Early Diagnosis of Alzheimer's Disease
Early Diagnosis of Alzheimer's Disease
Editor's Note:
Early diagnosis of Alzheimer's disease (AD) would be of great value so that potential disease-modifying therapies could be tested and applied before widespread, irreversible neuronal damage occurs. The Archives of Neurology published an article online on December 8 that described a blood-based panel of secreted signaling proteins that differentiates blinded samples from patients with AD and control subjects with high accuracy. The investigators of the study suggested that the same proteins also predicted progression to AD in patients with mild cognitive impairment (MCI) several years before they were clinically diagnosed with AD.
To learn more about the potential utility of this blood test and its impact on management of AD, Medscape interviewed Sid Gilman MD, FRCP, William J. Herdman Distinguished University Professor of Neurology and Director of the Michigan Alzheimer's Disease Research Center at the University of Michigan in Ann Arbor. Dr. Gilman was not involved with the Archives of Neurology study but was asked to provide independent commentary.
Medscape: What are the current difficulties in diagnosing AD in its earliest stages?
Sid Gilman, MD: In the earliest stages of AD, which usually manifests with MCI, many different dementing disorders can present with similar symptoms. This applies to AD, multiple infarct dementia, frontal-temporal dementia, and corticobasal degeneration, for example. The same problem occurs with pseudo-dementia associated with severe depression and the cognitive disorders resulting from vitamin B12 deficiency, thyroid disease, and other multiple disorders.
Medscape: What are the advantages of early diagnosis of AD?
Dr. Gilman: Although definitive neuropathologic disease-modifying therapies are not yet available, several are in current clinical trials, and application of these treatments at the earliest stage of the disease is vital to maintain cognitive functioning. These treatments include antibody therapies (bapineuzumab and the Lilly passive antibody therapy, for example), gamma-secretase inhibitors, beta-secretase inhibitors, and amyloid peptide binding agents (such as scyllo-inositol).
Moreover, early diagnosis now allows treatment with some improvement of cognitive functioning with cholinesterase inhibitors and memantine. Also, early diagnosis allows the patient and family to prepare for the future with financial and medical decision determinations.
Medscape: Please describe a blood-based panel of secreted signaling proteins that may help to distinguish patients with AD from control subjects, and its accuracy in diagnosis.
Dr. Gilman: Britschgi and Wyss-Coray, of Stanford University and Satoris Pharmaceuticals, described 18 plasma proteins that, in small clinical trials, helped distinguish patients with AD from control subjects. The panel of proteins distinguished 40 patients with mild-to-moderate AD from 40 age-matched controls without dementia.
In another study of about the same size, the plasma proteins discriminated with almost 90% accuracy patients with AD from patients with other neurologic disorders and patients with rheumatoid arthritis. These data, although promising, represent a small sample, and we do not have data available on a very large sample, nor do we have available accurate sensitivity or specificity.
Medscape: How useful is this panel in predicting disease progression from MCI to AD?
Dr. Gilman: In 47 patients with MCI, the panel predicted progression to AD in 20 of 22 patients (2 patients evidently had false-negative results). The same panel discriminated 8 patients with MCI in whom other types of dementia developed. The remaining 17 of the 47 patients with MCI have not converted at the time of publication. Again, these data, while promising, require verification in very large groups of subjects to have credibility.
Medscape: What are the strengths and limitations of this study?
Dr. Gilman: The strengths are that the hypothesis underlying the development of the plasma protein group to be tested was credible and logical, and that the study was conducted objectively and the results were promising.
The weaknesses are that the authors did not specify how they made the diagnosis of AD in subjects who progressed from MCI to other disorders. The diagnosis of AD, as the authors themselves stated, has about 80% sensitivity and 70% specificity. (Actually, in our center these figures are closer to 90% and 95%). Accordingly, the presumption that the plasma protein tests can be trusted depends upon the accuracy of final diagnosis, and this would need to be validated by autopsy examination. Hence, the figures provided leave a considerable number of questions regarding accuracy, sensitivity, and specificity of the authors' test.
Moreover, the article evaluated a very small sample, and to be credible, the sample must be considerably larger. Also, have the authors thoroughly examined neurologic disorders with neurodegeneration such as amyotrophic lateral sclerosis, multiple system atrophy, progressive supranuclear palsy, and Parkinson's disease? How about dementia with Lewy bodies? These neurodegenerative disorders may have some of the same plasma proteins that are active as in AD, and if so, this would diminish the specificity of their test considerably.
Medscape: Are there any potential drawbacks to the approach of using a blood-based panel for AD diagnosis?
Dr. Gilman: The principal drawbacks are the need for sensitivity and specificity values, and this requires verification of diagnosis. How can the authors be certain that a patient has AD and not AD plus multiple infarct dementia? They do not specify the "gold standards" they use for the diagnosis of AD; hence, they are testing their test (an unknown) against a clinical diagnosis (of AD), and their gold standard (clinical diagnosis) may reach only 80% sensitivity and 70% specificity. Given this problem, how then can we judge the sensitivity and specificity of their test, even in sufficiently large trials?
Medscape: If this approach is validated and widely implemented, what would be the potential impact on public health?
Dr. Gilman: If the authors can overcome the problems listed above, this approach would assist in predicting whether people may go on to develop AD, even prior to the MCI stage. This would make it possible to apply disease-modifying therapies sufficiently early in the disease process to salvage cognition to a considerably greater extent than would be possible if treatment were applied later in the course.
Medscape: What additional research needs to be done?
Dr. Gilman: The authors need to verify their findings in very large samples, ensure that they have studied other neurodegenerative disorders, provide "gold standards" for their diagnosis of AD vs other dementing disorders in credible fashion, and thereby provide numbers for sensitivity and specificity of their diagnostic test.
Editor's Note:
Early diagnosis of Alzheimer's disease (AD) would be of great value so that potential disease-modifying therapies could be tested and applied before widespread, irreversible neuronal damage occurs. The Archives of Neurology published an article online on December 8 that described a blood-based panel of secreted signaling proteins that differentiates blinded samples from patients with AD and control subjects with high accuracy. The investigators of the study suggested that the same proteins also predicted progression to AD in patients with mild cognitive impairment (MCI) several years before they were clinically diagnosed with AD.
To learn more about the potential utility of this blood test and its impact on management of AD, Medscape interviewed Sid Gilman MD, FRCP, William J. Herdman Distinguished University Professor of Neurology and Director of the Michigan Alzheimer's Disease Research Center at the University of Michigan in Ann Arbor. Dr. Gilman was not involved with the Archives of Neurology study but was asked to provide independent commentary.
Medscape: What are the current difficulties in diagnosing AD in its earliest stages?
Sid Gilman, MD: In the earliest stages of AD, which usually manifests with MCI, many different dementing disorders can present with similar symptoms. This applies to AD, multiple infarct dementia, frontal-temporal dementia, and corticobasal degeneration, for example. The same problem occurs with pseudo-dementia associated with severe depression and the cognitive disorders resulting from vitamin B12 deficiency, thyroid disease, and other multiple disorders.
Medscape: What are the advantages of early diagnosis of AD?
Dr. Gilman: Although definitive neuropathologic disease-modifying therapies are not yet available, several are in current clinical trials, and application of these treatments at the earliest stage of the disease is vital to maintain cognitive functioning. These treatments include antibody therapies (bapineuzumab and the Lilly passive antibody therapy, for example), gamma-secretase inhibitors, beta-secretase inhibitors, and amyloid peptide binding agents (such as scyllo-inositol).
Moreover, early diagnosis now allows treatment with some improvement of cognitive functioning with cholinesterase inhibitors and memantine. Also, early diagnosis allows the patient and family to prepare for the future with financial and medical decision determinations.
Medscape: Please describe a blood-based panel of secreted signaling proteins that may help to distinguish patients with AD from control subjects, and its accuracy in diagnosis.
Dr. Gilman: Britschgi and Wyss-Coray, of Stanford University and Satoris Pharmaceuticals, described 18 plasma proteins that, in small clinical trials, helped distinguish patients with AD from control subjects. The panel of proteins distinguished 40 patients with mild-to-moderate AD from 40 age-matched controls without dementia.
In another study of about the same size, the plasma proteins discriminated with almost 90% accuracy patients with AD from patients with other neurologic disorders and patients with rheumatoid arthritis. These data, although promising, represent a small sample, and we do not have data available on a very large sample, nor do we have available accurate sensitivity or specificity.
Medscape: How useful is this panel in predicting disease progression from MCI to AD?
Dr. Gilman: In 47 patients with MCI, the panel predicted progression to AD in 20 of 22 patients (2 patients evidently had false-negative results). The same panel discriminated 8 patients with MCI in whom other types of dementia developed. The remaining 17 of the 47 patients with MCI have not converted at the time of publication. Again, these data, while promising, require verification in very large groups of subjects to have credibility.
Medscape: What are the strengths and limitations of this study?
Dr. Gilman: The strengths are that the hypothesis underlying the development of the plasma protein group to be tested was credible and logical, and that the study was conducted objectively and the results were promising.
The weaknesses are that the authors did not specify how they made the diagnosis of AD in subjects who progressed from MCI to other disorders. The diagnosis of AD, as the authors themselves stated, has about 80% sensitivity and 70% specificity. (Actually, in our center these figures are closer to 90% and 95%). Accordingly, the presumption that the plasma protein tests can be trusted depends upon the accuracy of final diagnosis, and this would need to be validated by autopsy examination. Hence, the figures provided leave a considerable number of questions regarding accuracy, sensitivity, and specificity of the authors' test.
Moreover, the article evaluated a very small sample, and to be credible, the sample must be considerably larger. Also, have the authors thoroughly examined neurologic disorders with neurodegeneration such as amyotrophic lateral sclerosis, multiple system atrophy, progressive supranuclear palsy, and Parkinson's disease? How about dementia with Lewy bodies? These neurodegenerative disorders may have some of the same plasma proteins that are active as in AD, and if so, this would diminish the specificity of their test considerably.
Medscape: Are there any potential drawbacks to the approach of using a blood-based panel for AD diagnosis?
Dr. Gilman: The principal drawbacks are the need for sensitivity and specificity values, and this requires verification of diagnosis. How can the authors be certain that a patient has AD and not AD plus multiple infarct dementia? They do not specify the "gold standards" they use for the diagnosis of AD; hence, they are testing their test (an unknown) against a clinical diagnosis (of AD), and their gold standard (clinical diagnosis) may reach only 80% sensitivity and 70% specificity. Given this problem, how then can we judge the sensitivity and specificity of their test, even in sufficiently large trials?
Medscape: If this approach is validated and widely implemented, what would be the potential impact on public health?
Dr. Gilman: If the authors can overcome the problems listed above, this approach would assist in predicting whether people may go on to develop AD, even prior to the MCI stage. This would make it possible to apply disease-modifying therapies sufficiently early in the disease process to salvage cognition to a considerably greater extent than would be possible if treatment were applied later in the course.
Medscape: What additional research needs to be done?
Dr. Gilman: The authors need to verify their findings in very large samples, ensure that they have studied other neurodegenerative disorders, provide "gold standards" for their diagnosis of AD vs other dementing disorders in credible fashion, and thereby provide numbers for sensitivity and specificity of their diagnostic test.
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