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Article Dans Une Revue The Journal of prevention of Alzheimer's disease Année : 2014

The road ahead to cure Alzheimer’s disease: development of biological markers and neuroimaging methods for prevention trials across all stages and target populations

1 UPMC - Université Pierre et Marie Curie - Paris 6
2 IM2A - Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre]
3 PAD 2020 - Prevent Alzheimer’s Disease 2020 [Rockville]
4 Neuro - UC San Diego - Department of Neurosciences [Univ California San Diego]
5 Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations
6 Institute of Brain, Behaviour and Mental Health
7 Department of Radiology [Rochester]
8 Center for Alzheimer Research and Treatment [Boston]
9 Lou Ruvo Center for Brain Health [Las Vegas]
10 Department of Psychiatry and Neurochemistry [Goteborg]
11 IAADR - Institute for Aging and Alzheimer’s Disease Research [Fort Worth]
12 IRCCS San Giovanni, Laboratory of Epidemiology and Neuroimaging, Brescia
13 Alzheimer’s & Dementia [Rockville]
14 Karolinska Institutet [Stockholm]
15 Department of Psychiatry [Pittsburgh]
16 Federal Institute of Drugs and Medical Devices [Bonn]
17 LEASP - Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps
18 Service Epidémiologie clinique et santé publique [CHU Toulouse]
19 Natbrainlab, Department of Forensic and Neurodevelopmental Sciences
20 NEUROSPIN - Service NEUROSPIN
21 LNAO - Laboratoire de Neuroimagerie Assistée par Ordinateur
22 Department of Radiology and Nuclear Medicine [Amsterdam]
23 Department of Neurology [Boston]
24 Department of Psychosomatic Medicine [Rostock]
25 Department of Nuclear Medicine [Cologne]
26 Institute of Neuroscience
27 ARAMIS - Algorithms, models and methods for images and signals of the human brain = Algorithmes, modèles et méthodes pour les images et les signaux du cerveau humain [ICM Paris]
28 CHU Pitié-Salpêtrière [AP-HP]
29 Keck School of Medicine [Los Angeles]
Bruno Dubois
  • Fonction : Auteur
  • PersonId : 893169

Résumé

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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Dates et versions

hal-01098836 , version 1 (23-10-2017)

Identifiants

Citer

Enrica Cavedo, Simone Lista, Zaven S Khachaturian, Paul S Aisen, Philippe Amouyel, et al.. The road ahead to cure Alzheimer’s disease: development of biological markers and neuroimaging methods for prevention trials across all stages and target populations. The Journal of prevention of Alzheimer's disease, 2014, 1 (3), pp.181-202. ⟨10.14283/jpad.2014.32⟩. ⟨hal-01098836⟩
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