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Guest Editorial
Battle against Alzheimer’s Disease:
The Scope and Potential Value of Magnetic Resonance Imaging Biomarkers
Sophie Paquerault, PhD
This year marks the 111th anniversary of the first observation
of Alzheimer’s disease (AD). Although this singular observa-
tion may not have been viewed as particularly worrisome
on an epidemiologic basis at that time, current facts and
figures about AD are more than troublesome (1). AD has
grown at an alarming rate worldwide and such growth is
almost certainly tied to increased life expectancy (eg, at age
65, the life expectancy in the US population was about 11.9
years in 1900, 16.5 years in 1980, and 19.2 years in 2009
(2)) as well as the demographic baby boom after World War
II. Currently, about 33.9 million people worldwide (about
5.1 million people in the United States) have AD, and preva-
lence is expected to triple by 2050 (1,3). AD is the sixth-
leading cause of death across all ages in the United States,
and the fifth-leading cause of death for those age 65 and older
(1). Based on mortality statistics, between 2000 and 2008,
deaths from AD have risen by 66%.
AD, frequently termed with the sobriquet of ‘‘The Long
Goodbye,’’ is the most common cause of dementia among
older people, gradually gets worse over time, irreversibly
affects memory, thinking and behavior, and ultimately leads
to death in an average of 4 to 8 years (up to 20 years) after diag-
nosis (1). Over the duration of the illness, AD patients lose
their independence, and require significant assistance from
a caregiver. Because of the long duration of the illness and
medical care needs, it is evident that AD has a significant
impact on health care costs. For all dementias, aggregate
payments for health care, long-term care, and hospice care
are projected to increase from $183 billion in 2011 to $1.1 tril-
lion in 2050 (1).
AD is frequently diagnosed at the ‘‘mild’’ stage of the illness,
when memory loss worsens and changes in cognitive skills
become readily evident (eg, getting lost, trouble handling
money, repeating questions, being confused, and taking
longer to complete normal daily tasks). The diagnosis of
AD is made through physical and neurological exam, mental
status testing, neuropsychological testing, and brain imaging
including computed tomography, magnetic resonance
imaging (MRI), and positron emission tomography examina-
tions (4,5). However, diagnostic accuracies vary depending on
Acad Radiol 2012; 19:509–511
12300 Village Square Terrace (102), Rockville, MD 20852. Received February20, 2012; accepted February 22, 2012.
ªAUR, 2012doi:10.1016/j.acra.2012.02.003
the imaging technique used as well as the interpretive skills of
the doctors (6,7). AD diagnosis can be confirmed with
complete accuracy only after death with microscopic
examination of brain cells.
Even though advances in the understanding of AD have
been made in the past 30 years, the root cause(s) of AD still
remain a mystery. There is no cure and no preventive therapy
available to this day. As in many diseases, early diagnosis of AD
would clearly be beneficial for several reasons: planning care
and living arrangements, helping preserve function and inde-
pendence for as long as possible, research on diagnostic tests,
and testing new treatments and preventive strategies against
the disease. The challenge toward resolving this mystery and
thus ending (or at least reducing the impact of) this silent
epidemic is enormous for research, and ‘‘if we knew’’ what
AD is all about and ‘‘what it was we were doing, it wouldn’t be called
research, would it?’’ (Albert Einstein).
In this issue of Academic Radiology, a team of physicians and
scientists from The First Affiliated Hospital of HarbinMedical
University and Harbin Institute of Technology (Heilongjiang
Province, China) presents a study on MRI for quantifying
atrophy of the corpus callosum as a biomarker for the earliest
stage of AD (8). The development of such imaging
biomarkers is a critical first step in the battle against AD, and
is therefore a worthy topic for this editorial. The study by
Zhu et al (8), and the accompanying editorial, should serve
to highlight the importance of having accurate/ precise quan-
titative measurements for early detection of AD and under-
standing disease progression, the utility of publicly available
databases for research, and the importance of future research
toward treatment and preventive care for AD.
Identification of imaging (ie, anatomic and/or physiologic)
biomarkers is a critical first step toward understanding the
pattern of disease, early diagnosis, disease progression, and
assisting in treatment strategy as well as the assessment of treat-
ment effects (9). Advances in imaging technologies and
sophisticated computational processing techniques have
rendered the search for AD biomarkers almost unlimited.
MRI has become a key examination recommended by physi-
cians when investigating whether the patient has AD. Several
studies have confirmed that MRI can reveal patterns of brain
atrophy that occur in patients with AD (10,11), and rule out
other possible causes of cognitive impairment (eg, brain
tumor, blood clot).
Recent research has examined the use of MRI to detect
AD-related cortical atrophy as a biomarker for preclinical
509
PAQUERAULT Academic Radiology, Vol 19, No 5, May 2012
identification (ie, before clinical symptoms of AD appear) of
AD patients (12). Though a meta-analysis of using medial
temporal lobe atrophy has indicated that such an MRI
biomarker may not be very sensitive for detecting preclinical
AD (13), the idea is a step in the right direction. The study by
Zhu et al in this issue (8) discusses using a different MRI
biomarker (ie, atrophy of the corpus callosum) as a potential
key biomarker for detecting AD patients at an early stage.
The study was specific to measuring the atrophy of the corpus
callosum by comparison between groups of healthy patients
and AD patients with either ‘‘very mild’’ or ‘‘mild’’ dementia.
The study results of Zhu et al are consistent with previous
research that specifically investigated corpus callosum atrophy
as a possible indicator of region- and cell type–specific
neuronal degeneration in AD patients (14).
Even though limited, the study by Zhu et al further empha-
sizes not only the need to measure disease on a finer scale, as
opposed to using a categorical scale (eg, the Clinical Dementia
Rating scale that is certainly too limited for monitoring disease
progression and/or treatment effects in an accurate and precise
manner), but also the need for a biomarker that can be used to
measure disease progression—in this case, using a measure of
atrophy of the corpus callosum. As Sir William Thomson
(Lord Kelvin) is quoted as saying, ‘‘when you can measure what
you are speaking about, and express it in numbers, you know some-
thing about it; but when you cannot measure it, when you cannot
express it in numbers, your knowledge is of a meagre and unsatisfactory
kind. It might be the beginning of knowledge, but you have scarcely, in
your thoughts, advanced to the stage of science.’’ Certainly, the next
step is to validate such measurements as a potential useful
biomarker for the diagnosis and management of AD patients.
An important aspect of using any imaging biomarker, an
issue discussed by Zhu et al, is reader variability and the neces-
sity of having reproducible quantitative measurements.
Reader variability is well-known as being a problem in clinical
imaging practice. Even if the task of a reader is only to measure
the extent of a disease, or to segment out a region of interest
from an image, such a task is almost always subjective in some
aspects, and thus leads to so-called intra- and inter-reader vari-
ability. This means that a measurement may not achieve the
necessary level of reproducibility (or consistency). Low repro-
ducibility is very problematic when trying to assess differences
in disease state between two consecutive examinations of the
same patient, and thus when investigating whether there has
been any significant change in disease status over time. In
the last several decades, sophisticated computerized processing
techniques have replaced many of the manual tasks performed
by a reader (15). Such computerized techniques are probably
a necessary step to providing improved reproducibility, and
thus more accurate/ precise measurements. The work pre-
sented by Zhu et al (8) describes a semiautomatic technique
for measuring the brain structure and is therefore consistent
with the necessity of accounting for reader variability and
thus reducing such variability.
Identification and validation of biomarkers as well as devel-
opment and testing of sophisticated computerized measure-
510
ment techniques will require availability of large data sets,
which, however, may not be readily available to researchers.
In the last ten years, sharing data through publicly accessible
websites has become popular and may very well be another
critical element in AD research as in many other fields (16).
Publicly available databases, such as that used in the study by
Zhu et al (17,18), or that collected through the Alzheimer’s
Disease Neuroimaging Initiative (19), open the door to
many scientists with the goal of advancing the unmet challenge
posed byAD, andmore specifically offers the possibility to effi-
ciently perform comparisons of increasingly sophisticated
measures for the diagnosis and progression of AD. Develop-
ment and implementation of such public databases often
pose many scientific and logistical problems, especially when
there is no gold standard, nor consensus about the disease,
and variability in rating the symptoms that are associated
with the disease. As a general guideline, the more information
(accounting for patient’s ethical and privacy protections) that
accompanies each case in a database (eg, examination data,
imaging characteristics, device brand name and version,
imaging protocol, demographic data, health conditions,
symptoms), the better it is. For example, providing the
imaging protocol or following a standard imaging protocol is
absolutely essential for understandingwhether the observation
of what looks like a disease pattern or progression is not in fact
due to a difference in imaging characteristics or other
confounding factors. The study by Zhu et al (8) would have
certainly never seen the light of day without such a well-
documented publicly available database.
In sum, AD is a real worldwide epidemic danger and a chal-
lenging mystery that cannot be ignored, and ‘‘nothing in all the
world is more dangerous than sincere ignorance.’’ (20). The study
by Zhu et al in this issue of Academic Radiology (8) is an impor-
tant step forward toward dismantling the AD mystery, and, in
particular, allows us to focus on having biomarkers that can
potentially be used as a standard of care for early diagnosis
and monitoring of disease progression. As revealed by the
study of Zhu et al, there are many areas for research and
research would not be possible without sharing data.
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