| 1. |
- Aad, G, et al.
(author)
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- 2015
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swepub:Mat__t
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| 2. |
- Niemi, MEK, et al.
(author)
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- 2021
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swepub:Mat__t
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| 3. |
- Schael, S., et al.
(author)
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Electroweak measurements in electron positron collisions at W-boson-pair energies at LEP
- 2013
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In: Physics Reports. - : Elsevier BV. - 0370-1573 .- 1873-6270. ; 532:4, s. 119-244
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Research review (peer-reviewed)abstract
- Electroweak measurements performed with data taken at the electron positron collider LEP at CERN from 1995 to 2000 are reported. The combined data set considered in this report corresponds to a total luminosity of about 3 fb(-1) collected by the four LEP experiments ALEPH, DELPHI, 13 and OPAL, at centre-of-mass energies ranging from 130 GeV to 209 GeV. Combining the published results of the four LEP experiments, the measurements include total and differential cross-sections in photon-pair, fermion-pair and four-fermion production, the latter resulting from both double-resonant WW and ZZ production as well as singly resonant production. Total and differential cross-sections are measured precisely, providing a stringent test of the Standard Model at centre-of-mass energies never explored before in electron positron collisions. Final-state interaction effects in four-fermion production, such as those arising from colour reconnection and Bose Einstein correlations between the two W decay systems arising in WW production, are searched for and upper limits on the strength of possible effects are obtained. The data are used to determine fundamental properties of the W boson and the electroweak theory. Among others, the mass and width of the W boson, m(w) and Gamma(w), the branching fraction of W decays to hadrons, B(W -> had), and the trilinear gauge-boson self-couplings g(1)(Z), K-gamma and lambda(gamma), are determined to be: m(w) = 80.376 +/- 0.033 GeV Gamma(w) = 2.195 +/- 0.083 GeV B(W -> had) = 67.41 +/- 0.27% g(1)(Z) = 0.984(-0.020)(+0.018) K-gamma - 0.982 +/- 0.042 lambda(gamma) = 0.022 +/- 0.019. (C) 2013 Elsevier B.V. All rights reserved.
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| 4. |
- Schael, S, et al.
(author)
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Precision electroweak measurements on the Z resonance
- 2006
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In: Physics Reports. - : Elsevier BV. - 0370-1573 .- 1873-6270. ; 427:5-6, s. 257-454
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Research review (peer-reviewed)abstract
- We report on the final electroweak measurements performed with data taken at the Z resonance by the experiments operating at the electron-positron colliders SLC and LEP. The data consist of 17 million Z decays accumulated by the ALEPH, DELPHI, L3 and OPAL experiments at LEP, and 600 thousand Z decays by the SLID experiment using a polarised beam at SLC. The measurements include cross-sections, forward-backward asymmetries and polarised asymmetries. The mass and width of the Z boson, m(Z) and Gamma(Z), and its couplings to fermions, for example the p parameter and the effective electroweak mixing angle for leptons, are precisely measured: m(Z) = 91.1875 +/- 0.0021 GeV, Gamma(Z) = 2.4952 +/- 0.0023 GeV, rho(l) = 1.0050 +/- 0.0010, sin(2)theta(eff)(lept) = 0.23153 +/- 0.00016. The number of light neutrino species is determined to be 2.9840 +/- 0.0082, in agreement with the three observed generations of fundamental fermions. The results are compared to the predictions of the Standard Model (SM). At the Z-pole, electroweak radiative corrections beyond the running of the QED and QCD coupling constants are observed with a significance of five standard deviations, and in agreement with the Standard Model. Of the many Z-pole measurements, the forward-backward asymmetry in b-quark production shows the largest difference with respect to its SM expectation, at the level of 2.8 standard deviations. Through radiative corrections evaluated in the framework of the Standard Model, the Z-pole data are also used to predict the mass of the top quark, m(t) = 173(+10)(+13) GeV, and the mass of the W boson, m(W) = 80.363 +/- 0.032 GeV. These indirect constraints are compared to the direct measurements, providing a stringent test of the SM. Using in addition the direct measurements of m(t) and m(W), the mass of the as yet unobserved SM Higgs boson is predicted with a relative uncertainty of about 50% and found to be less than 285 GeV at 95% confidence level. (c) 2006 Elsevier B.V. All rights reserved.
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| 5. |
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| 6. |
- Vergallo, A., et al.
(author)
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Association of plasma YKL-40 with brain amyloid-β levels, memory performance, and sex in subjective memory complainers
- 2020
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In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 96, s. 22-32
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Journal article (peer-reviewed)abstract
- Neuroinflammation, a key early pathomechanistic alteration of Alzheimer's disease, may represent either a detrimental or a compensatory mechanism or both (according to the disease stage). YKL-40, a glycoprotein highly expressed in differentiated glial cells, is a candidate biomarker for in vivo tracking neuroinflammation in humans. We performed a longitudinal study in a monocentric cohort of cognitively healthy individuals at risk for Alzheimer's disease exploring whether age, sex, and the apolipoprotein E ε4 allele affect plasma YKL-40 concentrations. We investigated whether YKL-40 is associated with brain amyloid-β (Aβ) deposition, neuronal activity, and neurodegeneration as assessed via neuroimaging biomarkers. Finally, we investigated whether YKL-40 may predict cognitive performance. We found an age-associated increase of YKL-40 and observed that men display higher concentrations than women, indicating a potential sexual dimorphism. Moreover, YKL-40 was positively associated with memory performance and negatively associated with brain Aβ deposition (but not with metabolic signal). Consistent with translational studies, our results suggest a potentially protective effect of glia on incipient brain Aβ accumulation and neuronal homeostasis. © 2020 Elsevier Inc.
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| 7. |
- Vergallo, A., et al.
(author)
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Plasma amyloid beta 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease
- 2019
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In: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:6, s. 764-775
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Journal article (peer-reviewed)abstract
- Introduction: Blood-based biomarkers of pathophysiological brain amyloid beta (A beta) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. Methods: We investigated whether plasma concentrations of the A beta(1-40)/A beta(1-42) ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain A beta positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-apriori hypothesis study using machine learning. Results: The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma A beta(1-40)/A beta(1-42) ratio. The accuracy is not affected by the apolipoprotein E (APOE) epsilon 4 allele, sex, or age. Discussion: Our results encourage an independent validation cohort study to confirm the indication that the plasma A beta(1-40)/A beta(1-42) ratio, assessed via Simoa, may improve future standard of care and clinical trial design. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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| 8. |
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| 9. |
- Lista, S., et al.
(author)
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Evolving Evidence for the Value of Neuroimaging Methods and Biological Markers in Subjects Categorized with Subjective Cognitive Decline
- 2015
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In: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 48
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Journal article (peer-reviewed)abstract
- There is evolving evidence that individuals categorized with subjective cognitive decline (SCD) are potentially at higher risk for developing objective and progressive cognitive impairment compared to cognitively healthy individuals without apparent subjective complaints. Interestingly, SCD, during advancing preclinical Alzheimer's disease (AD), may denote very early, subtle cognitive decline that cannot be identified using established standardized tests of cognitive performance. The substantial heterogeneity of existing SCD-related research data has led the Subjective Cognitive Decline Initiative (SCD-I) to accomplish an international consensus on the definition of a conceptual research framework on SCD in preclinical AD. In the area of biological markers, the cerebrospinal fluid signature of AD has been reported to be more prevalent in subjects with SCD compared to healthy controls; moreover, there is a pronounced atrophy, as demonstrated by magnetic resonance imaging, and an increased hypometabolism, as revealed by positron emission tomography, in characteristic brain regions affected by AD. In addition, SCD individuals carrying an apolipoprotein epsilon 4 allele are more likely to display AD-phenotypic alterations. The urgent requirement to detect and diagnose AD as early as possible has led to the critical examination of the diagnostic power of biological markers, neurophysiology, and neuroimaging methods for AD-related risk and clinical progression in individuals defined with SCD. Observational studies on the predictive value of SCD for developing AD may potentially be of practical value, and an evidence-based, validated, qualified, and fully operationalized concept may inform clinical diagnostic practice and guide earlier designs in future therapy trials.
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| 10. |
- Cavedo, E, et al.
(author)
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The Road Ahead to Cure Alzheimer's Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across all Stages and Target Populations
- 2014
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In: The journal of prevention of Alzheimer's disease. - : SERDI. - 2274-5807. ; 1:3, s. 181-202
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Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) is a slowly progressing non-linear dynamic brain disease in which pathophysiological abnormalities, detectable in vivo by biological markers, precede overt clinical symptoms by many years to decades. Use of these biomarkers for the detection of early and preclinical AD has become of central importance following publication of two international expert working group's revised criteria for the diagnosis of AD dementia, mild cognitive impairment (MCI) due to AD, prodromal AD and preclinical AD. As a consequence of matured research evidence six AD biomarkers are sufficiently validated and partly qualified to be incorporated into operationalized clinical diagnostic criteria and use in primary and secondary prevention trials. These biomarkers fall into two molecular categories: biomarkers of amyloid-beta (Aβ) deposition and plaque formation as well as of tau-protein related hyperphosphorylation and neurodegeneration. Three of the six gold-standard ("core feasible) biomarkers are neuroimaging measures and three are cerebrospinal fluid (CSF) analytes. CSF Aβ 1-42 (Aβ1-42), also expressed as Aβ1-42 : Aβ1- 40 ratio, T-tau, and P-tau Thr181 & Thr231 proteins have proven diagnostic accuracy and risk enhancement in prodromal MCI and AD dementia. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up. Magnetic resonance imaging (MRI) at increasing field strength and resolution allows detecting the evolution of distinct types of structural and functional abnormality pattern throughout early to late AD stages. Anatomical or volumetric MRI is the most widely used technique and provides local and global measures of atrophy. The revised diagnostic criteria for “prodromal AD” and "mild cognitive impairment due to AD" include hippocampal atrophy (as the fourth validated biomarker), which is considered an indicator of regional neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both in regions of interest, such as the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced tractography as well as resting-state functional MRI provide useful additionally useful measures indicating the degree of fiber tract and neural network disintegration (structural, effective and functional connectivity) that may substantially contribute to early detection and the mapping of progression. These modalities require further standardization and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of early AD pathological processes and associated neurodegeneration. How to use, interpret, and disclose biomarker results drives the need for optimized standardization. Multimodal AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in secondary prevention trials to stratify and select individuals at genetic risk of AD. Although most of these biomarker candidates are not yet qualified and approved by regulatory authorities for their intended use in drug trials, they are nonetheless applied in ongoing clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic, electrophysiological, and neuroimaging markers for use in clinical trials are being developed. The current state-of-the-art and future perspectives on both biological and neuroimaging derived biomarker discovery and development as well as the intended application in prevention trials is outlined in the present publication.
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| 11. |
- O'Bryant, S. E., et al.
(author)
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Comparing biological markers of Alzheimer's disease across blood fraction and platforms: Comparing apples to oranges
- 2016
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In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 3, s. 27-34
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Journal article (peer-reviewed)abstract
- Introduction: This study investigated the comparability of potential Alzheimer's disease (AD) biomarkers across blood fractions and assay platforms. Methods: Nonfasting serum and plasma samples from 300 participants (150 AD patients and 150 controls) were analyzed. Proteomic markers were obtained via electrochemiluminescence or Luminex technology. Comparisons were conducted via Pearson correlations. The relative importance of proteins within an AD diagnostic profile was examined using random forest importance plots. Results: On the Meso Scale Discovery multiplex platform, 10 of the 21 markers shared >50% of the variance across blood fractions (serum amyloid A R2 = 0.99, interleukin (IL)10 R2 = 0.95, fatty acid-binding protein (FABP) R2 = 0.94, I309 R2 = 0.94, IL-5 R2 = 0.94, IL-6 R2 = 0.94, eotaxin3 R2 = 0.91, IL-18 R2 = 0.87, soluble tumor necrosis factor receptor 1 R2 = 0.85, and pancreatic polypeptide R2 = 0.81). When examining protein concentrations across platforms, only five markers shared >50% of the variance (beta 2 microglobulin R2 = 0.92, IL-18 R2 = 0.80, factor VII R2 = 0.78, CRP R2 = 0.74, and FABP R2 = 0.70). Discussion: The current findings highlight the importance of considering blood fractions and assay platforms when searching for AD relevant biomarkers. © 2016 The Authors.
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| 12. |
- Chatzikonstantinou, T, et al.
(author)
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COVID-19 severity and mortality in patients with CLL: an update of the international ERIC and Campus CLL study
- 2021
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In: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 3635:312, s. 3444-3454
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Journal article (peer-reviewed)abstract
- Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated.
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| 13. |
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| 14. |
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| 15. |
- Hampel, Harald, et al.
(author)
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Advances in the therapy of Alzheimer's disease : targeting amyloid beta and tau and perspectives for the future
- 2015
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In: Expert Review of Neurotherapeutics. - : Informa UK Limited. - 1473-7175 .- 1744-8360. ; 15:1, s. 83-105
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Research review (peer-reviewed)abstract
- Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer's disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis- and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre- and asymptomatic at-risk stages of AD.
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| 16. |
- Hampel, H., et al.
(author)
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beta-Secretase1 biological markers for Alzheimer's disease: state-of-art of validation and qualification
- 2020
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In: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
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Journal article (peer-reviewed)abstract
- beta -Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-beta pathway in Alzheimer's disease (AD). A robust body of evidence demonstrates an association between cerebrospinal fluid/blood BACE1 biomarkers and core pathophysiological mechanisms of AD, such as brain protein misfolding and aggregration, neurodegeneration, and synaptic dysfunction.In pharmacological trials, BACE1 candidate biomarkers may be applied to a wide set of contexts of use (CoU), including proof of mechanism, dose-finding, response and toxicity dose estimation. For clinical CoU, BACE1 biomarkers show good performance for prognosis and disease prediction.The roadmap toward validation and qualification of BACE1 biomarkers requires standardized pre-analytical and analytical protocols to reduce inter-site variance that may have contributed to inconsistent results.BACE1 biomarker-drug co-development programs, including biomarker-guided outcomes and endpoints, may support the identification of sub-populations with a higher probability to benefit from BACE1 inhibitors with a reduced risk of adverse effects, in line with the evolving precision medicine paradigm.
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| 17. |
- Hampel, Harald, et al.
(author)
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Perspective on Future Role of Biological Markers in Clinical Therapy Trials of Alzheimer's Disease: A Long-Range Point of View Beyond 2020.
- 2014
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In: Biochemical pharmacology. - : Elsevier BV. - 1873-2968 .- 0006-2952. ; 88:4, s. 426-449
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Journal article (peer-reviewed)abstract
- Recent advances in understanding the molecular mechanisms underlying various paths towards the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD.
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| 18. |
- Lemercier, P., et al.
(author)
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Association of plasma A beta 40/A beta 42 ratio and brain A beta accumulation: testing a whole-brain PLS-VIP approach in individuals at risk of Alzheimer's disease
- 2021
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In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 107, s. 57-69
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Journal article (peer-reviewed)abstract
- Molecular and brain regional/network-wise pathophysiological changes at preclinical stages of Alzheimer's disease (AD) have primarily been found through knowledge-based studies conducted in late-stage mild cognitive impairment/dementia populations. However, such an approach may compromise the objective of identifying the earliest spatial-temporal pathophysiological processes. We investigated 261 individuals with subjective memory complaints, a condition at increased risk of AD, to test a whole-brain, non-a-priori method based on partial least squares in unraveling the association between plasma A beta 42/A beta 40 ratio and an extensive set of brain regions characterized through molecular imaging of A beta accumulation and cortical metabolism. Significant associations were mapped onto large-scale networks, identified through an atlas and by knowledge, to elaborate on the reliability of the results. Plasma A beta 42/beta 40 ratio was associated with A beta-PET uptake (but not FDG-PET) in regions generally investigated in preclinical AD such as those belonging to the default mode network, but also in regions/networks normally not accounted including the central executive and salience networks which likely have a selective vulnerability to incipient A beta accumulation. The present whole-brain approach is promising to investigate early pathophysiological changes of AD to fully capture the complexity of the disease, which is essential to develop timely screening, detection, diagnostic, and therapeutic interventions. (C) 2021 Elsevier Inc. All rights reserved.
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| 19. |
- Lindstedt, B A, et al.
(author)
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Use of multilocus variable-number tandem repeat analysis (MLVA) in eight European countries, 2012
- 2013
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In: Eurosurveillance. - : European Centre for Disease Prevention and Control. - 1025-496X .- 1560-7917. ; 18:4
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Journal article (peer-reviewed)abstract
- Genotyping of important medical or veterinary prokaryotes has become a very important tool during the last decades. Rapid development of fragment-separation and sequencing technologies has made many new genotyping strategies possible. Among these new methods is multilocus variable-number tandem repeat analysis (MLVA). Here we present an update on the use of MLVA in eight European countries (Denmark, France, Germany, Ireland, Italy, the Netherlands, Norway and Sweden). Researchers in Europe have been active in developing and implementing a large array of different assays. MLVA has been used as a typing tool in several contexts, from aiding in resolving outbreaks of foodborne bacteria to typing organisms that may pose a bioterrorist threat, as well as in scientific studies.
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| 20. |
- Lista, S., et al.
(author)
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Biomarkers in Sporadic and Familial Alzheimer's Disease
- 2015
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In: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 47:2, s. 291-317
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Journal article (peer-reviewed)abstract
- Most forms of Alzheimer's disease (AD) are sporadic (sAD) or inherited in a non-Mendelian fashion, and less than 1% of cases are autosomal-dominant. Forms of sAD do not exhibit familial aggregation and are characterized by complex genetic and environmental interactions. Recently, the expansion of genomic methodologies, in association with substantially larger combined cohorts, has resulted in various genome-wide association studies that have identified several novel genetic associations of AD. Currently, the most effective methods for establishing the diagnosis of AD are defined by multi-modal pathways, starting with clinical and neuropsychological assessment, cerebrospinal fluid (CSF) analysis, and brain-imaging procedures, all of which have significant cost- and access-to-care barriers. Consequently, research efforts have focused on the development and validation of non-invasive and generalizable blood-based biomarkers. Among the modalities conceptualized by the systems biology paradigm and utilized in the "exploratory biomarker discovery arena", proteome analysis has received the most attention. However, metabolomics, lipidomics, transcriptomics, and epigenomics have recently become key modalities in the search for AD biomarkers. Interestingly, biomarker changes for familial AD (fAD), in many but not all cases, seem similar to those for sAD. The integration of neurogenetics with systems biology/physiology-based strategies and high-throughput technologies for molecular profiling is expected to help identify the causes, mechanisms, and biomarkers associated with the various forms of AD. Moreover, in order to hypothesize the dynamic trajectories of biomarkers through disease stages and elucidate the mechanisms of biomarker alterations, updated and more sophisticated theoretical models have been proposed for both sAD and fAD.
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| 21. |
- Lista, S, et al.
(author)
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Blood and cerebrospinal fluid biomarkers for Alzheimer’s disease
- 2017
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In: Dementia. David Ames, John T. O'Brien, Alistair Burns (red.). - Boca Raton : CRC Press. - 9781498703116 ; , s. 528-538
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Book chapter (other academic/artistic)abstract
- In general, a biomarker denes a biological process or disease characteristic that is objectively measured (Biomarkers Denitions Working Group, 2001). Such measurements may be used for diagnostic purposes, but also to study physiological or pathophysiological mechanisms and to evaluate desired pharmacodynamic eects or side eects of pharmacological treatments. According to Biomarkers Denitions Working Group: ‘Molecular and Biochemical Markers of Alzheimer’s Disease’, the ideal biomarker for Alzheimer’s disease (AD) should detect a fundamental feature of neuropathology and be validated in neuropathologically con-rmed cases as well as have a diagnostic accuracy of at least 80% (e Ronald and Nancy Reagan Research Institute of the Alzheimer’s Association and National Institute on Aging Working Group, 1998). With respect to clinically relevant questions, such as detection, diagnosis, prediction and treatment of a given disease, biomarkers may serve certain distinct functions
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| 22. |
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| 23. |
- Diaz-Galvan, P., et al.
(author)
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Differential response to donepezil in MRI subtypes of mild cognitive impairment
- 2023
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In: Alzheimer's Research & Therapy. - 1758-9193. ; 15:1
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Journal article (peer-reviewed)abstract
- BackgroundDonepezil is an approved therapy for the treatment of Alzheimer's disease (AD). Results across clinical trials have been inconsistent, which may be explained by design-methodological issues, the pathophysiological heterogeneity of AD, and diversity of included study participants. We investigated whether response to donepezil differs in mild cognitive impaired (MCI) individuals demonstrating different magnetic resonance imaging (MRI) subtypes.MethodsFrom the Hippocampus Study double-blind, randomized clinical trial, we included 173 MCI individuals (donepezil = 83; placebo = 90) with structural MRI data, at baseline and at clinical follow-up assessments (6-12-month). Efficacy outcomes were the annualized percentage change (APC) in hippocampal, ventricular, and total grey matter volumes, as well as in the AD cortical thickness signature. Participants were classified into MRI subtypes as typical AD, limbic-predominant, hippocampal-sparing, or minimal atrophy at baseline. We primarily applied a subtyping approach based on continuous scale of two subtyping dimensions. We also used the conventional categorical subtyping approach for comparison.ResultsDonepezil-treated MCI individuals showed slower atrophy rates compared to the placebo group, but only if they belonged to the minimal atrophy or hippocampal-sparing subtypes. Importantly, only the continuous subtyping approach, but not the conventional categorical approach, captured this differential response.ConclusionsOur data suggest that individuals with MCI, with hippocampal-sparing or minimal atrophy subtype, may have improved benefit from donepezil, as compared with MCI individuals with typical or limbic-predominant patterns of atrophy. The newly proposed continuous subtyping approach may have advantages compared to the conventional categorical approach. Future research is warranted to demonstrate the potential of subtype stratification for disease prognosis and response to treatment.
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| 24. |
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| 25. |
- Lista, S., et al.
(author)
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Cerebrospinal fluid analysis in Alzheimer's disease: technical issues and future developments
- 2014
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In: Journal of Neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 261:6, s. 1234-1243
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Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) is a leading cause of morbidity, mortality, and a major epidemic worldwide. Although clinical assessment continues to remain the keystone for patient management and clinical trials, such evaluation has important limitations. In this context, cerebrospinal fluid (CSF) biomarkers are important tools to better identify high-risk individuals, to diagnose AD promptly and accurately, especially at the prodromal mild cognitive impairment stage of the disease, and to effectively prognosticate and treat AD patients. Recent advances in functional genomics, proteomics, metabolomics, and bioinformatics will hopefully revolutionize unbiased inquiries into several putative CSF markers of cerebral pathology that may be concisely informative with regard to the various stages of AD progression through years and decades. Moreover, the identification of efficient drug targets and development of optimal therapeutic strategies for AD will increasingly rely on a better understanding and integration of the systems biology paradigm, which will allow predicting the series of events and resulting responses of the biological network triggered by the introduction of new therapeutic compounds. In this scenario, unbiased systems biology-based diagnostic and prognostic models in AD will consist of relevant comprehensive panels of molecules and key branches of the disease-affected cellular neuronal network. Such characteristic and unbiased biomarkers will more accurately and comprehensively reflect pathophysiology from the early asymptomatic and presymptomatic to the final prodromal and symptomatic clinical stages in individual patients (and their individual genetic disease predisposition), ultimately increasing the chances of success of future disease modifying and preventive treatments.
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| 26. |
- Shahim, Pashtun, 1984, et al.
(author)
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Cerebrospinal Fluid Stanniocalcin-1 as a Biomarker for Alzheimer’s Disease and Other Neurodegenerative Disorders
- 2017
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In: NeuroMolecular Medicine. - : Springer Science and Business Media LLC. - 1535-1084 .- 1559-1174. ; 19:1, s. 154-160
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Journal article (peer-reviewed)abstract
- © 2016 Springer Science+Business Media New YorkStanniocalcin-1 (STC-1) is a nerve cell-enriched protein involved in intracellular calcium homeostasis regulation. Changes in calcium regulation are hypothesized to play a role in the pathophysiology of Alzheimer’s disease (AD). The expression of STC-1 increases in response to ischemic stroke, but whether it is altered in neurodegenerative disorder, particularly Alzheimer’s disease (AD), has not been investigated before. We measured STC-1 in cerebrospinal fluid (CSF) samples from a total of 163 individuals including AD, prodromal AD (pAD), mixed AD, stable mild cognitive impairment (sMCI), and diagnoses of other dementia than AD, as well as cognitively normal controls (CNC) enrolled at academic centers in France and Sweden. STC-1 concentration was reliably measureable in all CSF samples and was significantly increased in the initial exploratory cohort of neurochemically enriched AD patients versus AD biomarker-negative controls. In the second cohort, STC-1 was increased in AD versus pAD, and other dementia disorders, but the difference was not statistically significant. In the third cohort, there was no significant difference in STC-1 concentration between AD and CNC; however, STC-1 concentration was significantly decreased in patients with other dementia disorders compared with AD and CNC. Taken together, CSF STC-1 showed an increasing trend in AD, but the findings were not consistent across the three study cohorts. In contrast, CSF STC-1 concentrations were reduced in patients with dementia diagnoses other than AD, as compared with both AD patients and CNC. The findings from these studies suggest CSF STC-1 as a potential biomarker in differential diagnosis of dementias.
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