3
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 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 Harbin Medical 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 Acad Radiol 2012; 19:509–511 12300 Village Square Terrace (102), Rockville, MD 20852. Received February 20, 2012; accepted February 22, 2012. ªAUR, 2012 doi:10.1016/j.acra.2012.02.003 509

Battle against Alzheimer's Disease

  • Upload
    sophie

  • View
    216

  • Download
    3

Embed Size (px)

Citation preview

Page 1: Battle against Alzheimer's Disease

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

Page 2: Battle against Alzheimer's Disease

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.

REFERENCES

1. Alzheimer’s Association. 2011 Alzheimer’s disease facts and figures.

Alzheimer’s & Dementia 2011;7:208–244. Available at: http://www.alz.

org/downloads/Facts_Figures_2011.pdf. Accessed February 12, 2012.

2. Centers for Disease Control and Prevention. National Center for Health

Statistics. Health Data Interactive. Available at: http://www.cdc.gov/

nchs/hdi.htm. Accessed February 12, 2012.

3. Mini~noAM,XuJ,KochanekKD.Deaths: preliminary data for 2008.Natl Vital

Stat Rep2010; 59:2. www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_02.pdf.

4. Chapman RM, Mapstone M, Porsteinsson AP, et al. Diagnosis of

Alzheimer’s disease using neuropsychological testing improved by multi-

variate analyses. J Clin Exp Neuropsychol 2010; 32:793–808.

5. http://www.mayoclinic.com/health/alzheimers-disease/DS00161/DSECTION=

tests-and-diagnosis. Accessed February 12, 2012.

6. Jobst KA, Barnetson LP, Shepstone BJ. Accurate prediction of histologi-

cally confirmed Alzheimer’s disease and the differential diagnosis of

dementia: the use of NINCDS-ADRDA and DSM-III-R criteria, SPECT,

X-ray CT, and Apo E4 in medial temporal lobe dementias. Oxford Project

to Investigate Memory and Aging. Int Psychogeriatr 1998; 10:271–302.

Page 3: Battle against Alzheimer's Disease

Academic Radiology, Vol 19, No 5, May 2012 GUEST EDITORIAL

7. Schmand B, Eikelenboom P, van Gool WA. Value of neuropsychological

tests, neuroimaging, and biomarkers for diagnosing Alzheimer’s disease

in younger and older age cohorts. J Am Geriatr Soc 2011; 59:1705–1710.

8. Zhu M, Gao W, Wang X, et al. Progression of corpus callosum atrophy in

early stage of Alzheimer’s disease: MRI based study. Acad Radiol 2012;

19:512–517.

9. Hampel H, Frank R, Broich K, et al. Biomarkers for Alzheimer’s disease:

academic, industry and regulatory perspectives. Nat Rev Drug Discovery

2010; 9:560–574.

10. Sabuncu MR, Desikan RS, Sepulcre J, et al. The dynamics of cortical and

hippocampal atrophy in Alzheimer disease. Arch Neurol 2011; 68:

1040–1048.

11. Shen KK, Fripp J, M�eriaudeau F, et al. Detecting global and local hippo-

campal shape changes in Alzheimer’s disease using statistical shape

models. Neuroimage 2012; 59:2155–2166.

12. Dickerson BC, Stoub TR, Shah RC, et al. Alzheimer-signature MRI

biomarker predicts AD dementia in cognitively normal adults. Neurology

2011; 76:1395–1402.

13. Schmand B, Huizenga HM, van Gool WA. Meta-analysis of CSF and MRI

biomarkers for detecting preclinical Alzheimer’s disease. Psychol Med

2010; 40:135–145.

14. Hampel H, Teipel SJ, Alexander GE, et al. Corpus callosum atrophy is

a possible indicator of region- and cell type–specific neuronal degenera-

tion in Alzheimer disease: a magnetic resonance imaging analysis. Arch

Neurol 1998; 55:193–198.

15. Urs R, Potter E, Barker W, et al. Visual rating system for assessing

magnetic resonance images: a tool in the diagnosis of mild cognitive

impairment and Alzheimer disease. J Comput Assist Tomogr 2009; 33:

73–78.

16. Clarke L, Croft B. Development of public resources to support quantitative

imaging methods in cancer. Acad Radiol 2007; 14:1438–1440.

17. Marcus DS, Wang TH, Parker J, et al. Open Access Series of Imaging

Studies (OASIS): cross-sectional MRI data in young, middle aged, nonde-

mented, and demented older adults. J Cogn Neurosci 2007; 19:

1498–1507.

18. The Washington University Alzheimer’s Disease Research Center. The

Open Access Series of Imaging Studies (OASIS). Available at: http://

www.oasis-brains.org/. Accessed February 12, 2012.

19. The University of California, Los Angeles. Alzheimer’s Disease Neuroimag-

ing Initiative (ADNI). Available at: http://adni.loni.ucla.edu/. Accessed

February 12, 2012.

20. Martin Luther King, Jr. Strength of Love. New York: Harper & Row; 1963.

511