Journal zyxwvutsrqponmlkjih of Neurochemistry Raven Press, New zyxwvutsrqp York zyxwvutsrqponm Q 1983 International Society for Neurochemistry zyxwvutsrqp 0022-3042183/020 zyx I -0503/$03. 00/0 Presynaptic Cholinergic Dysfunction in Patients with Dementia N. R. Sims, D. M. Bowen, S. J. Allen, C. C. T. Smith, *D. Neary, TD. J. Thomas, and A. N. Davison zyxw Miriuni Marks Department of Neirrocheniistry, Institirte of Neirrology. zyxwv London *Department oj Neitrology. Munchester Royd Infirmun, Munchester, untl tDepurtment of Neiirology, St. Mury’s Hospital, London, U.K. Abstract: Indices of presynaptic cholinergic nerve end- ings were assayed in neocortical biopsy samples from pa- tients with presenile dementia. For those patients in whom Alzheimer’s disease was histologically confirmed, [ 14C]acetylcholine synthesis, choline acetyltransferase activity and choline uptake were all found to be markedly reduced (at least 40%) below mean control values. The changes occurred in samples from both the frontal and temporal lobes and for [ 14C]acetylcholine synthesis the decrease was similar under conditions of high and low neuronal activity (as assessed by incubations in 31 mM and 5 mM K+ respectively). Samples from other de- mented patients, in whom the histological features of zy Alz- heimer’s disease were not detected, produced values for all three biochemical parameters which were similar to controls. For the total group of patients with presenile dementia there were correlations between values for the three markers of presynaptic cholinergic nerve endings suggestive of a loss of functional activity at these sites in Alzheimer’s disease. Key Words: Alzheimer’s dis- ease-Acetylcholine synthesis-Choline uptake-Cho- line acetyltransferase. Sims N. R. et al. Presynaptic cholinergic dysfunction in patients with dementia. J. Neiiroc.hc.tn. 40, 503-509 (1983). Dementia in the elderly is a disorder with wide- spread social and economic implications (Plum, 1979). It increases in prevalence with age, affecting one in five of the population over 80 years of age (Kay et al., 1964; 1970). Although appearing as a feature of a variety of conditions, dementia is most commonly associated with Alzheimer’s disease (Marsden and Harrison, 1972; Tomlinson, 1980; Bowen, 1981). A distinction has often been made between presenile and senile forms of this disease (based largely on the different prevalence rates), but this is now less commonly retained, as histological findings in postmortem brains from cases of the two groups indicate similar changes (Corsellis, 1976; Tomlinson, 1980). Thus, although the patients of the present study are all from the presenile group (less than 70 years), the results are likely to be relevant to senile cases and are discussed in relation to other studies involving these elderly patients. Histologically the diseased brain is characterized by the presence of abnormal numbers of neurofib- rillary tangles and of senile (or neuritic) plaques which are particularly numerous in the neocortex and hippocampus (see review by Tomlinson, 1980). The identification of these histological changes is essential for definitive diagnosis, and except for a small proportion of patients undergoing cerebral biopsy, the presence of the disease can only be positively confirmed on postmortem examination. An early finding in biochemical studies of post- mortem brains from Alzheimer’s disease patients was a marked reduction in the activity of an en- zyme, choline acetyltransferase (ChAT: EC 2.3.1.6, acetyl-CoA:choline 0-acetyltransferase) which is primarily located in nerve terminals (Tucek, 1967; Fonnum, 1970) and is responsible for synthesis of the neurotransmitter acetylcholine from its immedi- ate precursors, choline and acetyl-CoA. This re- duction to less than 50% of control values in the neocortex and hippocampus has been confirmed in all studies in which it has been examined (Bowen et al., 1976; Davies and Maloney, 1976; Perry et al., 1977; White et al., 1977; Reisine et a]., 1978; Davies, 1979; Rossor et al., 1980), including investi- Received May 27, 1982; revised July 27, 1982; accepted Au- Address correspondence and reprint requests to Dr. N. R. Sims, Neurochemistry Department, Institute of Neurology, 33 John’s Mews, London WClN 2NS, U.K. gust 13, 1982. Abbre,liation zyxwv MSC~: ChAT, Choline acetyltransferase. 503