Atlas of Biomarkers for Alzheimer's Disease

43 Pages·2014·1.925 MB·English

by  Manuel Menéndez González (auth.)

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
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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