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Cerebrospinal fluid acetylcholinesterase activity in senile dementia of the Alzheimer type.

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Cerebrospinal Fluid Acetylcholinesterase
Activity in Sede Dementia of the
Alzheimer Type
Larry Tune, MD, Stephen Gucker, BA, Marshal Folstein, MD, Leslie Oshida, BA, and Joseph T. Coyle, MD
Acetylcholinesterase (AChE) activity was measured in cerebrospinal fluid (CSF) samples from 36 individuals, including
12 persons with Alzheimer’s disease, 12 normal controls, and 12 patients with other dementias. AChE activity also was
measured in 47 normal subjects whose ages ranged from 20 to 84 to evaluate the effect of age on AChE activity. CSF
from patients with senile dementia of the Alzheimer type showed significantly lower mean AChE activity than in agematched controls and patients with other dementia syndromes. No correlation was found between duration of illness,
age, or severity of illness (as measured by the Mini-Mental State Examination score) and CSF AChE activity in Alzheimer’s disease. AChE increased significantly over the age range of 20 to 84. CSF AChE activity may prove to be a useful
diagnostic test to confirm the clinical diagnosis of moderate to severe Alzheimer’s disease.
Tune L, Gucker S, Folstein M, Oshida L, Coyle JT: Cerebrospinal fluid acetylcholinesterase activity in senile
dementia of the Alzheimer type. Ann Neurol 17:46-48, 1985
The cholinergic projections to the cortex and hippocampal formation are selectively damaged in Alzheimer’s disease (AD) and senile dementia of the
Alzheimer type (SDAT) [14, 151. Choline acetyltransferase (ChAT) and acetylcholinesterase (AChE),
but not pseudocholinesterase (e.g., butyrylcholinesterase), activities are reduced in the cerebral cortex and
hippocampal formation in patients dying of neuropathologically confirmed SDAT {lo1. The decreased
activity of both enzymes correlates significantly with
the severity of cognitive impairments and plaque density in postmortem samples taken from cortex and hippocampus [lo}. A number of groups have measured
the activity of acetylcholinesterase in cerebrospinal
fluid (CSF) [I-4, 121. Appleyard and colleagues [11
described markedly decreased postmortem ventricular
CSF AChE levels in patients dying of SDAT. Soininen
and associates [12} compared 2 1 patients with SDAT
with 9 controls, and found that patients with SDAT
had lower CSF AChE activity levels. We confirm here
that the activity level of AChE in CSF is significantly
lower in patients with “probable” SDAT than in agematched controls, and provide evidence that the level
is not reduced in other dementing illnesses.
CSF samples from 36 individuals were evaluated for AChE
activity. This cohort included 12 age-matched normal controls (age, mean +- SD, 69.4 +- 2.1 years; range, 60 to 84),
12 patients with SDAT (70.8 % 2.4 years; range, 50 to 80
years), and 12 patients with other forms of dementing illnesses (67.1 t 2.1 years; range, 5 1 to 77 years). The 12
controls were obtained from the Johns Hopkins Hospital
Myelogram Clinic; these were nondemented, drug-free subjects who were evaluated for low back pain.
Diagnoses were made according to DSM-111 criteria [ 5 ] .
In all groups a threshold for the diagnosis of a definite dementia syndrome was established as a Mini-Mental State
Examination (MMSE) [6} score of less than 24. Three patients with MMSE scores greater than or equal to 24 were
labeled as exhibiting “early” dementia. The criteria of the
Hachinski Ischemia Scale [ 8 } were used to assist in the diagnosis of multi-infarct dementia (MID). Two cases met the
criteria for definite MID, and one was identified as possible
MID. Six demented patients with other neurological diagnoses were included and labeled as exhibiting “other” forms
of dementia. Two of these patients had brain tumors, 2 patients were diagnosed as having normal pressure hydrocephalus (and had ventriculoperitoneal shunts installed), 1 patient
had neurosyphilis and alcoholism, and 1 had a history of
schizophrenia, MID, and delirium. For data analysis, patients
with “probable S D A T were compared with controls and
with patients with early dementia or other forms of dementia.
All patients with probable SDAT showed electroencephalographic evidence of diffuse slow wave changes, as has
been reported in A D [13J None of the 12 patients with
SDAT showed computed tomographic scan evidence of cerebral infarction, and all patients included in the MID group
showed such evidence of at least one cerebral infarction.
From the Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, Baltimore, MD 21205.
Received Nov 18, 1983, and in revised form Apr 16 and May 2,
1984. Accepted for publication May 2, 1984.
Materials and Methods
Address reprint requests to Dr Tune.
Early, Ot her
Patient Category
2 0 25 30 35 4 0 45 50 55 60 65 70 75 80 85
AGE (years)
Fig 1. Cerebrospinaljuid acetylcholinesterase(CSF AChE) activity as a function of age. CSF from 47 normal controls (age
range, 20 to 84 years) was measured for AChE activity (r =
In another sample an age curve for nondemented patients
was produced using CSF obtained from the Johns Hopkins
Hospital Myelogram Clinic. A total of 200 CSF samples was
collected initially. When CSF from patients with disorders or
drug treatments that might affect the central cholinergic
function were excluded, results in 47 patients were considered suitable to describe the normal age curve. This group
included the 12 patients used earlier as age-matched controls. The age range for this population was 20 to 84 years.
Cholinesterase was measured by a modification of the
radioenzymatic method of Fonnum 171 and Lehman and Fibiger c9f.
As Figure 1 demonstrates, CSF AChE activity increases with age. The curve for the data fits the equation y - 0.19% + 7.94; r = 0.52. Over the 65-year
span from age 20 to age 84, the average CSF AChE
level more than doubles.
As shown in Figure 2, the mean CSF AChE activity
level differed among the diagnostic categories. When
the AD/SDAT group was compared with normal agematched controls or those with other dementias, a
significant difference was obtained (F = 3.45 and
2.78, respectively; p < 0.05), albeit with considerable
individual overlap. When the AD/SDAT group was
compared with early or other dementia groups or with
age-matched controls, t tests indicated significant mean
differences at the 0.05 level. Chi square analysis of
patients with AD versus controls with CSF AChE activity levels above and below 15 nmol/ml per minute
showed a significant difference at the 0.01 level. When
patients considered to have early SDAT (i.e., MMSE
score of 24 or above but clinically appearing to have
Fig 2. Cerebrospinaljuidanticholinesterase (CSF AChE) activity in two patient groups and age-matched controls. The group
with senile dementia of the Alzheimer typelAlzheimeds disease
(SDATIAD) includes 12 patients with definiteSDATIAD.
The earlylother group includes those with otherform of dementing illness: 3 with possible early SDAT (Mini-Mental State
Examination scores of 24 or more), 3 with multi-infarct dementia (all with computed tomographic scan evidence of cerebral infarct and Hachinski scores of 8 or more), and 6 with other illnesses associated with dementia. The 12 age-matched controls
exhibited no symptoms of dementia. The patient whose data are
designated with an asterisk in the earlylother category had all of
the clinicalfeatures of SDATIAD but was diagnosed as having
normal pressure hydrocephalus.
manifestations of early AD) were included in the AD/
SDAT sample, no significant differences were found.
Low correlations were found between MMSE score ( r
= 0.33; n.s.), duration of illness ( Y = 0.33; n.s.), and
age (r = 0.31; n.s.) and CSF AChE activity in AD.
Our results confirm and extend earlier studies of CSF
AChE activity in patients with dementia syndromes.
These data suggest that CSF AChE activity is reduced
in AD/SDAT and, therefore, that it may prove
epidemiologically useful in distinguishing AD/SDAT
from other dementia syndromes. This finding is of
considerable importance, because a major impediment
to epidemiological studies of risk factors for AD and
of clinical drug trials is the lack of confirmatory laboratory tests. AChE levels do not appear to be individually diagnc tically useful, however, especially in
patients with minimal symptoms of dementia. One
possible explanation for this finding is that CSF AChE
activity may not change appreciably until considerable
neuronal degeneration has taken place; another is that
the diagnosis of early cases is uncertain.
AChE activity in CSF presumably reflects not only
enzyme released from cortical fields, but also AChE
activity derived from the entire central nervous sys-
Tune et al: Acetylcholinesterase in Alzheimer’s Dementia
tem, especially the spinal cord. This “dilutional” effect
may require that substantial reduction of cortical
AChE activity occur before enzyme activity is significantly decreased in lumbar CSF samples.
The finding that CSF AChE activity increases with
age may teflect either an accelerated turnover of
neuronal AChE or decreased clearance of CSF AChE.
This finding is at variance with studies of cerebral
AChE activity in animals {l11 and human postmortem
samples. Nevertheless, the age-related increase in CSF
AChE activity underlines the importance of using agematched controls in assessing abnormalities of CSF
AChE activity in disease states.
Supported by grants from the Eleanor and T Rowe Price Foundation, NS 16375, Meridian Corporation, Barnes Fund, and Stempler
The authors thank John Lehmann, PhD, for assistance In developing
the CSF AChE assay, Arlene J Bognanni, RN, for assistance with
lumbar punctures, and Ms Teresa James for excellent secretarial
Appleyard ME, Smith AD, Wilcock GK, Esiri MM: Decreased
CSF acetylcholinesterase activity in Alzheimer’s disease. Lancet
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cisternal CSF in dogs: effect of chlorpromazine. J Neurosci Res
3:335-339, 1978
Bowen DM: Alzheimer’s disease. In Thompson RHS, Davison
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Vol 17 No 1 January 1985
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Washington, DC, American Psychiatric Association, 1980
6. Folstein M, Folstein S, McHugh P: Mini-Mental State. J
Psychiatr Res 12:189-198, 1975
7. Fonnum F: Radiochemical assays for choline acetyltransferase
and acetylcholinesterase. In Rodnight R, Marks N (eds): Research Methods in Neurochemistry, ed 3. New York, Plenum,
1975, pp 253-275
8. Hachinski VC, Lassen NA, Marshall J: Multi-infarct dementia.
Lancet 1:207-210, 1974
9. Lehman J, Fibiger T: Acetylcholinesterase in the substantia nigra
and candate-putamen of the rat. J Neurochern 30:615-624,
10. Perry EK, Tornlinson B, Blessed G, et al: Correlations of cholinergic abnormalities with senile plaques and mental test scores
in senile dementia. Br Med J 2:1457-1459, 1978
11. Perry RH, Blessed G, Perry EK, Tornlinson BE: Histochemical
observations on cholinesterase activities in the brains of elderly
normal and demented (Alzheirner-type) patients. Age Ageing
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12. Soininen H , Halonen T, Reikkinen PJ: Acetylcholinesterase
activities in cerebrospinal fluid of patients with senile dementia
of the Alzheimer type. Acta Neurol Scand 64:217-224, 1981
13. Steele C, Lucas MJ, Tune L An approach to the management of
dementia syndromes. Johns Hopkins Med J 151:362-368,
14. Struble RC, Cork LC, Whitehouse PJ, Price D L Cholinergic
innervation in neuritic plaques. Science 23:4 13-4 15, 1982
15. Whitehouse PJ, Price DL, Struble RG, et al: Alzheimer’s disease and senile dementia: loss of neurons in the basal forebrain.
Science 215.1237-1239, 1982
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dementia, acetylcholinesterase, activity, typed, senile, alzheimers, fluid, cerebrospinal
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