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Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 NEUROSCIENCE RESEARCH PROGRESS

ALZHEIMER'S DIAGNOSIS

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or
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Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

rendering legal, medical or any other professional services.

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 NEUROSCIENCE RESEARCH PROGRESS
Additional books in this series can be found on Nova‘s website
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Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 NEUROSCIENCE RESEARCH PROGRESS

ALZHEIMER'S DIAGNOSIS

CHARLES E. RONSON
Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

EDITOR

Nova Science Publishers, Inc.

New York

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 Copyright © 2011 by Nova Science Publishers, Inc.

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Additional color graphics may be available in the e-book version of this book.

Library of Congress Cataloging-in-Publication Data

Alzheimer's diagnosis / editor, Charles E. Ronson.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-62081-680-6 (eBook)
1. Alzheimer's disease--Diagnosis. I. Ronson, Charles E.
[DNLM: 1. Alzheimer Disease--diagnosis. WT 155]
RC523.A36756 2011
616.8'31--dc22
2011004496

Published by Nova Science Publishers, Inc.† New York

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 Contents

Preface vii
Chapter I Quantitation of Amyloid-Β Oligomers in Human
Body Fluids for Alzheimer‘s Disease: Early
Diagnosis or Therapy Monitoring? 1
Susanne Aileen Funke and Dieter Willbold
Chapter II Visual Impairment in Alzheimer Disease: Clinical,
Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Pathophysiological and Instrumental Aspects 25

Ferdinando Sartucci, Tommaso Bocci, Elisa Giorli,
Vittorio Porciatti, Nicola Origlia
and Luciano Domenici
Chapter III Alzheimer‘s Disease Diagnosis: A New Approach 43
Ana Valverde and Sónia Costa
Chapter IV Mitochondrial Haplogroups Associated
with Japanese Alzheimer‘s Patients 61
Shigeru Takasaki
Chapter V Leading Role and Limits of 18F-FDG-PET Imaging
in Early Diagnosis of Alzheimer‘s Disease 81
Giorgio Treglia and Ernesto Cason

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 vi Contents

Chapter VI Artificial Neural Networks in Alzheimer's

Diagnosis: A Perspective 95
Patricio García Báez, Carmen Paz Suárez Araujo
and José Manuel Martínez García
Chapter VII Milestones and Difficulties
in Alzheimer‘s Disease Diagnosis 137
Lucia Picchi, Marco Vista and Monica Mazzoni
Chapter VIII The Role of Neuroimaging in the Early
Diagnosis of Alzheimer‘s Disease 175
Valentina Garibotto and Daniela Perani
Chapter IX Cerebrospinal Fluid Biomarkers
for Alzheimer‘s Disease 227
Eliana Venturelli, Chiara Villa and Elio Scarpini
Index 245
Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 Preface
The demographics of aging suggest a great need for an early diagnosis of
dementia and for the development of preventive strategies. Neurodegeneration
in Alzheimer's disease is estimated to start 20-30 years before clinical onset,
and the identification of biological markers for pre-clinical and early diagnosis
is the principal aim of research studies in the field. In this book, the authors
present topical research on Alzheimer's diagnosis including cerebrospinal fluid
biomarker Amyloid-B 1-42 identification; visual impairment in Alzheimer's
disease; cerebral glucose metabolism through F-fluoro-deoxy-glucose positron
Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

emission tomography and neuroimaging. (Imprint: Nova Biomedical Press)

Chapter I - Today, the diagnosis of Alzheimer‘s disease (AD) is based on
the identification of symptoms like dementia and other clinical indications.
Cerebrospinal fluid (CSF) biomarkers like the level of amyloid-β 1-42 (Aβ42),
which is lower in AD patients than in controls, or the levels of total Tau and
phosphorylated Tau, which are enhanced, are supposed to increase the
diagnostic accuracy or might even be valuable for earlier diagnosis. However,
the monomeric form of Aβ is not thought to be responsible for neurotoxocity
and neurodegeneration. Aβ monomers are non-pathogenic metabolic products
also abundant in healthy humans. Aβ oligomers were identified as the most
toxic species in AD which arise early in the disease progress and the amount
of Aβ oligomers in the brain correlates well with cognitive impairment.
Therefore, presence of Aβ oligomers can be expected to be a more direct
disease biomarker for AD and increasing effort is being made into the
development of methods suitable for the detection of different Aβ aggregates
in body fluids like CSF and plasma. Here, we review the current status of
assay development to reliably and routinely detect Aβ oligomers in body
fluids. Additionally, we compare the outcomes of the different assay systems.

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 viii Charles E. Ronson

Chapter II - Alzheimer‘s Disease (AD) is the most common cause of

dementia in the older adults world-wide. About 4.5 million individuals in USA
currently are estimated to be affected and by mid-century the prevalence will
be 11.3-16 million cases (Cronin-Golomb and Hof, 2004). AD is viewed as a
disorder primarily of memory, that represents usually the initial sign;
moreover, this disease is characterized by impairment in several additional
domains, including visual function. However, the NINCDS-ADRDA clinical
diagnostic criteria (Tierney et al., 1988) make no mention of sensory changes.
Several main fields of researches on vision in AD currently are undertaken,
from structure to function and behavior at this time, and current directions in
AD vision studies are extensively reported in many papers, including some
exhaustive books (Cronin-Golomb and Hof, 2004). In summary, this chapter
spans the visual impairment in AD patients, from structure to function, either
at retinal or cortical levels in an attempt to highlight visual sub-system
changes, particularly the magnocellular, in AD compared to normal aging and
other age-related degenerative disorders.
Chapter III - Clinical neuroscience has an increasing need for new
methods to identify the earliest features of neurodegenerative disorders such as
Alzheimer‘s disease (AD) and other dementias. This growing interest in the
pre-dementia phase of these conditions aims to identify them before functional
impairment is evident. Ideally before this phase, treatment of the underlying
Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

disease would postpone its process. A variety of clinical, imaging and

laboratory methods has emerged during the last decade to allow more accurate
diagnosis of AD. A review of these new markers will be made with reference
to the new diagnostic criteria proposed by the International Working Group in
Alzheimer‘s disease.
Chapter IV - The relations between Japanese Alzheimer‘s disease (AD)
patients and their mitochondrial single nucleotide polymorphism (mtSNP)
frequencies at individual mtDNA positions of the entire mitochondrial genome
were examined using the radial basis function (RBF) network and the
modified method. Japanese AD patients were associated with the haplogroups
G2a, B4c1, and N9b1. In addition, to compare mitochondrial haplogroups of
the AD patients with those of other classes of Japanese people, the relations
between four classes of Japanese people (i.e., Japanese centenarians,
Parkinson‘s disease (PD) patients, type 2 diabetic (T2D) patients, and non-
obese young males) and their mtSNPs were also analyzed by the proposed
method. The four classes of people were associated with following
haplogroups: Japanese centenarians—M7b2, D4b2a, and B5b; Japanese PD
patients—M7b2, B4e, and B5b; Japanese T2D patients—B5b, M8a1, G, D4,

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 Preface ix

and F1; and Japanese healthy non-obese young males— D4g and D4b1b. The
haplogroups of the AD patients are therefore different from those of other four
classes of Japanese people. As the analysis method described in this article can
predict a person‘s mtSNP constitution and the probabilities of becoming an
AD patient, centenarian, PD patient, or T2D patient, it may be useful in initial
diagnosis of various diseases.
Chapter V - Early detection of Alzheimer‘s disease (AD) is particularly
important to reveal preclinical pathological alterations, to monitor disease
progression and to evaluate treatment response. The study of cerebral glucose
metabolism through 18F-fluoro-deoxy-glucose positron emission tomography
(FDG-PET) plays a leading role in early detection of AD because the decrease
of cerebral glucose metabolism largely precedes the onset of AD symptoms.
This technique demonstrated high sensitivity in early diagnosis of AD
allowing a qualitative and quantitative estimate of cerebral glucose
metabolism. Furthermore FDG-PET imaging may help discriminate the
subjects who more probably could develop AD in a high-risk population (as
patients with mild cognitive impairment). A limit of FDG-PET is the lack of
specificity; in fact the decrease of cerebral glucose metabolism is a common
feature of various dementias. Nevertheless AD patients generally show
hypometabolism of medial temporal lobes and parieto-temporal posterior
cortices in early stage; other cortices are involved in more advanced AD
Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

stages. The combination of FDG-PET with other biomarkers such as genotype,

cerebrospinal fluid markers and tracers for amyloid plaque imaging may
increase the preclinical diagnostic accuracy and offer promising approaches to
assess individual prognosis in AD patients.
Chapter VI - A clear tendency of an aging population (2.5 billion elders
are estimated on a global scale by the year 2050) has brought about an increase
of its associated diseases, one of which is the higher prevalence dementia
focusing in Alzheimer’s Disease (AD). Today, it is estimated that there are 18
million people suffering from AD worldwide, and the disease affects 5% -10%
of 65-year old and more than 30% of 85-year old. This situation has important
repercussions in the scope of the patient but also in the familiar, social and
sanitary spheres. Therefore, early diagnosis of AD is a major public healthcare
concern, and the Differential Diagnosis of Dementia (DDD) is also one of the
crucial points to which clinical medicine faces at every level of attention. The
definite diagnosis of AD is only post-mortem. Furthermore, there are not yet a
specific set of diagnostic criteria for the confirmation of the diagnosis. In this
context it's necessary to develop new alternative methods and instruments of
diagnosis, especially on early and differential diagnosis, and introducing its

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 x Charles E. Ronson

use in all healthcare areas. This chapter will be dedicated to explore the ability
of a complementary approach to face these problems, the Artificial Neural
Networks (ANNs). The ANNs are highly non-linear systems. Its more
appealing property is its learning capability. Its behaviour emerges from
structural changes driven by local learning rules, having the capability of
generalisation. In addition to this approach, especially computer-intensive
algorithms based on ―ensemble learning‖-methods that generate many
classifiers and aggregate their results are being developed in regard of Mild
Cognitive Impairment (MCI), AD and DDD classification. We will present a
study of ANNs, where it will be analysed a new neural architecture,
HUMANN-S, which has shown to be a very suitable ANN for Alzheimer's
diagnosis scope. The neural network ensemble approach is introduced. Finally
we will discuss the ability of ANN and neural network ensembles, to address
this issue, describing the outcomes of implementations of such approaches for
AD, DDD and MCI diagnosis using for the inputs several types of data:
Electroencephalogram (EEG) type signals, neuroimages, like Single Photon
Emission Computerized Tomography (SPECT), and/or scores of different
neuropsychological tests, among others.
Chapter VII – Progressive aging of population will make Alzheimer‘s
Disease (AD) one of the most important health problems of the next years,
challenging social security and health systems of industrialized countries. The
Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

present work analyzes the resources and the difficulties of the diagnostic flow
charts in territorial reality where more important space is given to the clinical
activity rather than to research. When first symptoms of a possible dementia
appear, people contact general practioner, directly or pushed by their relatives.
The general practioner is very important for the screening in case of a possible
dementia because his/her attention and sensibility make early diagnosis
possible. General practioner, in fact, usually requires a consult to the specialist
(neurologist, psychiatric, geriatrician), which, working in équipe with the
psychologist, can begin a multi-dimentional evaluation of first level that
includes: 1) medical history; 2) general and neurological examination; 3)
neuropsychological screening; 4) evaluation of functional abilities; 5)
assessment of patient‘s relationship and family context; 6) routine and specific
blood tests; 7) at least one neuroimaging exam (e.g. CT scan). Undoubtedly,
the results of the clinical and instrumental investigations may provide useful
elements for the differential diagnosis of dementia and, therefore, for adequate
medical, psychological and socio-relational caring. However, the diagnostic
process remains, to date, a puzzle that clinicians build progressively due to the
lack of specific biomarkers.

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 Preface xi

Chapter VIII - The demographics of aging suggest a great need for an

early diagnosis of dementia and for the development of preventive strategies.
Neurodegeneration in Alzheimer‘s disease (AD) is estimated to start even 20–
30 years before clinical onset, and the identification of biological markers for
pre-clinical and early diagnosis is the principal aim of research studies in the
field. It is still difficult to make diagnosis in the early disease stages. At the
beginning the patient might have a deficit limited to memory or to another
single cognitive domain, without any disorder of instrumental and daily
activities. The cognitive impairment then might proceed to a degree that
allows the diagnosis of dementia. The transitional state between normal ageing
and mild dementia has been recently indicated by the term Mild Cognitive
Impairment (MCI). In the last few years, a wide range of studies addressed this
topic. Clinically, within the group of MCI subjects, two separate subgroups
have been described, those rapidly converting to AD (MCI converters), in
whom MCI represents the early stage of an ongoing AD-related process, and
those who remain stable (MCI non-converters), in whom the isolated cognitive
deficits represent a different condition without an increased risk to develop
dementia at short follow-up. In this line, reliable markers for early AD
detection could be useful both for prognosis, and for identifying a potential
target for therapeutic intervention, since treatments are emerging which rather
than reversing structural damage are likely to slow or halt the disease process.
Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

While currently no routine diagnostic test confirms AD presence, functional

neuroimaging techniques represent an important tool in biological neurology.
The challenge for neuroimaging methods is to achieve high specificity and
sensitivity in early disease stages and at single subject level. Functional
imaging, in particular, has the potential to detect very early brain dysfunction
even before clear-cut neuropsychological deficits emerge. Predicting
progression to AD in cases of MCI and supporting diagnosis and differential
diagnosis of dementia are the outmost important goals. The implications are
the identification of minimally symptomatic patients that could benefit from
treatment strategies, as well as the monitoring of treatment response and the
therapeutic deceleration of the disease. This chapter highlights recent cross-
sectional and longitudinal neuroimaging studies in the attempt to put into
perspective their value in diagnosing AD-like changes, particularly at an early
stage, providing diagnostic and prognostic specificity. There is now
considerable evidence supporting that early diagnosis is feasible through a
multimodal approach, including also a combination of multiple imaging
modalities.

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 xii Charles E. Ronson

Chapter IX - Alzheimer‘s disease (AD), Lewy-body disease (LBD) and

Frontotemporal Dementia (FTD) are the major causes of memory impairment
and dementia. As new therapeutic agents are under testing for the different
diseases, there is an ultimate need for an early differential diagnosis.
Biomarkers can serve as early diagnostic indicators or as markers of
preclinical pathological changes. Therefore, diagnostic markers in the
cerebrospinal fluid (CSF) have become a rapidly growing research field, since
CSF is in direct contact with the central nervous system (CNS) and is
supposed to reflect the brain environment. So far, three CSF biomarkers, the
42 amino acid form of β-amyloid (Aβ), total tau and phosphotau, have been
validated in a number of studies. These CSF markers have high sensitivity to
differentiate early and incipient AD from normal aging, depression, alcohol
dementia and Parkinson‘s disease, but lower specificity against other
dementias, such as FTD and LBD. This chapter reviews CSF biomarkers for
AD, with emphasis on their role in the clinical diagnosis.
Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 In: Alzheimer's Diagnosis ISBN: 978-1-61209-846-3
Editor: Charles E. Ronson, pp. 1-24 ©2011 Nova Science Publishers, Inc.

Chapter I

Quantitation of Amyloid-Β
Oligomers in Human Body Fluids
for Alzheimer’s Disease:
Early Diagnosis or Therapy
Monitoring?
Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Susanne Aileen Funke and Dieter Willbold

Institute of Complex Systems (ICS-6),
Forschungszentrum Jülich, Jülich, Germany
Institut für Physikalische Biologie, Heinrich-Heine-Universität,
Düsseldorf, Germany

Abstract
Today, the diagnosis of Alzheimer‘s disease (AD) is based on the
identification of symptoms like dementia and other clinical indications.
Cerebrospinal fluid (CSF) biomarkers like the level of amyloid-β 1-42
(Aβ42), which is lower in AD patients than in controls, or the levels of
total Tau and phosphorylated Tau, which are enhanced, are supposed to
increase the diagnostic accuracy or might even be valuable for earlier
diagnosis.

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 2 Susanne Aileen Funke and Dieter Willbold

However, the monomeric form of Aβ is not thought to be responsible

for neurotoxocity and neurodegeneration. Aβ monomers are non-
pathogenic metabolic products also abundant in healthy humans. Aβ
oligomers were identified as the most toxic species in AD which arise
early in the disease progress and the amount of Aβ oligomers in the brain
correlates well with cognitive impairment.
Therefore, presence of Aβ oligomers can be expected to be a more
direct disease biomarker for AD and increasing effort is being made into
the development of methods suitable for the detection of different Aβ
aggregates in body fluids like CSF and plasma.
Here, we review the current status of assay development to reliably
and routinely detect Aβ oligomers in body fluids. Additionally, we
compare the outcomes of the different assay systems.

Introduction
Alzheimer‘s disease (AD) is a devastating neurodegenerative disorder and
the most common cause of dementia, which accounts for 60 to 80 percent of
the estimated cases. The clinical characteristics are difficulties remembering
names and recent events, apathy and depression at the beginning, later
followed by impaired judegment, disorientation, confusion, behavior changes
and difficulties in speaking, swallowing and walking. The greatest risk factor
Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

for AD is advancing age (aged 65 or older), but most scientists agree that AD
is not a normal part of aging (Alzheimer‘s association). AD affects 27 million
people world-wide (1) with steadily increasing tendency, thereby raising
significant personal and economic problems.
Currently, the only definite diagnosis of AD is the post mortem detection
of amyloid plaques and neurofibrillary tangles in the brain tissue of the
deceased patient. Diagnosis of AD during lifetime is based on the
identification of the symptoms described above and physiological screening
tests for cognitive impairment like the Mini-Mental Status Examination
(MMSE) or the Alzheimer‘s Disease Assessment Scale (2, 3).
Even in specialized centers it is challenging to diagnose AD at early
stages, and diagnosis based on clinical symptoms will always fail to reveal
presymptomatic cases. The sensitivity and specificity of clinical diagnosis for
AD is 70 to 80 percent only in specialized centers and even lower for patients
with early AD or in primary care settings (4-6). Several publications support
the finding that plaques and tangles start to accumulate 10 to 20 years before
the symptoms appear, leading to substantial neuronal loss (7-9).

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 Quantitation of Amyloid-Β Oligomers … 3

Therefore, the challenge is to diagnose individuals at earlier stages, when

the disease is still presymptomatic and perhaps more amenable to treatment.
At present, only symptomatic treatment of AD is available, but several
compounds are currently being developed, most of them aiming at Aβ, e.g.
secretase inhibitors, immunotherapy and Aβ aggregation inhibitors (10, 11).
More than 10 compounds are currently in clinical phase III trials, and much
more in phases I or II (Alzforum). Referring to PubMed, hundreds of
compounds are in the preclinical state.
One of the biggest obstacles for AD therapy development is the lack of
biomarkers which reflect the core pathology of AD and the disease state and
progression, not dependent of clinical symptoms as they arise late in AD
pathology and are difficult to detect adequately.
One biomarker probably suited to fulfill the requirements is the amyloid-β
(Aβ) peptide. Aβ is the major component of the amyloid plaques. It consists of
39 to 43 amino acid residues. Aβ, especially Aβ42, is prone to aggregation and
undergoes formation from monomers to oligomers, larger intermediate forms
like protofibrils, insoluble fibrils and plaques (12). Aβ is derived from the
amyloid precursor protein (APP) by sequential activities of the β- and γ-
secretases (13-15). As originally suggested by the amyloid cascade hypothesis
(16), it appears likely that Aβ peptides and their aggregated forms initiate
cellular events leading to the pathologic effects of AD. According to a
Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

prevoius version of the amyloid cascade hypothesis, fibrillar forms of Aβ in

amyloid plaques have been thought to be responsible for neuronal dysfunction
(16, 17). More recent studies support that diffusable Aβ oligomers, including
protofibrils, prefibrillar aggregates and so called Aβ-derived diffusible ligands
(ADDLs), are the major toxic species during disease development and
progression (18-21).
More or less validated clinical methods for the determination of Aβ load
in vivo are the visualization of the amyloid plaque load in the living brain
using amyloid-binding tracers like Pittsburgh Compound B (PIB) in positron
emission tomography (PET) (22) or the detection of monomeric Aβ in the
cerebrospinal fluid (CSF) via ELISA or ELISA-like methods (23, 24).
PIB has relatively high sensitivity for the detection of amyloid plaques in
human brains in vivo (25) and several studies demonstrate significant PIB
binding in AD patients as compared to controls (24, 26). About 50 percent of
patients with mild cognitive impairment are PIB positive. Significant PIB
binding can also be found in about 22 percent of cognitive unimpaired elderly,
again supporting the finding that plaques accumulate before cognitive

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 4 Susanne Aileen Funke and Dieter Willbold

symptoms appear (9). Nevertheless, PIB retention during AD progression does

not increase to much extend (27).
During the recent years, CSF samples of subjects with probable AD were
assayed for total or monomeric Aβ40 or Aβ42 concentrations using classical
ELISA or ELISA-related methods with additional signal amplification. CSF
concentrations of monomeric Aβ42 are reduced by 30 to 50 percent in AD
patients compared to age-matched non-demented controls as confirmed in
many independent studies, with both sensitivity and specificity exceeding 80
% in most of the studies. Decrease of Aβ42 in the CSF has also been detected
during stages of mild cognitive impairment, the earliest clinical manifestation
of AD in a subset of individuals and also in individuals with very mild and
mild Alzheimer‘s (23, 24, 28, 29). Thus, it was suggested that low levels of
CSF Aβ42 might be useful for preclinical diagnosis.
Aβ monomer concentrations in blood were also investigated in several
studies. Blood-based biomarkers would be valuable as blood is less
complicated to collect than CSF. Unlike changes in the CSF, reports of
changes in Aβ levels of plasma in AD patients and non/pre AD are rather
inconsistent, which might be due to technical reasons (for reviews see (28, 30).
However, the monomeric form of Aβ is not thought to be responsible for
neurotoxicity and neurodegeneration. Aβ monomers are a natural metabolic
product also abundant in healthy humans and hence a natural component of
Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

serum and plasma (31). More than Aβ deposits in the brain - the hallmark of
AD - Aβ oligomers were identified to be the most toxic species, which arise
early in the disease progress. It was shown that the amount of Aβ oligomers in
the brain correlates well with cognitive impairment (18-21).
PET is currently available in specialized centers only and comparably
expensive. It is known to detect amyloid plaques, but not oligomers (32, 33).
According to Jack and co-workers, the first biomarker change detectable with
currently available methods is the decrease of CSF Aβ42, which might reflect
the formation of Aβ oligomers and smaller aggregates. This change is
followed by amyloid deposition which can be visualized using PIB-PET (34).
Therefore, the presence of Aβ oligomers can be expected to be a very
early and direct disease biomarker for AD and increasing effort is being made
in the development of methods suitable for the detection of Aβ oligomers in
body fluids like CSF and plasma.
Here, we review the current status of assay development to reliably and
routinely detect Aβ oligomers in body fluids like CSF and blood. Technical
progress was severely hampered by the low concentration of Aβ oligomers in
body fluids (less than 1 pM (35)) and the difficult nature of oligomer versus

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 Quantitation of Amyloid-Β Oligomers … 5

monomer detection per se. Additionally, we compare the outcomes of the

different assay systems and will discuss the drawbacks and opportunities.

Methods for Detection of Aβ Oligomers in

Body Fluids

Detection of One Signal for Oligomers

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Figure 1. Sandwich ELISA methods for specific Aβ oligomer detection. A: The same
antibody is used as a capture and for detection. At least a dimer is required to produce a
signal. B: Oligomer specific antibodies in the detection process prevent detection of Aβ
monomers.

In recent years, nanotechnology based tools, ELISA-based tools and one

mass spectroscopy tool were developed and tested on body fluid samples of
AD cases versus non demented controls. All tools described here are based on
Aβ caption using specific antibodies. To provide oligomer specificity, either
oligomer specific antibodies are employed, or the same general Aβ antibodies
were used twice in the system, as capture and for detection. This ensures that

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
 6 Susanne Aileen Funke and Dieter Willbold

only multimers (dimers as smallest detectable unit) of Aβ, but no monomers

are detected (see Fig. 1).
All methods described in this part of the chapter are summarized in Table
1. More ELISA methods for Aβ oligomer detection were already described,
but to date only applied to brain extract samples (36-39). Those are not
reviewed here, as the applicability of these assays for body fluids still is to be
proven.
Today, three articles are published, which describe the determination of
Aβ oligomer concentrations in CSF by ―sandwich‖ methods, with or without
additional signal amplification. In 2003, it has been demonstrated that ADDLs
(―Aβ derived diffusible ligands‖, referring to small soluble Aβ oligomers with
molecular weights between 17 and 42 kDa (18)), were present at significantly
elevated levels in brain samples from deceased AD patients (46), suggesting
that those oligomers might also be found in lower concentrations in CSF. In
2005, two articles about nanoparticle-based assays for the quantitation of
ADDLs in CSF were published.
Haes et al. developed and applied a nanoscale optical biosensor method
based on localized surface plasmon resonance (LSPR) spectroscopy combined
with Aβ oligomer specific antibodies, which was useful to monitor the
interaction between ADDLs and ADDL-specific antibodies. In short, ADDL-
specific polyclonal antibodies M71 (47) were attached to surface-confined
Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

silver (Ag) nanoparticles. Subsequently, the nanoparticles were exposed to

samples containing ADDLs or control samples. To enhance the LSPR shift
response, the samples were incubated a second time with ADDL M71
antibodies (sandwich principle). Transmission UV-vis spectroscopy was used
to monitor the optical properties (LSPR) of the Ag nanoparticles. In a very
preliminary study, the CSF of one AD patient had a higher concentration of
ADDLs than the CSF of one control. These preliminary results were
interpreted that LSPR nanosensor technology could be useful as a screening
method for human samples and possibly for disease diagnosis (35). After that
first publication, no subsequent articles referring to the method in combination
with ADDL detection were published.
About the same time, Georganopoulou et al. came up with an
ultrasensitive barcode assay for the detection of ADDLs in CSF samples. For
the assay, oligonucleotide (―barcode‖)-modified gold nanoparticles as well as
magnetic microparticles were functionalized with anti-ADDL antibodies
(polyclonal M90 and monoclonal 20C2) and added to the ADDL containing
samples.

Alzheimer's Diagnosis, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook Central,
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