Battle against Alzheimer's Disease: The Scope and Potential Value of Magnetic Resonance Imaging Biomarkers

Abstract

This year marks the 111th anniversary of the first observation of Alzheimer's disease (AD). Although this singular observation 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 (1Alzheimer'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.Google Scholar). 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 (2Centers 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.Google Scholar)) 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 prevalence is expected to triple by 2050 (1Alzheimer'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.Google Scholar, 3Miniño A.M. Xu J. Kochanek K.D. Deaths: preliminary data for 2008.Natl Vital Stat Rep. 2010; 59: 2www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_02.pdfGoogle Scholar). 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 (1Alzheimer'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.Google Scholar). 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 diagnosis (1Alzheimer'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.Google Scholar). 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 trillion in 2050 (1Alzheimer'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.Google Scholar).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 examinations (4Chapman R.M. Mapstone M. Porsteinsson A.P. et al.Diagnosis of Alzheimer's disease using neuropsychological testing improved by multivariate analyses.J Clin Exp Neuropsychol. 2010; 32: 793-808Crossref PubMed Scopus (35) Google Scholar, 5http://www.mayoclinic.com/health/alzheimers-disease/DS00161/DSECTION=tests-and-diagnosis. Accessed February 12, 2012.Google Scholar). However, diagnostic accuracies vary depending on the imaging technique used as well as the interpretive skills of the doctors (6Jobst K.A. Barnetson L.P. Shepstone B.J. Accurate prediction of histologically 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: 271-302Crossref PubMed Scopus (196) Google Scholar, 7Schmand B. Eikelenboom P. van Gool W.A. Value of neuropsychological tests, neuroimaging, and biomarkers for diagnosing Alzheimer's disease in younger and older age cohorts.J Am Geriatr Soc. 2011; 59: 1705-1710Crossref PubMed Scopus (45) Google Scholar). 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 independence 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 (8Zhu 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: 512-517Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). 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 (8Zhu 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: 512-517Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar), and the accompanying editorial, should serve to highlight the importance of having accurate/ precise quantitative measurements for early detection of AD and understanding 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 treatment effects (9Hampel H. Frank R. Broich K. et al.Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives.Nat Rev Drug Discovery. 2010; 9: 560-574Crossref PubMed Scopus (511) Google Scholar). 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 physicians 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 (10Sabuncu M.R. Desikan R.S. Sepulcre J. et al.The dynamics of cortical and hippocampal atrophy in Alzheimer disease.Arch Neurol. 2011; 68: 1040-1048Crossref PubMed Scopus (211) Google Scholar, 11Shen K.K. Fripp J. Mériaudeau F. et al.Detecting global and local hippocampal shape changes in Alzheimer's disease using statistical shape models.Neuroimage. 2012; 59: 2155-2166Crossref PubMed Scopus (73) Google Scholar), 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 identification (ie, before clinical symptoms of AD appear) of AD patients (12Dickerson B.C. Stoub T.R. Shah R.C. et al.Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults.Neurology. 2011; 76: 1395-1402Crossref PubMed Scopus (227) Google Scholar). 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 (13Schmand B. Huizenga H.M. van Gool W.A. Meta-analysis of CSF and MRI biomarkers for detecting preclinical Alzheimer's disease.Psychol Med. 2010; 40: 135-145Crossref PubMed Scopus (75) Google Scholar), the idea is a step in the right direction. The study by Zhu et al in this issue (8Zhu 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: 512-517Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar) 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 (14Hampel H. Teipel S.J. Alexander G.E. et al.Corpus callosum atrophy is a possible indicator of region- and cell type–specific neuronal degeneration in Alzheimer disease: a magnetic resonance imaging analysis.Arch Neurol. 1998; 55: 193-198Crossref PubMed Scopus (178) Google Scholar).Even though limited, the study by Zhu et al further emphasizes 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 something 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 necessity 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 variability. This means that a measurement may not achieve the necessary level of reproducibility (or consistency). Low reproducibility 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 (15Urs 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: 73-78Crossref PubMed Scopus (42) Google Scholar). Such computerized techniques are probably a necessary step to providing improved reproducibility, and thus more accurate/ precise measurements. The work presented by Zhu et al (8Zhu 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: 512-517Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar) 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 development and testing of sophisticated computerized measurement 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 (16Clarke L. Croft B. Development of public resources to support quantitative imaging methods in cancer.Acad Radiol. 2007; 14: 1438-1440Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). Publicly available databases, such as that used in the study by Zhu et al (17Marcus D.S. Wang T.H. Parker J. et al.Open Access Series of Imaging Studies (OASIS): cross-sectional MRI data in young, middle aged, nondemented, and demented older adults.J Cogn Neurosci. 2007; 19: 1498-1507Crossref PubMed Scopus (1041) Google Scholar, 18The 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.Google Scholar), or that collected through the Alzheimer's Disease Neuroimaging Initiative (19The University of California, Los Angeles. Alzheimer's Disease Neuroimaging Initiative (ADNI). Available at: http://adni.loni.ucla.edu/. Accessed February 12, 2012.Google Scholar), open the door to many scientists with the goal of advancing the unmet challenge posed by AD, and more specifically offers the possibility to efficiently perform comparisons of increasingly sophisticated measures for the diagnosis and progression of AD. Development 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 understanding whether 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 (8Zhu 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: 512-517Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar) 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 challenging mystery that cannot be ignored, and “nothing in all the world is more dangerous than sincere ignorance …” (20Martin Luther King, Jr. Strength of Love. New York: Harper & Row; 1963.Google Scholar). The study by Zhu et al in this issue of Academic Radiology (8Zhu 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: 512-517Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar) is an important 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. This year marks the 111th anniversary of the first observation of Alzheimer's disease (AD). Although this singular observation 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 (1Alzheimer'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.Google Scholar). 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 (2Centers 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.Google Scholar)) 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 prevalence is expected to triple by 2050 (1Alzheimer'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.Google Scholar, 3Miniño A.M. Xu J. Kochanek K.D. Deaths: preliminary data for 2008.Natl Vital Stat Rep. 2010; 59: 2www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_02.pdfGoogle Scholar). 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 (1Alzheimer'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.Google Scholar). 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 diagnosis (1Alzheimer'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.Google Scholar). 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 trillion in 2050 (1Alzheimer'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.Google Scholar). 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 examinations (4Chapman R.M. Mapstone M. Porsteinsson A.P. et al.Diagnosis of Alzheimer's disease using neuropsychological testing improved by multivariate analyses.J Clin Exp Neuropsychol. 2010; 32: 793-808Crossref PubMed Scopus (35) Google Scholar, 5http://www.mayoclinic.com/health/alzheimers-disease/DS00161/DSECTION=tests-and-diagnosis. Accessed February 12, 2012.Google Scholar). However, diagnostic accuracies vary depending on the imaging technique used as well as the interpretive skills of the doctors (6Jobst K.A. Barnetson L.P. Shepstone B.J. Accurate prediction of histologically 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: 271-302Crossref PubMed Scopus (196) Google Scholar, 7Schmand B. Eikelenboom P. van Gool W.A. Value of neuropsychological tests, neuroimaging, and biomarkers for diagnosing Alzheimer's disease in younger and older age cohorts.J Am Geriatr Soc. 2011; 59: 1705-1710Crossref PubMed Scopus (45) Google Scholar). 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 independence 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 (8Zhu 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: 512-517Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). 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 (8Zhu 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: 512-517Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar), and the accompanying editorial, should serve to highlight the importance of having accurate/ precise quantitative measurements for early detection of AD and understanding 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 treatment effects (9Hampel H. Frank R. Broich K. et al.Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives.Nat Rev Drug Discovery. 2010; 9: 560-574Crossref PubMed Scopus (511) Google Scholar). 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 physicians 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 (10Sabuncu M.R. Desikan R.S. Sepulcre J. et al.The dynamics of cortical and hippocampal atrophy in Alzheimer disease.Arch Neurol. 2011; 68: 1040-1048Crossref PubMed Scopus (211) Google Scholar, 11Shen K.K. Fripp J. Mériaudeau F. et al.Detecting global and local hippocampal shape changes in Alzheimer's disease using statistical shape models.Neuroimage. 2012; 59: 2155-2166Crossref PubMed Scopus (73) Google Scholar), 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 identification (ie, before clinical symptoms of AD appear) of AD patients (12Dickerson B.C. Stoub T.R. Shah R.C. et al.Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults.Neurology. 2011; 76: 1395-1402Crossref PubMed Scopus (227) Google Scholar). 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 (13Schmand B. Huizenga H.M. van Gool W.A. Meta-analysis of CSF and MRI biomarkers for detecting preclinical Alzheimer's disease.Psychol Med. 2010; 40: 135-145Crossref PubMed Scopus (75) Google Scholar), the idea is a step in the right direction. The study by Zhu et al in this issue (8Zhu 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: 512-517Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar) 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 (14Hampel H. Teipel S.J. Alexander G.E. et al.Corpus callosum atrophy is a possible indicator of region- and cell type–specific neuronal degeneration in Alzheimer disease: a magnetic resonance imaging analysis.Arch Neurol. 1998; 55: 193-198Crossref PubMed Scopus (178) Google Scholar). Even though limited, the study by Zhu et al further emphasizes 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 something 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 necessity 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 variability. This means that a measurement may not achieve the necessary level of reproducibility (or consistency). Low reproducibility 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 (15Urs 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: 73-78Crossref PubMed Scopus (42) Google Scholar). Such computerized techniques are probably a necessary step to providing improved reproducibility, and thus more accurate/ precise measurements. The work presented by Zhu et al (8Zhu 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: 512-517Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar) 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 development and testing of sophisticated computerized measurement 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 (16Clarke L. Croft B. Development of public resources to support quantitative imaging methods in cancer.Acad Radiol. 2007; 14: 1438-1440Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar). Publicly available databases, such as that used in the study by Zhu et al (17Marcus D.S. Wang T.H. Parker J. et al.Open Access Series of Imaging Studies (OASIS): cross-sectional MRI data in young, middle aged, nondemented, and demented older adults.J Cogn Neurosci. 2007; 19: 1498-1507Crossref PubMed Scopus (1041) Google Scholar, 18The 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.Google Scholar), or that collected through the Alzheimer's Disease Neuroimaging Initiative (19The University of California, Los Angeles. Alzheimer's Disease Neuroimaging Initiative (ADNI). Available at: http://adni.loni.ucla.edu/. Accessed February 12, 2012.Google Scholar), open the door to many scientists with the goal of advancing the unmet challenge posed by AD, and more specifically offers the possibility to efficiently perform comparisons of increasingly sophisticated measures for the diagnosis and progression of AD. Development 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 understanding whether 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 (8Zhu 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: 512-517Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar) 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 challenging mystery that cannot be ignored, and “nothing in all the world is more dangerous than sincere ignorance …” (20Martin Luther King, Jr. Strength of Love. New York: Harper & Row; 1963.Google Scholar). The study by Zhu et al in this issue of Academic Radiology (8Zhu 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: 512-517Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar) is an important 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.