Abstract
The effects of a single oral dose of the acetylcholinesterase inhibitor velnacrine maleate on word and object recognition memory and regional uptake of99mTc-exametazime were examined in patients with Alzheimer's disease. Word recognition memory was marginally improved 2 h after 75 mg velnacrine. With the same dose of velnacrine a relative increase in superior frontal uptake of99mTc-exametazime was shown with single photon emission computed tomography (SPECT). This suggests increased regional perfusion and metabolism as a consequence of cholinergic stimulation. The effect did not co-vary with the degree of memory improvement, but, instead, more cognitively impaired patients showed a greater increase in tracer uptake after velnacrine, suggesting cholinergic hypersensitivity in the brains of Alzheimer patients.
Similar content being viewed by others
References
American Psychiatric Association (1987) Diagnostic and statistical manual of mental disorders. American Psychiatric Association, Washington
Blessed G, Tomlinson BE, Roth M (1968) The association between quantitative measures of dementia and of senile dementia in the cerebral grey matter of elderly subjects. Br J Psychiatry 114:791–811
Crawford JR, Besson JAO, Evans NTS, Roeda D, Kulkarni V, Parker DM, Ebmeier KP, Allan KM, Mallard JR (1991a) Cerebral blood flow in Alzheimer's disease imaged by positron emission tomography: the effects of physostigmine infusion. In: Kalousek M (ed) Janssen Symposium 17 Geronto-Psychiatrie. Janssen, Neuss (in press)
Crawford JR, Besson JAO, Ebmeier KP (1991b) Dementia: the role of neurotransmitter deficits. In: Dinan TG (ed) Principles and practice of biological psychiatry. Clinical Neuroscience, London, pp 105–134
Cutler NR, Murphy MF, Nash RJ, Prior PL, De Luna DM (1990) Clinical safety, tolerance, and plasma levels of the oral anti-cholinesterase 1,2,3,4-tetrahydro-9-aminoacridin-1-ol-maleate (HP 029) in Alzheimer's disease: preliminary findings. J Clin Pharmacol 30:556–561
Eagger SA, Levy R, Sahakian BJ (1991) Tacrine in Alzheimer's disease. Lancet i:989–992
Ebmeier KP, Dougal N, Austin M-PV, Murray CL, Curran SM, O'Carroll R, Moffoot APR, Hannan J, Goodwin GM (1991) The split dose technique for the study of psychological and pharmacological activation with the cerebral blood flow marker exametazime and single photon emission computed tomography (SPECT): reproducibility and rater reliability. Intr. J Methods Psychiatr Res 1:27–38
Fielding S, Cornfeldt ML, Szewczak MR, Ellis DB, Huger FP, Davis K, Wilker JC, Shutske GM (1989) HP 029, a new drug for the treatment of Alzheimer's disease: its pharmacological profile. In: Kewitz H, Thomson T, Bickel U (eds) Pharmacological interventions on central cholinergic mechanisms in senile dementia (Alzheimer's disease) W. Zuckschwerdt, München
Folstein MF, Folstein SE, McHugh PA (1975) Mini-mental state: a practical method for grading the cognitive state sof patients for the clinician. J Psychiatr Res 12:189–198
Geaney DP, Soper N, Shepstone BJ, Cowen PJ (1990) Effect of central cholinergic stimulation on regional cerebral blood flow in Alzheimer's disease. Lancet i:1484–1487
Gemmell HG, Evans NTS, Besson JAO, Roeda D, Davidson J, Dodd MG, Sharp PF, Smith FW, Crawford JR, Newton RH, Kulkarni V, Mallard JR (1990) Regional cerebral blood flow imaging: a quantitative comparison of technetium-99m-HMPAO SPECT with C15O2PET. J Nucl Med 31:1595–1600
Gustavson L, Edwinson L, Dahlgren N, Hagberg B, Risberg J, Rosen I, Fernö H (1987) Intravenous physostigmine treatment of Alzheimer's disease evaluated by psychometric testing, regional cerebal blood flow measurement, and EEG. Psychopharmacology 93:31–35
Hachinski NC, Iliff CD, Zilkla E (1975) Cerebral blood flow in dementia. Arch Neurol 32:632–637
Hagstadius S, Risberg J (1989) Regional cerebral blood flow characteristics and variations with age in resting normal subjects. Brain Cogn 10:28–43
Halgren E (1984) Human hippocampal recording and stimulation: evidence for a neural model of recent memory. In: Squire L, Butlers N (eds) The neurophysiology of memory. Guilford, New York, pp 165–181
Hamilton M (1960) Rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62
Hoffman WE, Albrecht RF, Miletich DJ, Hagen TZ, Cook JM (1986) Cerebrovascular and cerebral metabolic effects of physostigmine, midazolam, and a benzodiazepine antagonist. Anesth Analg 65:639–644
Honer WG, Prohovnik J, Smith G, Lucas LR (1988) Scopolamine reduces frontal cortex perfusion. J Cereb Blood Flow Metab 8:635–641
Hunter R, Wyper DJ, Patterson J, Hansen MT, Goodwin GM (1991) Cerebral pharmacodynamics of physostigmine in Alzheimer's disease investigated using99mTc-HMPAO SPET imaging. Br J Psychiary 158:351–357
Klinger A, de Leon MJ, George JD, Wolf AP (1988) Elevated cerebellar glucose metabolism in microvascular white matter disease: normal aging and Alzheimer's disease. J Cereb Blood Flow Metab 8:433–435
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) 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 34:939–944
Miller E (1975) Impaired recall and the memory, disturbance in presenile dementia. Br J Soc Clin Psychol 14:73–79
Murphy MF, Hardiman, ST, Nash RJ, Huff FJ, Demkovich JJ, Dobson C, Knappe UE (1991) Evaluation of HP 029 (velnacrine maleate) in Alzheimer's disease. In: Growdon H, Corkin S, Ritter-Walker E, Wurtman RJ (eds) Aging and Alzheimer's disease (Proceedings of the 6th Meeting of the International International Study Group on the Pharmacology of Memory Disorders Associated with Aging). Zürich, Feb 15–17 1991, pp 337–352
Neirinckx RD, Canning LR, Piper IM (1984) Technetium-99m d, I-HM-PAO: a new radiopharmaceutical for SPECT imaging of regional cerebral blood perfusion. J Nucl Med 28:191–202
Nelson ST, Doull J, Tockman BA, Cristiano PJ, Samson FE (1978) Regional brain metabolism changes induced by acetylcholinesterase inhibitors. Brain Res 157:186–197
Nissen MJ, Knopman DS, Schacter DL (1987) Neurochemical dissociation of memory systems. Neurology 37:789–794
Nordberg A, Larsson C, Adolfson R, Alafutoff I, Winblad B (1983) Muscarinic receptor compensation in hippocampus of Alzheimer patients. J Neural Transm 56:13–19
Norusis MJ (1985) SPSS X Advanced statistics guide. SPSS, Chicago
Rossor MN, Iversen LL, Reynolds GP, Mountjoy CQ, Rogh M (1984) Neurochemical characteristics of early and late onset types of Alzheimer's disease. BMJ 288:961–964
Shedlack KJ, Hunter R, Wyper D, McCluskie R, Fink G, Goodwin GM (1991) The pattern of cerebral activity underlying verbal fluency shown by split-dose single photon emission tomography (SPET or SPECT) in normal volunteers. Psychol Med 21:687–696
Siegfried K, Exner M (1990) Subacute effects of velnacrine (HP 029) in a placebo-controlled cross-over study in patients with Alzheimer's disease. Abstracts of the 17th Congress of Collegium Internationale Neuro-Psychopharmacologicum (CINP), vol 2. Kyoto (Japan), September 10–14 1990, p 235
Sofroniew MV, Galletly NP, Isacson O, Svendsen CN (1990) Survival of adult basal forebrain cholinergic neurons after loss of target neurons. Science 247:338–342
Summers WK, Majowski LV, Marsh GM, Tachiki K, Kling A (1986) Oral tetrahydroaminoacridine in long term treatment of senile dementia, Alzheimer type. N Engl J Med 315:1241–1245
Sunderland T, Tariot PN, Weingartner H, Murphy DL, Newhouse PA, Mueller EA, Cohen RM (1986) Pharmacological modelling of Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 10:599–610
Weinberger DR, Gibson RE, Coppola R (1989) Distribution of muscarinic receptors in patients with dementia: a controlled study of123I-QNB and SPECT. J Cereb Blood Flow Metab 9:S537
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ebmeier, K.P., Hunter, R., Curran, S.M. et al. Effects of a single dose of the acetylcholinesterase inhibitor velnacrine on recognition memory and regional cerebral blood flow in Alzheimer's disease. Psychopharmacology 108, 103–109 (1992). https://doi.org/10.1007/BF02245293
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02245293