THE CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES Activities and Kinetic Properties of Lumbar Cerebrospinal Fluid Cholinesterases in Relation to Clinical Diagnosis, Severity, and Progression of Alzheimer's Disease

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities of lumbar cerebrospinal fluid (CSF) have been measured in seventeen patients with a clinical diagnosis of probable Alzheimer's disease (Prob AD), possible Alzheimer's disease (Poss AD), or dementia of non-Alzheimer aetiology (Non-AD). The three diagnostic groups did not differ with regard to the Km or saturation kinetic properties of AChE and BChE. The CSF AChE activity was significantly higher in Prob AD than in Non-AD patients. The groups did not differ significantly in BChE activity. The ratio of AChE to BChE activity was significantly higher in both the Prob AD and Poss AD groups than in the Non-AD group, and the ranges of values in the Prob AD and Non-AD groups did not overlap. Among patients in the Prob AD group, severity of dementia was correlated with both AChE activity and the AChE/BChE ratio, and progression of dementia over time was also correlated with AChE/BChE. The AChE/BChE ratio correlated more strongly than AChE with severity and progression of dementia in Prob AD patients, and also better distinguished them from Non-AD patients, suggesting that AChE/BChE may be the more useful marker for diagnosis of AD. It is not clear from the results whether AChE/BChE is useful for diagnosis of the complex dementia cases in the Poss AD group. RESUME: Activite et proprietes cinetiques des cholinesterases du liquide cephalo-rachidien lombaire en relation avec le diagnostic clinique, la severite et la progression de la maladie d'Alzheimer L'activite de ['acetylcholinesterase (AChE) et de la butyrylcholinesterase (BChE) du liquide cephalo-rachidien (LCR) lombaire ont et6 mesur6es chez dix-sept patients avec un diagnostic de maladie d'Alzheimer probable (Prob MA), maladie d'Alzheimer possible (Poss MA), ou demence d'etiologie autre (Non-MA). Les trois groupes de patients ne differaient pas quant au Km ou auz proprietes cinetiques de saturation de 1'AChE et de la BChE. L'activite de 1'AChE dans le LCR etait significativement plus elevee chez les Prob MA que chez les Non-MA. Les deux groupes ne differaient pas significativement quant a l'activite de la BChE. Le rapport entre l'activite AChE et l'activite BChE etait significativement plus eleve dans les groupes Prob MA et Poss MA que dans le groupe Non-MA, et l'ecart des valeurs dans les groupes Prob MA et Non-MA ne se chevauchaient pas. Parmi les patients du groupe Prob MA, la severite de la d6mence etait en correlation avec l'activite de 1'AChE et le rapport AChE/BChE, et la progression de la demence dans le temps etait egalement en correlation avec l'activite de 1'AChE et le rapport AChE/BChE, et la progression de la demence dans le temps 6tait egalement en correlation avec 1'AChE/BChE. La correlation entre le rapport AChE/BChE et la severite et la progression de la demence chez les patients Prob MA etait plus forte que celle de 1'AChE et les distinguait mieux des patients Non-MA, suggerant que 1'AChE/BChE peut etre le marqueur le plus utile pour le diagnostic de la MA. Ces resultats ne nous permettent pas de determiner si 1'AChE/BChE est utile dans le diagnostic des cas complexes de demence du groupe Poss MA. Can. J, Neurol. Sci. 1989; 16: 406-410 A deficiency of acetylcholinesterase (AChE) has been cholinesterase activity attributable to butyrylcholinesterase observed in brain tissue from patients with Alzheimer's disease (BChE) has also been found in AD brain, and the decreased (AD), and association of this deficit with a deficiency of choline AChE and increased BChE in AD are correlated both with the acetyltransferase suggests that it results from a loss of cholinnumber of senile plaques in the brain and the clinical severity of ergic neurons in the brain.An increase in nonspecific dementia.' Because both AChE and BChE activities are meaFrom the Departments of Neurology and Psychiatry, Alzheimer's Disease Research Center, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine Received March 9, 1989. Accepted May 22, 1989 Reprint requests to: F. Jacob Huff, M.D., Neuroscience Research Group, Hoechst-Roussel Pharmaceuticals, Routes 202-206, Building M-338, Somerville, N.J. USA 08876 406 https:/www.cambridge.org/core/terms. https://doi.org/10.1017/S0317167100029474 Downloaded from https:/www.cambridge.org/core. IP address: 54.191.125.211, on 16 Jan 2017 at 12:28:30, subject to the Cambridge Core terms of use, available at LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES surable in the cerebrospinal fluid (CSF), numerous studies have attempted to establish whether or not the brain abnormalities of these enzymes in AD are detectable in the CSF. Studies comparing AD patients to nondemented control cases have produced conflicting results: AChE in lumbar CSF and AD cases has been reported to be decreased in some studies but unchanged in others' whereas BChE activity has been variously reported to be decreased-' or unchanged.-'Because the brain abnormalities of AChE and BChE in AD are in opposite directions from the norm, the AChE/BChE ratio in CSF has been studied, again with conflicting results.---''' The variable results in these studies may be due to methodological differences among them. Many investigators did not inhibit BChE when assaying AChE activity, and thus measured total cholinesterase activity rather than specific AChE activity. Most studies have relied on clinical criteria for diagnosis of AD, and inclusion of patients with mixed dementia in the AD group of some studies may have affected the results, in view of the evidence that patients with Non-AD dementia have different patterns of CSF cholinesterase abnormalities than patients with AD. In a recent study of lumbar CSF in AD cases diagnosed on the basis of cortical biopsy, BChE activity was decreased and the AChE/BChE ratio was increased in AD compared to non-demented control cases. In the same study, the AChE/BChE ratio was increased in ventricular CSF from AD cases diagnosed by autopsy. These results provide strong evidence that the cholinesterase abnormalities in AD brain are reflected in CSF, and suggest that the AChE/BChE ratio in lumbar CSF may be useful in the diagnosis of AD. The present investigation incorporated a number of methodological improvements over previous clinical studies. AChE was measured in the presence of an inhibitor of BChE. Moreover, the quantitative measures of AChE and BChE activity used in the present study were extrapolated estimates of Vmax derived from assays at five subsaturation substrate concentrations. Under conditions of substrate saturation, AChE undergoes inhibition, whereas BChE activity is enhanced due to cooperative kinetics, resulting in a lower estimation of the AChE activity and a higher estimation of the BChE activity in a specimen. The extrapolated Vmax measures used in the present study thus enhance the precision in determining the AChE/BChE ratio, and also allow determination of the degree of substrate inhibition of AChE. Previous studies have indicated that AChE from cerebral cortex and ventricular CSF of patients with AD does not exhibit the normal substrate inhibition. Another methodological issue addressed in the present study was the diagnostic classification of patients. Patients were diagnosed according to the NINCDS-ADRDA criteria, which were developed by a Task Force convened under the auspices of the National Institutes of Health of the United States. These criteria distinguish patients with "probable AD", in whom all other identifiable causes of dementia have been excluded, from patients with "possible AD", in whom another condition that may cause dementia is present but is not considered to be sufficient alone to account for the patient's dementia symptoms. By distinguishing patients in these diagnostic categories, the present investigation permitted analyses of the degree to which the relationship of CSF cholinesterases to the severity and rate of progression of dementia may be specific to AD, and of possible differences in the sensitivity of CSF cholinesterases for diagnosing AD depending on whether the latter is the sole aetiology for dementia or is present in conjunction with other aetiologies. The comparison group for evaluating the usefulness of CSF cholinesterases in the diagnosis of AD was a group of patients with dementia that was entirely attributable to an aetiology other than AD. In an effort to enhance the accuracy of the clinical diagnoses, as well as to measure the progression of dementia, patients in the present investigation were re-examined longitudinally after their initial examination.