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Diagnosis of Alzheimer's disease with cerebrospinal fluid tau protein and aspartate aminotransferase
THE LANCET
M Riemenschneider, K Buch, M Schmolke, A Kurz, W G Guder
In Alzheimer’s disease neuronal degeneration leads to the release of the microtubule-associated protein tau into the extracellular space and cerebrospinal fluid (CSF). CSF tau concentration is substantially increased compared with controls in mild Alzheimer’s disease and in other forms of dementia,1 suggesting that raised tau concentration is a non-specific marker of neuronal degeneration. Impairment of glucose metabolism is another feature of Alzheimer’s, and some workers have suggested that the use of glucogenic aminoacids as alternative sources of energy may lead to increased activity of aminotransferases including aspartate aminotransferase (AST).2 We postulated that AST could be a complementary biological marker for Alzheimer’s disease in CSF, provided that other disorders with raised AST, such as brain ischaemia and subarachnoid haemorrhage, were excluded.3 We measured tau concentration and AST activity in the CSF of 39 patients who fulfilled NINCDS-ADRDA4 criteria for probable Alzheimer’s disease, 12 patients with other causes of dementia (normal pressure hydrocephalus [three], frontal lobe degeneration [three], cerebrovascular dementia [two], progressive supranuclear palsy [two], and unclassified dementia [two]), and in 30 cognitively healthy controls. 19 of the 39 Alzheimer’s disease patients had a mini-mental state score of 25 or above indicating very mild cognitive impairment. Tau protein was measured with an ELISA that detects unphosphorylated tau and phosphorylated tau (Innogenetics, Zwijndrecht, Belgium). AST activity was measured with kinetic enzyme activity test at 25°C (Boehringer Mannheim), on a Hitachi 717 analyser. CSF tau concentrations were substantially increased in both dementia groups compared with controls, but Alzheimer’s disease patients had significantly higher tau values than patients with other dementias (table). By contrast, there was no significant difference in AST activity between demented patients and controls, but AST activity was significantly raised in the Alzheimer’s disease group. Combining both markers increased specificity from 50% (tau only) to 83% in the differential diagnosis of dementia. We also found a strong correlation between tau concentration and AST activity (r=0·78). These preliminary findings show that tau is a sensitive marker of neuronal degeneration. They also suggest that AST could be a complementary marker more specific for Alzheimer’s disease than tau which might be useful in distinguishing this condition from other types of dementia. Marker
Controls (n=30)
Other dementia (n=12)
Alzheimer’s disease (n=39)
Tau protein (ng/L)
173 (12)
320 (40)
722 (76)
AST (U/L)
5·7 (0·2)
p<0·001* 6·7 (0·6) NS
p<0·001*, p<0·05† 9·9 (0·5) p<0·001*, p<0·005†
All values are mean (SE). NS=not significant. p values (Wilcoxon, Mann–Whitney U test) marked * are compared with controls, those marked † are compared with other dementias.
Tau protein concentrations and AST activity in patients with dementia and in controls 1
Riemenschneider M, Buch K, Schmolke M, Kurz A, Guder WG. Cerebrospinal protein tau is elevated in early Alzheimer’s disease. Neurosci Lett 1996; 212: 209–11.
784
2
3
4
Hoyer S, Nitsch R. Cerebral excess release of neurotransmitter amino acids subsequent to reduced cerebral glucose metabolism in early onset dementia of Alzheimer type. J Neural Transm 1989; 75: 227–32. Katzman R, Fishman R, Goldensohn E. Glutamic-oxalacetic transminase activity in spinal fluid. Neurology 1957; 8: 853–55. 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 the Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 1984; 34: 939–44.
Institute of Clinical Chemistry, Städtisches Krankenhaus Bogenhausen, Munich 81925, Germany (M Riemenschneider); and Department of Psychiatry, Technische Universität, Munich
Biochemical diagnosis of aortic dissection by raised concentrations of creatine kinase BB-isozyme Toru Suzuki, Hirohisa Katoh, Masahiko Kurabayashi, Yoshio Yazaki, Ryozo Nagai
Aortic dissection is associated with a high mortality and morbidity. Despite advancements in surgical and medical treatment, aortic dissection is often diagnosed too late or is overlooked. There have been improvements in diagnostic imaging, such as transesophageal echocardiography and magnetic resonance imaging, but biochemical diagnosis have not been explored. We have reported raised serum smooth-muscle-myosin heavy chain concentrations in aortic dissection;1–3 we now show creatine kinase BBisozyme concentrations to be raised in acute aortic dissection. Creatine kinase is found abundantly in muscle and brain with isozymes for different tissues. We postulated that the BB-isozyme in smooth muscle tissue might also be a potential marker in biochemical diagnosis of aortic dissection since aortic smooth muscle is damaged in the disease. We measured serial serum concentrations of creatine kinase BB-isozyme by electrophoresis in ten consecutive patients with acute aortic dissection. The concentration of creatine kinase BB-isozyme was significantly higher in the patients than in a group of 20 controls (3·4 [SE 1·0] vs 0·2 [0·1] IU/L). Total serum creatine kinase concentrations were within the normal 10·0
7·5 CK-BB (IU/L)
Diagnosis of Alzheimer’s disease with cerebrospinal fluid tau protein and aspartate aminotransferase
5·0
2·5
0 0
12
24
36
48
60
72
Time after onset (h) Overlayed temporal curves of creatine kinase BB-isozyme (CK-BB) concentrations in the ten patients with aortic dissection by time after onset of clinical symptoms
Vol 350 • September 13, 1997
M Riemenschneider, K Buch, M Schmolke, A Kurz, W G Guder
In Alzheimer’s disease neuronal degeneration leads to the release of the microtubule-associated protein tau into the extracellular space and cerebrospinal fluid (CSF). CSF tau concentration is substantially increased compared with controls in mild Alzheimer’s disease and in other forms of dementia,1 suggesting that raised tau concentration is a non-specific marker of neuronal degeneration. Impairment of glucose metabolism is another feature of Alzheimer’s, and some workers have suggested that the use of glucogenic aminoacids as alternative sources of energy may lead to increased activity of aminotransferases including aspartate aminotransferase (AST).2 We postulated that AST could be a complementary biological marker for Alzheimer’s disease in CSF, provided that other disorders with raised AST, such as brain ischaemia and subarachnoid haemorrhage, were excluded.3 We measured tau concentration and AST activity in the CSF of 39 patients who fulfilled NINCDS-ADRDA4 criteria for probable Alzheimer’s disease, 12 patients with other causes of dementia (normal pressure hydrocephalus [three], frontal lobe degeneration [three], cerebrovascular dementia [two], progressive supranuclear palsy [two], and unclassified dementia [two]), and in 30 cognitively healthy controls. 19 of the 39 Alzheimer’s disease patients had a mini-mental state score of 25 or above indicating very mild cognitive impairment. Tau protein was measured with an ELISA that detects unphosphorylated tau and phosphorylated tau (Innogenetics, Zwijndrecht, Belgium). AST activity was measured with kinetic enzyme activity test at 25°C (Boehringer Mannheim), on a Hitachi 717 analyser. CSF tau concentrations were substantially increased in both dementia groups compared with controls, but Alzheimer’s disease patients had significantly higher tau values than patients with other dementias (table). By contrast, there was no significant difference in AST activity between demented patients and controls, but AST activity was significantly raised in the Alzheimer’s disease group. Combining both markers increased specificity from 50% (tau only) to 83% in the differential diagnosis of dementia. We also found a strong correlation between tau concentration and AST activity (r=0·78). These preliminary findings show that tau is a sensitive marker of neuronal degeneration. They also suggest that AST could be a complementary marker more specific for Alzheimer’s disease than tau which might be useful in distinguishing this condition from other types of dementia. Marker
Controls (n=30)
Other dementia (n=12)
Alzheimer’s disease (n=39)
Tau protein (ng/L)
173 (12)
320 (40)
722 (76)
AST (U/L)
5·7 (0·2)
p<0·001* 6·7 (0·6) NS
p<0·001*, p<0·05† 9·9 (0·5) p<0·001*, p<0·005†
All values are mean (SE). NS=not significant. p values (Wilcoxon, Mann–Whitney U test) marked * are compared with controls, those marked † are compared with other dementias.
Tau protein concentrations and AST activity in patients with dementia and in controls 1
Riemenschneider M, Buch K, Schmolke M, Kurz A, Guder WG. Cerebrospinal protein tau is elevated in early Alzheimer’s disease. Neurosci Lett 1996; 212: 209–11.
784
2
3
4
Hoyer S, Nitsch R. Cerebral excess release of neurotransmitter amino acids subsequent to reduced cerebral glucose metabolism in early onset dementia of Alzheimer type. J Neural Transm 1989; 75: 227–32. Katzman R, Fishman R, Goldensohn E. Glutamic-oxalacetic transminase activity in spinal fluid. Neurology 1957; 8: 853–55. 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 the Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 1984; 34: 939–44.
Institute of Clinical Chemistry, Städtisches Krankenhaus Bogenhausen, Munich 81925, Germany (M Riemenschneider); and Department of Psychiatry, Technische Universität, Munich
Biochemical diagnosis of aortic dissection by raised concentrations of creatine kinase BB-isozyme Toru Suzuki, Hirohisa Katoh, Masahiko Kurabayashi, Yoshio Yazaki, Ryozo Nagai
Aortic dissection is associated with a high mortality and morbidity. Despite advancements in surgical and medical treatment, aortic dissection is often diagnosed too late or is overlooked. There have been improvements in diagnostic imaging, such as transesophageal echocardiography and magnetic resonance imaging, but biochemical diagnosis have not been explored. We have reported raised serum smooth-muscle-myosin heavy chain concentrations in aortic dissection;1–3 we now show creatine kinase BBisozyme concentrations to be raised in acute aortic dissection. Creatine kinase is found abundantly in muscle and brain with isozymes for different tissues. We postulated that the BB-isozyme in smooth muscle tissue might also be a potential marker in biochemical diagnosis of aortic dissection since aortic smooth muscle is damaged in the disease. We measured serial serum concentrations of creatine kinase BB-isozyme by electrophoresis in ten consecutive patients with acute aortic dissection. The concentration of creatine kinase BB-isozyme was significantly higher in the patients than in a group of 20 controls (3·4 [SE 1·0] vs 0·2 [0·1] IU/L). Total serum creatine kinase concentrations were within the normal 10·0
7·5 CK-BB (IU/L)
Diagnosis of Alzheimer’s disease with cerebrospinal fluid tau protein and aspartate aminotransferase
5·0
2·5
0 0
12
24
36
48
60
72
Time after onset (h) Overlayed temporal curves of creatine kinase BB-isozyme (CK-BB) concentrations in the ten patients with aortic dissection by time after onset of clinical symptoms
Vol 350 • September 13, 1997