Cholinergic deficit in Alzheimer's disease: A study based on CSF and autopsy data

Cholinesterase (ChE) activity was measured as a possible marker of cholinergic neurotransmission of the brain in CSF of 93 patients with probable Alzheimer's disease/senile dementia of the Alzheimer type (AD/SDAT) and of 29 control patients. ChE activity in CSF was decreased significantly in the AD/SDAT patients as compared to the controls. This reduction correlated significantly with the various measures of the severity of dementia. However, the reduction of ChE activity was only moderate (25–30%) even in patients with the most severe dementia and nonsignificant in patients with early symptoms of AD/SDAT. The significance of various confounding factors, which may interfere with CSF ChE measurements is discussed. Our findings seem to indicate that the deficiency of cholinergic neurons is not directly reflected in CSF and that the measurements of ChE activities in CSF are not helpful in diagnosing AD/SDAT. In the autopsy study the activities of cholineacetyltransferase (ChAT) and ChE were determined for ten brain areas of 20 AD/SDAT patients and of 14 controls. In AD/SDAT patients ChAT activity was profoundly decreased (50–85% decrease) in the cortical areas and hippocampus, but was unchanged or only mildly reduced in other subcortical brain areas. This study further confirms that the affection of cholinergic neurons is limited to projections from nucleus basalis to cortex and hippocampus, whereas other cholinergic neurons, like in striatum, seem to be relatively spared. In general, the activities of ChAT and ChE were lower in Alzheimer patients dying at younger age suggesting more severe disease process with these patients.

[1]  O. H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[2]  K. Courtney,et al.  A new and rapid colorimetric determination of acetylcholinesterase activity. , 1961, Biochemical pharmacology.

[3]  E. Domino,et al.  Cholinergic enzymatic activity of cerebrospinal fluid of patients with various neurologic diseases. , 1971, Clinica chimica acta; international journal of clinical chemistry.

[4]  F. Fonnum,et al.  A rapid radiochemical method for the determination of choline acetyltransferase , 1975, Journal of neurochemistry.

[5]  I. T. Draper,et al.  LURIA'S NEUROPSYCHOLOGICAL INVESTIGATION , 1976 .

[6]  E. Giacobini,et al.  Acetylcholinesterase activity in ventricular and cisternal csf of dogs: Effect of chlorpromazine , 1978, Journal of neuroscience research.

[7]  E K Perry,et al.  Correlation of cholinergic abnormalities with senile plaques and mental test scores in senile dementia. , 1978, British medical journal.

[8]  E. Bird,et al.  Pre- and postsynaptic neurochemical alterations in Alzheimer's disease , 1978, Brain Research.

[9]  W. Meier-Ruge,et al.  ACCELERATED AGEING OR SELECTIVE NEURONAL LOSS AS AN IMPORTANT CAUSE OF DEMENTIA? , 1979, The Lancet.

[10]  P. Davies.  Neurotransmitter-related enzymes in senile dementia of the alzheimer type , 1979, Brain Research.

[11]  R. Katzman.,et al.  Pathological verification of ischemic score in differentiation of dementias , 1980, Annals of neurology.

[12]  A. Brun,et al.  Regional pattern of degeneration in Alzheimer's disease: neuronal loss and histopathological grading , 1981, Histopathology.

[13]  T. Halonen,et al.  Acetylcholinesterase activities in cerebrospinal fluid of patients with senile dementia of Alzheimer type , 1981, Acta neurologica Scandinavica.

[14]  S. Hunt,et al.  The substantia innominata in alzheimer's disease: an histochemical and biochemical study of cholinergic marker enzymes , 1982, Neuroscience Letters.

[15]  J. Coyle,et al.  Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain. , 1982, Science.

[16]  M N Rossor,et al.  A post-mortem study of the cholinergic and GABA systems in senile dementia. , 1982, Brain : a journal of neurology.

[17]  R. Bartus,et al.  The cholinergic hypothesis of geriatric memory dysfunction. , 1982, Science.

[18]  M. Esiri,et al.  Alzheimer's disease Correlation of cortical choline acetyltransferase activity with the severity of dementia and histological abnormalities , 1982, Journal of the Neurological Sciences.

[19]  S. Cajal,et al.  Reduced lumbar CSF somatostatin levels in Alzheimer's disease. , 1982, Life sciences.

[20]  E K Perry,et al.  Human brain neurochemistry - some postmortem problems. , 1983, Life sciences.

[21]  J. E. Vaughn,et al.  Organization and morphological characteristics of cholonergic neurons: an immunocytochemical study with a monoclonal antibody to choline acetyltransferase , 1983, Brain Research.

[22]  S. M. Sumi,et al.  Alzheimer's disease: Choline acetyltransferase activity in brain tissue from clinical and pathological subgroups , 1983, Annals of neurology.

[23]  Robert H. Perry,et al.  Molecular forms of acetylcholinesterase in senile dementia of Alzheimer type: Selective loss of the intermediate (10S) form , 1983, Neuroscience Letters.

[24]  G. K. Wilcock,et al.  DECREASED CSF ACETYLCHOLINESTERASE ACTIVITY IN ALZHEIMER'S DISEASE , 1983, The Lancet.

[25]  K. Davis,et al.  Acetylcholinesterase activity in CSF in schizophrenia, depression, Alzheimer's disease and normals. , 1983, Biological psychiatry.

[26]  Venn Rd.  The Sandoz Clinical Assessment-Geriatric (SCAG) scale. A general-purpose psychogeriatric rating scale. , 1983 .

[27]  S. Greenfield.  Acetylcholinesterase may have novel functions in the brain , 1984, Trends in Neurosciences.

[28]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[29]  V. Bigl,et al.  DECREASED RATIO OF CSF ACETYLCHOLINESTERASE TO BUTYRYLCHOLINESTERASE ACTIVITY IN ALZHEIMER'S DISEASE , 1984, The Lancet.

[30]  L. Iversen,et al.  Neurochemical characteristics of early and late onset types of Alzheimer's disease. , 1984, British medical journal.

[31]  G K Wilcock,et al.  Neurotransmitter dysfunction and atrophy of the caudate nucleus in Alzheimer's disease. , 1984, Neurochemical pathology.

[32]  T. Halonen,et al.  Reduced cholinesterase activity and somatostatin-like immunoreactivity in the cerebrospinal fluid of patients with dementia of the Alzheimer type , 1984, Journal of the Neurological Sciences.

[33]  J. Coyle,et al.  Cerebrospinal fluid acetylcholinesterase activity in senile dementia of the Alzheimer type , 1985, Annals of neurology.

[34]  B. Reisberg.  Alzheimer's Disease Update , 1985 .

[35]  T. Arendt,et al.  Neuronal loss in different parts of the nucleus basalis is related to neuritic plaque formation in cortical target areas in alzheimer's disease , 1985, Neuroscience.

[36]  Giancarlo Di Battista,et al.  Hyperthermia after discontinuance of levodopa and bromocriptine therapy , 1985, Neurology.

[37]  D. Mann,et al.  Some morphometric observations on the cerebral cortex and hippocampus in presenile Alzheimer's disease, senile dementia of Alzheimer type and Down's syndrome in middle age , 1985, Journal of the Neurological Sciences.

[38]  E. Perry,et al.  Blood acetyl- and butyrylcholinesterases in senile dementia of Alzheimer type , 1985, Journal of the Neurological Sciences.

[39]  L. Thal.  Changes in Cerebrospinal Fluid Associated with Dementia , 1985, Annals of the New York Academy of Sciences.

[40]  S. Gauthier,et al.  CSF acetylcholinesterase in dementia and in sequential samples of lumbar CSF , 1984, Neurobiology of Aging.

[41]  D L Price,et al.  Alzheimer's disease and related dementias: selective involvement of specific neuronal systems. , 1985, CRC critical reviews in clinical neurobiology.

[42]  Z. Khachaturian.  Diagnosis of Alzheimer's disease. , 1985, Archives of neurology.

[43]  M. Silveri,et al.  Molecular forms of cholinesterases in CSF of Alzheimer's disease/senile dementia of Alzheimer type patients and matched neurological controls. , 1986, Life sciences.

[44]  D. Neary,et al.  Cerebral biopsy in the investigation of presenile dementia due to cerebral atrophy. , 1986, Journal of neurology, neurosurgery, and psychiatry.

[45]  Leighton R. James,et al.  L‐Carnitine treatment in glutaric aciduria type I , 1986, Neurology.

[46]  E. Perry,et al.  Molecular Forms of Acetylcholinesterase and Butyrylcholinesterase in the Aged Human Central Nervous System , 1986, Journal of neurochemistry.

[47]  Péter Kása.  The cholinergic systems in brain and spinal cord , 1986, Progress in Neurobiology.

[48]  E. Bird,et al.  Distribution of the molecular forms of acetylcholinesterase in human brain: Alterations in dementia of the Alzheimer type , 1986, Annals of neurology.

[49]  S. Younkin,et al.  Molecular forms of acetylcholinesterases in Alzheimer's disease. , 1986, Federation proceedings.

[50]  E. Perry.  The cholinergic hypothesis--ten years on. , 1986, British medical bulletin.

[51]  D. Neary,et al.  Alzheimer's disease: a correlative study. , 1986, Journal of neurology, neurosurgery, and psychiatry.

[52]  C. Mountjoy.  Correlations between neuropathological and neurochemical changes. , 1986, British medical bulletin.

[53]  S. Corkin,et al.  Cholinesterases in cerebrospinal fluid Correlations with clinical measures in Alzheimer's disease , 1986, Journal of the Neurological Sciences.

[54]  Shigenobu Nakamura,et al.  Acetylcholinesterase activity in cerebrospinal fluid of patients with Alzheimer's disease and senile dementia , 1986, Journal of the Neurological Sciences.

[55]  R. Katzman.,et al.  Alzheimer's disease. , 1986, The New England journal of medicine.

[56]  R. Elble,et al.  Cholinesterases in Cerebrospinal Fluid: A Longitudinal Study in Alzheimer Disease , 1987 .

[57]  S. Greenfield,et al.  Does the substantia nigra have a cholinergic innervation? , 1987, Neuroscience Letters.

[58]  P. Whitehouse.  The cholinergic deficit in Alzheimer's disease. , 1998, The Journal of clinical psychiatry.