Atlas of Biomarkers for Alzheimer's Disease PDF
Preview Atlas of Biomarkers for Alzheimer's Disease
Manuel Menéndez González Atlas of Biomarkers for Alzheimer’s Disease Atlas of Biomarkers for Alzheimer’s Disease Manuel Mene´ndez Gonza´lez Atlas of Biomarkers for Alzheimer’s Disease 123 Manuel Menéndez González Department of Neurology Hospital Álvarez-Buylla Mieres Asturias Spain ISBN 978-3-319-07988-2 ISBN 978-3-319-07989-9 (eBook) DOI 10.1007/978-3-319-07989-9 SpringerChamHeidelbergNewYorkDordrechtLondon LibraryofCongressControlNumber:2014942059 (cid:2)SpringerInternationalPublishingSwitzerland2014 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeor part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,recitation,broadcasting,reproductiononmicrofilmsorinanyotherphysicalway, andtransmissionorinformationstorageandretrieval,electronicadaptation,computersoftware, orbysimilarordissimilarmethodologynowknownorhereafterdeveloped.Exemptedfromthis legalreservationarebriefexcerptsinconnectionwithreviewsorscholarlyanalysisormaterial suppliedspecificallyforthepurposeofbeingenteredandexecutedonacomputersystem,for exclusiveusebythepurchaserofthework.Duplicationofthispublicationorpartsthereofis permitted only under the provisions of the Copyright Law of the Publisher’s location, in its currentversion,andpermissionforusemustalwaysbeobtainedfromSpringer.Permissionsfor use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liabletoprosecutionundertherespectiveCopyrightLaw. Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthis publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesare exemptfromtherelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. Whiletheadviceandinformationinthisbookarebelievedtobetrueandaccurateatthedateof publication, neither the authors nor the editors nor the publisher can accept any legal responsibilityforanyerrorsoromissionsthatmaybemade.Thepublishermakesnowarranty, expressorimplied,withrespecttothematerialcontainedherein. Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) To my grandmother Lola, who died with Alzheimer’s disease. Her funny sayings still resound in my mind as the first day Preface Neurodegenerative diseases are strongly linked with age, with older people beingathigherrisk.Globalpopulationdemographicsshowthattheworldis rapidlyaging,andsotheprevalenceofneurodegenerativediseasesisrising, withAlzheimer’sdisease(AD)leadingthestatistics.Inviewofthegrowing prevalence of AD worldwide, better diagnostic tools and more effective therapeutic interventions are urgently needed, and much work in this field has been done in recent decades. A major goal of current clinical research in AD is to improve early detectionofdiseaseandpresymptomaticdetectionofneuronaldysfunction, concurrently with the development of better tools to assess disease pro- gressioninthisgroupofdisorders.Theputativecorrelatesusedfordetection and assessment are commonly referred to as AD-related biomarkers. The ideal biomarker should be easy to detect and quantify, reproducible, not subject to wide variation in the general population, and unaffected by comorbid factors. To evaluate therapies, a biomarker needs to change lin- early with disease progression and closely correlate with established clini- copathological parameters of the disease. The vast number of important applications in this field, combined with the untamed diversity of already identified biomarkers, highlights the pressing need to structure the research on AD biomarkers into a solid, a comprehensive, and an easy-to-use tool to be used in clinical settings. To date, few publications have systematically compiled results on this topic, andnoatlashasbeenpublished.Theobjectiveofthisbookistocollectand summarize the most important studies in this field. Readers can find here a guide for reviewing the current status of research while easily visualizing outstandingresults.Thechaptersofthisatlascoverearlydiagnosisandrisk of conversion, differential diagnosis, tracking of disease progression, and application of biomarkers in clinical practice. Each of these chapters includes an introduction and sections on biomarkers in cerebrospinal fluid and neuroimaging biomarkers. Although some other biomarkers have also been explored, we focus on the most important ones. vii Contents 1 Early Diagnosis and Risk of Conversion from Presymptomatic Stages . . . . . . . . . . . . . . . . . . . . . . . 1 1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.1.1 Key Concepts. . . . . . . . . . . . . . . . . . . . . . . . . . 3 1.2 CSF Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 1.2.1 Key Concepts. . . . . . . . . . . . . . . . . . . . . . . . . . 7 1.3 Neuroimaging Biomarkers . . . . . . . . . . . . . . . . . . . . . . 8 1.3.1 MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 1.3.2 FDG PET. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 1.3.3 Molecular Neuroimaging . . . . . . . . . . . . . . . . . . 9 1.3.4 Key Concepts. . . . . . . . . . . . . . . . . . . . . . . . . . 13 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 2 Differential Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 2.2 CSF Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 2.3 Neuroimaging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2.3.1 MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2.3.2 FDG PET. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 2.3.3 Molecular Neuroimaging . . . . . . . . . . . . . . . . . . 19 2.4 Key Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 3 Tracking the Progression. . . . . . . . . . . . . . . . . . . . . . . . . . 23 3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 3.2 CSF Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 3.3 Neuroimaging Biomarkers . . . . . . . . . . . . . . . . . . . . . . 24 3.3.1 MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 3.3.2 FDG PET. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 3.3.3 Molecular Neuroimaging . . . . . . . . . . . . . . . . . . 25 3.4 Key Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 4 Application of Alzheimer Biomarkers in Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 4.2 CSF Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 4.3 Neuroimaging Biomarkers . . . . . . . . . . . . . . . . . . . . . . 32 ix x Contents 4.3.1 MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 4.3.2 FDG PET. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 4.3.3 Molecular Neuroimaging . . . . . . . . . . . . . . . . . . 32 4.4 Diagnostic Criteria and Impact on Clinical Outcomes . . . 33 4.5 Key Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 1 Early Diagnosis and Risk of Conversion from Presymptomatic Stages stages: subjective cognitive impairment (SCI) 1.1 Introduction and mild cognitive impairment (MCI). SCI is defined as a person’s belief that his or her The relevance of the early diagnosis of Alzhei- thinking abilities, including memory, are not as mer’s disease (AD) relies on the hypothesis that good as they were (Fig. 1.1). It is a change pharmacological interventions with disease- people notice in themselves, without being told modifying compounds are likely to produce by others and without significant disturbance in clinicallyrelevantbenefitsifstartedearlyenough neuropsychological assessment. It is a personal in the continuum towards dementia. Currently, conviction that people see as a problem. The many potential disease-modifying therapies are most common complaints are due to memory beingdevelopedandevaluatedatthepreclinical issues. SCI is much more common in later life stage and will lead to clinical trials in the near thantheobjectiveproblemsthatsuggestMCIor futureforwhichbiomarkersareurgentlyneeded. dementia. In addition, depression is associated Biomarkersarevariables(physical,chemical,or with subjective memory problems, as are older anatomical)thatcanbemeasuredinapersonand age,femalesex,andloweducationalattainment. reflect the state ofa disease. Thesearchfor bio- Depression is itself a risk factor for dementia, markers of preclinical AD is becoming increas- making the diagnostic task even more difficult. ingly important because pathogenesis-targeted SCI is not simply a characteristic of the neuroprotective strategies are being developed ‘‘worried well’’; it should be taken seriously. forfutureusein‘‘atrisk’’populations.Advances The poorer memory performance at follow-up in new neuroimaging probes and technologies; and the association of reduced longitudinal identificationofnewbiochemicalmarkersofAD memory performance with hypometabolism in inplasma,blood,andcerebrospinal fluid(CSF); the precuneus at baselinesupportthe conceptof and breakthroughs in molecular genetics and SMIastheearliest manifestation ofAD(Scheef basic neurosciencearegraduallytranslatinginto et al. 2012). better understanding of predisposing and pre- MCI is the point at which others begin to clinical factorsthatleadtoprogressiveneurode- recognize that something’s going on with a generation and finally to cognitive and person’s memory or cognitive functions. Per- behavioralsymptomsanddementia. haps a doctor can detect deficits from a clinical The notion of preclinical AD designates interview,orco-workersmaynoticeachangein cognitively normal subjects harboring early AD performance (Figs. 1.1 and 1.2). Although MCI pathology that is not severe enough to induce can present with a variety of symptoms, when significative cognitive signs and functional memory loss is the predominant symptom it is deterioration. There are two main predementia termed amnestic MCI (aMCI) and is frequently M.MenéndezGonzález,AtlasofBiomarkersforAlzheimer’sDisease, 1 DOI:10.1007/978-3-319-07989-9_1,(cid:2)SpringerInternationalPublishingSwitzerland2014 2 1 EarlyDiagnosisandRiskofConversion Normal aging Asymptomatic AD (pre-clinical P nal Subjective cognitive impairment stage) laq nctioance Mild cognitive MCI due to AD ues a um impairment (MCI) (pre-dementia) n gnitive/fpefor Clinically d tangle o Dementia defined s C AD Progression of deficits from normal aging to dementia Threshold to subjective cognitive impairment Threshold to objective phase: MCI Threshold to dementia: cognitive + functional impairment Progression of neuropathological events Fig.1.1 HypotheticalmodelofthepathologicalprocessesinAlzheimer’sdisease(AD),focusingontheamyloidb peptide(Ab)cascade(fromForlenzaetal.2010) D A Overproduction of Aβ c) Abnormal APP metabolism ati Reduced Aβ clearance m AD-mutations pto (APP, PS1, PS2 genes) Aging m y as Risk-genes al ( (apolipoprotein E) Amyloid-β Unknown factors c accumulation ni cli e- r P Activation of a neurotoxic cascades Fibrillary Aβ Hyperphosphorylation nti Decreased neurotrophic Aβ oligomers of TAU e m support e d e- r P Amyloid plaques Synaptic dysfunction Glial activation a Axonal dysfunction nti Inflammation Collapse of cytoskeleton e Oxidative stress m e Mitochondrial dysfunction Neuritic plaques d al c ni Cli Neurofibrillary Dementia tangles Fig.1.2 Relationship between the progression of cog- manifest dementia of the AD type. Ab—amyloid beta; nitiveandfunctional symptomsandtheneuropathologi- APP—amyloid precursor protein (from Forlenza et al. cal events in the transition from asymptomatic AD to 2010) mild cognitive impairment due to AD and clinically
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