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Biochem Pharmacol. 2014 Apr 15;88(4):426-49. doi: 10.1016/j.bcp.2013.11.009. Epub 2013 Nov 22.

Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: a long-range point of view beyond 2020.

Author information

1
Université Pierre et Marie Curie, Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Pavillon François Lhermitte, Hôpital de la Salpêtrière, Paris, France. Electronic address: harald.hampel@psl.aphp.fr.
2
Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany. Electronic address: slista@libero.it.
3
Department of Psychosomatic Medicine, University of Rostock, Rostock, Germany; German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Rostock, Germany.
4
Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology, and Radiotherapy, University of Rome "Tor Vergata", Rome, Italy; IRCCS San Raffaele Pisana, Rome and San Raffaele Cassino, Cassino, Italy.
5
Department of Physiology and Pharmacology, University of Rome "La Sapienza", Rome, Italy; IRCSS Santa Lucia Foundation, Rome, Italy.
6
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
7
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; University College London Institute of Neurology, Queen Square, London, UK.
8
Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
9
Laboratoire de Neuropathologie Raymond-Escourolle, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, Paris, France.
10
IM2A - Institute of Memory and Alzheimer's Disease, Paris, France; IHU-A-ICM - Paris Institute of Translational Neurosciences Pitié-Salpêtrière University Hospital, Paris, France.
11
Department of Nuclear Medicine, University Hospital of Cologne, Cologne, Germany.
12
Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière, UMR-S975 Paris, France; Inserm, U975, Paris, France; CNRS, UMR 7225, Paris, France; ICM - Institut du Cerveau et de la Moelle Épinière, Paris, France; INRIA, Aramis Team, Centre de Recherche Paris-Rocquencourt, France.
13
Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié Salpêtrière, Paris, France; Université Pierre et Marie Curie, Paris, France.
14
Federal Institute of Drugs and Medical Devices (BfArM), Bonn, Germany.
15
IHU-A-ICM - Paris Institute of Translational Neurosciences Pitié-Salpêtrière University Hospital, Paris, France; Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière, UMR-S975 Paris, France; Inserm, U975, Paris, France; CNRS, UMR 7225, Paris, France; ICM - Institut du Cerveau et de la Moelle Épinière, Paris, France.
16
Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière, UMR-S975 Paris, France; Inserm, U975, Paris, France; CNRS, UMR 7225, Paris, France; ICM - Institut du Cerveau et de la Moelle Épinière, Paris, France; AP-HP, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, Paris, France.
17
The Campaign to Prevent Alzheimer's Disease by 2020 (PAD2020), Potomac, MD, USA.
18
Department of Neurosciences, University of California, San Diego, San Diego, CA, USA.

Abstract

Recent advances in understanding the molecular mechanisms underlying various paths toward 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.

KEYWORDS:

Alzheimer's disease; CSF/blood biomarkers; Clinical trials; PET imaging markers; Structural/functional MRI markers

PMID:
24275164
DOI:
10.1016/j.bcp.2013.11.009
[Indexed for MEDLINE]

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