C.Q. Mountjoy

Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia

To examine the possibility that senile dementia may be associated with a loss of noradrenergic neurons that innervate the cerebral cortex, we used a Quantimet 720 image analyzer to estimate the number of neurons in the nucleus locus ceruleus in elderly patients with the clinical diagnosis of senile dementia. In all but one case, the diagnosis was established histopathologically as senile dementia of the Alzheimer type (SDAT). In a subgroup characterized by a high dementia score and relatively young age at death, there was a loss of about 80% of locus ceruleus neurons. This loss of neurons indicates a deficit of noradrenergic innervation to cerebral cortex in a group of patients which may represent a variant of SDAT.

Reduced amounts of immunoreactive somatostatin in the temporal cortex in senile dementia of Alzheimer type.

Post-mortem brain tissue from 15 patients dying with a diagnosis of senile dementia of Alzheimer type (SDAT) was compared with tissue obtained from 16 control patients at routine post-mortem. A significant fall in choline acetyltransferase (ChAT) activity was observed in the cortex, hippocampus and amygdala of the SDAT cases and was maximal in the temporal cortex. The fall in ChAT activity observed in the temporal cortex was accompanied by a significant reduction (47%) in immunoreactive somatostatin.

Neurochemical characteristics of early and late onset types of Alzheimer's disease.

Brains of 49 patients who had died with Alzheimers disease and 54 controls were examined. The Alzheimer group exhibited noticeably reduced activity of the cholinergic marker enzyme choline acetyltransferase in the cerebral cortex, but cortical concentrations of noradrenaline, gamma-aminobutyric acid, and somatostatin were also significantly reduced. Analysis of the results according to age at death showed that the older patients, dying in their 9th and 10th decades, had a relatively pure cholinergic deficit confined to temporal lobe and hippocampus, together with a reduced concentration of somatostatin confined to temporal cortex. By contrast, the younger patients, dying in their 7th and 8th decades, had a widespread and severe cholinergic deficit together with the abnormalities of noradrenaline, gamma-aminobutyric acid, and somatostatin, and the younger patients accounted for most of the abnormalities in these systems observed in the overall group. Comparison of the young subjects with Alzheimers disease with the older controls did not support the concept of Alzheimers disease representing an acceleration of the aging process. These results suggest that Alzheimers disease in people aged under 80 may represent a distinct form of presenile dementia which differs in important respects from the dementia of old age.

Loss of pigmented dopamine-β-hydroxylase positive cells from locus coeruleus in senile dementia of alzheimer's type

Serial sections of human brainstem were used to determine the total number of pigmented cells in locus coeruleus and, by immunohistochemical staining using an antiserum directed against human dopamine-beta-hydroxylase (DBH), the number of DBH-positive cells. In 12 brains from elderly control and dementia subjects there wer not significant differences in the total cell populations determined in the same brain by the two techniques. In 6 patients with senile dementia of Alzheimers type there was a variable loss (average about 60% reduction) in locus coeruleus cells when compared to controls of similar age. The loss of noradrenergic neurones from locus coeruleus was accompanied by an average reduction of similar magnitude in noradrenaline concentration in temporal cortex, with no change or an increase in dopamine content. There was also a significant reduction in the cholinergic marker choline acetyltransferase in cortex samples from the dementia cases.

The substantia innominata in Alzheimer's disease: an histochemical and biochemical study of cholinergic marker enzymes.

Acetylcholinesterase staining was examined in the substantia innominata of 3 normal human brains. Large intensely stained neurones were seen within the region of the basal nucleus of Meynert which is believed to be the origin of the cholinergic projection to the neocortex in animals. On the basis of the acetylcholinesterase staining pattern, the substantia innominata was dissected from post-mortem brain tissue of 19 cases of Alzheimers disease (AD) and 16 controls so as to include the basal nucleus. Choline acetyltransferase (ChAT) activity was found to be reduced in the substantia innominata and amygdala in AD but not in the adjacent lentiform nucleus and hypothalamus.

Reduced binding of [3H]ketanserin to cortical 5-HT2 receptors in senile dementia of the Alzheimer type

Using [3H]ketanserin, a specific ligand for the 5-HT2 receptor, the amount of specific binding was measured in preparations of post-mortem frontal cortex from subjects diagnosed as suffering from dementia. A highly significant 42% loss of binding was observed which reflected a decrease in receptor density compared to psychiatrically normal controls. This was found to be independent of age in the demented patients and thus unlikely to be related to the cholinergic deficit. Measurement of 5-HT and its metabolite 5-HIAA indicated a smaller, non-significant decrease in presynaptic 5-HT function.

Reduced corticol choline acetyltransferase activity in senile dementia of Alzheimer type is not accompanied by changes in vasoactive intestinal polypeptide

Post-mortem brain tissue from 7 patients who died with a diagnosis of senile dementia of Alzheimer type (SDAT) was compared with tissue obtained from 7 control patients at routine post mortem. A significant fall in choline acetyltransferase (ChAT) activity was apparent in the cerebral cortex of the SDAT cases which was maximal in the temporal lobe. The fall in ChAT activity was not accompanied by changes in cortical vasoactive intestinal polypeptide (VIP) measured by radioimmunoassay.

Neuronal degeneration in locus ceruleus and cortical correlates of Alzheimer disease.

Abstract.Relationships were examined between neuronal degeneration in the nucleus locus ceruleus (nLC), a parameter of central noradrenergic impairment, and neocortical markers of Alzheimer disease (AD). The loss of nLC neurons was found to correlate significantly with norepinephrine concentration, choline acetyltransferase (ChAT) activity, and numbers of plaques and tangles in Brodmann area 24 (cingulate); ChAT and plaque counts in area 21 (temporal); and with ChAT activity in area 10 (frontal). In addition, nLC neuronal counts were correlated significantly with the severity and estimated duration of dementia. The number of neurofibrillary tangles in nLC, which did not correlate significantly with neocortical markers of AD, correlated with the estimated duration and severity of dementia. These data suggest that changes in central noradrenergic pathways are related to the pathophysiology of AD.

Neurofibrillary degeneration and neuronal loss in Alzheimer's disease

Neuronal loss in Alzheimers disease, especially in cerebral cortex and hippocampus, appears closely associated with the process of neurofibrillary degeneration. In certain noncortical nuclei neuronal loss appears not to depend upon the formation of neurofibrillary tangles. Neurofibrillary tangles and neurons were counted in the same populations of neurons in five brain regions. In the locus ceruleus and nucleus basalis, where tangles have a loose or globose structure, correlations with neuronal counts were not significant. In cerebral cortex and hippocampus, tangles have a more dense and often a flame-like appearance and their correlations with neuronal counts were significant. The relationships between tangles and noncortical neurons reported here suggest that the appearance of tangles does not necessarily herald the demise of a neuron in Alzheimers disease. It can be reasonably anticipated that these relationships depend upon the clinical heterogeneity of Alzheimers disease, regional differences in the brain and/or the macromolecular composition of neurofibrillary tangles.

Normal cortical concentration of cholecystokinin-like immunoreactivity with reduced choline acetyltransferase activity in senile dementia of Alzheimer type

Abstract Choline acetyltransferase (ChAT) activity and cholecystokinin immunoreactivity (CCK-I) were determined in ten brains from patients dying with a diagnosis of senile dementia of Alzheimer type (SDAT) and in ten brains from control cases. The post-mortem stability of CCK-I was high, as determined using a mouse brain model. Although ChAT activity was significantly reduced in the cerebral cortex, hippocampus and caudate nucleus in the SDAT cases, there was no difference in CCK-I content between the two groups in any brain area. Thus the population of intrinsic cortical cells which contains CCK-I does not appear to be significantly affected in SDAT.