NMDA receptor density as measured by the specific binding of [3H]MK 801 was significantly decreased (about 20%) in the frontal but not in the parietal cortex of postmortem brain samples of Alzheimer's disease (AD) patien...NMDA receptor density as measured by the specific binding of [3H]MK 801 was significantly decreased (about 20%) in the frontal but not in the parietal cortex of postmortem brain samples of Alzheimer's disease (AD) patients (n = 21), when compared with control brains (n = 20). Membrane fluidity was not altered in the frontal cortex samples, but was slightly reduced in the parietal cortex samples of the AD patients. Since AD-specific histopathological changes (densities of senile plaques and neurofibrillary tangles) were about similar in both areas, it is concluded that the reductions of NMDA receptor densities in the frontal cortex is independent of AD-specific histopathological changes and of changes of membrane fluidity.
Cognitive deficits are the most important symptoms in the diagnosis of dementia. Changes in noncognitive behavioural areas often go unrecognised at examination or are considered insignificant. These abnormalities, howeve...Cognitive deficits are the most important symptoms in the diagnosis of dementia. Changes in noncognitive behavioural areas often go unrecognised at examination or are considered insignificant. These abnormalities, however, contribute most to the caregiver's burden, interfere with the individual well-being of the patient, and are predictors of early institutionalization. Psychotherapeutic interventions in dementia complete the treatment effects achieved by psychopharmacology, cognitive enhancers, and cognitive training of target functions. Psychotherapy in dementia should be based on an interacting form of therapy, i.e. a contingency management in the natural environments of the dementia sufferer where the primary caregiver, as a mediator, takes over the main therapeutic tasks.
Preliminary to a multicenter trial, an open-label study was conducted of prednisone treatment in Alzheimer's disease. Prednisone was given at an initial dose of 10 mg (part 1) or 20 mg (part 2) and tapered over 7 weeks....Preliminary to a multicenter trial, an open-label study was conducted of prednisone treatment in Alzheimer's disease. Prednisone was given at an initial dose of 10 mg (part 1) or 20 mg (part 2) and tapered over 7 weeks. There were no serious adverse events attributed to the medication, and there were no significant changes in either mean cognitive or behavioral assessment scores with treatment during either part. Serum levels of the acute phase proteins alpha-1-antichymotrypsin and C-reactive protein did not change significantly during part 1, but were suppressed by the higher dose given in part 2. Thus, a prednisone regimen with an initial dose of 20 mg is tolerable and results in suppression of the acute phase response in Alzheimer's disease.
Pre- and postsynaptic elements of the 5-hydroxytryptamine (5-HT, serotonin) system were studied in a control group and in patients with vascular dementia (VAD). The 5-HT uptake site was used as a presynaptic marker for 5...Pre- and postsynaptic elements of the 5-hydroxytryptamine (5-HT, serotonin) system were studied in a control group and in patients with vascular dementia (VAD). The 5-HT uptake site was used as a presynaptic marker for 5-HT terminals and 5-HT1A and 5HT2 receptors were used as postsynaptic markers. The binding sites were quantified with radioligand binding techniques, where the radioligands used were [3H]paroxetine, [3H]8-OH-DPAT and [3H]ketanserin, respectively. The presynaptic uptake site was studied in frontal and temporal cortices and caudate nucleus. 5-HT1A and 5-HT2 receptors were studied only in frontal and temporal cortices. There were no differences between control and VAD groups in any of the regions investigated with respect to the number of binding sites (Bmax) and binding affinity (Kd). This indicates that both pre- and postsynaptic parts of the 5-HT system are intact in these brain areas in VAD.
Xanomeline, a substituted TZTP, is a new M1 selective muscarinic agonist in clinical trials for Alzheimer's disease. The brain uptake of [11C]xanomeline and the analog [11C]butylthio-TZTP was examined by positron emissio...Xanomeline, a substituted TZTP, is a new M1 selective muscarinic agonist in clinical trials for Alzheimer's disease. The brain uptake of [11C]xanomeline and the analog [11C]butylthio-TZTP was examined by positron emission tomography (PET). Radioactivity accumulated most markedly in the neocortex and the striatum. Pharmacological characterization in vitro and in cynomolgus monkeys in vivo by PET indicated specific [11C]butylthio-TZTP binding to muscarinic receptors and to sigma-1 recognition sites. More than 5% of the radioactivity was in the human brain 5 min after i.v. injection of [11C]xamomeline or [11C]butylthio-TZTP. This high brain uptake may be clinically advantageous in the sense that substituted TZTP may induce central muscarinic agonist effects at a dose level for which there is a low risk of peripheral side-effects.
In clinical practice, Alzheimer's disease (AD), multi-infarct Dementia (MID) and depression are often difficult to differentiate and may coexist. This study reports the findings of CT and MRI focused on hippocampal atrop...In clinical practice, Alzheimer's disease (AD), multi-infarct Dementia (MID) and depression are often difficult to differentiate and may coexist. This study reports the findings of CT and MRI focused on hippocampal atrophy (HA). Quantitative volumetric MRI measurements of the hippocampus showed a reduced volume in AD patients compared to normal controls with no overlap. CT studies reported a significant widening of the hippocampal fissure in AD patients. Because volumetric measurements are not available for routine examinations, so far we are required to use the finding of hippocampal lucency in CT and dilatation of the directly visible hippocampal fissure in coronal MRI scans as criteria for HA. These findings were visually classified on a 4-point scale by 2 neuroradiologists, who had no knowledge of the clinical diagnosis. The examinations of 80 patients (42 with AD, 22 with major depression, 3 with MID, 6 classified as age-associated memory impairment (AAMI) and 8 'normals' with only subjective memory impairment) showed that the HA strongly supports the diagnosis of AD, by correctly identifying 95% of the AD patients and 47.8% of the patients without AD. These results suggest that CT and MRI examinations of the hippocampus are capable of demonstrating HA in clinical practice, which is strongly correlated with the diagnosis of AD.
It has been reported that many tau sites in neurofibrillary tangles (NFT) are abnormally phosphorylated. We investigated the phosphorylation of tau in the hippocampus of nondemented patients and Alzheimer's disease patie...It has been reported that many tau sites in neurofibrillary tangles (NFT) are abnormally phosphorylated. We investigated the phosphorylation of tau in the hippocampus of nondemented patients and Alzheimer's disease patients by immunostaining with five site-specific antibodies against phosphorylated tau. In the pretangle stage, tau in neuropil threads was phosphorylated at serines 199, 202 and 409, numbered according to the longest human tau isoform, whereas tau in some neuronal soma was phosphorylated at serines 199, 202, 409 and 422. Tau at the stage of NFT was phosphorylated at serine 396 and threonine 231 in addition to serines 199, 202, 409 and 422. In the advanced stage, tau in ghost tangles was phosphorylated mainly at serine 396. These results suggest that the phosphorylation of each site in tau differs among the maturing stages of neurofibrillary change and that abnormal phosphorylation of tau in the neuronal soma occurs at 199, 202, 409 and 422 earlier than at threonine 231 and serine 396.
An increased apolipoprotein E (ApoE) type epsilon 4 allele frequency is associated with both sporadic and familial late-onset Alzheimer's disease (AD). The age of onset of disease in patients homozygous for the epsilon 4...An increased apolipoprotein E (ApoE) type epsilon 4 allele frequency is associated with both sporadic and familial late-onset Alzheimer's disease (AD). The age of onset of disease in patients homozygous for the epsilon 4 allele appears to be decreased by approximately 15 years compared with E2/3 individuals. In order to assess the influence of this allele on both dementia and cognitive decline in the elderly we have determined the ApoE genotype of 150 individuals over the age of 75 years who have taken part in a longitudinal study. Homozygosity for the epsilon 4 allele was rare. Of the 2 homozygotes, 1 was severely demented but the other did not receive a clinical diagnosis of dementia. The latter individual did demonstrate marked cognitive decline over a 28-month period. There was a consistent association between the presence of an epsilon 4 allele and both the clinical diagnosis of dementia and cognitive decline. These findings confirm a genetic heterogeneity in late-onset sporadic AD and prompt caution in the use of ApoE genotype to predict an elderly individual's susceptibility to either dementia or cognitive decline.
The cascade of reactions caused by ischemia in brain tissue is complex and not completely understood, but intensive investigation has led to convincing hypotheses. A disturbed calcium homeostasis and oxygen radicals seem...The cascade of reactions caused by ischemia in brain tissue is complex and not completely understood, but intensive investigation has led to convincing hypotheses. A disturbed calcium homeostasis and oxygen radicals seem to play a major role in postischemic neuronal damage. In accordance to these hypotheses drugs with different mechanisms of action have been developed. The aim of this paper is to give an overview over pathobiochemical mechanisms in cerebral ischemia and possibilities of pharmacological intervention.
We report the behavioural abnormalities, neuroimaging, and neuropsychological results of a 62-year-old patient, i.p., who shows a clinical profile that fulfils all characteristics of dementia of frontal lobe type. The pa...We report the behavioural abnormalities, neuroimaging, and neuropsychological results of a 62-year-old patient, i.p., who shows a clinical profile that fulfils all characteristics of dementia of frontal lobe type. The patient has been followed up over 5 years with psychometric testing. Comparing her cognitive profiles across examinations, her performance was substantially unchanged apart from behavioural disturbances and performance on frontal tasks which showed a progressive worsening. MRI finding evidenced marked ventricular enlargement, prevalent frontal atrophy and hypertrophy of the genus of corpus callosum. SPECT investigation showed a considerable reduction of cerebral blood flow in the mesial parts of the frontal lobes, in the lateral surface of the right fronto-parietal lobe, and hypo-perfusion in the right thalamic area. The results are discussed with reference to the features (clinical and neuropsychological) which distinguish different profiles of dementia.
A physiopathological role for acetylcholine (ACh) was hypothesized during ageing and related neurodegenerative diseases, e.g. dementia. This research was aimed to study acetylcholinesterase (AChE) activity during develop...A physiopathological role for acetylcholine (ACh) was hypothesized during ageing and related neurodegenerative diseases, e.g. dementia. This research was aimed to study acetylcholinesterase (AChE) activity during development and ageing of the frontal cerebral cortex of 4-, 8-, 12-, 16-, 20- and 24-month-old rats. This study was performed on synaptic plasma membranes, the specific subcellular compartment where the enzyme is located in vivo both in control animals and after in vivo acute treatment with L-acetylcarnitine. Maximum AChE activity was unaffected by age, and L-acetylcarnitine treatment increased enzyme activity in synaptic plasma membranes of 8-month-old rats. A comprehensive analysis of these results suggests: (a) the observed alterations in protein can substantially affect neurochemical data if results are presented as specific activities per unit protein; (b) energy metabolism plays the major role in the disturbed ACh metabolism during ageing and (c) the understanding of the mode of action of L-acetylcarnitine in treatment of dementia.
The present study is a retrospective study of remoxipride therapy. A total of 103 patients, 65 years or older, with a DSM-III-R diagnosis of dementia or delirium, were included. They had all been treated with remoxipride...The present study is a retrospective study of remoxipride therapy. A total of 103 patients, 65 years or older, with a DSM-III-R diagnosis of dementia or delirium, were included. They had all been treated with remoxipride because of psychotic symptoms or behavioural disturbances. The dose range of remoxipride was 50-300 mg, the median dose being 75 mg. The clinical effect was rated as good in two thirds of the patients, and side-effects were noted in one fourth. When psychomotor hyperactivity was the dominating problem, a good effect was rated in 81% of the patients. Side-effects were few and mild, the most common being tiredness; only 5 patients showed extrapyramidal symptoms.
Individual differences in the development of neurofibrillary changes were examined in eight cortical regions in the brains of 43 subjects with Down syndrome (DS; age range, 15-69 years) using sections stained with monocl...Individual differences in the development of neurofibrillary changes were examined in eight cortical regions in the brains of 43 subjects with Down syndrome (DS; age range, 15-69 years) using sections stained with monoclonal antibodies (mAb) tau-1 and 3-39. Neurofibrillary pathology was found in 4 cases below 36 years of age and in all 20 cases above that age. In the 24 positive cases, numerical density of pretangles stained with tau-1 and 3-39, respectively, was 6.1/mm2 and 0/mm2; early tangles, 5.0/mm2 and 5.3/mm2; mature tangles, 4.0/mm2 and 5.0/mm2 (p < 0.01); and end-stage tangles, 0.04/mm2 and 2.5/mm2 (p < 0.001). Numerical density of pretangles stained with mAb tau-1 and tangles and plaques stained with mAb 3-39 correlates weakly with age (r = 0.43; p< 0.02), and together with the wide range of numerical densities suggested heterogeneity of the population examined. Cluster analysis based on two variables - i.e., numerical density of pretangles stained with mAb tau-1 and neurofibrillary tangles (NFTs) and plaques stained with mAB 3-39, distinguished three groups of subjects with severe, moderate and weak changes. The severely affected group of 5 subject (21%) had an average 54.6/mm2 of neurons and 13.9/mm/ plaques with neurofibrillary changes, whereas the moderately affected group (6 subjects; 25%) showed a significantly lower numerical density of neurons and plaques with neurofibrillary changes (25.7/mm2 and 8.1/mm2, respectively) as compared with the most affected group. Most of the subjects (13; 54%) belong to the third group with only 2.2/mm2 of neurons and 1.4/mm2 plaques with neurofibrillary pathology. Comparison of these three groups of Down syndrome subjects representing high, moderate, and low susceptibility to neurofibrillary changes with the general population suggests that the risk of Alzheimer disease is similar but the onset of pathological changes is earlier in DS.
The most important new development during recent years in the field of degenerative dementia concerns synaptic pathology. So far it has been investigated in some regions and some cortical laminae in Alzheimer's disease (...The most important new development during recent years in the field of degenerative dementia concerns synaptic pathology. So far it has been investigated in some regions and some cortical laminae in Alzheimer's disease (AD). The present communication is a more comprehensive study of all laminae in four different regions, the prefrontal, parietal, inferior temporal and posterior cingulate cortex. Against the background of normal aging, AD was compared with another degenerative disorder, frontal lobe degeneration of non-Alzheimer type (FLD). The synapse density was measured using synaptophysin as a marker. Astrocytes were also counted in the molecular layer. In normals, the cortex showed successively lower synaptic density from layer I to layer VI and relatively lowest density in the prefrontal cortex and a general decline with increasing age. A 46-49% decrease in synaptic density was found in all laminae in all regions of AD brains, a finding different from that in FLD. The number of astrocytes increased significantly in the prefrontal cortex both in AD and FLD but parietally only in AD. These results contribute to the understanding of normal synaptic organization of cortex, demonstrate the laminar and regional distribution of synaptic loss in AD and underscore the difference between AD and FLD. The gliosis appears to be secondary to the neurodegenerative changes. Synaptic loss is likely to be a common pathogenetic feature of neurodegenerative disorders and a likely cause of clinical symptoms and regional metabolic decrements in dementia.
We have analyzed the tendency of amyloid load, neuritic plaques and neurofibrillary tangles (NFT) in the hippocampus and neocortex to occur in clusters in 49 consecutive cases of Alzheimer's disease (AD). This clustering...We have analyzed the tendency of amyloid load, neuritic plaques and neurofibrillary tangles (NFT) in the hippocampus and neocortex to occur in clusters in 49 consecutive cases of Alzheimer's disease (AD). This clustering tendency of the pathology was analysed in relation to severity of clinical disease assessed within 6 months before death, duration and age at onset of disease and at death. Amyloid plaques showed only a slight tendency to cluster together while neuritic plaques and, even more, NFT were clearly clustered. A greater clustering tendency was associated with more severe clinical impairment with particularly strong correlations being found between the clustering tendency of NFT in the hippocampus and clinical memory deficit, and between the clustering tendency of NFT in the parietal neocortex and overall cognitive deficit. Neuritic plaques showed similar but less pronounced and robust correlations between clustering and cognitive status. In the hippocampus NFT clustering was also negatively correlated with age at death, but not duration of disease nor age of disease onset. We conclude that clustering characterises neuritic pathology but not diffuse amyloid deposits and significantly affects cognition. The discrepancies between the group diagnosed as AD-only and the patient group that contained all patients, including the ones with mixed pathology, lead us to believe that any additional pathology might have a significant effect on the cognitive status of AD patients.
The pharmacokinetics of the cholinesterase inhibitor tacrine was studied in 5 Alzheimer patients during 12-31 months of treatment. A mean average steady-state concentration in plasma ranging from 1.1 to 30 ng/ml was obta...The pharmacokinetics of the cholinesterase inhibitor tacrine was studied in 5 Alzheimer patients during 12-31 months of treatment. A mean average steady-state concentration in plasma ranging from 1.1 to 30 ng/ml was obtained with doses ranging from 40 to 160 mg of tacrine daily. During treatment with 80 mg daily a maximal plasma concentration of tacrine (8.7 +/- 0.6 ng/ml) was obtained 1.3 +/- 0.2 h after intake of the morning dose. The mean elimination half-life was estimated at 5-7 h and remained unchanged when the tacrine dose was increased. The plasma concentration of tacrine was stable during long-term treatment with tacrine and no tolerance was observed regarding its cholinesterase inhibitory effect. A maximal 40% inhibition of plasma cholinesterase (ChE) activity and 60% inhibition of acetylcholinesterase activity in red blood cells was measured following treatment with the highest dose of 160 mg tacrine daily. A significant correlation was obtained between the plasma concentration of tacrine and the inhibition of ChE activity (p < 0.001). The tacrine concentration in CSF was measured in each patient on 1-3 occasions during the treatment and the ratio CSF/plasma concentration was estimated to be 0.47 +/- 0.09 (n = 11).
Patient EDS presented with an amnesic disorder of insidious onset (4 years) that remained stable and restricted to memory functions over a 10-year course. Repeated neuropsychological evaluations over 6 years showed a mod...Patient EDS presented with an amnesic disorder of insidious onset (4 years) that remained stable and restricted to memory functions over a 10-year course. Repeated neuropsychological evaluations over 6 years showed a moderate-to-severe, stable impairment of long-term memory and of memory for public events, and a milder, stable impairment of autobiographic memory and of short-term memory. Language, perception, praxis and 'frontal' functions were fully preserved. MRI showed atrophy of the right hippocampus, of the right mammillary body and of the sylvian fissure (bilaterally, but more marked on the left). On PET scan, metabolic activity in the mesial temporal structures was significantly reduced on the right and was at lower normal levels on the left. The disorder observed in EDS is similar to that recently reported in other patients. Possible etiologies of the selective amnesia observed in EDS are considered and their implications discussed.