Changes in blood glucose and insulin secretion in patients with senile dementia of Alzheimer type

A retrospective study of 839 hospital records with various dementia diagnoses showed that 63 cases had a diagnosis of diabetes mellitus as well. None of these were found in the group of patients with senile dementia of Alzheimer type (SDAT). Oral glucose tolerance tests (OGTT) were performed in patients with SDAT, multiinfarct dementia (MID), cerebrovascular disease (CVD), hospitalized control patients (Chosp) and healthy elderly persons (Celd). Fasting blood sugar was significantly lower and the areas under the OGTT curves were significantly smaller in the SDAT group than in the CVD and the Chosp group. SDAT patients had higher insulin levels than Celd during the OGTT and on a statistically significant level 90 min after ingestion of sugar. Our findings suggest that SDAT and diabetes mellitus may not co-exist and that patients with SDAT have decreased blood sugar concentrations and elevated serum insulin levels. It is discussed whether this is an effect of the transmitter deficiencies in SDAT or may serve to explain these deficiencies.     

Cerebrospinal fluid amino acids in Alzheimer's disease

Twenty-two amino acids are measured in cerebrospinal fluid of fourty patients with senile dementia of the Alzheimer type (SDAT) and of ten age matched healthy control subjects. There is no significant difference between these two groups.     

Herpes simplex virus type 1 DNA is present in specific regions of brain from aged people with and without senile dementia of the Alzheimer type.

We have investigated the possible involvement of viruses, specifically Herpes simplex virus type 1, in senile dementia of the Alzheimer type (SDAT). Using the highly sensitive polymerase chain reaction, we have detected the viral thymidine kinase gene in post-mortem brain from 14/21 cases of senile dementia of the Alzheimer type and 9/15 elderly normals. The temporal cortex and hippocampus were usually virus-positive; in contrast, the occipital cortex was virus-negative in 9/9 SDAT cases and 5/5 elderly normals. Temporal and frontal cortex from younger normals (five infants and five middle-aged) were negative. Thus, the presence of Herpes simplex virus type 1 DNA is a region-dependent feature of the aged brain.     

Quantitative study of neurofibrillary tangles in subdivisions of the hippocampus. CA2 as a special area in normal aging and senile dementia of the Alzheimer type.

The frequency of neurofibrillary tangles (NFTs) in relation to aging was examined in five regions of the hippocampus of 139 normal controls (60 to 106 years) and 14 patients with senile dementia of the Alzheimer type (SDAT). The regions were CA4, CA3, CA2 and CA1, the latter being subdivided into CA1a (the region near CA2) and CA1b (the region near the subiculum). Only CA2 showed no correlation of NFTs with normal aging. CA2 in SDAT was the site most vulnerable to NFT formation. Therefore, it is considered that CA2 is a special region in both normal aging and SDAT. CA1 was characterized by the early appearance of large amounts of NFT, and was the most reliable marker of senile change related to aging. Like CA1, both CA3 and CA4 showed an increase of NFTs with normal aging, but their aging process was far less marked. In addition, statistical analysis based on a "normal" distribution was considered to be unsuitable for quantitative study of senile change, because no histogram of NFTs in any subdivisions for any age showed such a distribution.     

The effects of aging and dementia on concept formation as measured on an object‐sorting task

This study was designed to investigate abstract problem‐solving abilities in elderly normals and in patients with senile dementia of the Alzheimer type (SDAT). A pair of tasks was administered to 17 young normals, 22 aged normals, and 51 patients with SDAT (28 early dementia, 23 advanced dementia). Twenty‐five common household items were simultaneously displayed on a video monitor screen. On both tasks, participants were required to select a subgroup of 8 of the 25 items. On the control task, the selection principle was supplied to the participant. Aged normals were unimpaired on this task, whereas early dementia patients were modestly impaired, and advanced dementia patients were markedly impaired. On the concept‐formation task, the selection principle defining the subgroup of 8 items was deduced by the participant. All participant groups performed significantly more poorly on the concept‐formation version of the task than on the control task. The increase in errors was greatest in the early dementia patients, less in the aged normals, and least in the young normals and advanced dementia patients. The performance of the severely demented participants on the concept‐formation task approached floor levels. Because this test procedure provides a relatively isolated measure of abstract problem‐solving ability and elicits a clear deficit from both aged normals and SDAT patients, it might be useful in the assessment of treatment effects on age‐related cognitive impairment.     

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.     

Neuromorphology and neurochemistry of senile dementias in the light of studies on glial response]

The present study describes a few morphological and neurochemical disturbances in astroglial cells in senile dementia of the Alzheimer type (SDAT). The greatly elevated number of fibrous astrocytes in brain samples with SDAT is observed. The content of glial fibrillar acid protein is elevated in these cells. Glial filaments are detected to surround lipid centers. Moreover, there are deviations in energy metabolism: a profound decrease in the levels of the brain creatine kinase CKBB that is one of the principle ATP-regulation enzyme. It is suggested that there is a relationship between all the disturbances observed in glial cells of SDAT patients. These disturbances are likely to be links of the same process which leads to abnormal brain ageing.     

Quantitative Study of Neurofibrillary Tangles in Subdivisions of the Hippocampus

The frequency of neurofibrillary tangles (NFTs) in relation to aging was examined in five regions of the hippocampus of 139 normal controls (60 to 106 years) and 14 patients with senile dementia of the Alzheimer type (SDAT). The regions were CA4, CA3, CA2 and CA1, the latter being subdivided into CA1a (the region near CA2) and CAlb (the region near the subiculum). Only CA2 showed no correlation of NFTs with normal aging. CA2 in SDAT was the site most vulnerable to NFT formation. Therefore, it is considered that CA2 is a special region in both normal aging and SDAT. CA1 was characterized by the early appearance of large amounts of NFT, and was the most reliable marker of senile change related to aging. Like CA1, both CA3 and CA4 showed an increase of NFTs with normal aging, but their aging process was far less marked. In addition, statistical analysis based on a "normal" distribution was considered to be unsuitable for quantitative study of senile change, because no histogram of NFTs in any subdivisions for any age showed such a distribution. Acta Pathol Jpn 41: 597-603, 1991.     

VIP-sensitive adenylate cyclase, guanylate cyclase, muscarinic receptors, choline acetyltransferase and acetylcholinesterase, in brain tissue afflicted by Alzheimer's disease/senile dementia of the Alzheimer type

Biochemical parameters were determined in autopsy material from several brain regions of thirteen patients with Alzheimer's disease/senile dementia of Alzheimer type (AD/SDAT) (mean age 75 years) and from brains of ten age-matched controls (mean age 76 years). Choline acetyltransferase specific activity was significantly lower in the nucleus caudatus, putamen, left thalamus, hippocampus and the cortex from gyrus hippocampus and the temporal lobe in AD/SDAT, acetylcholinesterase specific activity was significantly lower in the hippocampus, parietal and left frontal lobe in AD/SDAT samples than in corresponding samples from aged-matched controls. A compensatory increase of muscarinic receptors was found in the nucleus caudatus and left frontal lobe samples in AD/SDAT. Guanylate cyclase activity was not significantly altered in AD/SDAT in the brain regions examined. The basal, non-stimulated activity of adenylate cyclase was significantly (p less than 0.05) elevated in hippocampus samples from AD/SDAT patients and the enzyme activity stimulated by the vasoactive intestinal polypeptide VIP (2 microM) or forskolin (10 microM) was also elevated in AD/SDAT although not significantly.     

Altered lymphocyte acetylcholinesterase activity in patients with senile dementia

Reductions in the acetylcholinesterase (AChE) activity of certain brain areas in patients with senile dementia of Alzheimer type (SDAT) have been found to correlate with the severity of the disease, suggesting a central cholinergic lesion. Since AChE is expressed on the surface of various blood cells too, the AChE activity of lymphocytes and erythrocytes was determined to test the possibility whether the cholinergic lesion is also reflected on these readily available cells. The AChE activity of lymphocytes in SDAT and in alcoholic dementia (AD) were significantly lower as compared to those of the age-matched healthy volunteers. In contrast, there was no significant difference in the activity of lymphocyte AChE between age-matched healthy controls and patients with multi-infarct dementia of vascular origin (MID). No changes could be demonstrated in the erythrocyte AChE activities of the patients studied, and the age-matched healthy individuals, when comparing them to the healthy blood donors. The AChE activity of lymphocytes may thus be a useful marker to follow the alterations in the metabolism of acetylcholine (ACh) in the central nervous system (CNS) of different types of dementia.     

Dementia,ageing, and the structure of human memory

The memory performance of patients suffering from senile dementia of the Alzheimer type (SDAT) (N = 29), normal subjects of equivalent age and education (N = 58), and young normal controls (N = 42) was tested using free recall and verbal and nonverbal span. Three measures were derived from the free recall task: primacy based on the first item, secondary memory based on the middle serial positions, and primary memory based on recency and the Waugh-Norman correction factor. The SDAT patients differed from the normal elderly on all free recall and span measures except for primary memory. The elderly were clearly inferior to the young on secondary memory, and were marginally poorer on primary memory and the two span measures. Three possible explanations of this pattern of results are considered, based on the dichotomous modal model of memory, levels of processing, and working memory. It is suggested that the assumption that SDAT patients suffer from a deficit in the central executive component of working memory offers the best of these interpretations.     

Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR

HLA-DR is a class II cell surface glycoprotein of the human histocompatibility complex usually expressed on the surface of cells that are simultaneously presenting foreign antigen to T-lymphocytes. Using immunohistochemical procedures with two specific monoclonal antibodies to HLA-DR, HLA-DR-positive reactive microglia were found in gray matter throughout the cortex of postmortem brains of patients with senile dementia of the Alzheimer type (SDAT) and were particularly concentrated in the areas of senile plaque formation. Double immunostaining with antibodies to glial fibrillary acidic protein (GFAP) showed that the HLA-DR-positive cells were different from the reactive astrocytes although the occasional positively staining giant astrocyte was also seen. Small numbers of resting microglia were HLA-DR-positive in white matter of both normal and SDAT brains. The SDAT cases also had reduced cortical choline acetyltransferase (ChAT) levels. In the 11 brains studied, the number of hippocampal HLA-DR-positive cells was positively correlated with the numbers of plaques and negatively correlated with average cortical ChAT.     

Alpha 1-antichymotrypsin is present in diffuse senile plaques. A comparative study of beta-protein and alpha 1-antichymotrypsin immunostaining in the Alzheimer brain.

Immunocytochemical examinations of the brains of patients with senile dementia of the Alzheimer type, Down''s syndrome, and Gerstmann-Sträusslar-Scheinker disease were performed to clarify the relationship between alpha 1-antichymotrypsin and senile plaque amyloids. Alpha 1-antichymotrypsinlike immunoreactivity was enhanced by protease digestion but not by formic acid pretreatment. Almost all of the diffuse plaques and some small amyloid deposits, which were widely distributed in the cerebral cortex and/or subcortical regions of SDAT brains, were labeled by alpha 1-antichymotrypsin immunostaining. All types of senile plaques, eosinophilic tangles, and some neurons and astrocytes were labeled by alpha 1-antichymotrypsin staining. Diffuse plaques in a Down''s syndrome frontal lobe and in a senile dementia of the Alzheimer type cerebellum also were labeled by alpha 1-antichymotrypsin immunostaining. However neither subpial amyloid deposits nor subcortical small amyloid deposits could be detected by alpha 1-antichymotrypsin immunostaining. Kuru plaques in a Gerstmann-Sträusslar-Scheinker disease cerebellum also were not labeled by alpha 1-antichymotrypsin immunostaining. These results suggest that alpha 1-antichymotrypsin is associated with the early to late stages of amyloid deposition and senile plaque formation in senile demential of the Alzheimer type.     

Immunohistochemical and in situ hybridisation detection of adenovirus early region 1A (E1A) gene in the microglia of human brain tissue.

To investigate whether brain tissue is infected latently by adenovirus via a monocyte/microglia-mediated entry mechanism, brain tissue resected at necropsy from seven senile subjects (five with senile dementia of Alzheimer type (SDAT) and two subjects without pathological changes) was examined for adenovirus early region 1A (E1A) gene and its expression using in situ hybridisation and immunohistochemical staining. HLA-DR positive, reactive microglial cells in both SDAT and normal brain tissue showed positive hybridisation and immunoreactive expression of adenovirus E1A. Thus there may be monocyte/microglia-mediated entry of adenovirus in the central nervous system which would be a novel and presumably common interaction between brain tissue and adenovirus.     

Senile dementia and Alzheimer's disease: lack of changes of the cortical content of quinolinic acid

The content of Quinolinic Acid (QUIN) was fragmentographically measured in the frontal, parietal and temporal cortex obtained at autopsy from patients affected by Alzheimer's disease-senile dementia Alzheimer type (AD/SDAT) or matched controls. The density of large cholinergic neurons in the nucleus basalis magnocellularis and the density of plaques in the hippocampal formation, parietal and frontal cortex of these patients was also evaluated in order to obtain a quantitative estimation of the Alzheimer type changes. In the three cortical areas studied, the content of QUIN was similar in AD/SDAT patients and age matched controls. The AD/SDAT patients had an important reduction of the number of large cholinergic neurons in the nucleus basalis magnocellularis and a much higher density of plaques in cortex and in hippocampus than age matched controls. The data reported here do not support the possibility than an accumulation of QUIN plays a role in the neuronal degeneration occurring in the cortex of patients affected by AD/SDAT.     

Effects of acute tryptophan depletion on cognitive function in Alzheimer's disease and in the healthy elderly

BACKGROUND: The cholinergic system is profoundly impaired in senile dementia of Alzheimer type (SDAT) and replacement therapy produces only modest clinical benefits. The serotonergic system is also impaired and may contribute both to cognitive and non-cognitive symptoms in SDAT. To investigate this further we assessed the effects of lowering brain serotonin using the technique of acute tryptophan depletion on cognitive function in patients with SDAT and in age matched control subjects. METHOD: Sixteen patients with probable SDAT and 17 healthy elderly subjects received two amino acid drinks in a within subject, double-blind, placebo-controlled, counterbalanced, crossover design. One of the drinks was nutritionally balanced and contained tryptophan (placebo), the other was identical but contained no tryptophan. A battery of detailed neuropsychological tests was performed between 4 and 6 h after the drink. Mood rating scales and other ratings of behavioural and emotional symptoms were also performed on both occasions. RESULTS: Acute tryptophan depletion resulted in impairment on tasks of working memory in both groups. There was no group specific effect. Female SDAT subjects performed better on a task of pattern recognition during acute tryptophan depletion compared with placebo. There were no changes in behavioural symptoms during acute tryptophan depletion in either group. CONCLUSION: Compromised serotonergic function may be an important contributor to cognitive decline in SDAT and in ageing. Strategies targeting specific 5HT receptors may be helpful in SDAT.     

Dihydropteridine reductase activity in dried blood spots: effects of aging and senile dementia of the Alzheimer type.

Dihydropteridine reductase (EC 1.6.99.7) (DHPR) activity was measured in blood spots from 50 neonates, 52 healthy adults aged 30-62 years, and 21 elderly controls aged 67-97 years, as well as 32 demented patients of whom 25 had senile dementia of the Alzheimer type. Enzyme activity was stable for seven days at 4 degrees C and for at least 14 days at -20 degrees C. No important difference was found between the DHPR activity of venous and capillary blood. DHPR activity was considerably lower in the healthy adult group compared with neonates and the elderly group, and there was no sex difference at any age. The erythrocyte DHPR activity of patients with senile dementia of the Alzheimer type was similar to that of elderly controls. This result differs from that previously reported for leucocytes.     

Molecular size distribution of somatostatin-like immunoreactivity in the cerebrospinal fluid of patients with degenerative brain disease

The molecular size distribution of somatostatin-like immunoreactivity (SLI) in the cerebrospinal fluid (CSF) of patients with brain disease was investigated by separation with a Sephadex G-25 superfine column and subsequent radioimmunoassay of the eluate. Marked heterogeneity of SLI in the CSF of control subjects as well as in demented patients, was observed. Controls and schizophrenics exhibited an SLI distribution pattern consisting mainly of two pronounced peaks: the first eluting with the void volume of the column; the second being compatible with a peptide of N-terminally extended somatostatin-14. SLI from the CSF of patients with senile dementia of the Alzheimer type (SDAT), multi-infarct dementia (MID) and normal pressure hydrocephalus (NPH) showed the same two peaks found in controls and schizophrenics; and in addition, a third peak co-eluting with somatostatin-14. However, this peak was more pronounced in patients with SDAT and MID than in patients with NPH. Re-chromatography of G-25 sf void volume immunoreactivity afforded two fractions of an apparent molecular weight of about 10,000 daltons and 15,500 daltons, respectively.     

Biogenic amines and their metabolites in Alzheimer's disease: noradrenaline, 5-hydroxytryptamine and 5-hydroxyindole-3-acetic acid depleted in hippocampus but not in substantia innominata

The following monoamine transmitters and related neurochemicals were analyzed in hippocampus and substantia innominata from postmortem brain tissue of subjects with senile dementia of the Alzheimer's type (SDAT): tryptophan (TP), 5-hydroxytryptamine (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA), noradrenaline (NA), dopamine (DA) and homovanillic acid (HVA). The results were compared to those obtained in postmortem brain samples obtained from normal subjects matched for age, sex and time between collection of tissue and freezing. There were no significant differences in concentrations of TP, DA or HVA between normals and SDAT subjects in either brain region. While hippocampal 5-HT, 5-HIAA and NA concentrations were markedly reduced in SDAT patients relative to normals, the substantia innominata concentrations of these three were not significantly different between controls and SDAT patients, emphasizing the importance of detailed regional analyses when conducting neurochemical studies in SDAT.     

Acute effects of oral pyridostigmine on memory and cognitive function in SDAT

This study reports the effects of the anticholinesterase pyridostigmine on cognitive function in 15 elderly patients with senile dementia of the Alzheimer type (SDAT). Each patient was given placebo and pyridostigime 60 mg orally four times over 26 hours, with a seven day washout between, using a randomized double-blind cross-over design. There was no significant improvement in cognitive function following placebo or pyridostigmine. We did not perform any preliminary dose-finding trials to find the optimum dose of pyridostigmine, but gave the drug in a predetermined fixed dosage to each patient. We conclude that with this dosage, pyridostigmine did not significantly improve cognitive function more than placebo in this group of elderly patients.