The PredictAD project: development
of novel biomarkers and analysis
rsfs.royalsocietypublishing.org
Research
Cite this article: Antila K, Lötjönen J,
Thurfjell L, Laine J, Massimini M, Rueckert D,
Downloaded from https://royalsocietypublishing.org/ on 15 October 2021
Zubarev RA, Orešič M, van Gils M, Mattila J,
Hviid Simonsen A, Waldemar G, Soininen H.
2013 The PredictAD project: development
of novel biomarkers and analysis
software for early diagnosis of the Alzheimer’s
disease. Interface Focus 3: 20120072.
http://dx.doi.org/10.1098/rsfs.2012.0072
One contribution of 25 to a Theme Issue ‘The
virtual physiological human: integrative
approaches to computational biomedicine’.
Subject Areas:
computational biology, biomedical
engineering, systems biology
Keywords:
Alzheimer’s disease, early diagnosis,
clinical decision support systems
Author for correspondence:
Kari Antila
e-mail: kari.antila@vtt.fi
software for early diagnosis of the
Alzheimer’s disease
Kari Antila1, Jyrki Lötjönen1, Lennart Thurfjell2, Jarmo Laine3,
Marcello Massimini4, Daniel Rueckert5, Roman A. Zubarev6, Matej Orešič1,
Mark van Gils1, Jussi Mattila1, Anja Hviid Simonsen7, Gunhild Waldemar7
and Hilkka Soininen8
1
VTT Technical Research Centre of Finland, PO Box 1300, 33101 Tampere, Finland
2
GE Healthcare, Stockholm, Sweden
3
Nexstim Ltd, Helsinki, Finland
4
University of Milan, Milan, Italy
5
Imperial College London, London, UK
6
Karolinska Institutet, Stockholm, Sweden
7
Rigshospitalet, Copenhagen, Denmark
8
University of Eastern Finland, Kuopio, Finland
Alzheimer’s disease (AD) is the most common cause of dementia affecting
36 million people worldwide. As the demographic transition in the devel-
oped countries progresses towards older population, the worsening ratio
of workers per retirees and the growing number of patients with age-related
illnesses such as AD will challenge the current healthcare systems and
national economies. For these reasons AD has been identified as a health pri-
ority, and various methods for diagnosis and many candidates for therapies
are under intense research. Even though there is currently no cure for AD, its
effects can be managed. Today the significance of early and precise diagnosis
of AD is emphasized in order to minimize its irreversible effects on the ner-
vous system. When new drugs and therapies enter the market it is also vital
to effectively identify the right candidates to benefit from these. The main
objective of the PredictAD project was to find and integrate efficient bio-
markers from heterogeneous patient data to make early diagnosis and to
monitor the progress of AD in a more efficient, reliable and objective
manner. The project focused on discovering biomarkers from biomolecular
data, electrophysiological measurements of the brain and structural, func-
tional and molecular brain images. We also designed and built a statistical
model and a framework for exploiting these biomarkers with other available
patient history and background data. We were able to discover several
potential novel biomarker candidates and implement the framework in soft-
ware. The results are currently used in several research projects, licensed to
commercial use and being tested for clinical use in several trials.
1. Introduction
Alzheimer’s disease (AD) is the most common cause of dementia. Costs associ-
ated with dementia account for equivalent to about 1 per cent of the gross
domestic product of the whole world [1]. Currently, dementia affects approxi-
mately 36 million people worldwide. This number is expected to double during
the next 20 years [1]. The prevalence of AD in Europe will rise rapidly with the
ageing population. According to [2] the current ratio of four European working
age people per retiree will change to 2 : 1 by the year 2050. This will challenge
the current healthcare systems and national economies with the problem of
& 2013 The Author(s) Published by the Royal Society. All rights reserved.
 providing good quality care to a growing number of people
with fewer resources available per patient.
The current consensus is that the preventive actions and
therapies for AD should be started as soon as possible in
order to be effective. This emphasizes the importance of
early diagnosis. In Europe, the diagnosis of AD is made
about 20 months after the appearance of symptomatic
memory problems [3]. However, the disease is known to pro-
gress for several years or even decades prior to appearance
of the first clear symptoms. Despite this long period of
progression, early diagnosis of AD remains a great challenge.
Unfortunately, there is currently no cure for AD although
different strategies for treating and managing AD and its
effects are under investigation. Some of these are therapies
targeting the illness directly, such as anti-amyloid plaque
agents, or prevention strategies, such as lifestyle changes.
When new drugs or prevention strategies become available,
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early diagnosis becomes even more essential because the can-
didates in need and to benefit from these therapies are to be
identified at earliest possible stage. Moreover, objective and
evidence-based observation of the success of the treatment
is vital when following the efficacy of the chosen therapy.
This is especially important when developing and testing
new drugs and other candidates for therapies.
Today AD is clinically diagnosed by taking physical and
neurological examinations, and checking other signs of intellectual
impairment through standard neuropsychological and cogni-
tive tests. In addition to these measures, the current guidelines
for the diagnostics of AD [4–6] emphasize the role of various
biomarkers. These include measures from magnetic resonance
imaging (MRI), positron emission tomography (PET), cerebro-
spinal fluid (CSF) protein profiles as well as genetic risk profiles.
The main objective of the PredictAD (www.predictad.eu)
EU-funded VPH research project (June 2008 to November
2011) was to find and integrate efficient biomarkers from
heterogeneous patient data to make early diagnosis, and pro-
gress monitoring of AD in a more efficient, reliable and
objective manner. This article summarizes the work done in
biomarker discovery from different data sources, and in
developing a data-driven clinical decision support tool for
combining and effectively exploiting the information in
these biomarkers. The main types of data and steps of
analysis are shown in figure 1.
2. Data and methods
2.1. Biomarkers from biomolecular data
Reliable indicators of AD such as traces of beta-amyloid and
protein tau in the brain can be extracted from CSF. Unfortunately,
collecting of CSF is a rather invasive and even somewhat risky
procedure. This makes the extraction of CSF-based biomarkers
challenging and unpractical for early detection by large-scale
screenings. Developing CSF-based biomarkers is also challen-
ging owing to the sensitive measurements required, which
often leads to poor cross-institutional consistency. For these
reasons, the possibilities of using easily available and low cost
blood samples are gaining more attention.
Metabolites are by definition the small molecules in the
blood involved in metabolism, which is a common definition
for the vital series of chemical reactions that take place in the
living body. The existence of different metabolites in blood
give indications on how cells live, breathe and communicate,
2
proteomics PET imaging MRI
rsfs.royalsocietypublishing.org
biomarker
metabolomics extraction and TMS/EEG
quantification
statistical
memory and modelling and patient info
other tests analysis (age, sex, etc.)
Interface Focus 3: 20120072
best biomarkers and optimal models, implementation
in software for computer-assisted diagnosis
Figure 1. Types of data, steps of analysis and the flow of information as realized in
the PredictAD project. The types of input data are shown in parallelograms. Blue
parallelograms represent data which are required to be quantified for statistical
analysis, whereas orange represent data already in quantified and measurable
form. The two main steps of analysis are shown generalized in two red squares.
The main results are shown in a green rounded rectangle.
and whether the metabolic interactions follow their normal
pathways. In the case of a disease such as AD, these inter-
actions are presumably disturbed. In the project, we used
metabolomics to reveal potential biomarkers for detecting
AD [7]. This was done by analysing blood serum samples
from three different groups: healthy controls, patients with
mild cognitive impairment (MCI), a possible pre-stage of AD,
and patients with AD. The samples were analysed with sensi-
tive mass spectrometer platforms capable of detecting tiny
differences in concentrations of metabolites. The mass
spectrometer data were analysed with a software platform
designed to detect the presence of known and yet unknown
metabolite groups and to compare the differences in metabolite
concentrations between the three groups of subjects. The results
were used to test which kind of metabolites have potential to
be biomarkers indicating the processes related to AD.
Proteins are large macromolecules that take part in most
functions of the living cell from structural formation to guid-
ing the various biological processes in the cell. The synthesis
and function of proteins especially in the neurons of the brain
are affected by AD. During the project, in a rather similar way
to metabolites, protein concentrations were analysed with a
sensitive mass spectrometer and a special software was
developed and used, and to analyse and interpret the results
[8]. This analysis was first done by pooling the samples from
four different groups: healthy, stable MCI (SMCI), progress-
ive MCI (PMCI), a condition to be progressed to AD, and
AD to find stronger signals of differences with these groups
and to narrow the scope of potential proteins. These analyses
were then repeated for individual samples to identify the best
protein biomarker candidates for indicating AD.
2.2. Biomarkers from electrophysiology
AD is known to cause abnormal structural and functional
degeneration of the brain. The brain goes through constant
changes during lifetime, and the challenge is to identify
which of those are related to normal ageing and which are
caused by AD or other diseases. Electroencephalography
(EEG) can be used for characterizing the electrophysiology of
 the brain, known to be affected in AD. Measuring typical
evoked responses requires interaction with the subject, which
can be challenging with patients having severe symptoms.
One approach to overcome this is to measure how the brain
will respond to external electromagnetic stimulus. Transcranial
magnetic stimulation combined with EEG (TMS/EEG) is a
novel non-invasive tool for measuring the strength of the
neural connectivity of the brain. According to the method,
magnetic pulse is first applied to an area on the brain cortex
and its response is immediately measured using EEG. Precise
localization of the coils sending the TMS pulses and the elec-
trodes recording EEG with respect to the brain allows
directing of the stimulation to the areas of interest and map-
ping of the responses around the cortex with great spatial
and temporal resolution. With the help of MRI, features of
brain anatomy can be correlated with recorded potentials.
TMS/EEG can be used to estimate the functional state of
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brain unbiased by the cognitive impairment and subjective
functional performance of patients with AD.
In the project, we studied the responses of stimulating the
frontal cortex of healthy young volunteers, healthy elderly
volunteers and subjects with AD [9]. In another study [10],
the motor cortex of three subject groups, healthy, MCI and
AD were stimulated and recorded. Our purpose was to ana-
lyse the correlation between the thickness of the cortex and
strength of the electromagnetic field as a result to the stimu-
lation. A unified mathematical framework was developed to
analyse the TMS/EEG data, at the sensor as well as at the
source level, including statistical analysis for identifying
the spatio-temporal pattern of brain activity significantly
evoked by TMS. The methods for the data analysis were
implemented in Matlab.
2.3. Biomarkers from imaging data
The presence of medial temporal lobe atrophy (tissue loss) is
a hallmark indicator of the AD. MRI provides an excellent
tool for quantifying early and disproportionate brain atrophy.
Because manual delineation of different structures is highly
laborious and subjective, automated and objective methods
are needed. A high number of image analysis techniques
have been developed for quantifying the size and shape of
different brain structures, especially the hippocampus, amyg-
dala and entorhinal cortex in the context of AD. Other
commonly used measures are cortical thickness, atrophy
rate from longitudinal data and voxel- and region-based
characteristics using morphometric techniques [11]. Although
automated tools are developed actively in many research
groups, the development of robust, accurate and fast auto-
matic methods has proved to be a very challenging
problem and automatic methods are still very much lacking
in clinical practice.
In addition to structural imaging, functional imaging
offers complementary information about the status of the
brain. For example, fludeoxyglucose (FDG) PET images
show response to the glucose metabolism in the brain,
which is highly correlated with the loss of neurons owing
to AD, and is hence useful for monitoring the progression
and for determining the severity of the disease. MRI and
FDG-PET both show secondary effects of the disease process.
It is hypothesized that AD is caused by accumulation of amy-
loid plaques in the brain. Because of this there has been an
increased interest in in vivo imaging of amyloid deposits.
One of the most promising methods in the early diagnosis 3
of AD is PET imaging using a molecular tracer that binds
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to amyloid plaques.
During the project, we developed methods for the seg-
menting and extracting features of spatio-temporal brain
structures in MR and PET images. We focused on developing
fast and robust segmentation of the hippocampus, brain atro-
phy-rate measurements, tensor-based morphometry and
manifold learning [12 –15]. We also developed tools for the
analysis of FDG-PET and PET amyloid imaging [16,17]. The
clinical usefulness of these methods was evaluated in terms
of robustness, accuracy and computation times by analysing
Interface Focus 3: 20120072
data from several patient cohorts.
2.4. Model and software for integrating biomarkers
The availability of data in massive scientific cohorts collected
by large healthcare systems is a tremendous asset for scientific
research. However making, holistic, truthful and objective view
of the state of the patient becomes very challenging as the data-
bases grow or when new databases or biomarkers become
available. Effective use of the whole spectrum of data require
simple, reliable, fast and intuitive ways of comparing new,
undiagnosed subject data against the existing databases.
Information sciences have developed a wealth of methods
for processing and analysing multi-dimensional heterogeneous
data. Most publications discussing the detection of AD from
multiple patient measurements use the common classifiers
of statistics such as support vector machines. These classi-
fiers define the most probable class label for a given patient
using a decision model derived from the training data. The
use of such classifiers in the clinical practice requires either
very high classification accuracy validated in large patient
cohorts or an estimate about the reliability of the classification
result for each respective case. When analysing complex dis-
eases, the biomarkers may not contain enough information to
separate the healthy from ill with high accuracy. Therefore,
tools that enable the assessment of the reliability of the classifi-
cation are needed. Another challenge is that the transition from
the healthy state to the disease state is not typically a discrete
event, especially in neurodegenerative diseases where the dis-
ease progresses very slowly. An index that reflects the disease
probability or disease severity could provide a solution for
both of these challenges.
We addressed these needs by developing a novel frame-
work combining heterogeneous multi-source data and
providing an evidence-based index reflecting the probability
of the disease in the case of an individual subject [18]. This
index, called the Disease State Index (DSI), is computed by
comparing the measurements of a yet undiagnosed case
against a large number of measurements from healthy and dis-
eased subjects collected to databases. In addition, a graphical
counterpart of DSI, the Disease State Fingerprint (DSF) was
developed for visualizing the state of the patient in a way
that a clinician can easily see and understand how different
measures of various biomarkers contribute to the index. A
measure of relevance was defined to estimate the reliability
of DSI assessment in making every individual decision. The
framework was realized in the PredictAD software tool
(figure 2) for the Microsoft Windows environment. The soft-
ware was implemented with an intuitive user interface and
the relevant components integrated so that it could be used
as stand-alone clinical decision support system (CDSS).
 4

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Interface Focus 3: 20120072
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Figure 2. Screenshot of the PredictAD software tool. Top-left: Patient details window contains basic information about the patient. Bottom-left: timeline of Entries
window shows an overview of all patient measurement in function of time. It shows also if the measured value points towards a disease or healthy state. The window is
interactive and pressing any of the measurements provides details in the Entry preview window. Top-centre: Entry preview window provides details of different patient
measurements (here Mini Mental State Examination). The ‘Analyze’ button directs the user to detailed analysis of data, e.g. image segmentation. Top-right: Disease state
fingerprint (DSF) window shows the DSF of the patient. DSF is interactive and the user can study freely different hierarchical levels of the tree. Detailed analysis of DSF
can be entered by the ‘Explore’-button. Bottom-right: Disease state index (DSI) window shows the DSI of the patient. This window is linked to the DSF window. As user
selects any of the items in the DSF, the details of the item are shown, i.e. probability density distributions with the patient measurement overlaid, number of cases used
for computing the distributions and contributions of different measures at the lower hierarchical levels to the selected item.

verified with individual samples ( p  0.01). Higher levels of

3. Results
3.1. Biomarkers from biomolecular data
In our study of metabolites, we found groups of molecules
which show significantly lower levels in subjects with AD
[7]. Our data included samples from the first entry to the hos-
pital and from the follow-up visit several years later when the
symptoms were severe enough to make the diagnosis. The
best power ( p ¼ 0.0135) of separating the subjects with AD
at the baseline was found in a group of ether phospholipids
that are significant building blocks of cell membranes. The
best model having a combination of metabolites included
with age was able to separate patients with AD area under
curve (AUC) performance 0.81. The setting gave us the
opportunity to test the power of different sets of metabolites
in predicting which MCI patients will eventually progress to
AD (PMCI) and which will remain stable (SMCI). The model
with the best power of predicting the progression had three
metabolites (2,4-dihydroxybutanoic acid, unidentified car-
boxylic acid a phosphatidylcholine). With this setting, we
were able to achieve reasonably good AUC ¼ 0.77.
Our main discovery in proteomics was the high level of
isoaspartyl (isoAsp) residues ( p ¼ 0.03) in blood plasma of
patients with AD [8]. Increased levels were discovered by
pooling and analysing samples from healthy controls against
samples from MCI and AD patients. These results were
isoAsp were also found on females. This study together
with previous findings gives grounds to a hypotheses that
isoAsp might be a significant marker in early processes
resulting to AD.
To summarize, we managed to achieve promising results
by discovering novel and verifying previously hypothesized
molecular level signatures. Our findings suggest that hypoxia,
oxidative stress, membrane lipid remodelling and abnormal
protein aggregation might have role in early AD. Establish-
ment of pathogenic relevance of predictive biomarkers such
as these may not only facilitate early diagnosis, but may also
help identify new therapeutic avenues.
3.2. Biomarkers from electrophysiology
We were able to demonstrate, that TMS-evoked potentials
applied to frontal cortex are reduced in AD patients when
compared with age-matched or younger healthy controls
[9]. Interestingly no significant difference in the TMS-
evoked potentials between healthy young and healthy elderly
controls was found. This suggests that normal age-related
frontal lobe atrophy does not affect cortical excitability, but
is weakened on patients with AD. We also discovered a cor-
relation between cortical thinning and weaker cortical
excitability on the motor cortex [10]. The previously reported
 effect of increased excitability in AD on the sensorimotor
cortex, possibly compensating the loss of cortical volume,
was also recorded. This mechanism was not found on MCI
patients, which might indicate that the progression of the dis-
ease proceeds with different dynamics in the structure and
function of neuronal circuits from normal conditions via
MCI to AD.
When combined, the results show that it is possible to
extract synthetic indices of cortical excitability and effective
connectivity from TMS/EEG data that significantly correlate
with clinical measures of cognitive decline. Thus, TMS/EEG
technology has clear potential in defining novel biomarkers
for the diagnostics of AD.
3.3. Biomarkers from imaging data
We developed a method of segmenting the hippocampus,
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which is one of the first areas of the brain affected by AD,
from MRI images [12]. The reliability of method was verified
by comparing the results against a semi-automatic method.
A Dice similarity of 0.87 between the methods was achieved.
The speed of the method was found sufficient for use in clini-
cal practice. The rates of hippocampal atrophy, i.e. tissue loss,
in consecutive MRI scans were also studied [13]. We devel-
oped a method which segments image pairs or triplets in a
single step in order to compute an estimate of the rate. We
found different patterns of atrophy between the healthy
and subjects with AD and significant ( p , 0.01) correlations
between atrophy measurements and other clinical variables
such as Mini Mental State Examination. Beyond hippocampus,
we studied whole brain feature extraction using tensor-based
morphometry [14]. We found that use of a selection of multiple
templates gives significantly better classification accuracy
(normal versus AD 86%, stable MCI versus progressive MCI
72,1%) than can be achieved with conventional single template
methods. Changes in total of 84 brain areas were analysed and
the best ones in classifying normal versus AD were found to
be close to the hippocampus. In another study, modern mani-
fold-learning-based techniques were used to map similar
patients close to each other in the new manifold space [15].
When brain image biomarkers were combined non-imaging
biomarkers, we found that the addition of biomarkers such
as genotype, and the concentration of beta-amyloid residue
in CSF to the classifier improved the classification results
(normal versus AD, stable MCI versus progressive MCI and
normal versus progressive MCI).
In the study of Gray et al. [16], we focused on combining
functional FDG-PET data with MRI images. By co-registering
FDG-PET and MRI images, and analysing FDG-PET signal
strengths on several brain areas in two time points, we
were able achieve state of the art level classification accuracy
(normal versus AD 88%, SMCI versus PMCI 65%). In another
PET study [17], we explored the relation between hippocam-
pal atrophy in MRI images and beta-amyloid deposit signals
traced with [18F]flutemetamol. The study showed that MRI
and PET provide complementary information for diagnostics.
Overall, we did a comprehensive validation for used and
developed MR image analysis methods: data from six cohorts
consisting of almost 2000 subjects in total were used. In a
specific comparison study, it was found that no single
method appeared clearly superior to the others [19]. It was
shown that the combination of the results from all developed
method improves the diagnostic accuracy.
3.4. Model and software 5
In the study of Mattila et al. [18], we used the baseline data
rsfs.royalsocietypublishing.org
from the Alzheimer’s disease neuroimaging initiative (ADNI;
http://www.adni-info.org/, accessed 26 October 2012.) to
benchmark the ability of the DSI to model disease progression
from elderly healthy controls to AD and its ability to predict
conversion from MCI to AD. We found that the DSI provides
well-behaving AD state estimates that correspond well with
the existing diagnoses. For predicting conversion from MCI
to AD, the DSI attains performance similar to state of the art
reference classifiers. The results suggest that the DSF estab-
Interface Focus 3: 20120072
lishes an effective decision support and data visualization
framework for improving AD diagnostics, allowing clinicians
to rapidly analysse large quantities of diverse patient data.
The validation of the implementation of DSI/DSF frame-
work in a software solution (figure 2) showed that its use
improves clinicians’ diagnostic accuracy and their confidence
about their decisions compared with current diagnostic
work-flows [20,21]. Our results show that using the tool diag-
nosis could be made with high accuracy for 50 per cent of MCI
cases about twelve months earlier than is currently possible
[22]. One of the innovations in PredictAD is the stratification
of populations, i.e. patients can be categorized to clear and
less-clear cases based on the property of continuity of the
DSI. As the ADNI data from about 400 cases was used in
this study, these numbers do not contain improvements that
are obtained by including the novel blood, amyloid-PET and
TMS/EEG-based biomarkers. If these markers were used,
the numbers would presumably be significantly better. Unfor-
tunately there is yet no cohort having all these data available.
4. Discussion
The significance of early diagnosis of AD has been recog-
nized and emphasized in many different forums and
contexts. Success in developing effective means for the
early diagnosis would have major impact first in the devel-
oped countries and later in the rest of the world owing
to the demographic transition towards older population.
Despite large past and on-going efforts in developing early
diagnosis of AD the problem remains largely unsolved. It is
the current understanding that no simple and easy solution
will likely be discovered soon.
Our contribution to solving the problem was not to focus
on finding a single indicator, but to develop a methodology
which is capable of using the little clues and hints collected
along the patient history in a systematic fashion. The signifi-
cance and relevance of the available information were tested
against past data on similar patients whose outcome has been
documented. This way decisions on whether to take more
tests or give diagnosis and estimate the state of the disease
on already collected information could be made. This meth-
odology was realized in a usable and intuitive way and so
that the reliability and accuracy of the developed methods
were verifiable. By putting together a team of experts of sev-
eral disciplines such as molecular chemistry, bioinformatics,
medical imaging, statistics, software engineering, business
and clinical medicine, we were able to study, develop and
oversee steps from fundamental research to clinically usable
software implementation. We also believe that having scien-
tists, engineers, and clinicians working in collaboration,
 there are significantly better chances of enabling results of impact in several ways. Accurate an early diagnosis would 6
fundamental research to benefit the clinical routine. delay the progression AD, and thus likely reduce the need

Many approaches of using multiple biomarkers in the early
detection of AD have been and are currently being studied. For
example, Fan et al. [23] have successfully combined biomarkers
from structural and molecular imaging to classify the samples
to MCI and AD patients. In recent work by Fonteijn et al. [24],
the disease progression is modelled successfully through a
series of consecutive events where a number of measurements
of different biomarkers have been taken. A rough disease pro-
gression model as proposed by Jack et al. [25] was used as
a basis. The same progression model is used in the work by Jedy-
rsfs.royalsocietypublishing.org
for institutional care significantly. This point will become
critical when more effective therapies will emerge. Efficient
use of CDSSs would bring give more value to existing infor-
mation collected to reference databases and to the data
collected by testing the subject being diagnosed. CDSSs will
help in objectively defining the point where enough evidence
has been collected and no potentially expensive, laborious or
even risky further test are needed. Evidence suggesting solid
cost versus benefit gains when using [18] was found based on
the cost per procedure data from project partner hospitals.

Interface Focus 3: 20120072

nak et al. [26]. There a disease progression score was composed
from a number of sigmoid functions each of which were intro-
duced to estimate the disease progression as indicated by a
respective biomarker. In contrast to our work the methods pro-
posed in recent studies [24,26], assume a monotonic progression
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These results are yet to be published.
To conclude, PredictAD took various steps towards
more objective and efficient diagnostics in AD on several
fronts. We were able to make new discoveries by acquiring
and analysing new data, developing novel, and redefining

of the disease in light of the many measured biomarkers. As a
potential advantage over our approach, the possible relative
power of biomarkers in estimating the disease state during the
course of the disease is taken into account. A particular benefit
of our approach over many other disease models is the ability
to visualize the individual contributions of different biomarkers
with the DSF (figure 2) in the final disease index value.
Utilization of clinical disease support systems, such as
discussed in Mattila et al. [18], has potential economic
current methods for reprocessing existing data and build-
ing a framework in software that is capable of integrating
and visualizing masses of heterogeneous data for the foun-
dation of evidence-based clinical decisions. The project
provided several novel tools for biomarker discovery and a
novel data-driven and evidence-based disease profiling.
The results are currently used in several research projects,
licensed to commercial use and being tested for clinical use
in several trials.

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