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      Biological markers for early detection and pharmacological treatment of Alzheimer's disease Translated title: Marcadores biológicos para la detección y el tratamiento precoz de la Enfermedad de Alzheimer Translated title: Marqueurs biologiques de détection et traitement précoces de la maladie d'Alzheimer

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          Abstract

          The introduction of biological markers in the clinical management of Alzheimer's disease (AD) will not only improve diagnosis relating to early detection of neuropathology with underlying molecular mechanisms, but also provides tools for the assessment of objective treatment benefits. In this review, we identify a number of in vivo neurochemistry and neuroimaging techniques, which can reliably assess aspects of physiology, pathology, chemistry, and neuroanatomy of AD, and hold promise as meaningful biomarkers in the early diagnostic process, as well as for the tracking of disease-modifying pharmacological effects. These neurobiological measures appear to relate closely to pathophysiological, neuropathological, and clinical data, such as hyperphosphorylation of tau, abeta metabolism, lipid peroxidation, pattern and rate of atrophy, loss of neuronal integrity, and functional and cognitive decline, as well as risk of future decline. As a perspective, the important role of biomarkers in the development of innovative drug treatments for AD and the related regulatory process is discussed.

          Translated abstract

          La introducción de marcadores biológicos en el manejo clínico de la Enfermedad de Alzheimer (EA) no sólo mejorará el diagnóstico relacionado con la detección precoz de la neuropatología y los mecanismos moleculares subyacentes, sino que también proveerá herramientas para la evaluación de los beneficios objetivos del tratamiento. En esta revisión se identifican varias técnicas neuroquímicas y de neuroimágenes in vivo, que pueden evaluar de manera confiable aspectos fisiológicos, patológicos, químicos y neuroanatómicos de la EA y se destacan prometedores biomarcadores significativos en los procesos del diagnóstico precoz, como también para el monitoreo de los efectos farmacológicos que van modificando la enfermedad. Las mediciones neurobiológicas parecen relacionarse estrechamente con datos fisiopatológicos, neuropatológicos y clínicos, tales como la hiperfosforilación de tau, el metabolisme beta-amiloide, la peroxidacíon de Iípidos, los patrones y frecuencias de la atrofia, la pérdida de la integridad neuronal, y la declinación cognitiva y funcional, como también el riesgo de futuros deterioros. Con una visión a futuro se discute el importante papel de los biomarcadores en el desarrollo de innovadoras terapias farmacológicas para la EA y los procesos relacionados con las agencias reguladoras.

          Translated abstract

          L'introduction des marqueurs biologiques dans la prise en charge clinique de la maladie d'Alzheimer (MA) devrait non seulement améliorer le diagnostic grâce à une détection précoce de la neuropathologie et de ses mécanismes moléculaires sous-jacents, mais également fournir des outils pour l'évaluation des bénéfices objectifs du traitement. Nous individualisons dans cet article un certain nombre de techniques de neurochimie et de neuro-imagerie in vivo, qui permettent d'évaluer de façon fiable les aspects physiologiques, pathologiques, chimiques et neuroanatomiques de la MA et qui semblent prometteuses comme biomarqueurs du diagnostic précoce, et comme outils de surveillance des effets pharmacologiques modifiant la maladie. Ces mesures neurobiologiques sont étroitement liées aux données cliniques, neuropathologiques et physiopathologiques, telles que l'hyperphosphorylation de tau, le métabolisme de abêta, la peroxydation lipidique, le modèle et le taux d'atrophie, la perte d'intégrité neuronale et d'autonomie et l'altération cognitive ainsi que le risque de déclin futur. Nous nous proposons donc d'analyser le róle important des biomarqueurs dans le développement de traitements innovants de la MA et les dispositions réglementaires qui s'y rapportent.

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          Principles of diffusion tensor imaging and its applications to basic neuroscience research.

          The brain contains more than 100 billion neurons that communicate with each other via axons for the formation of complex neural networks. The structural mapping of such networks during health and disease states is essential for understanding brain function. However, our understanding of brain structural connectivity is surprisingly limited, due in part to the lack of noninvasive methodologies to study axonal anatomy. Diffusion tensor imaging (DTI) is a recently developed MRI technique that can measure macroscopic axonal organization in nervous system tissues. In this article, the principles of DTI methodologies are explained, and several applications introduced, including visualization of axonal tracts in myelin and axonal injuries as well as human brain and mouse embryonic development. The strengths and limitations of DTI and key areas for future research and development are also discussed.
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            A new rating scale for age-related white matter changes applicable to MRI and CT.

            MRI is more sensitive than CT for detection of age-related white matter changes (ARWMC). Most rating scales estimate the degree and distribution of ARWMC either on CT or on MRI, and they differ in many aspects. This makes it difficult to compare CT and MRI studies. To be able to study the evolution and possible effect of drug treatment on ARWMC in large patient samples, it is necessary to have a rating scale constructed for both MRI and CT. We have developed and evaluated a new scale and studied ARWMC in a large number of patients examined with both MRI and CT. Seventy-seven patients with ARWMC on either CT or MRI were recruited and a complementary examination (MRI or CT) performed. The patients came from 4 centers in Europe, and the scans were rated by 4 raters on 1 occasion with the new ARWMC rating scale. The interrater reliability was evaluated by using kappa statistics. The degree and distribution of ARWMC in CT and MRI scans were compared in different brain areas. Interrater reliability was good for MRI (kappa=0.67) and moderate for CT (kappa=0.48). MRI was superior in detection of small ARWMC, whereas larger lesions were detected equally well with both CT and MRI. In the parieto-occipital and infratentorial areas, MRI detected significantly more ARWMC than did CT. In the frontal area and basal ganglia, no differences between modalities were found. When a fluid-attenuated inversion recovery sequence was used, MRI detected significantly more lesions than CT in frontal and parieto-occipital areas. No differences were found in basal ganglia and infratentorial areas. We present a new ARWMC scale applicable to both CT and MRI that has almost equal sensitivity, except for certain regions. The interrater reliability was slightly better for MRI, as was the detectability of small lesions.
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              Surrogate end points in clinical trials: are we being misled?

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                Author and article information

                Contributors
                Department of Psychiatry, Ludwig-Maximilian University Munich, Alzheimer Memorial Center, Munich, Germany; Discipline of Psychiatry, School of Medicine & Trinity College Institute of Neuroscience (TCIN), Laboratory of Neuroimaging & Biomarker Research, Trinity College, University of Dublin, Ireland
                Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany
                Department of Psychiatry, Ludwig-Maximilian University Munich, Alzheimer Memorial Center, Munich, Germany
                Department of Psychiatry, Psychosomatics and Psychotherapy, Hospital of the Johann Wolfgang Goethe University Frankfurt, Germany
                Journal
                Dialogues Clin Neurosci
                Dialogues Clin Neurosci
                Dialogues in Clinical Neuroscience
                Les Laboratoires Servier (France )
                1294-8322
                1958-5969
                June 2009
                : 11
                : 2
                : 141-157
                Affiliations
                Department of Psychiatry, Ludwig-Maximilian University Munich, Alzheimer Memorial Center, Munich, Germany; Discipline of Psychiatry, School of Medicine & Trinity College Institute of Neuroscience (TCIN), Laboratory of Neuroimaging & Biomarker Research, Trinity College, University of Dublin, Ireland
                Bundesinstitut für Arzneimittel und Medizinprodukte, Bonn, Germany
                Department of Psychiatry, Ludwig-Maximilian University Munich, Alzheimer Memorial Center, Munich, Germany
                Department of Psychiatry, Psychosomatics and Psychotherapy, Hospital of the Johann Wolfgang Goethe University Frankfurt, Germany
                Author notes
                Article
                10.31887/DCNS.2009.11.2/hhampel
                3181918
                19585950
                97b7dd6b-a6ea-4b34-ad4a-c441f18a10ea
                Copyright: © 2009 LLS

                This is an open-access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Categories
                Translational Research

                Neurosciences
                disease modification,alzheimer's disease neuroimaging initiative,diagnosis,drug development,alzheimer's disease,biomarker

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