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2 Aβ42 and Tau as Markers of Alzheimer's Disease
Neurobiology of Aging, Vol. 17, No. 4S, pp. S1-$214, 1996 Copyright © 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0197-4580/96 $15.00 + .00 ELSEVIER
S0197-4580(96)00101-7
ABSTRACTS W O R K S H O P A: R O L E O F B I O C H E M I C A L M A R K E R S IN ALZHEIMER'S DISEASE 1 of a detailed clinical protocol to examine these markers and Apo E genotypes will be presented as well as clinical implications of these diagnostic tests.
A clinical and neurochemical approach to the use of diagnostic markers f o r Alzheimer's disease K Blennow, Dept of Clinical Neuroscience, Univ. of G0teborg, Sweden Biochemical markers for AD would be of great use both to improve the clinical diagnostic accuracy in scientific studies and treatment trials, and to follow the biochemical and therapeutic effect of potential drugs Since the extracellular space in the brain is continuous with the cerebrospinal fluid (CSF), analyses of CSF might reflect biochemical changes in the brain. However, although new CSF-assays for different proteins involved in AD pathogenesis (e.g. [3-amyloid, tau protein, synaptic proteins) are available, there are no CSF-analysis that can discriminate AD from normal aging or other dementias with high enough sensitivity and specificity. The reason for this is probably related to methodological issues:
3 Interpreting Cerebrospinal fluid tau levels in Alzheimer's disease D. Galasko ,1, R. Motter 2, p. Seubert 2 1 Department of Neurosciences, University of California, San Diego, and VAMC, 3350 La Jolla Village Drive, San Diego, CA 92161 and 2 Athena Neurosciences, 800 Gateway Boulevard, South San Francisco, CA 94080, USA Nine published studies have found that CSF tau levels are significantly elevated in Alzheimer's Disease (AD) compared to either nondemented controls (NC) or patients with neurological diseases (ND). Each study used a sensitive ELISA that measured all forms of tau regardless of phospborylation state. In a recent study (Motter et al., Ann Neurol 1995;38:643-648), using a cutoff that optimized specificity (>95%), we found that CSF tau was increased (> 312 pg/ml) in about 60% of AD patients. To explore why CSF tau levels are not uniformly increased in AD, we have undertaken further studies. We first examined whether short-term fluctuation of CSF tau occurs by obtaining two serial CSF samples each from 7 AD patients. Over 6 - 16 weeks, CSF tau varied by only 2 - 20% within patients. Therefore CSF tau levels are relatively stable. We next considered whether CSF tau is elevated early in AD, by studying 36 patients with mild AD (Mini-Mental State Examination score [MMSE] > 20/30). Their CSF tau was 499 + 232 pg/ml, significantly higher than tau levels in NC or ND. Of 11 patients with MMSE > 25 in this group, 8 had CSF tau > 312 pg/ml. Overall we have not found a significant correlation between tau and MMSE scores in AD. Finally, 11 demented patients whose CSF tau was measured during life have come to autopsy. 8 met CERAD criteria for AD, with abundant plaques and neurofibrillary tangles (NFT); 1 had "plaque only" AD, with NFT restricted to the hippocampus; 3 had Lewy Body variant of AD (LBV), with diffuse LB and rare NFT. CSF tau was lower in the "plaque only" and LBV patients than in the 8 "pure AD" patients. From this we infer that CSF tau likely reflects the rate of N F r formation in AD. We conclude that CSF tau is elevated in most patients with AD. Increased levels occur early in the course of AD and persist as dementia progresses. The release of soluble tan into the CSF may be accelerated by processes related to NFT formation in AD. D.G is supported by NIH grant AG05131.
1) What is the pathophysiological specificity for a CSF-marker? For example, does ~-amyloid deposition discriminate normal aging and AD? And does an increase in CSF-tau protein reflect neurofibrillary tangles, acute brain damage, chronic neuronal degeneration, or aU three? 2) To what degree do CSF analyses reflect CNS biochemistry? Does a reduced CSF-level of a protein reflect a reduced production in the brain, or is it secondary to brain atrophy, or dilution secondary to increased CSF-spaces? 3) How important is it to consider different confounding factors, such as proteolysis or aggregation during CSF storage, blood-brain barrier function, concentration gradients, and possible vanation in CSF flow, when evatuating CSF markers? 4) How important is it to evaluate the analytical specificity, for example possible cross reactivity due to shared sequence between isoforms (e.g. APP), different truncation (e.g. 13-amyloid)and phosphorylation state (e.g tau protein)? 5) How important are different clinical parameters, e.g. accurate diagnostic critena, possible subgroups of AD (e.g. sporadic/familial, eady-/late-onset forms), the stage / severity of disease, adequate control population, and possible age and gender variation, when evaluating a potential CSF'marker? 6) Will it ever be possible to use one CSF-marker, or do we need a set of CSF markers, to identify the different pathophysiologicel processes in AD (e.g. amyloid deposition, neuronal and synaptic degeneration), and to exclude other types of pathology (e.g. white-matter demyelination)?
2 AI34z and Tau as M a r k e r s of AIzheimer's Disease D. Schenk*, R, Motter, D. Kholodenko, I. Lieberburg, P. Seubert Athena Neurosciences, Inc., 800 Gateway Blvd., S. San Francisco, CA 94080 Phone: 415-877-0900, Fax: 415-877-8370 Recent efforts to identify biochemical markers that might be of diagnostic utility for Alzheimer's disease have shown that microtubule associated protein tau is often elevated in the CSF of AD patients. The specificity of this elevation is high ( > 90%) and has been confirmed by at least eight independent research groups including our own. Collectively, these findings establish the elevation of CSF tau in AD. A second marker that has been recently identified as having diagnostic utility for AD is A1342. We have found that this long form of AI3 is decreased in the CSF of AD patients. This finding is so consistent that elevated CSF A [~42 is a very strong indicator of the presence of non-AD neurological disease. The combined use of A~42 and tau CSF levels is therefore very promising for diagnosis of AD. Results
4 Combination of tau/phospho-tau with other biochemical markers to improve the specificity of an Alzheimer's disease test A. Van de Voorde*, E. Vanmechelen', K. Bleanow and P. Cras *Innogenetics N.V., Gent, Belgium Levels of tau proteim are comistently and significantly increased in the cerebrospinal fluid (CSF) of Alzheimer patients versus levels in normal controls. However, the sole use of this biochemical marker as a test for Alzheimer's disease is hampered by mediocre specificity since tau concentrations may also be elevated in certain other neurological disorders (OND). In order to improve specificity, we therefore analyzed levels of S1
S0197-4580(96)00101-7
ABSTRACTS W O R K S H O P A: R O L E O F B I O C H E M I C A L M A R K E R S IN ALZHEIMER'S DISEASE 1 of a detailed clinical protocol to examine these markers and Apo E genotypes will be presented as well as clinical implications of these diagnostic tests.
A clinical and neurochemical approach to the use of diagnostic markers f o r Alzheimer's disease K Blennow, Dept of Clinical Neuroscience, Univ. of G0teborg, Sweden Biochemical markers for AD would be of great use both to improve the clinical diagnostic accuracy in scientific studies and treatment trials, and to follow the biochemical and therapeutic effect of potential drugs Since the extracellular space in the brain is continuous with the cerebrospinal fluid (CSF), analyses of CSF might reflect biochemical changes in the brain. However, although new CSF-assays for different proteins involved in AD pathogenesis (e.g. [3-amyloid, tau protein, synaptic proteins) are available, there are no CSF-analysis that can discriminate AD from normal aging or other dementias with high enough sensitivity and specificity. The reason for this is probably related to methodological issues:
3 Interpreting Cerebrospinal fluid tau levels in Alzheimer's disease D. Galasko ,1, R. Motter 2, p. Seubert 2 1 Department of Neurosciences, University of California, San Diego, and VAMC, 3350 La Jolla Village Drive, San Diego, CA 92161 and 2 Athena Neurosciences, 800 Gateway Boulevard, South San Francisco, CA 94080, USA Nine published studies have found that CSF tau levels are significantly elevated in Alzheimer's Disease (AD) compared to either nondemented controls (NC) or patients with neurological diseases (ND). Each study used a sensitive ELISA that measured all forms of tau regardless of phospborylation state. In a recent study (Motter et al., Ann Neurol 1995;38:643-648), using a cutoff that optimized specificity (>95%), we found that CSF tau was increased (> 312 pg/ml) in about 60% of AD patients. To explore why CSF tau levels are not uniformly increased in AD, we have undertaken further studies. We first examined whether short-term fluctuation of CSF tau occurs by obtaining two serial CSF samples each from 7 AD patients. Over 6 - 16 weeks, CSF tau varied by only 2 - 20% within patients. Therefore CSF tau levels are relatively stable. We next considered whether CSF tau is elevated early in AD, by studying 36 patients with mild AD (Mini-Mental State Examination score [MMSE] > 20/30). Their CSF tau was 499 + 232 pg/ml, significantly higher than tau levels in NC or ND. Of 11 patients with MMSE > 25 in this group, 8 had CSF tau > 312 pg/ml. Overall we have not found a significant correlation between tau and MMSE scores in AD. Finally, 11 demented patients whose CSF tau was measured during life have come to autopsy. 8 met CERAD criteria for AD, with abundant plaques and neurofibrillary tangles (NFT); 1 had "plaque only" AD, with NFT restricted to the hippocampus; 3 had Lewy Body variant of AD (LBV), with diffuse LB and rare NFT. CSF tau was lower in the "plaque only" and LBV patients than in the 8 "pure AD" patients. From this we infer that CSF tau likely reflects the rate of N F r formation in AD. We conclude that CSF tau is elevated in most patients with AD. Increased levels occur early in the course of AD and persist as dementia progresses. The release of soluble tan into the CSF may be accelerated by processes related to NFT formation in AD. D.G is supported by NIH grant AG05131.
1) What is the pathophysiological specificity for a CSF-marker? For example, does ~-amyloid deposition discriminate normal aging and AD? And does an increase in CSF-tau protein reflect neurofibrillary tangles, acute brain damage, chronic neuronal degeneration, or aU three? 2) To what degree do CSF analyses reflect CNS biochemistry? Does a reduced CSF-level of a protein reflect a reduced production in the brain, or is it secondary to brain atrophy, or dilution secondary to increased CSF-spaces? 3) How important is it to consider different confounding factors, such as proteolysis or aggregation during CSF storage, blood-brain barrier function, concentration gradients, and possible vanation in CSF flow, when evatuating CSF markers? 4) How important is it to evaluate the analytical specificity, for example possible cross reactivity due to shared sequence between isoforms (e.g. APP), different truncation (e.g. 13-amyloid)and phosphorylation state (e.g tau protein)? 5) How important are different clinical parameters, e.g. accurate diagnostic critena, possible subgroups of AD (e.g. sporadic/familial, eady-/late-onset forms), the stage / severity of disease, adequate control population, and possible age and gender variation, when evaluating a potential CSF'marker? 6) Will it ever be possible to use one CSF-marker, or do we need a set of CSF markers, to identify the different pathophysiologicel processes in AD (e.g. amyloid deposition, neuronal and synaptic degeneration), and to exclude other types of pathology (e.g. white-matter demyelination)?
2 AI34z and Tau as M a r k e r s of AIzheimer's Disease D. Schenk*, R, Motter, D. Kholodenko, I. Lieberburg, P. Seubert Athena Neurosciences, Inc., 800 Gateway Blvd., S. San Francisco, CA 94080 Phone: 415-877-0900, Fax: 415-877-8370 Recent efforts to identify biochemical markers that might be of diagnostic utility for Alzheimer's disease have shown that microtubule associated protein tau is often elevated in the CSF of AD patients. The specificity of this elevation is high ( > 90%) and has been confirmed by at least eight independent research groups including our own. Collectively, these findings establish the elevation of CSF tau in AD. A second marker that has been recently identified as having diagnostic utility for AD is A1342. We have found that this long form of AI3 is decreased in the CSF of AD patients. This finding is so consistent that elevated CSF A [~42 is a very strong indicator of the presence of non-AD neurological disease. The combined use of A~42 and tau CSF levels is therefore very promising for diagnosis of AD. Results
4 Combination of tau/phospho-tau with other biochemical markers to improve the specificity of an Alzheimer's disease test A. Van de Voorde*, E. Vanmechelen', K. Bleanow and P. Cras *Innogenetics N.V., Gent, Belgium Levels of tau proteim are comistently and significantly increased in the cerebrospinal fluid (CSF) of Alzheimer patients versus levels in normal controls. However, the sole use of this biochemical marker as a test for Alzheimer's disease is hampered by mediocre specificity since tau concentrations may also be elevated in certain other neurological disorders (OND). In order to improve specificity, we therefore analyzed levels of S1