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Notes: Abstract: The pattern of basement membrane (BM) deposition was assessed in 20 cases of pure ductal carcinoma in situ (DCIS) and in 10 cases of DCIS with a focus of microinvasive carcinoma (DCISM) of the breast, using an indirect immunoperoxidase technique to detect type IV collagen. The presence and frequency of breaks in the BM was analyzed quantitatively. Normal breast tissue, benign breast lesions, and non-neoplastic mammary ducts adjacent to DCIS showed a continuous BM. In pure DCIS small areas of discontinuity in the BM were observed. The BM pattern of DCISM was similar to pure DCIS except at the point of microinvasion, where there was fragmentation of BM and wider areas of discontinuity with the presence of neoplastic cells extruding into the stroma. There was a significant correlation between the number of BM breaks in DCIS and histological type (p 〈 0.001) and nuclear grade (p 〈 0.001) with comedo type, high nuclear grade (grade 3) DCIS showing the largest numbers of discontinuities. Although there is a trend towards increased numbers of breaks in DCISM compared with non-invasive disease, this does not reach statistical significance (p 〉 0.05). We, therefore, suggest that the finding of a focus of microinvasion in DCIS is not an ominous prognostic indicator and the natural history of this entity is more similar to pure DCIS rather than to invasive breast cancer. Clinical follow-up was available for all the patients and the period ranged 21 to 55 months from the time of diagnosis. No patients have had a documented recurrence during this period. However, a longer term follow-up is needed to confirm this observation in this small series of patients who had undergone optimal treatment for the disease.BM staining, using type IV collagen antibodies may be of value to the diagnostic histopathologist in selected cases of DCIS to confirm a suspicious focus of invasion and to define accurately the morphologic nature of the lesion.

Notes: Abstract: The measurement of cholinesterase activities in either plasma or cerebrospinal fluid (CSF) may ultimately prove to be relevant in the diagnosis of neurological and neuropsychiatric disorders. However, studies to date have examined only total enzyme activities. Therefore in the present study we have examined the distribution of the individual molecular forms of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in plasma and CSF using sucrose density gradient centrifugation. Although the total activities of AChE were of the same order of magnitude in plasma and CSF, there was a considerable difference (120–500-fold) between total BChE activity in the CSF and the BChE-rich plasma. The analysis of the individual molecular forms revealed that the predominant molecular species of AChE and BChE in the CSF—both lumbar and ventricular—was the G4 form. The G4 form also constituted the majority of the plasma BChE activity and, on average, over half (56%) of the plasma AChE activity. The significance of the AChE and BChE molecular form compositions of both plasma and CSF and their possible relationship to pathological states are discussed.

Notes: The distributions of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) molecular forms and their solubility characteristics were examined, using density gradient centrifugation, in various regions of the postmortem human CNS. Total AChE activity varied extensively (50-fold) among the regions investigated, being highest in the telencephalic subcortical structures (caudate nucleus and nucleus of Meynert); intermediate in the substantia nigra, cerebellum, and spinal cord; and least in the fornix and cortical regions (hippocampus and temporal and parietal cortex). Total BChE activity was, in contrast, much more evenly distributed, with only a threefold variation between the regions studied. Although the patterns of molecular forms of each enzyme were broadly similar among the different areas, regional variations in the distribution and abundance of the various forms of AChE were much greater than those of BChE. Thus, although the tetrameric G4 form of AChE constituted the majority of the total AChE activity in all regions examined, the ratio of the G4 form to the monomeric Gl form, the latter of which constituted the majority of the remaining activity, varied markedly, ranging from 21 in the caudate nucleus to 1.7 in the tem poral cortex. In addition to the G4 and Gl forms of AChE, the dimeric G2 form was observed in the nucleus of Meynert and a fast-sedimenting (16S) species was found in samples of both the parietal cortex and spinal cord. In contrast, the G4 and Gl forms of BChE were the only molecular species observed in the different areas and the G4.G1 ratio varied from 3.3 in the substantia nigra to 0.9 in the temporal cortex. Regarding the solubility characteristics of the individual AChE and BChE molecular forms, the majority of the G4 form of AChE was extractable only in the presence of detergent, indicating a predominantly membrane-bound localization of this species. The smaller AChE forms (Gl and G2) and both the Gl and G4 forms of BChE were all relatively evenly distributed between soluble and membrane-bound species. These findings are discussed in relation to neurochemical and neuroanatomical, particularly cholinergic, features of the regions examined.

Notes: Abstract: Senile dementia of Lewy body type is characterized clinically by a relatively acute onset of fluctuating memory loss and confusion, frequently accompanied by visual hallucinations. Neurochemical analyses of temporal cortex has revealed a distinction between hallucinating and nonhallucinating patients in both cholinergic and monaminergic transmitter activities. In contrast with the cholinergic enzyme choline acetyltransferase, which was more extensively reduced in hallucinating individuals, serotonergic S2 receptor binding and both dopamine and serotonin metabolites were significantly decreased in nonhallucinating cases. These results suggest that an imbalance between monaminergic and cholinergic transmitters is involved in hallucinogenesis in the human brain.

Notes: Total muscarinic receptor levels, the levels of the subtypes exhibiting high and low affinity for pirenzepine, and the high- and low-affinity agonist states of the receptor were investigated in hippocampal tissue obtained at autopsy from mentally normal individuals and the following pathological groups: Alzheimer's disease, Parkinson's disease, Down's syndrome, alcoholic dementia, Huntington's chorea, and motor-neurone disease. A moderate decrease in the density of both high-affinity pirenzepine and high-affinity agonist subtypes was found in Alzheimer's disease, whereas a trend towards an increase in the overall muscarinic receptor density was apparent in the parkinsonian patients without dementia, mainly due to an increase in the low-affinity agonist state; the differences between the Alzheimer's disease and nondemented parkinsonian cases were highly significant. As previously reported, the levels of both choline acetyltransferase and acetylcholinesterase were markedly reduced in both Alzheimer's disease and Parkinson's disease—with a greater loss of both enzymes in the demented subgroup of parkinsonian patients. Activities of the cholinergic enzymes were also extensively reduced in Down's syndrome, accompanied by a loss of high-affinity pirenzepine binding. There were no significant receptor or enzyme alterations in the other groups studied. These observations suggest that in the human brain, extensive degeneration of cholinergic axons to the hippocampus, as indicated by a loss of cholinergic enzymes, is not necessarily accompanied by extensive muscarinic receptor abnormalities (as might be expected if a major subpopulation were presynaptic). Moreover, the opposite changes in muscarinic binding in Parkinson's and Alzheimer's diseases may be related to the greater severity of dementia in the latter disease. Key Words: Muscarinic receptor subtypes—Human hippocampus—Alzheimer's disease—Parkinson's disease —Down's syndrome. Smith C. J. et al. Muscarinic cholinergic receptor subtypes in hippocampus in human cognitive disorders.

Notes: Abstract: The total levels of butyrylcholinesterase (BChE) activity and, more specifically, the distribution of BChE molecular forms were measured in the human neocortex during fetal development. Both the amount of total activity and the abundance of the different molecular forms (G1 and G4) remained relatively constant between gestational ages of 8-22 weeks and were similar to those observed in samples of cortex from aged brain. In addition, in both Alzheimer-type and parkinsonian dementia, the levels of total BChE activity as well as the relative abundance of the G1 and G4 molecular forms were similar to those observed in control tissue. Hence, both the levels of total activity and the distribution of molecular forms did not change significantly either during fetal development or in the neurodegenerative disorders of Alzheimer-type and parkinsonian dementias. Because these situations are accompanied by changes in the cortical cholinergic system (including an increase and decrease in levels of the G4 form of acetylcholinesterase, respectively), it is concluded that, at least in the human neocortex, BChE is unrelated to cholinergic neurotransmission associated with subcortical cholinergic projection fibres.

Notes: Abstract In the human fetus, obtained postmortem at estimated gestational ages of 8–22 weeks, biochemical activities of cortical choline acetyltransferase (ChAT) and acetylcho-linesterase (AChE) were comparable to those of adult brain tissue. In contrast cholinergic receptor binding, including muscarinic Ml and M2 subtypes (measured by displacement of [3H]N-methylscopolamine with, respectively, pirenzepine and carbachol) and [3H]nicotine (putative nicotinic) binding were undetectable before 13–14 weeks and even at 22 weeks were substantially (three- to fourfold) below the respective adult values. Cortical ChAT activity decreased significantly with gestational age whereas binding to the three receptors, including the proportion M1/M2, increased significantly. AChE was present at all ages investigated as the two molecular monomeric (G1) and tetrameric (G4) forms. The proportion of G4, which was much more soluble in fetal compared with adult cortex, increased approximately threefold. Histochemically AChE, although intense in the nucleus of Meynert, was generally confined to subcortical white matter at early fetal developmental periods, appearing later in the cortex localized to nerve fibres and occasional cell bodies. These observations suggest that during the second trimester of human fetal development, cortical cholinergic function may be preceded by relatively high ChAT activity and paralleled not only by increasing receptor binding but also by a proportional increase in the tetrameric form and histochemical reactivity of AChE.

Notes: Abstract: Dementia with Lewy bodies (DLB) forms the second most common pathological subgroup of dementia after Alzheimer's disease. The present study compares the levels of oxidative damage to proteins, lipids, and DNA bases in cortical brain areas from patients with DLB with levels in matched control tissues. Overall, there was a trend for protein carbonyl levels to be increased in all areas, but a significant difference was found only in the parietal and temporal lobes. No differences were observed in the levels of lipid peroxidation. Measurement of products of damage to DNA bases showed increased levels of thymine glycol, 8-hydroxyguanine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, 5-hydroxycytosine, 5-hydroxyuracil, 5-hydroxymethyluracil, and xanthine. Xanthine levels were increased in the DLB group in the parietal, occipital, and temporal lobes, indicating that peroxynitrite or other deaminating species may be involved. The finding of increased protein carbonyls and increased DNA base products in cortical regions from DLB patients indicates that oxidative stress may play a role in DLB.