depositing in plaques. Importantly, Aβ toxicity appears related to its soluble oligomeric intermediates. In particular, recombinant Aβ studies described Aβ hexamers as critical oligomeric nuclei. We recently identified hexameric Aβ assemblies in a cellular model, and revealed their ability to enhance recombinant Aβ aggregation in vitro. Here, we assessed the contribution of similar hexameric-like Aβ assemblies to the development of amyloid pathology. We report their early presence in both transgenic mice brains exhibiting human Aβ pathology and cerebrospinal fluid of AD patients, suggesting hexameric Aβ as a putative novel AD biomarker. Using isolated cell-derived hexameric Aβ, we report the potential of these assemblies to seed other human Aβ species, resulting in neuronal toxicity in vitro and amyloid deposition aggravation in vivo. In order to identify key contributors to their formation in a cellular context, we investigated the role of presenilin-1 (PS1) and presenilin-2 (PS2) in the formation of hexameric-like Aβ assemblies. As catalytic subunits of the γ-secretase complex, PS1 and PS2 can differentially participate in Aβ generation. Using CRISPR-Cas9-modified neuronal-like cell lines knockdown for each of the two presenilins, we present experimental evidence suggesting a direct link between the PS2-dependent pathway and the release of hexameric-like Aβ assemblies in extracellular vesicles.

Published
2021

29. Diagnostic Performance of Automated MRI Volumetry by icobrain dm for Alzheimer’s Disease in a Clinical Setting: A REMEMBER Study

Author

Gaëtane Picard, Jos Tournoy, Eric Mormont, Hanne Struyfs, Eric Triau, Sebastiaan Engelborghs, Annemie Ribbens, Maria Bjerke, Jean Christophe Bier, Erik Fransen, Peter Paul De Deyn, Evert Thiery, Olivier Deryck, Mandy Melissa Jane Wittens, Ruben Houbrechts, Anne Sieben, Jan Versijpt, Christine Bastin, Eric Salmon, Kurt Segers, Adrian Ivanoiu, Bruno Bergmans, Diana M. Sima, Ellis Niemantsverdriet, Bernard Hanseeuw, Florence Benoit, Anne-Marie Vanbinst, Dirk Smeets, Ezequiel de la Rosa, Jean-Claude Lemper, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (MGD) Service de neurologie, UCL - (SLuc) Service de neurologie, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, Geriatrics, Medicine and Pharmacy academic/administration, Supporting clinical sciences, Radiology, and Clinical Biology

Subjects
NATIONAL INSTITUTE, 0301 basic medicine, Male, PREDICTION, Diagnostic accuracy, Disease, GUIDELINES, Hippocampus, RECOMMENDATIONS, Lateral ventricles, 0302 clinical medicine, MARKERS, Image Processing, Computer-Assisted, magnetic resonance imaging, Cognitive decline, Cognitive impairment, medicine.diagnostic_test, General Neuroscience, Brain, General Medicine, Alzheimer's disease, Magnetic Resonance Imaging, Psychiatry and Mental health, Clinical Psychology, ASYMMETRY, Female, Radiology, ASSOCIATION WORKGROUPS, Life Sciences & Biomedicine, Alzheimer’s disease, Research Article, medicine.medical_specialty, HIPPOCAMPAL SEGMENTATION, Imaging data, 03 medical and health sciences, mild cognitive impairment, Alzheimer Disease, medicine, Dementia, Humans, Cognitive Dysfunction, Biology, Aged, Retrospective Studies, Science & Technology, business.industry, neurology, Neurosciences, biomarkers, Magnetic resonance imaging, medicine.disease, automated volumetry, CONVERSION, 030104 developmental biology, Neurosciences & Neurology, Human medicine, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Software
Abstract

BACKGROUND: Magnetic resonance imaging (MRI) has become important in the diagnostic work-up of neurodegenerative diseases. icobrain dm, a CE-labeled and FDA-cleared automated brain volumetry software, has shown potential in differentiating cognitively healthy controls (HC) from Alzheimer's disease (AD) dementia (ADD) patients in selected research cohorts. OBJECTIVE: This study examines the diagnostic value of icobrain dm for AD in routine clinical practice, including a comparison to the widely used FreeSurfer software, and investigates if combined brain volumes contribute to establish an AD diagnosis. METHODS: The study population included HC (n = 90), subjective cognitive decline (SCD, n = 93), mild cognitive impairment (MCI, n = 357), and ADD (n = 280) patients. Through automated volumetric analyses of global, cortical, and subcortical brain structures on clinical brain MRI T1w (n = 820) images from a retrospective, multi-center study (REMEMBER), icobrain dm's (v.4.4.0) ability to differentiate disease stages via ROC analysis was compared to FreeSurfer (v.6.0). Stepwise backward regression models were constructed to investigate if combined brain volumes can differentiate between AD stages. RESULTS: icobrain dm outperformed FreeSurfer in processing time (15-30 min versus 9-32 h), robustness (0 versus 67 failures), and diagnostic performance for whole brain, hippocampal volumes, and lateral ventricles between HC and ADD patients. Stepwise backward regression showed improved diagnostic accuracy for pairwise group differentiations, with highest performance obtained for distinguishing HC from ADD (AUC = 0.914; Specificity 83.0%; Sensitivity 86.3%). CONCLUSION: Automated volumetry has a diagnostic value for ADD diagnosis in routine clinical practice. Our findings indicate that combined brain volumes improve diagnostic accuracy, using real-world imaging data from a clinical setting. ispartof: JOURNAL OF ALZHEIMERS DISEASE vol:83 issue:2 pages:623-639 ispartof: location:Netherlands status: published

Published
2021

30. Default-Mode Network Connectivity Changes During the Progression Toward Alzheimer's Dementia: A Longitudinal Functional Magnetic Resonance Imaging Study

Author

Vincent Malotaux, Laurence Dricot, Lisa Quenon, Renaud Lhommel, Adrian Ivanoiu, Bernard Hanseeuw, and UCL - SSS/IONS/NEUR - Clinical Neuroscience

Subjects
General Neuroscience
Abstract

Background/Purpose: Brain function changes with Alzheimer’s disease (AD) progression. Evaluating those changes longitudinally is important to understand the complex relationships between brain pathologies and cognition. We aimed (1) to identify longitudinal changes in functional connectivity in patients with mild cognitive impairment (MCI) characterized for amyloid-b (Ab) status and (2) to relate these functional changes to clinical progression. Methods: Forty-four patients with MCI were followed using serial functional magnetic resonance imaging (fMRI) over 1.2 years (three sessions) and cognitive testing over 3.1 years (five sessions). Intra and inter-network connectivities were computed to assess changes in brain connectivity using a network atlas adapted for late adulthood. Sixteen low-Ab clinically normal older adults underwent a single fMRI session for group comparisons at baseline. Linear mixed-effects models with random intercept and slope were used to predict changes in connectivity based on Ab status and progression to dementia. Results: At baseline, intra and inter-network resting-state fMRI connectivities did not differ by baseline clinical diagnosis, Ab status, or clinical progression to dementia. At the final imaging session, progressive MCI had significantly higher connectivity compared with stable MCI, specifically within the default-mode network (DMN). Longitudinally, progressive MCI had increasing intra-DMN connectivity over time compared with stable MCI, and the rate of changes in connectivity was significantly associated with the rate of cognitive decline. Conclusions: Intra-DMN connectivity increases in MCI patients progressing toward dementia, suggesting aberrant synchronization in the symptomatic stages of AD.

Published
2022

31. Pathological correlates of impaired self-awareness of memory function in Alzheimer’s disease

Author

Patrizia Vannini, Cristina Lois, Bernard Hanseeuw, Geoffroy Gagliardi, Madeline Kuppe, UCL - SSS/IONS/NEUR - Clinical Neuroscience, and UCL - (SLuc) Service de neurologie

Subjects
0301 basic medicine, medicine.medical_specialty, Amyloid, Neurology, Cognitive Neuroscience, tau Proteins, Neurosciences. Biological psychiatry. Neuropsychiatry, Disease, Audiology, Logical address, 03 medical and health sciences, 0302 clinical medicine, Cognition, Alzheimer Disease, medicine, Humans, Cognitive Dysfunction, RC346-429, Pathological, Amyloid beta-Peptides, business.industry, Amyloidosis, Anosognosia, Research, Awareness, medicine.disease, Temporal Lobe, 030104 developmental biology, Tauopathies, Positron-Emission Tomography, Neurology (clinical), Tauopathy, Neurology. Diseases of the nervous system, Tau, business, Alzheimer’s disease, 030217 neurology & neurosurgery, RC321-571
Abstract

Introduction Impaired self-awareness of memory function, a.k.a. anosognosia, is a common symptom in Alzheimer’s disease (AD); however, its pathological correlates remain unclear. Here, we investigated the impact of amyloid and tau on memory self-awareness. Methods Two hundred thirty-six clinically normal (N) and 102 impaired (I) participants from the ADNI cohort were included. Amyloid (global) and tau burden (in entorhinal and inferior temporal cortices) were assessed using positron emission tomography (PET). Self-awareness of memory was assessed using discrepancy indexes of subjective participant-informant ratings, as well as participant-objective scores of memory performance. Subjective and objective values were derived from the Everyday Cognition memory questionnaire and Logical Memory (delayed recall). Results Lower awareness (both methods) of memory function was associated with higher levels of pathology in the I group as compared to N. There was a significant effect of tauopathy, but not amyloidosis, on individual complaint, such that higher levels of tau associated with lower awareness. Discussion Impaired self-awareness appears progressively in the evolution of the disease related to AD biomarkers. Discordant subjective and objective measures may be important for clinical consideration.

Published
2021

32. Alzheimer disease's cerebrospinal fluid biomarkers differences between immigrants and natives in a Belgian memory clinic

Author

Louisien Lebrun, Bernard Hanseeuw, Vincent van Pesch, Adrian Ivanoiu, and UCL - SSS/IONS/NEUR - Clinical Neuroscience

Subjects
Neurology (clinical), General Medicine
Abstract

Background Diagnosis of neurodegenerative diseases can raise difficulties among immigrant patients due to language, educational or sociocultural differences with natives. CSF biomarkers of Alzheimer’s disease are useful tools to early diagnose neurodegeneration. Yet very few studies have investigated differences of those biomarkers between immigrant and native populations. Objective We aimed to characterize differences between CSF biomarkers of Alzheimer’s disease within Belgian native and immigrant patients analyzed at Saint Luc Neurochemistry Lab (Brussels, Belgium). Methods CSF samples from patients consulting at Saint Luc Memory Clinic (n = 356) or at others hospitals (n = 2430) were analyzed by Saint Luc Neurochemistry Lab between 2010 and 2014. We conducted linear regressions predicting CSF biomarkers with demographic data: age, sex and presumed ethnic origin. For the last one, we subdivided the cohort in natives and immigrants according to their surnames. Results Immigrant patients benefit from a CSF sample analysis at a younger age than natives (p < 0.001). After linear regressions, age showed a significant impact on all biomarkers (p < 0.005). Ethnicity showed a significant impact on T-Tau (p = 0.007) and on T-Tau/amyloid-β42 ratio (p = 0.009). Sex showed a significant impact on T-Tau (p = 0.002). ANCOVA analysis suggested that the effect of Age on Aβ42 manifests differently according to the ethnicity of the individual. Conclusion This study shows higher T-Tau and T-Tau/amyloid-β42 ratio values in younger native patients from a Belgian Memory Clinic. Aβ42 values tend to follow a different dynamic in time according to the ethnic origin of patients, with pathological values at older ages in immigrants.

Published
2022

33. A multisite analysis of the concordance between visual image interpretation and quantitative analysis of [18F]flutemetamol amyloid PET images

Author

Renaud Lhommel, Alex Whittington, Cyrille Sur, José Luis Molinuevo, Vincent Dore, Irina Savitcheva, Juan Domingo Gispert, Bernard Hanseeuw, Gill Farrar, Christopher C. Rowe, Gemma Salvadó, Lyduine E. Collij, Mahnaz Shekari, Agneta Nordberg, Christopher Buckley, Roger N. Gunn, Marco Bucci, and Oskar Hansson

Subjects
medicine.diagnostic_test, business.industry, Concordance, Amyloid pet, General Medicine, medicine.disease, [18F]flutemetamol, Visual inspection, Image interpretation, Amyloid PET, Positron emission tomography, Quantification, Equating, medicine, Radiology, Nuclear Medicine and imaging, Medical diagnosis, Alzheimer's disease, Nuclear medicine, business, Alzheimer’s disease, Quantitative analysis (chemistry), Emission computed tomography
Abstract

Background [18F]flutemetamol PET scanning provides information on brain amyloid load and has been approved for routine clinical use based upon visual interpretation as either negative (equating to none or sparse amyloid plaques) or amyloid positive (equating to moderate or frequent plaques). Quantitation is however fundamental to the practice of nuclear medicine and hence can be used to supplement amyloid reading methodology especially in unclear cases. Methods A total of 2770 [18F]flutemetamol images were collected from 3 clinical studies and 6 research cohorts with available visual reading of [18F]flutemetamol and quantitative analysis of images. These were assessed further to examine both the discordance and concordance between visual and quantitative imaging primarily using thresholds robustly established using pathology as the standard of truth. Scans covered a wide range of cases (i.e. from cognitively unimpaired subjects to patients attending the memory clinics). Methods of quantifying amyloid ranged from using CE/510K cleared marked software (e.g. CortexID, Brass), to other research-based methods (e.g. PMOD, CapAIBL). Additionally, the clinical follow-up of two types of discordance between visual and quantitation (V+Q- and V-Q+) was examined with competing risk regression analysis to assess possible differences in prediction for progression to Alzheimer’s disease (AD) and other diagnoses (OD). Results Weighted mean concordance between visual and quantitation using the autopsy-derived threshold was 94% using pons as the reference region. Concordance from a sensitivity analysis which assessed the maximum agreement for each cohort using a range of cut-off values was also estimated at approximately 96% (weighted mean). Agreement was generally higher in clinical cases compared to research cases. V-Q+ discordant cases were 11% more likely to progress to AD than V+Q- for the SUVr with pons as reference region. Conclusions Quantitation of amyloid PET shows a high agreement vs binary visual reading and also allows for a continuous measure that, in conjunction with possible discordant analysis, could be used in the future to identify possible earlier pathological deposition as well as monitor disease progression and treatment effectiveness.

Published
2021

34. Biomarker counseling, disclosure of diagnosis and follow‐up in patients with mild cognitive impairment: A European Alzheimer's disease consortium survey

Author

Mathieu Ceccaldi, Timo Grimmer, Vesna Jelic, Luiza Spiru, Pierre Jean Ousset, Stephanie Sloan, Marcel G. M. Olde Rikkert, Isabel Santana, Sebastiaan Engelborghs, Bruno Dubois, Milica G. Kramberger, David Robinson, Lucrezia Hausner, Latchezar Traykov, Mercè Boada, Robert Perneczky, Gunhild Waldemar, Alberto Lleó, Elisabet Sánchez, Thomas R. Nielsen, Tomasz Gabryelewicz, Olivier Rouaud, Nikolaos Scarmeas, Alexandre de Mendonça, Jacques Hugon, Kristian Steen Frederiksen, Bernard Hanseeuw, Lutz Frölich, Flavio Nobili, Görsev Yener, Mario Riverol, Ildebrando Appollonio, Audrey Gabelle, Birgitte Bo Andersen, Elka Stefanova, Katerina Sheardova, Jakub Hort, Anne M Koivisto, Thibaud Lebouvier, Clinical sciences, Neuroprotection & Neuromodulation, Neurology, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Frederiksen, K, Nielsen, T, Appollonio, I, Andersen, B, Riverol, M, Boada, M, Ceccaldi, M, Dubois, B, Engelborghs, S, Frolich, L, Hausner, L, Gabelle, A, Gabryelewicz, T, Grimmer, T, Hanseeuw, B, Hort, J, Hugon, J, Jelic, V, Koivisto, A, Kramberger, M, Lebouvier, T, Lleo, A, de Mendonca, A, Nobili, F, Ousset, P, Perneczky, R, Olde Rikkert, M, Robinson, D, Rouaud, O, Sanchez, E, Santana, I, Scarmeas, N, Sheardova, K, Sloan, S, Spiru, L, Stefanova, E, Traykov, L, Yener, G, Waldemar, G, University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), Universitat Internacional de Catalunya [Barcelona] (UIC), Instituto de Salud Carlos III [Madrid] (ISC), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Antwerp (UA), Vrije Universiteit Brussel (VUB), Heidelberg University, Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Mossakowski Medical Research Centre (CMDIK), Polska Akademia Nauk = Polish Academy of Sciences (PAN), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Université Catholique de Louvain = Catholic University of Louvain (UCL), University Hospital Motol [Prague], Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Karolinska University Hospital [Stockholm], University of Eastern Finland, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of Ljubljana, Université de Lille, Hospital de la Santa Creu i Sant Pau, Universidade de Lisboa = University of Lisbon (ULISBOA), Università degli studi di Genova = University of Genoa (UniGe), IRCCS Ospedale Policlinico San Martino [Genoa, Italy], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Ludwig-Maximilians University [Munich] (LMU), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Imperial College London, Radboud University Medical Center [Nijmegen], St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Hospital Universitario Ramón y Cajal [Madrid], Universidad de Alcalá - University of Alcalá (UAH), University of Coimbra [Portugal] (UC), National and Kapodistrian University of Athens (NKUA), Columbia University Irving Medical Center (CUIMC), St. Anne’s University Hospital [Brno], Ninewells Hospital and Medical School [Dundee], University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), University of Belgrade [Belgrade], and Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ)

Subjects
Counseling, Advance care planning, Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1], diagnosis, Disease, 0302 clinical medicine, Medicine, 030212 general & internal medicine, survey experiment, Cognitive decline, Cognitive impairment, Response rate (survey), diagnosis [Alzheimer Disease], Alzheimer's disease, 3. Good health, Europe, diagnosi, Psychiatry and Mental health, Disease Progression, biomarker, Biomarker (medicine), biomarker counseling, biomarkers, dementia, diagnostic disclosure, mild cognitive impairment, survey, medicine.medical_specialty, Referral, Neuroscience(all), Clinical Neurology, Disclosure, Sensitivity and Specificity, 03 medical and health sciences, Alzheimer Disease, Humans, Dementia, Cognitive Dysfunction, ddc:610, MED/26 - NEUROLOGIA, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, medicine.disease, diagnosis [Cognitive Dysfunction], Family medicine, Human medicine, Geriatrics and Gerontology, business, Biomarkers, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Contains fulltext : 231797.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Mild cognitive impairment (MCI) is associated with an increased risk of further cognitive decline, partly depending on demographics and biomarker status. The aim of the present study was to survey the clinical practices of physicians in terms of biomarker counseling, management, and follow-up in European expert centers diagnosing patients with MCI. METHODS: An online email survey was distributed to physicians affiliated with European Alzheimer's disease Consortium centers (Northern Europe: 10 centers; Eastern and Central Europe: 9 centers; and Southern Europe: 15 centers) with questions on attitudes toward biomarkers and biomarker counseling in MCI and dementia. This included postbiomarker counseling and the process of diagnostic disclosure of MCI, as well as treatment and follow-up in MCI. RESULTS: The response rate for the survey was 80.9% (34 of 42 centers) across 20 countries. A large majority of physicians had access to biomarkers and found them useful. Pre- and postbiomarker counseling varied across centers, as did practices for referral to support groups and advice on preventive strategies. Less than half reported discussing driving and advance care planning with patients with MCI. CONCLUSIONS: The variability in clinical practices across centers calls for better biomarker counseling and better training to improve communication skills. Future initiatives should address the importance of communicating preventive strategies and advance planning.

Published
2020

35. The presubiculumlinks incipient amyloid and tau pathology to memory function in older persons

Author

Rebecca E. Amariglio, Jean C. Augustinack, Aaron P. Schultz, Dorene M. Rentz, Keith A. Johnson, Reisa A. Sperling, Heidi I.L. Jacobs, Joseph J. Locascio, Kathryn V. Papp, Bernard Hanseeuw, Psychiatrie & Neuropsychologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, and UCL - (SLuc) Service de neurologie

Subjects
Male, 0301 basic medicine, Aging, Amyloid, Clinical Dementia Rating, Clinical Neurology, Amyloidogenic Proteins, tau Proteins, Hippocampal formation, Hippocampus, SURFACE-BASED ANALYSIS, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Alzheimer Disease, Memory, mental disorders, medicine, Humans, Aging brain, HIPPOCAMPAL SUBFIELDS, ENTORHINAL CORTEX, IN-VIVO, Aged, Aged, 80 and over, medicine.diagnostic_test, business.industry, Neurodegeneration, medicine.disease, HUMAN BRAIN, Magnetic Resonance Imaging, ALZHEIMERS-DISEASE, EX-VIVO, 030104 developmental biology, chemistry, Positron emission tomography, Positron-Emission Tomography, PARAHIPPOCAMPAL SUBREGIONS, Parahippocampal Gyrus, Female, Neurology (clinical), Alzheimer's disease, business, Pittsburgh compound B, Neuroscience, 030217 neurology & neurosurgery, BETA-PROTEIN, PERFORANT PATHWAY
Abstract

ObjectiveTo identify the hippocampal subregions linking initial amyloid and tau pathology to memory performance in clinically normal older individuals, reflecting preclinical Alzheimer disease (AD).MethodsA total of 127 individuals from the Harvard Aging Brain Study (mean age 76.22 ± 6.42 years, 68 women [53.5%]) with a Clinical Dementia Rating score of 0, a flortaucipir tau-PET scan, a Pittsburgh compound B amyloid-PET scan, a structural MRI scan, and cognitive testing were included. From these images, we calculated neocortical, hippocampal, and entorhinal amyloid pathology; entorhinal and hippocampal tau pathology; and the volumes of 6 hippocampal subregions and total hippocampal volume. Memory was assessed with the selective reminding test. Mediation and moderation analyses modeled associations between regional markers and memory. Analyses included covariates for age, sex, and education.ResultsNeocortical amyloid, entorhinal tau, and presubiculum volume univariately associated with memory performance. The relationship between neocortical amyloid and memory was mediated by entorhinal tau and presubiculum volume, which was modified by hippocampal amyloid burden. With other biomarkers held constant, presubiculum volume was the only marker predicting memory performance in the total sample and in individuals with elevated hippocampal amyloid burden.ConclusionsThe presubiculum captures unique AD-related biological variation that is not reflected in total hippocampal volume. Presubiculum volume may be a promising marker of imminent memory problems and can contribute to understanding the interaction between incipient AD-related pathologies and memory performance. The modulation by hippocampal amyloid suggests that amyloid is a necessary, but not sufficient, process to drive neurodegeneration in memory-related regions.

Published
2020

36. Interdisciplinary and Transdisciplinary Perspectives: On the Road to a Holistic Approach to Dementia Prevention and Care

Author

Jonathan D. Jackson, Caitlin Ware, Bernard Hanseeuw, Francisca S Rodriguez Then, Rebekah Churchyard, UCL - SSS/IONS/NEUR - Clinical Neuroscience, and UCL - (SLuc) Service de neurologie

Subjects
Cognitive Symptoms, treatment, General Neuroscience, Treatment process, Human science, Review, Disease, Alzheimer’s disease, dementia, interdisciplinary, research methods, medicine.disease, Psychiatry and Mental health, Clinical Psychology, Field experience, Multidisciplinary approach, medicine, Dementia, Engineering ethics, ddc:610, Geriatrics and Gerontology, Psychology, Discipline
Abstract

Dementia, of which the most frequent form is Alzheimer's disease, is a chronic and terminal condition with multi-factorial causes and numerous consequences on a patient's life. Combining perspectives from different disciplines seems necessary for unraveling dementia's entangled issues. Current dementia management is a multidisciplinary effort; however, integrating different disciplines as a holistic treatment process is often hindered due to different responsibilities, various conceptual approaches, and distinctive research methods. With this paper, we raise some of the challenges that need to be addressed in order to initiate an interdisciplinary or even transdisciplinary research agenda. We also outline recommendations on how to integrate multiple disciplinary perspectives in dementia care and research. We see opportunities for young investigators to draw from different fields of research in dementia as their research focus is still developing. By establishing common objectives with investigators from other fields, we can pursue the goal of improving treatment and care as a team-meaning accomplishing different tasks but sharing a common purpose. It is necessary to address the communication between fields that limits the understanding of connections between cognitive symptoms, biological processes, treatment, lifestyle, and care giving in order to reach the aim of developing a holistic, person-centered, patient-first approach. Associating biomedical research to field experience from care professionals and the study of human science will promote a more independent, social, and sustainable lifestyle for people with dementia.

Published
2020

37. Sequential early cognitive changes sensitive to rising beta‐amyloid and tau pathology in preclinical AD

Author

Michelle E. Farrell, Kate V. Papp, Rachel F. Buckley, Heidi I.L. Jacobs, Aaron P Schultz, Michael J Properzi, Patrizia Vannini, Bernard Hanseeuw, Dorene M. Rentz, Keith A. Johnson, and Reisa A. Sperling

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2021

38. Longitudinal associations between amyloid and tau‐PET: Impact for prevention trials

Author

Bernard Hanseeuw, Heidi I.L. Jacobs, Alex Becker, Rachel F. Buckley, Michael J. Properzi, Michelle E. Farrell, Aaron P. Schultz, Justin S. Sanchez, Jasmeer P. Chhatwal, Julie C. Price, Reisa A. Sperling, and Keith A. Johnson

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published
2021

39. Premature termination codon mutations in ABCA7 contribute to Alzheimer's disease risk in Belgian patients

Author

Peter Paul De Deyn, Sebastiaan Engelborghs, Liene Bossaerts, Patrick Cras, Bernard Hanseeuw, Christine Van Broeckhoven, Rik Vandenberghe, Elisabeth Hens, Neurology, Clinical sciences, Neuroprotection & Neuromodulation, and BELNEU Consortium

Subjects
0301 basic medicine, Oncology, NATIONAL INSTITUTE, Male, Aging, Geriatrics & Gerontology, endocrine system diseases, Disease, CD2AP, medicine.disease_cause, ABCA7, 0302 clinical medicine, Belgium, Loss of Function Mutation, ASSOCIATION GUIDELINES, Medicine, Family history, PTC mutations, Aged, 80 and over, Mutation, education.field_of_study, biology, General Neuroscience, COMMON VARIANTS, Premature termination codon, Middle Aged, Alzheimer's disease, Cohort, Female, EPHA1, Life Sciences & Biomedicine, Risk, medicine.medical_specialty, NEUROPATHOLOGIC ASSESSMENT, Population, Loss-of function, DIAGNOSIS, APOLIPOPROTEIN-E, MECHANISMS, 03 medical and health sciences, Alzheimer Disease, Internal medicine, Humans, education, Codon, Gene, Genetic association, Aged, Science & Technology, business.industry, neurology, Neurosciences, 030104 developmental biology, biology.protein, ATP-Binding Cassette Transporters, Neurology (clinical), Neurosciences & Neurology, Human medicine, Geriatrics and Gerontology, CD33, business, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

The ATP-Binding Cassette Subfamily A Member 7 gene (ABCA7) was identified as a risk gene for Alzheimer's disease (AD) in genome-wide association studies of large cohorts of late-onset AD (LOAD) patients. Extended resequencing of the ABCA7 coding regions identified mutations that lead to premature termination codons (PTC) and loss of function of ABCA7. PTC mutations were enriched in LOAD patients and were frequently present in patients with early-onset AD (EOAD). We aimed at assessing the contribution of ABCA7 PTC mutations to AD in the Belgian population by screening the ABCA7 coding region in a Belgian AD cohort of 1376 patients, including LOAD and EOAD patients, and in a Belgian control cohort of 976 individuals. We identified a PTC mutation in 67 AD patients (4.9%) and in 18 control individuals (1.8%) confirming the enrichment of ABCA7 PTC mutations in Belgian AD patients. The patient carriers had a mean onset age of 69.7 ± 9.8 years with a wide onset age range of 42 years (48-90 years). In 77.3% of the families of ABCA7 carriers, there were AD patients present suggestive of a positive family history of disease, but a Mendelian co-segregation of ABCA7 PTC mutations with disease is not clear. Overall, our genetic data predict that PTC mutations in ABCA7 are common in the Belgian population and are present in LOAD and EOAD patients. ispartof: NEUROBIOLOGY OF AGING vol:106 ispartof: location:United States status: published

Published
2021

40. Pragmatic, Data-Driven Method to Determine Cutoffs for CSF Biomarkers of Alzheimer Disease Based on Validation Against PET Imaging

Author

Julien, Dumurgier, Séverine, Sabia, Henrik, Zetterberg, Charlotte, Teunissen, Bernard, Hanseeuw, Adelina, Orellana, Susanna, Schraen, Audrey, Gabelle, Mercè, Boada, Thibaud, Lebouvier, Eline A J, Willemse, Emmanuel, Cognat, Agustin, Ruiz, Claire, Hourregue, Matthieu, Lilamand, Elodie, Bouaziz-Amar, Jean-Louis, Laplanche, Sylvain, Lehmann, Florence, Pasquier, Philip, Scheltens, Kaj, Blennow, Archana, Singh-Manoux, Claire, Paquet, UCL - SSS/IONS/NEUR - Clinical Neuroscience, Laboratory Medicine, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Neuroinfection & -inflammation, and Neurology

Subjects
Male, Amyloid beta-Peptides, Alzheimer Disease, Positron-Emission Tomography, Humans, Female, tau Proteins, Neurology (clinical), Biomarkers, Peptide Fragments, Aged
Abstract

Background and ObjectivesTo elaborate a new algorithm to establish a standardized method to define cutoffs for CSF biomarkers of Alzheimer disease (AD) by validating the algorithm against CSF classification derived from PET imaging.MethodsLow and high levels of CSF phosphorylated tau were first identified to establish optimal cutoffs for CSF β-amyloid (Aβ) peptide biomarkers. These Aβ cutoffs were then used to determine cutoffs for CSF tau and phosphorylated tau markers. We compared this algorithm to a reference method, based on tau and amyloid PET imaging status (ADNI study), and then applied the algorithm to 10 large clinical cohorts of patients.ResultsA total of 6,922 patients with CSF biomarker data were included (mean [SD] age: 70.6 [8.5] years, 51.0% women). In the ADNI study population (n = 497), the agreement between classification based on our algorithm and the one based on amyloid/tau PET imaging was high, with Cohen's kappa coefficient between 0.87 and 0.99. Applying the algorithm to 10 large cohorts of patients (n = 6,425), the proportion of persons with AD ranged from 25.9% to 43.5%.DiscussionThe proposed novel, pragmatic method to determine CSF biomarker cutoffs for AD does not require assessment of other biomarkers or assumptions concerning the clinical diagnosis of patients. Use of this standardized algorithm is likely to reduce heterogeneity in AD classification.

Published
2021

42. Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Author

Götz Thomalla, Florent Boutitie, Henry Ma, Masatoshi Koga, Peter Ringleb, Lee H Schwamm, Ona Wu, Martin Bendszus, Christopher F Bladin, Bruce C V Campbell, Bastian Cheng, Leonid Churilov, Martin Ebinger, Matthias Endres, Jochen B Fiebach, Mayumi Fukuda-Doi, Manabu Inoue, Timothy J Kleinig, Lawrence L Latour, Robin Lemmens, Christopher R Levi, Didier Leys, Kaori Miwa, Carlos A Molina, Keith W Muir, Norbert Nighoghossian, Mark W Parsons, Salvador Pedraza, Peter D Schellinger, Stefan Schwab, Claus Z Simonsen, Shlee S Song, Vincent Thijs, Danilo Toni, Chung Y Hsu, Nils Wahlgren, Haruko Yamamoto, Nawaf Yassi, Sohei Yoshimura, Steven Warach, Werner Hacke, Kazunori Toyoda, Geoffrey A Donnan, Stephen M Davis, Christian Gerloff, Boris Raul Acosta, Karen Aegidius, Christian Albiker, Anna Alegiani, Miriam Almendrote, Angelika Alonso, Katharina Althaus, Pierre Amarenco, Hemasse Amiri, Bettina Anders, Adriana Aniculaesei, Jason Appleton, Juan Arenillas, Christina Back, Christian Bähr, Jürgen Bardutzky, Flore Baronnet-Chauvet, Rouven Bathe-Peters, Anna Bayer-Karpinska, Juan L. Becerra, Christoph Beck, Olga Belchí Guillamon, Amandine Benoit, Nadia Berhoune, Daniela Bindila, Julia Birchenall, Karine Blanc-Lasserre, Miguel Blanco Gonzales, Tobias Bobinger, Ulf Bodechtel, Eric Bodiguel, Urszula Bojaryn, Louise Bonnet, Benjamin Bouamra, Paul Bourgeois, Lorenz Breuer, Ludovic Breynaert, David Broughton, Raf Brouns, Sébastian Brugirard, Bart Bruneel, Florian Buggle, Serkan Cakmak, Ana Calleja, David Calvet, David Carrera, Hsin-Chieh Chen, Bharath Cheripelli, Tae-Hee Cho, Chi-un Choe, Lillian Choy, Hanne Christensen, Mareva Ciatipis, Geoffrey Cloud, Julien Cogez, Elisa Cortijo, Sophie Crozier, Dorte Damgaard, Krishna Dani, Beatrijs De Coene, Isabel De Hollander, Jacques De Keyser, Nina De Klippel, Charlotte De Maeseneire, Ann De Smedt, Maria del Mar Castellanos Rodrigo, Sandrine Deltour, Jelle Demeestere, Laurent Derex, Philippe Desfontaines, Ralf Dittrich, Anand Dixit, Laurens Dobbels, Valérie Domigo, Laura Dorado, Charlotte Druart, Kristina Hougaard Dupont, Anne Dusart, Rainer Dziewas, Matthias Ebner, Myriam Edjali-Goujon, Philipp Eisele, Salwa El Tawil, Ahmed Elhfnawy, Ana Etexberria, Nicholas Evans, Simon Fandler, Franz Fazekas, Sandra Felix, Jochen B. Fiebach, Jens Fiehler, Alexandra Filipov, Katharina Filipski, Robert Fleischmann, Christian Foerch, Ian Ford, Alexandra Gaenslen, Ivana Galinovic, Elena Meseguer Gancedo, Ramanan Ganeshan, Carlos García Esperón, Alicia Garrido, Thomas Gattringer, Olivia Geraghty, Rohat Geran, Stefan Gerner, Sylvie Godon-Hardy, Jos Göhler, Amir Golsari, Meritxell Gomis, David Gorriz, Verena Gramse, Laia Grau, Martin Griebe, Cristina Guerrero, Damla Guerzoglu, Sophie Guettier, Vincent Guiraud, Christoph Gumbinger, Ignaz Gunreben, Florian Haertig, Christian Hametner, Bernard Hanseeuw, Andreas Hansen, Jakob Hansen, Thomas Harbo, Andreas Harloff, Peter Harmel, Karl Georg Häusler, Florian Heinen, Valentin Held, Simon Hellwig, Dimitri Hemelsoet, Michael Hennerici, Juliane Herm, Sylvia Hermans, María Hernández, Jose Hervas Vicente, Niels Hjort, Cristina Hobeanu, Carsten Hobohm, Elmar Höfner, Katharina Hohenbichler, Marc Hommel, Julia Hoppe, Eva Hornberger, Carolin Hoyer, Xuya Huang, Nils Ipsen, Irina Isern, Lourdes Ispierto, Helle Iversen, Lise Jeppesen, Marta Jimenez, Jan Jungehülsing, Eric Jüttler, Dheeraj Kalladka, Bernd Kallmünzer, Arindam Kar, Lars Kellert, André Kemmling, Tobias Kessler, Usman Khan, Matthias Klein, Christoph Kleinschnitz, Matti Klockziem, Michael Knops, Luzie Koehler, Martin Koehrmann, Heinz Kohlfürst, Rainer Kollmar, Peter Kraft, Thomas Krause, Bo Kristensen, Jan M. Kröber, Natalia Kurka, Alexandre Ladoux, Patrice Laloux, Catherine Lamy, Emmanuelle Landrault, Arne Lauer, Claire Lebely, Jonathan Leempoel, Kennedy Lees, Anne Leger, Laurence Legrand, Lin Li, Anna-Mareike Löbbe, Frederic London, Elena Lopez-cancio, Matthias Lorenz, Stephen Louw, Caroline Lovelock, Manuel Lozano Sánchez, Giuseppe Lucente, Janos Lückl, Alain Luna, Kosmas Macha, Alexandre Machet, Daniel Mackenrodt, Dominik Madzar, Charles Majoie, Anika Männer, Vicky Maqueda, Jacob Marstrand, Alicia Martinez, Annika Marzina, Laura Mechthouff, Per Meden, Guy Meersman, Julia Meier, Charles Mellerio, Oliver Menn, Nadja Meyer, Dominik Michalski, Peter Michels, Lene Michelsen, Monica Millán Torne, Jens Minnerup, Boris Modrau, Sebastian Moeller, Anette Møller, Nathalie Morel, Fiona Moreton, Ludovic Morin, Thierry Moulin, Barry Moynihan, Anne K. Mueller, Keith W. Muir, Patricia Mulero, Sibu Mundiyanapurath, Johannes Mutzenbach, Simon Nagel, Oliver Naggara, Arumugam Nallasivan, Irene Navalpotro, Alexander H. Nave, Paul Nederkoorn, Lars Neeb, Hermann Neugebauer, Tobias Neumann-Haefelin, Stefan Oberndorfer, Christian Opherk, Lorenz Oppel, Catherine Oppenheim, Johannes Orthgieß, Leif Ostergaard, Perrine Paindeville, Ernest Palomeras, Verena Panitz, Bhavni Patel, Andre Peeters, Dirk Peeters, Anna Pellisé, Johann Pelz, Anthony Pereira, Natalia Pérez de la Ossa, Richard Perry, Salvador Petraza, Stéphane Peysson, Waltraud Pfeilschifter, Alexander Pichler, Alexandra Pierskalla, Hans-Werner Pledl, Sven Poli, Katrin Pomrehn, Marika Poulsen, Luis Prats, Silvia Presas, Elisabeth Prohaska, Volker Puetz, Josep Puig, Josep Puig Alcántara, Jan Purrucker, Veronique Quenardelle, Sankaranarayanan Ramachandran, Soulliard Raphaelle, Nicolas Raposo, Tilman Reiff, Michel Remmers, Pauline Renou, Martin Ribitsch, Hardy Richter, Martin Ritter, Thomas Ritzenthaler, Gilles Rodier, Christine Rodriguez-Regent, Manuel Rodríguez-Yáñez, Maria Roennefarth, Christine Roffe, Sverre Rosenbaum, Charlotte Rosso, Joachim Röther, Michal Rozanski, Noelia Ruiz de Morales, Francesca Russo, Matthieu Rutgers, Sharmilla Sagnier, Yves Samson, Josep Sánchez, Tamara Sauer, Jan H. Schäfer, Simon Schieber, Josef Schill, Dennis Schlak, Ludwig Schlemm, Sein Schmidt, Wouter Schonewille, Julian Schröder, Andreas Schulz, Johannes Schurig, Sönke Schwarting, Alexander Schwarz, Christopher Schwarzbach, Matthias Seidel, Alexander Seiler, Jochen Sembill, Joaquin Serena Leal, Ashit Shetty, Igor Sibon, Claus Z. Simonsen, Oliver Singer, Aravinth Sivagnanaratham, Ide Smets, Craig Smith, Peter Soors, Nikola Sprigg, Maximilian Spruegel, David Stark, Susanne Steinert, Sebastian Stösser, Markus Stuermlinger, Bart Swinnen, Ruben Tamazyan, Jose Tembl, Mikel Terceno Izaga, Emmanuel Touze, Thomas Truelsen, Guillaume Turc, Gaetane Turine, Serdar Tütüncü, Pippa Tyrell, Xavier Ustrell, Wilfried Vadot, Anne-Evelyne Vallet, Pauline Vallet, Lucie van den Berg, Sophie van den Berg, Cecile van Eendenburg, Robbert-Jan Van Hooff, Isabelle van Sloten, Peter Vanacker, Evelien Vancaester, Patrick Vanderdonckt, Yves Vandermeeren, Frederik Vanhee, Roland Veltkamp, Karsten Vestergaard, Alain Viguier, Dolores Vilas, Kersten Villringer, Dieke Voget, Jörg von Schrader, Paul von Weitzel, Elisabeth Warburton, Claudia Weber, Jörg Weber, Karl Wegscheider, Mirko Wegscheider, Christian Weimar, Karin Weinstich, Christopher Weise, Gesa Weise, Chris Willems, Klemens Winder, Matthias Wittayer, Marc Wolf, Martin Wolf, Valerie Wolff, Christian Wollboldt, Frank Wollenweber, Anke Wouters, Bertrand Yalo, Marion Yger, Nadia Younan, Laetita Yperzeele, Vesna Zegarac, Pia Zeiner, Ulf Ziemann, Thomas Zonneveld, Mathieu Zuber, Tsugio Akutsu, Junya Aoki, Shuji Arakawa, Ryosuke Doijiri, Yusuke Egashira, Yukiko Enomoto, Eisuke Furui, Konosuke Furuta, Seiji Gotoh, Toshimitsu Hamasaki, Yasuhiro Hasegawa, Teryuki Hirano, Kazunari Homma, Masahiko Ichijyo, Toshihiro Ide, Shuichi Igarashi, Yasuyuki Iguchi, Masafumi Ihara, Hajime Ikenouchi, Tsuyoshi Inoue, Ryo Itabashi, Yasuhiro Ito, Toru Iwama, Kenji Kamiyama, Shoko Kamiyoshi, Haruka Kanai, Yasuhisa Kanematsu, Takao Kanzawa, Kazumi Kimura, Jiro Kitayama, Takanari Kitazono, Rei Kondo, Kohsuke Kudo, Masayoshi Kusumi, Ken Kuwahara, Shoji Matsumoto, Hideki Matsuoka, Ban Mihara, Kazuo Minematsu, Ken Miura, Naomi Morita, Wataru Mouri, Kayo Murata, Yoshinari Nagakane, Taizen Nakase, Hiromi Ohara, Nobuyuki Ohara, Hideyuki Ohnishi, Hajime Ohta, Masafumi Ohtaki, Ryo Ohtani, Toshiho Ohtsuki, Hideo Ohyama, Takashi Okada, Yasushi Okada, Masato Osaki, Nobuyuki Sakai, Yoshiki Sanbongi, Naoshi Sasaki, Makoto Sasaki, Shoichiro Sato, Kenta Seki, Wataru Shimizu, Yoshiaki Shiokawa, Takashi Sozu, Junichiro Suzuki, Rieko Suzuki, Yasushi Takagi, Shunya Takizawa, Norio Tanahashi, Eijiro Tanaka, Ryota Tanaka, Yohei Tateishi, Tomoaki Terada, Tadashi Terasaki, Kenichi Todo, Azusa Tokunaga, Akira Tsujino, Toshihiro Ueda, Yoshikazu Uesaka, Mihoko Uotani, Takao Urabe, Masao Watanabe, Yoshiki Yagita, Yusuke Yakushiji, Keizo Yasui, Toshiro Yonehara, Shinichi Yoshimura, K. Aarnio, F. Alemseged, C. Anderson, T. Ang, M.L. Archer, J. Attia, P. Bailey, A. Balabanski, A. Barber, P.A. Barber, J. Bernhardt, A. Bivard, D. Blacker, C.F. Bladin, A. Brodtmann, D. Cadilhac, B.C.V. Campbell, L. Carey, S. Celestino, L. Chan, W.H. Chang, A. ChangI, C.H. Chen, C.-I. Chen, H.F. Chen, T.C. Chen, W.H. Chen, Y.Y. Chen, C.A. Cheng, E. Cheong, Y.W. Chiou, P.M. Choi, H.J. Chu, C.S. Chuang, T.C. Chung, L. Churilov, B. Clissold, A. Connelly, S. Coote, B. Coulton, E. Cowley, J. Cranefield, S. Curtze, C. D'Este, S.M. Davis, S. Day, P.M. Desmond, H.M. Dewey, C. Ding, G.A. Donnan, R. Drew, S. Eirola, D. Field, T. Frost, C. Garcia-Esperon, K. George, R. Gerraty, R. Grimley, Y.C. Guo, G. Hankey, J. Harvey, S.C. Ho, K. Hogan, D. Howells, P.M. Hsiao, C.H. Hsu, C.T. Hsu, C.-S. Hsu, J.P. Hsu, Y.D. Hsu, Y.T. Hsu, C.J. Hu, C.C. Huang, H.Y. Huang, M.Y. Huang, S.C. Huang, W.S. Huang, D. Jackson, J.S. Jeng, S.K. Jiang, L. Kaauwai, O. Kasari, J. King, T.J. Kleinig, M. Koivu, J. Kolbe, M. Krause, C.W. Kuan, W.L. Kung, C. Kyndt, C.L. Lau, A. Lee, C.Y. Lee, J.T. Lee, Y. Lee, Y.C. Lee, C. Levi, C.R. Levi, L.M. Lien, J.C. Lim, C.C. Lin, C.H. Lin, C.M. Lin, D. Lin, C.H. Liu, J. Liu, Y.C. Lo, P.S. Loh, E. Low, C.H. Lu, C.J. Lu, M.K. Lu, J. Ly, H. Ma, L. Macaulay, R. Macdonnell, E. Mackey, M. Macleod, J. Mahadevan, V. Maxwell, R. McCoy, A. McDonald, S. McModie, A. Meretoja, S. Mishra, P.J. Mitchell, F. Miteff, A. Moore, C. Muller, F. Ng, F.C. Ng, J-L. Ng, W. O'Brian, V. O'Collins, T.J. Oxley, M.W. Parsons, S. Patel, G.S. Peng, L. Pesavento, T. Phan, E. Rodrigues, Z. Ross, A. Sabet, M. Sallaberger, P. Salvaris, D. Shah, G. Sharma, G. Sibolt, M. Simpson, S. Singhal, B. Snow, N. Spratt, R. Stark, J. Sturm, M.C. Sun, Y. Sun, P.S. Sung, Y.F. Sung, M. Suzuki, M. Tan, S.C. Tang, T. Tatlisumak, V. Thijs, M. Tiainen, C.H. Tsai, C.K. Tsai, C.L. Tsai, H.T. Tsai, L.K. Tsai, C.H. Tseng, L.T. Tseng, J. Tsoleridis, H. Tu, H.T-H. Tu, W. Vallat, J. Virta, W.C. Wang, Y.T. Wang, M. Waters, L. Weir, T. Wijeratne, C. Williams, W. Wilson, A.A. Wong, K. Wong, T.Y. Wu, Y.H. Wu, B. Yan, F.C. Yang, Y.W. Yang, N. Yassi, H.L. Yeh, J.H. Yeh, S.J. Yeh, C.H. Yen, D. Young, C.L. Ysai, W.W. Zhang, H. Zhao, L. Zhao, Katharina Althaus-Knaurer, Jörg Berrouschot, Erich Bluhmki, Paolo Bovi, Gilles Chatellier, Lynda Cove, Stephen Davis, A. Dixit, Geoffrey Donnan, Christina Ehrenkrona, Christoph Eschenfelder, Marc Fatar, Juan Francisco Arenillas, Franz Gruber, Lalit Kala, Peter Kapeller, Markku Kaste, Christof Kessler, Martin Köhrmann, Rico Laage, Kennedy R. Lees, Alain Luna Rodriguez, Jean-Louis Mas, Robert Mikulik, Carlos Molina, Girish Muddegowda, Keith Muir, Kurt Niederkorn, Xavier Nuñez, Peter Schellinger, Joaquin Serena, Jan Sobesky, Thorsten Steiner, Ann-Sofie Svenson, Rüdiger von Kummer, Joanna Wardlaw, Rebecca A. Betensky, Gregoire Boulouis, Raphael A. Carandang, William A. Copen, Pedro Cougo, Shawna Cutting, Kendra Drake, Andria L. Ford, John Hallenbeck, Gordon J. Harris, Robert Hoesch, Amie Hsia, Carlos Kase, Lawrence Latour, Michael H. Lev, Alona Muzikansky, Nandakumar Nagaraja, Lee H. Schwamm, Eric Searls, Shlee S. Song, Sidney Starkman, Albert J. Yoo, Ramin Zand, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Monash University [Melbourne], National Cerebral and Cardiovascular Center (NCCC - OSAKA), Osaka University [Osaka], University of Heidelberg, Medical Faculty, Massachusetts General Hospital [Boston], University of Melbourne, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Royal Adelaide Hospital [Adelaide Australia], National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Flanders Make [Leuven], Flanders Make, University of Newcastle [Australia] (UoN), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Vall d'Hebron University Hospital [Barcelona], University of Glasgow, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Girona Biomedical Research Institute [Girona, Spain] (IDIBGI), Ruhr-Universität Bochum [Bochum], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Aarhus University Hospital, Cedars-Sinai Medical Center, Florey Institute of Neuroscience and Mental Health [Melbourne, Victoria, Australia], Austin Health, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], China Medical University Hospital [Taichung], Karolinska Institutet [Stockholm], The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Texas at Austin [Austin], Collaborators Evaluation of unknown Onset Stroke thrombolysis trials (EOS) investigators: Boris Raul Acosta, Karen Aegidius, Christian Albiker, Anna Alegiani, Miriam Almendrote, Angelika Alonso, Katharina Althaus, Pierre Amarenco, Hemasse Amiri, Bettina Anders, Adriana Aniculaesei, Jason Appleton, Juan Arenillas, Christina Back, Christian Bähr, Jürgen Bardutzky, Flore Baronnet-Chauvet, Rouven Bathe-Peters, Anna Bayer-Karpinska, Juan L Becerra, Christoph Beck, Olga Belchí Guillamon, Amandine Benoit, Nadia Berhoune, Daniela Bindila, Julia Birchenall, Karine Blanc-Lasserre, Miguel Blanco Gonzales, Tobias Bobinger, Ulf Bodechtel, Eric Bodiguel, Urszula Bojaryn, Louise Bonnet, Benjamin Bouamra, Paul Bourgeois, Florent Boutitie, Lorenz Breuer, Ludovic Breynaert, David Broughton, Raf Brouns, Sébastian Brugirard, Bart Bruneel, Florian Buggle, Serkan Cakmak, Ana Calleja, David Calvet, David Carrera, Hsin-Chieh Chen, Bastian Cheng, Bharath Cheripelli, Tae-Hee Cho, Chi-Un Choe, Lillian Choy, Hanne Christensen, Mareva Ciatipis, Geoffrey Cloud, Julien Cogez, Elisa Cortijo, Sophie Crozier, Dorte Damgaard, Krishna Dani, Beatrijs De Coene, Isabel De Hollander, Jacques De Keyser, Nina De Klippel, Charlotte De Maeseneire, Ann De Smedt, Maria Del Mar Castellanos Rodrigo, Sandrine Deltour, Jelle Demeestere, Laurent Derex, Philippe Desfontaines, Ralf Dittrich, Anand Dixit, Laurens Dobbels, Valérie Domigo, Laura Dorado, Charlotte Druart, Kristina Hougaard Dupont, Anne Dusart, Rainer Dziewas, Martin Ebinger, Matthias Ebner, Myriam Edjali-Goujon, Philipp Eisele, Salwa El Tawil, Ahmed Elhfnawy, Matthias Endres, Ana Etexberria, Nicholas Evans, Simon Fandler, Franz Fazekas, Sandra Felix, Jochen B Fiebach, Jens Fiehler, Alexandra Filipov, Katharina Filipski, Robert Fleischmann, Christian Foerch, Ian Ford, Alexandra Gaenslen, Ivana Galinovic, Elena Meseguer Gancedo, Ramanan Ganeshan, Carlos García Esperón, Alicia Garrido, Thomas Gattringer, Olivia Geraghty, Rohat Geran, Christian Gerloff, Stefan Gerner, Sylvie Godon-Hardy, Jos Göhler, Amir Golsari, Meritxell Gomis, David Gorriz, Verena Gramse, Laia Grau, Martin Griebe, Cristina Guerrero, Damla Guerzoglu, Sophie Guettier, Vincent Guiraud, Christoph Gumbinger, Ignaz Gunreben, Florian Haertig, Christian Hametner, Bernard Hanseeuw, Andreas Hansen, Jakob Hansen, Thomas Harbo, Andreas Harloff, Peter Harmel, Karl Georg Häusler, Florian Heinen, Valentin Held, Simon Hellwig, Dimitri Hemelsoet, Michael Hennerici, Juliane Herm, Sylvia Hermans, María Hernández, Jose Hervas Vicente, Niels Hjort, Cristina Hobeanu, Carsten Hobohm, Elmar Höfner, Katharina Hohenbichler, Marc Hommel, Julia Hoppe, Eva Hornberger, Carolin Hoyer, Xuya Huang, Nils Ipsen, Irina Isern, Lourdes Ispierto, Helle Iversen, Lise Jeppesen, Marta Jimenez, Jan Jungehülsing, Eric Jüttler, Dheeraj Kalladka, Bernd Kallmünzer, Arindam Kar, Lars Kellert, André Kemmling, Tobias Kessler, Usman Khan, Matthias Klein, Christoph Kleinschnitz, Matti Klockziem, Michael Knops, Luzie Koehler, Martin Koehrmann, Heinz Kohlfürst, Rainer Kollmar, Peter Kraft, Thomas Krause, Bo Kristensen, Jan M Kröber, Natalia Kurka, Alexandre Ladoux, Patrice Laloux, Catherine Lamy, Emmanuelle Landrault, Arne Lauer, Claire Lebely, Jonathan Leempoel, Kennedy Lees, Anne Leger, Laurence Legrand, Robin Lemmens, Lin Li, Anna-Mareike Löbbe, Frederic London, Elena Lopez-Cancio, Matthias Lorenz, Stephen Louw, Caroline Lovelock, Manuel Lozano Sánchez, Giuseppe Lucente, Janos Lückl, Alain Luna, Kosmas Macha, Alexandre Machet, Daniel Mackenrodt, Dominik Madzar, Charles Majoie, Anika Männer, Vicky Maqueda, Jacob Marstrand, Alicia Martinez, Annika Marzina, Laura Mechthouff, Per Meden, Guy Meersman, Julia Meier, Charles Mellerio, Oliver Menn, Nadja Meyer, Dominik Michalski, Peter Michels, Lene Michelsen, Monica Millán Torne, Jens Minnerup, Boris Modrau, Sebastian Moeller, Anette Møller, Nathalie Morel, Fiona Moreton, Ludovic Morin, Thierry Moulin, Barry Moynihan, Anne K Mueller, Keith W Muir, Patricia Mulero, Sibu Mundiyanapurath, Johannes Mutzenbach, Simon Nagel, Oliver Naggara, Arumugam Nallasivan, Irene Navalpotro, Alexander H Nave, Paul Nederkoorn, Lars Neeb, Hermann Neugebauer, Tobias Neumann-Haefelin, Norbert Nighoghossian, Stefan Oberndorfer, Christian Opherk, Lorenz Oppel, Catherine Oppenheim, Johannes Orthgieß, Leif Ostergaard, Perrine Paindeville, Ernest Palomeras, Verena Panitz, Bhavni Patel, Andre Peeters, Dirk Peeters, Anna Pellisé, Johann Pelz, Anthony Pereira, Natalia Pérez de la Ossa, Richard Perry, Salvador Petraza, Stéphane Peysson, Waltraud Pfeilschifter, Alexander Pichler, Alexandra Pierskalla, Hans-Werner Pledl, Sven Poli, Katrin Pomrehn, Marika Poulsen, Luis Prats, Silvia Presas, Elisabeth Prohaska, Volker Puetz, Josep Puig, Josep Puig Alcántara, Jan Purrucker, Veronique Quenardelle, Sankaranarayanan Ramachandran, Soulliard Raphaelle, Nicolas Raposo, Tilman Reiff, Michel Remmers, Pauline Renou, Martin Ribitsch, Hardy Richter, Peter Ringleb, Martin Ritter, Thomas Ritzenthaler, Gilles Rodier, Christine Rodriguez-Regent, Manuel Rodríguez-Yáñez, Maria Roennefarth, Christine Roffe, Sverre Rosenbaum, Charlotte Rosso, Joachim Röther, Michal Rozanski, Noelia Ruiz de Morales, Francesca Russo, Matthieu Rutgers, Sharmilla Sagnier, Yves Samson, Josep Sánchez, Tamara Sauer, Jan H Schäfer, Simon Schieber, Josef Schill, Dennis Schlak, Ludwig Schlemm, Sein Schmidt, Wouter Schonewille, Julian Schröder, Andreas Schulz, Johannes Schurig, Sönke Schwarting, Alexander Schwarz, Christopher Schwarzbach, Matthias Seidel, Alexander Seiler, Jochen Sembill, Joaquin Serena Leal, Ashit Shetty, Igor Sibon, Claus Z Simonsen, Oliver Singer, Aravinth Sivagnanaratham, Ide Smets, Craig Smith, Peter Soors, Nikola Sprigg, Maximilian Spruegel, David Stark, Susanne Steinert, Sebastian Stösser, Markus Stuermlinger, Bart Swinnen, Ruben Tamazyan, Jose Tembl, Mikel Terceno Izaga, Vincent Thijs, Götz Thomalla, Emmanuel Touze, Thomas Truelsen, Guillaume Turc, Gaetane Turine, Serdar Tütüncü, Pippa Tyrell, Xavier Ustrell, Wilfried Vadot, Anne-Evelyne Vallet, Pauline Vallet, Lucie van den Berg, Sophie van den Berg, Cecile van Eendenburg, Robbert-Jan Van Hooff, Isabelle van Sloten, Peter Vanacker, Evelien Vancaester, Patrick Vanderdonckt, Yves Vandermeeren, Frederik Vanhee, Roland Veltkamp, Karsten Vestergaard, Alain Viguier, Dolores Vilas, Kersten Villringer, Dieke Voget, Jörg von Schrader, Paul von Weitzel, Elisabeth Warburton, Claudia Weber, Jörg Weber, Karl Wegscheider, Mirko Wegscheider, Christian Weimar, Karin Weinstich, Christopher Weise, Gesa Weise, Chris Willems, Klemens Winder, Matthias Wittayer, Marc Wolf, Martin Wolf, Valerie Wolff, Christian Wollboldt, Frank Wollenweber, Anke Wouters, Bertrand Yalo, Marion Yger, Nadia Younan, Laetita Yperzeele, Vesna Zegarac, Pia Zeiner, Ulf Ziemann, Thomas Zonneveld, Mathieu Zuber, Tsugio Akutsu, Junya Aoki, Junya Aoki, Shuji Arakawa, Ryosuke Doijiri, Yusuke Egashira, Yukiko Enomoto, Mayumi Fukuda-Doi, Eisuke Furui, Konosuke Furuta, Seiji Gotoh, Toshimitsu Hamasaki, Yasuhiro Hasegawa, Teryuki Hirano, Kazunari Homma, Masahiko Ichijyo, Toshihiro Ide, Shuichi Igarashi, Yasuyuki Iguchi, Masafumi Ihara, Hajime Ikenouchi, Manabu Inoue, Tsuyoshi Inoue, Ryo Itabashi, Yasuhiro Ito, Toru Iwama, Kenji Kamiyama, Shoko Kamiyoshi, Haruka Kanai, Yasuhisa Kanematsu, Takao Kanzawa, Kazumi Kimura, Jiro Kitayama, Takanari Kitazono, Masatoshi Koga, Rei Kondo, Kohsuke Kudo, Masayoshi Kusumi, Ken Kuwahara, Shoji Matsumoto, Hideki Matsuoka, Ban Mihara, Kazuo Minematsu, Ken Miura, Kaori Miwa, Naomi Morita, Wataru Mouri, Kayo Murata, Yoshinari Nagakane, Taizen Nakase, Hiromi Ohara, Nobuyuki Ohara, Hideyuki Ohnishi, Hajime Ohta, Masafumi Ohtaki, Ryo Ohtani, Toshiho Ohtsuki, Hideo Ohyama, Takashi Okada, Yasushi Okada, Masato Osaki, Nobuyuki Sakai, Yoshiki Sanbongi, Naoshi Sasaki, Makoto Sasaki, Shoichiro Sato, Kenta Seki, Wataru Shimizu, Yoshiaki Shiokawa, Takashi Sozu, Junichiro Suzuki, Rieko Suzuki, Yasushi Takagi, Shunya Takizawa, Norio Tanahashi, Eijiro Tanaka, Ryota Tanaka, Yohei Tateishi, Tomoaki Terada, Tadashi Terasaki, Kenichi Todo, Azusa Tokunaga, Kazunori Toyoda, Akira Tsujino, Toshihiro Ueda, Yoshikazu Uesaka, Mihoko Uotani, Takao Urabe, Masao Watanabe, Yoshiki Yagita, Yusuke Yakushiji, Haruko Yamamoto, Keizo Yasui, Toshiro Yonehara, Sohei Yoshimura, Shinichi Yoshimura, K Aarnio, F Alemseged, C Anderson, T Ang, M L Archer, J Attia, P Bailey, A Balabanski, A Barber, P A Barber, J Bernhardt, A Bivard, D Blacker, C F Bladin, A Brodtmann, D Cadilhac, B C V Campbell, L Carey, S Celestino, L Chan, W H Chang, A ChangI, C H Chen, C-I Chen, H F Chen, T C Chen, W H Chen, Y Y Chen, C A Cheng, E Cheong, Y W Chiou, P M Choi, H J Chu, C S Chuang, T C Chung, L Churilov, B Clissold, A Connelly, S Coote, B Coulton, E Cowley, J Cranefield, S Curtze, C D'Este, S M Davis, S Day, P M Desmond, H M Dewey, C Ding, G A Donnan, R Drew, S Eirola, D Field, T Frost, C Garcia-Esperon, K George, R Gerraty, R Grimley, Y C Guo, G Hankey, J Harvey, S C Ho, K Hogan, D Howells, P M Hsiao, C H Hsu, C T Hsu, C-S Hsu, J P Hsu, Y D Hsu, Y T Hsu, C J Hu, C C Huang, H Y Huang, M Y Huang, S C Huang, W S Huang, D Jackson, J S Jeng, S K Jiang, L Kaauwai, O Kasari, J King, T J Kleinig, M Koivu, J Kolbe, M Krause, C W Kuan, W L Kung, C Kyndt, C L Lau, A Lee, C Y Lee, J T Lee, Y Lee, Y C Lee, C Levi, C R Levi, L M Lien, J C Lim, C C Lin, C H Lin, C M Lin, D Lin, C H Liu, J Liu, Y C Lo, P S Loh, E Low, C H Lu, C J Lu, M K Lu, J Ly, H Ma, L Macaulay, R Macdonnell, E Mackey, M Macleod, J Mahadevan, V Maxwell, R McCoy, A McDonald, S McModie, A Meretoja, S Mishra, P J Mitchell, F Miteff, A Moore, C Muller, F Ng, F C Ng, J-L Ng, W O'Brian, V O'Collins, T J Oxley, M W Parsons, S Patel, G S Peng, L Pesavento, T Phan, E Rodrigues, Z Ross, A Sabet, M Sallaberger, P Salvaris, D Shah, G Sharma, G Sibolt, M Simpson, S Singhal, B Snow, N Spratt, R Stark, J Sturm, M C Sun, Y Sun, P S Sung, Y F Sung, M Suzuki, M Tan, S C Tang, T Tatlisumak, V Thijs, M Tiainen, C H Tsai, C K Tsai, C L Tsai, H T Tsai, L K Tsai, C H Tseng, L T Tseng, J Tsoleridis, H Tu, H T-H Tu, W Vallat, J Virta, W C Wang, Y T Wang, M Waters, L Weir, T Wijeratne, C Williams, W Wilson, A A Wong, K Wong, T Y Wu, Y H Wu, B Yan, F C Yang, Y W Yang, N Yassi, H L Yeh, J H Yeh, S J Yeh, C H Yen, D Young, C L Ysai, W W Zhang, H Zhao, L Zhao, Katharina Althaus-Knaurer, Martin Bendszus, Jörg Berrouschot, Erich Bluhmki, Paolo Bovi, Gilles Chatellier, Lynda Cove, Stephen Davis, A Dixit, Geoffrey Donnan, Rainer Dziewas, Christina Ehrenkrona, Christoph Eschenfelder, Marc Fatar, Juan Francisco Arenillas, Franz Gruber, Werner Hacke, Lalit Kala, Peter Kapeller, Markku Kaste, Christof Kessler, Martin Köhrmann, Rico Laage, Kennedy R Lees, Didier Leys, Alain Luna Rodriguez, Jean-Louis Mas, Robert Mikulik, Carlos Molina, Girish Muddegowda, Keith Muir, Kurt Niederkorn, Xavier Nuñez, Catherine Oppenheim, Sven Poli, Peter Ringleb, Peter Schellinger, Stefan Schwab, Joaquin Serena, Jan Sobesky, Thorsten Steiner, Ann-Sofie Svenson, Danilo Toni, Roland Veltkamp, Rüdiger von Kummer, Nils Wahlgren, Joanna Wardlaw, Rebecca A Betensky, Gregoire Boulouis, Raphael A Carandang, William A Copen, Pedro Cougo, Shawna Cutting, Kendra Drake, Andria L Ford, John Hallenbeck, Gordon J Harris, Robert Hoesch, Amie Hsia, Carlos Kase, Lawrence Latour, Arne Lauer, Michael H Lev, Alona Muzikansky, Nandakumar Nagaraja, Lee H Schwamm, Eric Searls, Shlee S Song, Sidney Starkman, Steven Warach, Ona Wu, Albert J Yoo, Ramin Zand, University of Newcastle [Callaghan, Australia] (UoN), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CarMeN, laboratoire, Yperzeele, Laetitia, Evaluation of Unknown Onset Stroke Thrombolysis trials (EOS) investigators, UCL - SSS/IONS - Institute of NeuroScience, UCL - (MGD) Service de neurologie, Supporting clinical sciences, UZB Other, Physical Medicine and Rehabilitation, Clinical sciences, Neuroprotection & Neuromodulation, Radiology and Nuclear Medicine, ANS - Neurovascular Disorders, Neurology, ACS - Atherosclerosis & ischemic syndromes, Graduate School, Center of Experimental and Molecular Medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Microcirculation

Subjects
medicine.medical_treatment, [SDV]Life Sciences [q-bio], Ischemic Stroke/*diagnostic imaging/*drug therapy, Tomography, X-Ray Computed/methods, Fibrinolytic Agents/adverse effects/*therapeutic use, 030204 cardiovascular system & hematology, Ischemic Stroke/diagnostic imaging, surgery, 0302 clinical medicine, Modified Rankin Scale, 030212 general & internal medicine, 10. No inequality, Infusions, Intravenous, Stroke, Tomography, Time-to-Treatment, General Medicine, Thrombolysis, X-Ray Computed/methods, Tissue Plasminogen Activator/adverse effects, 3. Good health, [SDV] Life Sciences [q-bio], Diffusion Magnetic Resonance Imaging/methods, Treatment Outcome, Meta-analysis, Tissue Plasminogen Activator, Intravenous, medicine.medical_specialty, Infusions, Intravenous thrombolysis, Neuroimaging, Neuroscience(all), Placebo, Tissue Plasminogen Activator/adverse effects/*therapeutic use, 03 medical and health sciences, Fibrinolytic Agents, Internal medicine, medicine, Humans, ddc:610, Ischemic Stroke, business.industry, neurology, Fibrinolytic Agents/adverse effects, Odds ratio, Recovery of Function, medicine.disease, Clinical research, Diffusion Magnetic Resonance Imaging, Human medicine, business, Tomography, X-Ray Computed, Fibrinolytic agent
Abstract

International audience; BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I(2)=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [\textless1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

Published
2020

43. Comparing PET and MRI Biomarkers Predicting Cognitive Decline in Preclinical Alzheimer Disease

Author

Jorge Sepulcre, Kirsten A. Moody, Keith A. Johnson, Aaron P. Schultz, Julie C. Price, Danielle V. Mayblyum, Samantha Katz, Justin S. Sanchez, Bernard Hanseeuw, Heidi I.L. Jacobs, Reisa A. Sperling, Patrizia Vannini, Zoe B. Rubinstein, J. Alex Becker, Rachel F. Buckley, Kathryn V. Papp, Dorene M. Rentz, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, and Psychiatrie & Neuropsychologie

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, BETA, METABOLISM, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Aging brain, Cognitive decline, Fluorodeoxyglucose, business.industry, Cognition, ASSOCIATION, Entorhinal cortex, medicine.disease, 030104 developmental biology, chemistry, Biomarker (medicine), TAU PET, Neurology (clinical), Alzheimer's disease, Pittsburgh compound B, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

ObjectiveTo compare how structural MRI, fluorodeoxyglucose (FDG), and flortaucipir (FTP) PET signals predict cognitive decline in high-amyloid vs low-amyloid participants with the goal of determining which biomarker combination would result in the highest increase of statistical power for prevention trials.MethodsIn this prospective cohort study, we analyzed data from clinically normal adults from the Harvard Aging Brain Study with MRI, FDG, FTP, and Pittsburgh compound B (PiB)-PET acquired within a year and prospective cognitive evaluations over a mean 3-year follow-up. We focused analyses on predefined regions of interest: inferior temporal, isthmus cingulate, hippocampus, and entorhinal cortex. Cognition was assessed with the Preclinical Alzheimer's Cognitive Composite. We evaluated the association between biomarkers and cognitive decline using linear mixed-effect models with random intercepts and slopes, adjusting for demographics. We generated power curves simulating prevention trials.ResultsData from 131 participants (52 women, age 73.98 ± 8.29 years) were analyzed in the study. In separate models, most biomarkers had a closer association with cognitive decline in the high-PiB compared to the low-PiB participants. A backward stepwise regression including all biomarkers demonstrated that only neocortical PiB, entorhinal FTP, and entorhinal FDG were independent predictors of subsequent cognitive decline. Power analyses revealed that using both high PiB and low entorhinal FDG as inclusion criteria reduced 3-fold the number of participants needed in a hypothetical trial compared to using only high PiB.DiscussionIn preclinical Alzheimer disease, entorhinal hypometabolism is a strong and independent predictor of subsequent cognitive decline, making FDG a potentially useful biomarker to increase power in clinical trials.Classification of EvidenceThis study provides Class II evidence that in people with preclinical Alzheimer disease, entorhinal hypometabolism identified by FDG-PET is predictive of subsequent cognitive decline.

Published
2021

44. CSF1R inhibition rescues tau pathology and neurodegeneration in an A/T/N model with combined AD pathologies, while preserving plaque associated microglia

Author

Astrid Bottelbergs, Pablo Botella Lucena, Chritica Lodder, Bernard Hanseeuw, Niels Cremers, Hannah Vanrusselt, Tim Vanmierlo, Ilse Dewachter, Jean-Noël Octave, Isabelle Scheyltjens, Sarah Vanherle, Bert Brône, Manuel Gutiérrez de Ravé, Ilie-Cosmin Stancu, Kiavash Movahedi, Laboratory of Molecullar and Cellular Therapy, Department of Bio-engineering Sciences, Basic (bio-) Medical Sciences, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, UCL - SSS/IONS/NEUR - Clinical Neuroscience, and UCL - (SLuc) Service de neurologie

Subjects
Apolipoprotein E, ATN-continuum, Tau pathology, Plaque, Amyloid, tau Proteins, Microgliosis, Pathology and Forensic Medicine, Pathogenesis, Amyloid beta-Protein Precursor, Mice, Cellular and Molecular Neuroscience, Atrophy, Downregulation and upregulation, Alzheimer Disease, medicine, Animals, Humans, Neurodegeneration, RC346-429, Amyloid pathology, Microglia, business.industry, Research, Microglial profiling, neurodegeneration, Brain, Neurofibrillary Tangles, Alzheimer's disease, medicine.disease, Phenotype, Disease Models, Animal, medicine.anatomical_structure, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Nerve Degeneration, CSF1R inhibition, Neurology. Diseases of the nervous system, Neurology (clinical), business, Neuroscience, Alzheimer’s disease
Abstract

Alzheimer's disease (AD) is characterized by a sequential progression of amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), constituting ATN pathology. While microglia are considered key contributors to AD pathogenesis, their contribution in the combined presence of ATN pathologies remains incompletely understood. As sensors of the brain microenvironment, microglial phenotypes and contributions are importantly defined by the pathologies in the brain, indicating the need for their analysis in preclinical models that recapitulate combined ATN pathologies, besides their role in A and T models only. Here, we report a new tau-seed model in which amyloid pathology facilitates bilateral tau propagation associated with brain atrophy, thereby recapitulating robust ATN pathology. Single-cell RNA sequencing revealed that ATN pathology exacerbated microglial activation towards disease-associated microglia states, with a significant upregulation of Apoe as compared to amyloid-only models (A). Importantly, Colony-Stimulating Factor 1 Receptor inhibition preferentially eliminated non-plaque-associated versus plaque associated microglia. The preferential depletion of non-plaque-associated microglia significantly attenuated tau pathology and neuronal atrophy, indicating their detrimental role during ATN progression. Together, our data reveal the intricacies of microglial activation and their contributions to pathology in a model that recapitulates the combined ATN pathologies of AD. Our data may provide a basis for microglia-targeting therapies selectively targeting detrimental microglial populations, while conserving protective populations. This work was supported by Innoviris (Attract grant, BB2B 2015–2) to KM; FRA-SAO (Fondation Recherche Alzheimer—Stichting Alzheimer Onderzoek, Belgium – 20180028 & 2020022) to IDW, VLAIO (Vlaams Agentschap Innoveren en Ondernemen) and FWO (Fonds Wetenschappelijk Onderzoek—Vlaanderen—G0C6819N & 1259621 N and the fellowship of I.S.). Acknowledgements We thank Yvon Elkrim and the VIB Nucleomics core for technical assistance, VIB Tech Watch for support regarding single-cell RNA sequencing technologies.

Published
2021

45. Analytical and clinical performances of the automated Lumipulse cerebrospinal fluid Aβ42 and T-Tau assays for Alzheimer’s disease diagnosis

Author

Adrian Ivanoiu, Jean-Louis Bayart, Vincent Van Pesch, and Bernard Hanseeuw

Subjects
Oncology, medicine.medical_specialty, Neurology, Receiver operating characteristic, business.industry, Concordance, Memory clinic, Context (language use), Disease, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Internal medicine, medicine, Biomarker (medicine), 030212 general & internal medicine, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

Cerebrospinal fluid (CSF) biomarkers are increasingly used to diagnose Alzheimer’s disease (AD). However, important methodological and technical remain regarding measurement variability between kit providers and users. We compared the Lumipulse fully automated assays with the manual INNOTEST assays (both from Fujirebio Europe NV, Gent, Belgium) on a clinically representative sample of patients and controls. CSF samples of 156 patients were used to quantify Amyloid Aβ1–42 peptide (Aβ1–42) and Total-Tau (T-Tau) protein by chemiluminescent enzyme-immunoassay (Lumipulse). Patients were divided into several subgroups: Alzheimer (AD = 44), mild-cognitive impairment (MCI = 23), other dementias (OD = 36), non-dementing neurological conditions (ND = 11), and controls (CTRL = 42). Clinical cut-offs were determined by comparing AD and CTRL with ROC curves for the two markers and their related ratio (T-Tau/Aβ1–42). Subgroups of 58 (for phosphorylated-Tau) and 115 samples (for Aβ1–42 and T-Tau) were used to evaluate the concordance of this analyzer with the INNOTEST assays. Lumipulse and INNOTEST assays showed good concordance for all markers, but systematic bias was observed justifying the need to redefine new clinical cut-offs. To discriminate AD from CTRL subjects, T-Tau/Aβ1–42 ratio was the best biomarker, with a cut-off value of 1.12 (sensitivity 81.8% and specificity 92.9%). Similar clinical performances were observed for the Lumipulse and Innotests assays on the subsample of 115 subjects. Our results demonstrate that the Lumipulse Aβ1–42 and T-Tau assays show good analytical and clinical performances in the context of patient evaluation referred to a memory clinic. Automated analyzers should be preferred for the measurement of CSF AD biomarkers to reduce inter- and intra-laboratory variability.

Published
2019

46. Striatal amyloid is associated with tauopathy and memory decline in familial Alzheimer’s disease

Author

Daniel J. Norton, Enmanuelle Pardilla-Delgado, Edmarie Guzmán-Vélez, Kewei Chen, Yakeel T. Quiroz, Jennifer R. Gatchel, Ana Baena, Keith A. Johnson, Bernard Hanseeuw, David X. Jin, Aaron P. Schultz, Eric M. Reiman, Francisco Lopera, Reisa A. Sperling, UCL - SSS/IONS/NEUR - Clinical Neuroscience, and UCL - (SLuc) Service de neurologie

Subjects
0301 basic medicine, Male, Neurology, Striatum, lcsh:RC346-429, chemistry.chemical_compound, Early-onset autosomal dominant Alzheimer’s disease, 0302 clinical medicine, Neocortex, Middle Aged, medicine.anatomical_structure, Tauopathies, Female, Tauopathy, Adult, medicine.medical_specialty, Amyloid, Heterozygote, Cognitive Neuroscience, Presenilin, lcsh:RC321-571, 03 medical and health sciences, Alzheimer Disease, Memory, medicine, Humans, Tau PET, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, lcsh:Neurology. Diseases of the nervous system, Memory Disorders, business.industry, Research, Entorhinal cortex, medicine.disease, Corpus Striatum, 030104 developmental biology, Cross-Sectional Studies, chemistry, nervous system, Amyloid PET, Positron-Emission Tomography, Neurology (clinical), Pittsburgh compound B, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

Background Autosomal dominant Alzheimer’s disease (ADAD) is distinguished from late-onset AD by early striatal amyloid-β deposition. To determine whether striatal Pittsburgh compound B (PiB)-PET measurements of amyloid-β can help predict disease severity in ADAD, we compared relationships of striatal and neocortical PiB-PET to age, tau-PET, and memory performance in the Colombian Presenilin 1 E280A kindred. Methods Fourteen carriers (age = 28–42, Mini-Mental State Examination = 26–30) and 20 age-matched non-carriers were evaluated using PiB, flortaucipir (FTP; tau), and memory testing (CERAD Word List Learning). PiB-PET signal was measured in neocortical and striatal aggregates. FTP-PET signal was measured in entorhinal cortex. Results Compared to non-carriers, mutation carriers had age-related elevations in both neocortical and striatal PiB binding. The PiB elevation in carriers was significantly greater in the striatum than in the neocortex. In mutation carriers, PiB binding in both the neocortex and the striatum is related to entorhinal FTP; however, the association was stronger with the striatum. Only striatal PiB was associated with worse memory. Remarkably, PiB binding in the striatum, but not in the neocortex, predicted entorhinal FTP and lower memory scores after adjusting for age, indicating that striatal PiB identified the carriers with the most severe disease. Conclusions Based on these preliminary cross-sectional findings, striatal PiB-PET measurements may offer particular value in the detection and tracking of preclinical ADAD, informing a mutation carrier’s prognosis and evaluating amyloid-β-modifying ADAD treatments.

Published
2019

47. Regional Tau Correlates of Instrumental Activities of Daily Living and Apathy in Mild Cognitive Impairment and Alzheimer’s Disease Dementia

Author

Martha Muniz, Nancy J. Donovan, Kathryn V. Papp, Aaron P. Schultz, Rebecca E. Amariglio, Dorene M. Rentz, Reisa A. Sperling, Gad A. Marshall, Bernard Hanseeuw, Keith A. Johnson, Jennifer R. Gatchel, J. Alex Becker, Jasmeer P. Chhatwal, UCL - SSS/IONS/NEUR - Clinical Neuroscience, and UCL - (SLuc) Service de neurologie

Subjects
Male, 0301 basic medicine, Activities of daily living, Neuropsychological Tests, chemistry.chemical_compound, 0302 clinical medicine, Surveys and Questionnaires, Activities of Daily Living, Medicine, Apathy, Aged, 80 and over, Aniline Compounds, General Neuroscience, Cognition, General Medicine, Middle Aged, Functional Activities Questionnaire, Psychiatry and Mental health, Clinical Psychology, Female, medicine.symptom, Alzheimer’s disease, Clinical psychology, Amyloid, Positron emission tomography, tau Proteins, Article, 03 medical and health sciences, Atrophy, Alzheimer Disease, mental disorders, Instrumental activities of daily living, Humans, Dementia, Cognitive Dysfunction, Aged, Amyloid beta-Peptides, business.industry, Mild cognitive impairment, medicine.disease, Entorhinal cortex, Thiazoles, 030104 developmental biology, chemistry, Positron-Emission Tomography, Tau, Geriatrics and Gerontology, Pittsburgh compound B, business, human activities, 030217 neurology & neurosurgery
Abstract

Background Instrumental activities of daily living (IADL) impairment and apathy occur in early-stage Alzheimer's disease (AD) and are associated with regional atrophy and hypometabolism in vivo and greater tau burden at autopsy. Objective To explore the association between IADL impairment, apathy, and in vivo regional tau in mild cognitive impairment (MCI) and AD dementia. Methods Forty participants (24 MCI, 16 AD dementia) underwent assessments of IADL (Functional Activities Questionnaire, FAQ) and apathy (Apathy Evaluation Scale Informant report, AES-I). Regional tau was assessed using flortaucipir positron emission tomography (PET) and amyloid using Pittsburgh Compound B PET. Regions with unadjusted associations of p≤0.01 were entered into regression models assessing the relationship between tau and FAQ or AES-I, adjusting for age, sex, and cognition, with/without a tau by amyloid interaction. Results Unadjusted IADL impairment but not apathy was associated with greater tau in multiple regions. After adjusting for covariates, for medial orbitofrontal and entorhinal cortex the interaction between tau and amyloid was associated with IADL impairment and for anterior cingulate it was not but independent associations with both tau and amyloid were retained. With whole brain analyses, similar results were seen for IADL, while for apathy tau in small clusters within the right anterior cingulate and dorsolateral prefrontal cortices were seen, which were more pronounced in individuals with greater amyloid. Conclusions This exploratory study suggests that IADL impairment in AD is associated with medial temporal and frontal tau, especially in individuals with elevated amyloid, while apathy may be associated with right frontal tau.

Published
2019

48. Vascular Risk and β -Amyloid Are Synergistically Associated with Cortical Tau

Author

Gad A. Marshall, Keith A. Johnson, Trey Hedden, Jasmeer P. Chhatwal, Dorene M. Rentz, Anand Viswanathan, Jennifer S. Rabin, Hannah Klein, Hyun-Sik Yang, Emily P. Kilpatrick, Aaron P. Schultz, Vaishnavi Rao, Jennifer R. Gatchel, Dylan Kirn, Bernard Hanseeuw, Reisa A. Sperling, Wai-Ying Wendy Yau, and Rachel F. Buckley

Subjects
0301 basic medicine, Temporal cortex, Oncology, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Neurodegeneration, medicine.disease, Entorhinal cortex, 3. Good health, Temporal lobe, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Framingham Heart Study, Neurology, Positron emission tomography, Internal medicine, medicine, Dementia, Neurology (clinical), Alzheimer's disease, business, 030217 neurology & neurosurgery
Abstract

OBJECTIVE: Neuropathological studies have demonstrated that cerebrovascular disease and Alzheimer disease (AD) pathology frequently co-occur in older adults. The extent to which cerebrovascular disease influences the progression of AD pathology remains unclear. Leveraging newly available positron emission tomography (PET) imaging, we examined whether a well-validated measure of systemic vascular risk and β-amyloid (Aβ) burden have an interactive association with regional tau burden. METHODS: Vascular risk was quantified at baseline in 152 clinically normal older adults (mean age = 73.5 ± 6.1 years) with the office-based Framingham Heart Study cardiovascular disease risk algorithm (FHS-CVD). We acquired Aβ (11 C-Pittsburgh compound B) and tau (18 F-flortaucipir) PET imaging on the same participants. Aβ PET was performed at baseline; tau PET was acquired on average 2.98 ± 1.1 years later. Tau was measured in the entorhinal cortex (EC), an early site of tau deposition, and in the inferior temporal cortex (ITC), an early site of neocortical tau accumulation associated with AD. Linear regression models examined FHS-CVD and Aβ as interactive predictors of tau deposition, adjusting for age, sex, APOE e4 status, and the time interval between baseline and the tau PET scan. RESULTS: We observed a significant interaction between FHS-CVD and Aβ burden on subsequently measured ITC tau (p < 0.001), whereby combined higher FHS-CVD and elevated Aβ burden was associated with increased tau. The interaction was not significant for EC tau (p = 0.16). INTERPRETATION: Elevated vascular risk may influence tau burden when coupled with high Aβ burden. These results suggest a potential link between vascular risk and tau pathology in preclinical AD. Ann Neurol 2019; 1-8 ANN NEUROL 2019;85:272-279.

Published
2019

49. Disclosing tau tangles using PET imaging: a pharmacological review of the radiotracers available in 2021

Author

Éléonore, Van Wambeke, Thomas, Gérard, Renaud, Lhommel, and Bernard, Hanseeuw

Subjects
Tauopathies, Alzheimer Disease, Positron-Emission Tomography, Brain, Humans, Neurodegenerative Diseases, tau Proteins
Abstract

Neurological symptoms depend on the topography of the lesions in the nervous system, hence the importance of brain imaging for neurologists. Neurological treatment, however, depends on the biological nature of the lesions. The development of radiotracers specific for the proteinopathies observed in neurodegenerative disorders is, therefore, crucially important for better understanding the relationships between the pathology and the clinical symptoms, as well as the efficacy of therapeutical interventions. The tau protein is involved in several neurodegenerative disorders, that can be distinguished both biologically and clinically as the type of tau isoforms and filaments observed in brain aggregates, and the brain regions affected differ between tauopathies. Over the past few years, several tracers have been developed for imaging tauopathies with positron emission tomography. The present review aims to compare the binding properties of these tracers, with a specific focus on how these properties might be relevant for neurologists using these biomarkers to characterize the pathology of patients presenting with clinical symptoms suspect of a neurodegenerative disorder.

Published
2021

50. The cortical origin and initial spread of medial temporal tauopathy in Alzheimer’s disease assessed with positron emission tomography

Author

Dorene M. Rentz, Georges El Fakhri, Heidi I.L. Jacobs, J. Alex Becker, Alexa S. Beiser, Jean C. Augustinack, Reisa A. Sperling, Yakeel T. Quiroz, Michael J. Properzi, Aaron P. Schultz, Claudia L. Satizabal, Shu Jiang, Justin S. Sanchez, Charles DeCarli, Marc D. Normandin, Bernard Hanseeuw, Sudha Seshadri, Teresa Gomez-Isla, Samantha Katz, Julie C. Price, Adrienne O’Donnell, Keith A. Johnson, Ronald J. Killiany, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, and Psychiatrie & Neuropsychologie

Subjects
NATIONAL INSTITUTE, 0301 basic medicine, MILD COGNITIVE IMPAIRMENT, Aging, Neurodegenerative, Alzheimer's Disease, Medical and Health Sciences, 0302 clinical medicine, 2.1 Biological and endogenous factors, Aetiology, Cognitive decline, Neocortex, medicine.diagnostic_test, Neurodegeneration, PATHOLOGICAL PROCESS, General Medicine, Biological Sciences, medicine.anatomical_structure, Tauopathies, Positron emission tomography, Neurological, Tauopathy, autopsy cohort, Adult, tau pathology, age-related tauopathy, tau Proteins, SURFACE-BASED ANALYSIS, Article, Temporal lobe, 03 medical and health sciences, Alzheimer Disease, HUMAN PERIRHINAL CORTEX, Acquired Cognitive Impairment, medicine, Humans, Dementia, Amyloid beta-Peptides, business.industry, Prevention, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), medicine.disease, Brain Disorders, 030104 developmental biology, Rhinal sulcus, neurofibrillary tangles, Positron-Emission Tomography, HUMAN CEREBRAL-CORTEX, business, Neuroscience, 030217 neurology & neurosurgery
Abstract

Advances in molecular positron emission tomography (PET) have enabled anatomic tracking of brain pathology in longitudinal studies of normal aging and dementia, including assessment of the central model of Alzheimer's disease (AD) pathogenesis, according to which TAU pathology begins focally but expands catastrophically under the influence of amyloid-beta (A beta) pathology to mediate neurodegeneration and cognitive decline. Initial TAU deposition occurs many years before A beta in a specific area of the medial temporal lobe. Building on recent work that enabled focus of molecular PET measurements on specific TAU-vulnerable convolutional temporal lobe anatomy, we applied an automated anatomic sampling method to quantify TAU PET signal in 443 adult participants from several observational studies of aging and AD, spanning a wide range of ages, A beta burdens, and degrees of clinical impairment. We detected initial cortical emergence of tauopathy near the rhinal sulcus in clinically normal people and, in a subset with longitudinal 2-year follow-up data (n = 104), tracked A beta-associated spread of TAU from this site first to nearby neocortex of the temporal lobe and then to extratemporal regions. Greater rate of TAU spread was associated with baseline measures of both global A beta burden and medial temporal lobe TAU. These findings are consistent with clinicopathological correlation studies of Alzheimer's tauopathy and enable precise tracking of AD-related TAU progression for natural history studies and prevention therapeutic trials.

Published
2021

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