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TABLE I--CHOLINE ACETYLASE ([L mol/h/g WET WEIGHT)

Letters to the Editor

SELECTIVE LOSS OF CENTRAL CHOLINERGIC

NEURONS IN ALZHEIMER’S DISEASE
SIR,-Alzheimer’s disease is a progressive cerebral degener-
ation which continues without remission until death, usually
in profound dementia. Morphologically, the disease is charac-
terised by large numbers of senile plaques and neurofibrillary
tangles in the brain, these tangles being especially abundant in
the cerebral cortex. Neurochemical studies are still in their in-
fancy, and we know nothing of the molecular basis of the dis-
ease.
We have studied the enzymes associated with the putative
neurotransmitters acetylcholine, y-aminobutyric acid, dopa-
mine, noradrenaline and 5-hydroxytryptamine in twenty re-
gions of brains obtained at necropsy from three patients with TABLE II-ACETYLCHOLINESTERASE (MMOWG WET WEIGHT)
Alzheimer’s disease and from ten individuals who died without
evidence of neurological or psychiatric disorder. The brains
were removed 24-36 h after death, and each brain was
divided in half down the mid-line. The right half was used for
biochemical analyses, whilst the left half was fixed in formalin
for neuropathological examination. Alzheimer’s disease was
confirmed histologically. There was no evidence of cerebrovas-
cular disease in any of the thirteen cases. The ten controls
ranged in age from 46 to 74; the Alzheimer patients were aged
61, 70, and 75. Tissues from the right half of the brain were
stored at -190°C. Choline acetyltransferase (C.A.T.) and ace-
tylcholinesterase (A.C.E.) activities were measured by the
methods of Fonnum,and glutamic acid decarboxylase (G.A.D.)
activity by the method of Roberts and Simonsen.2
C.A.T. activity in the Alzheimer’s disease brains was much
reduced in the amygdala, hippocampus, and cortex (table I).
Only three Alzheimer brains have been studied but the extent treatment issymptomatic. All three patients were given nitra-
of the reduction in these areas strongly suggests this is not a
zepam, but this drug was also given to five of the ten control
chance occurrence. The activity of A.C.E. is dramatically
patients during their terminal illness. Opiates were adminis-
reduced in the same areas of the cerebral cortex that show tered to two of the Alzheimer patients and five of the con-
reductions in C.A.T. activity (table II), and is below the levels
trols, and phenothiazines were given to one and two patients,
found in the normal brains in all the other areas. The areas
of the cerebral cortex which show the maximum reductions in
respectively. Thus no drug treatment was exclusive to the Alz-
heimer’s disease patients, and it seems improbable that the
c.A.T. and A.C.E. activity are those which contain the greatest
deficit in C.A.T. and A.C.E. activity in the cortex of these indi-
density of neurofibrillary tangles. viduals is drug induced.
The reductions in the activity of the enzymes involved in the
metabolism of acetylcholine are not a result of non-specific
Expression of results relative to protein, D.N.A., or R.N.A.
content does not alter the pattern of the results significantly.
degenerative process. The activity of G.A.D. in all the areas of If these data can be confirmed in a larger series of cases the
the Alzheimer’s disease brains studied appears to be well
concept of Alzheimer’s disease as a cholinergic system failure
within the normal range, means ranging from 74% to 121% of
may have important consequences for research on this condi-
control activities. That this is the case in the cortical areas tion.
which show large losses of c.A.T. and A.C.E. supports the notion
M.R.C. Brain Metabolism Unit,
that a selective degenerative process has occurred. The normal
University Department of Pharmacology,
values obtained for G.A.D. are of special significance because this 1 George Square,
enzyme is particularly sensitive to ante-mortem hypoxia.3 It Edinburgh EH8 9JZ P. DAVIES
seems unlikely, therefore, that the decreased activity of University Department of Pathology,
enzymes associated with cholinergic transmission can be Royal Infirmary of Edinburgh, and
ascribed to this cause; none of the patients with Alzheimer’s Department of Neuropathology,
Western GeneralHospital,
disease had prolonged terminal hypoxic episodes. A. F. MALONEY
Edinburgh J.
Preliminary studies of tyrosine hydroxylase, aromatic amino-
acid decarboxylase, dopamine-&bgr;-hydroxylase, and monoamine
oxidase indicate no loss of these enzyme activities in Alz-
heimer’s disease and lend weight to the notion that a selective HEADACHE AFTER LUMBAR PUNCTURE
destruction of the cortical cholinergic system is an important SiR,—The frequency of headache after lumbar puncture in
feature of this condition. the four large series cited by Wolff was 25%.’ The headache
We considered the possibility that selective loss of choliner- is thought to be due to continued leakage of cerebrospinal fluid
gic system components could be due to prolonged drug (c.s.F.) through the hole in the theca, the subsequent low pres-
regimens used in the patients with Alzheimer’s disease. How- sure in the c.s.F. pathways inducing pain by traction on the
ever, there is no standard drug therapy for Alzheimer’s, and pain-sensitive neural endings in the dura and intracranial
venous sinuses and arteries. Aqueous vasopressin injection
1. Fonnum, F. Biochem. J. 1969, 115, 465. (’Pitressin’) as a prophylactic measure was popular some years
2. Roberts, E., Simonsen, D. E. Biochem. Pharmac. 1963, 12, 113.
3. Bowen, D. M., Davison, A. N. in Biochemistry and Neurological Disease
edited by A. N. Davison); p. 2. Oxford, 1976. 1. Wolff, H. G. Headache and Head Pain; p. 112. New York, 1963.