- Email: [email protected]
Commentary on “Diagnosis of Alzheimer’s disease: Two decades of progress”
Alzheimer’s & Dementia 1 (2005) 107–108
Commentary on “Diagnosis of Alzheimer’s disease: Two decades of progress” Robert Katzman* University of California, San Diego, Department of Neurosciences, 9500 Gilman Drive, 0949, La Jolla, CA 92093-0949 USA
In “Diagnosis of Alzheimer’s Disease: Two Decades of Progress” [1], Dr. Khachaturian has done a superb job describing the role of the National Institute on Aging (NIA) in advancing our ability to diagnose Alzheimer’s disease (AD) and other degenerative dementia and identifying those with minimal cognitive impairment (MCI) who are at risk for AD. As noted by Dr. Khachaturian, clinical–neuropathologic correlations have been of particular importance in developing diagnostic tools for AD and for defining the non-AD dementing illnesses. NIA support of Alzheimer Disease Research Centers and Alzheimer Disease Centers has greatly augmented the number of well-studied autopsied cases and accelerated the pace of research. I would like to add 3 pre-1985 historical facets. First, in 1977, the newly formed National Institute on Aging joined with the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and National Institute of Mental Health (NIMH) in sponsoring a workshop– conference on “Alzheimer’s Disease: Senile Dementia and Related Disorders” [2], which was held on the National Institutes of Health (NIH) Bethesda campus. This conference was organized Dr. Robert Terry, and Dr. Katherine Bick, and myself. There were 84 participants. These included established authorities on AD such as Robert Terry and Martin Roth, investigators from 2 of the 3 groups who had independently discovered the major loss of choline acetyl transferase in the AD brain—Alan Davison and Peter Davies, clinicians such as Martin Albert and Robert Cohn, and important scientists whose skill had not yet been applied to dementing illnesses—such as Edith McGeer and George Glenner. Glenner, a pathologist and molecular chemist and an authority on systemic amyloidoses, then began working on AD. By 1984, Glenner had successfully isolated and characterized the amyloid in the AD brain opening up a major area of investigation in the pathogenesis of AD [3].
*Tel:1-858-622-5850; fax: 1-858-622-1016. E-mail address: [email protected]
Second, operational criteria for the diagnosis of the syndrome of dementia were introduced in the third edition of the American Psychiatric Association’s Diagnostic and Statistical Manual, published in 1980. Third, these criteria for the dementia syndrome were used as the basis of the 1984 diagnostic criteria for AD developed “under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease” [4]. The availability of accepted criteria for the diagnosis of dementia and AD has greatly expedited clinical, epidemiologic, genetic, and most important, pharmaceutical studies, making it possible to demonstrate quickly the efficacy of cholinomimetic drugs for partial symptomatic relief in early AD. It has become evident that AD begins many years before patients meet criteria for dementia. Studying more than 1,400 elderly participants in the Baltimore Longitudinal Study of Aging, Kawas et al [5] found that impairment on the Benton Visual Retention test began up to 15 years before the diagnosis of dementia could be made. In a major longitudinal study carried out in Bordeaux, Amieva et al [6] showed a 9-year cognitive decline with acceleration 3 years before AD could be diagnosed. Petersen et al [7] introduced the term, mild cognitive impairment or MCI to describe measurable cognitive changes preceding the diagnosis of dementia. In their study, many subjects with MCI went on to have Alzheimer’s disease. The APOE ⑀4 allele status was a strong predictor of clinical progression. The Peterson criteria, based primarily on memory tests, are now being broadened to include subjects whose initial impairments are in other areas of cognition. The clear definition of MCI makes it possible to carry out clinical trials of putative protective factors. A plethora of wellconducted longitudinal studies of dementia have been developed and a number of possible protective factors identified, in part because of the interest of NIA. A 5-year delay in onset of AD would halve the prevalence of the disorder [8]. Protective factors identified by observational epidemiology, however, have to be confirmed in clinical trials. In one of the first of such
1552-5260/05/$ – see front matter © 2005 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2005.09.010
108
R. Katzman / Alzheimer’s & Dementia 1 (2005) 107–108
trials, vitamin E failed to delay the onset of AD in MCI patients [9]. Clinical trials of other putative protective factors will hopefully be positive. Accurate clinical diagnosis has helped identification of genetic risk factors that predispose to late onset AD. The most important is the allele APOE 4, but the mechanism by which this gene acts is not yet understood. Another interesting recent example is the insertion and deletion polymorphism found in Japanese and other populations in the gene for the angiotensinconverting enzyme (ACE) [10]. ACE has been found to degrade the amyloid peptide [11, 12]. The pharmaceutical industry is very familiar with ACE inhibitors for the treatment of hypertension; perhaps this industry might be interested in this new role of ACE and seek to develop new drugs that would prevent amyloid from forming. Along with advances in clinical diagnoses, imaging techniques have become increasingly reliable and objective, especially since computerized analyses of many parameters now available. Emphasis has been on magnetic resonance imaging evidence of very early atrophy of entorhinal cortex and medial temporal lobe structures, a region involved in memory processes. However, as Buckner et al [13] have reminded us, data from positron emission tomography (PET) studies have consistently shown parietal temporal and retrosplenial association cortex hypometabolism as an early marker of AD. And now there is evidence that amyloid is deposited in the parietal lobe and adjacent areas early in AD as measured on PET by the [11C] Pittsburgh Compound-B [14]. Buckner et al [13] argued that these regions are active in “default activity” that is important for memory retrieval in young adults. Thus, the progress that has been made in clinical diagnosis and imaging impact significantly our understanding of the pathogenesis of AD. Khachaturian envisions that in the future, imaging techniques might make it possible to visualize other biological parameters including synapse loss, the major correlate of dementia—an exciting prospect. References [1] Khachaturian Z. Diagnosis of Alzheimer’s disease: Two decades of progress. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 2005;1(2):93– 8.
[2] Katzman R, Terry RD, Bick KL, Eds. Aging, Vol. 7, Alzheimer’s disease: senile dementia and related disorders. New York: Raven Press, 1978, p. 595. [3] Glenner GG, Wong CW. Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984;120:885–90. [4] McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34(7):939 – 44. [5] Kawas CH, Corrada MM, Brookmeyer R, Morrison A, Resnick SM, Zonderman AB, et al. Visual memory predicts Alzheimer’s disease more than a decade before diagnosis. Neurology 2003;60(7):1089 – 93. [6] Amieva H, Jacqmin-Gadda H, Orgogozo JM, Le Carret N, Helmer C, Letenneur L, et al. The 9 year cognitive decline before dementia of the Alzheimer type: A prospective population-based study. Brain 2005;128(5):1093–1101. [7] Petersen RC, Smith GE, Ivnik RJ, Tangalos EG, Schaid DJ, Thibodeau SN, et al. Apolipoprotein E status as a predictor of the development of Alzheimer’s disease in memory-impaired individuals. JAMA 1995;273(16):1274 – 8. [8] Khachaturian Z. The five-five, ten-ten plan for Alzheimer’s disease. Neurobiol Aging 1992;13(2):197– 8. [9] Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, et al. Alzheimer’s Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352(23):2379 – 88. [10] Hu J, Miyatake F, Aizu Y, Nakagawa H, Nakamura S, Tamaoka A, et al.Angiotensin-converting enzyme genotype is associated with Alzheimer disease in the Japanese population. Neurosci Lett 1999; 277(1):65–71. [11] Hu J, Igarashi A, Kamata M, Nakagawa H. Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta ); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem 2001;276(51):47863– 8. [12] Hemming ML, Selkoe DJ. Amyloid beta -protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. JBC Papers in press. Published on September 9, 2005 as Manuscript MS08460200, www.jbc.org; J Biol Chem 2005; Sept 9. [13] Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, et al. Molecular, structural, and functional characterization of Alzheimer’s disease: Evidence for a relationship between default activity, amyloid, and memory. J Neurosci 2005;25(34):7709 –17. [14] Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 2004;55(3):306 –19.
Commentary on “Diagnosis of Alzheimer’s disease: Two decades of progress” Robert Katzman* University of California, San Diego, Department of Neurosciences, 9500 Gilman Drive, 0949, La Jolla, CA 92093-0949 USA
In “Diagnosis of Alzheimer’s Disease: Two Decades of Progress” [1], Dr. Khachaturian has done a superb job describing the role of the National Institute on Aging (NIA) in advancing our ability to diagnose Alzheimer’s disease (AD) and other degenerative dementia and identifying those with minimal cognitive impairment (MCI) who are at risk for AD. As noted by Dr. Khachaturian, clinical–neuropathologic correlations have been of particular importance in developing diagnostic tools for AD and for defining the non-AD dementing illnesses. NIA support of Alzheimer Disease Research Centers and Alzheimer Disease Centers has greatly augmented the number of well-studied autopsied cases and accelerated the pace of research. I would like to add 3 pre-1985 historical facets. First, in 1977, the newly formed National Institute on Aging joined with the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and National Institute of Mental Health (NIMH) in sponsoring a workshop– conference on “Alzheimer’s Disease: Senile Dementia and Related Disorders” [2], which was held on the National Institutes of Health (NIH) Bethesda campus. This conference was organized Dr. Robert Terry, and Dr. Katherine Bick, and myself. There were 84 participants. These included established authorities on AD such as Robert Terry and Martin Roth, investigators from 2 of the 3 groups who had independently discovered the major loss of choline acetyl transferase in the AD brain—Alan Davison and Peter Davies, clinicians such as Martin Albert and Robert Cohn, and important scientists whose skill had not yet been applied to dementing illnesses—such as Edith McGeer and George Glenner. Glenner, a pathologist and molecular chemist and an authority on systemic amyloidoses, then began working on AD. By 1984, Glenner had successfully isolated and characterized the amyloid in the AD brain opening up a major area of investigation in the pathogenesis of AD [3].
*Tel:1-858-622-5850; fax: 1-858-622-1016. E-mail address: [email protected]
Second, operational criteria for the diagnosis of the syndrome of dementia were introduced in the third edition of the American Psychiatric Association’s Diagnostic and Statistical Manual, published in 1980. Third, these criteria for the dementia syndrome were used as the basis of the 1984 diagnostic criteria for AD developed “under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease” [4]. The availability of accepted criteria for the diagnosis of dementia and AD has greatly expedited clinical, epidemiologic, genetic, and most important, pharmaceutical studies, making it possible to demonstrate quickly the efficacy of cholinomimetic drugs for partial symptomatic relief in early AD. It has become evident that AD begins many years before patients meet criteria for dementia. Studying more than 1,400 elderly participants in the Baltimore Longitudinal Study of Aging, Kawas et al [5] found that impairment on the Benton Visual Retention test began up to 15 years before the diagnosis of dementia could be made. In a major longitudinal study carried out in Bordeaux, Amieva et al [6] showed a 9-year cognitive decline with acceleration 3 years before AD could be diagnosed. Petersen et al [7] introduced the term, mild cognitive impairment or MCI to describe measurable cognitive changes preceding the diagnosis of dementia. In their study, many subjects with MCI went on to have Alzheimer’s disease. The APOE ⑀4 allele status was a strong predictor of clinical progression. The Peterson criteria, based primarily on memory tests, are now being broadened to include subjects whose initial impairments are in other areas of cognition. The clear definition of MCI makes it possible to carry out clinical trials of putative protective factors. A plethora of wellconducted longitudinal studies of dementia have been developed and a number of possible protective factors identified, in part because of the interest of NIA. A 5-year delay in onset of AD would halve the prevalence of the disorder [8]. Protective factors identified by observational epidemiology, however, have to be confirmed in clinical trials. In one of the first of such
1552-5260/05/$ – see front matter © 2005 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2005.09.010
108
R. Katzman / Alzheimer’s & Dementia 1 (2005) 107–108
trials, vitamin E failed to delay the onset of AD in MCI patients [9]. Clinical trials of other putative protective factors will hopefully be positive. Accurate clinical diagnosis has helped identification of genetic risk factors that predispose to late onset AD. The most important is the allele APOE 4, but the mechanism by which this gene acts is not yet understood. Another interesting recent example is the insertion and deletion polymorphism found in Japanese and other populations in the gene for the angiotensinconverting enzyme (ACE) [10]. ACE has been found to degrade the amyloid peptide [11, 12]. The pharmaceutical industry is very familiar with ACE inhibitors for the treatment of hypertension; perhaps this industry might be interested in this new role of ACE and seek to develop new drugs that would prevent amyloid from forming. Along with advances in clinical diagnoses, imaging techniques have become increasingly reliable and objective, especially since computerized analyses of many parameters now available. Emphasis has been on magnetic resonance imaging evidence of very early atrophy of entorhinal cortex and medial temporal lobe structures, a region involved in memory processes. However, as Buckner et al [13] have reminded us, data from positron emission tomography (PET) studies have consistently shown parietal temporal and retrosplenial association cortex hypometabolism as an early marker of AD. And now there is evidence that amyloid is deposited in the parietal lobe and adjacent areas early in AD as measured on PET by the [11C] Pittsburgh Compound-B [14]. Buckner et al [13] argued that these regions are active in “default activity” that is important for memory retrieval in young adults. Thus, the progress that has been made in clinical diagnosis and imaging impact significantly our understanding of the pathogenesis of AD. Khachaturian envisions that in the future, imaging techniques might make it possible to visualize other biological parameters including synapse loss, the major correlate of dementia—an exciting prospect. References [1] Khachaturian Z. Diagnosis of Alzheimer’s disease: Two decades of progress. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 2005;1(2):93– 8.
[2] Katzman R, Terry RD, Bick KL, Eds. Aging, Vol. 7, Alzheimer’s disease: senile dementia and related disorders. New York: Raven Press, 1978, p. 595. [3] Glenner GG, Wong CW. Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984;120:885–90. [4] McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34(7):939 – 44. [5] Kawas CH, Corrada MM, Brookmeyer R, Morrison A, Resnick SM, Zonderman AB, et al. Visual memory predicts Alzheimer’s disease more than a decade before diagnosis. Neurology 2003;60(7):1089 – 93. [6] Amieva H, Jacqmin-Gadda H, Orgogozo JM, Le Carret N, Helmer C, Letenneur L, et al. The 9 year cognitive decline before dementia of the Alzheimer type: A prospective population-based study. Brain 2005;128(5):1093–1101. [7] Petersen RC, Smith GE, Ivnik RJ, Tangalos EG, Schaid DJ, Thibodeau SN, et al. Apolipoprotein E status as a predictor of the development of Alzheimer’s disease in memory-impaired individuals. JAMA 1995;273(16):1274 – 8. [8] Khachaturian Z. The five-five, ten-ten plan for Alzheimer’s disease. Neurobiol Aging 1992;13(2):197– 8. [9] Petersen RC, Thomas RG, Grundman M, Bennett D, Doody R, Ferris S, et al. Alzheimer’s Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352(23):2379 – 88. [10] Hu J, Miyatake F, Aizu Y, Nakagawa H, Nakamura S, Tamaoka A, et al.Angiotensin-converting enzyme genotype is associated with Alzheimer disease in the Japanese population. Neurosci Lett 1999; 277(1):65–71. [11] Hu J, Igarashi A, Kamata M, Nakagawa H. Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta ); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity. J Biol Chem 2001;276(51):47863– 8. [12] Hemming ML, Selkoe DJ. Amyloid beta -protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. JBC Papers in press. Published on September 9, 2005 as Manuscript MS08460200, www.jbc.org; J Biol Chem 2005; Sept 9. [13] Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, et al. Molecular, structural, and functional characterization of Alzheimer’s disease: Evidence for a relationship between default activity, amyloid, and memory. J Neurosci 2005;25(34):7709 –17. [14] Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 2004;55(3):306 –19.