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Biomedical subjects

I Alafuzoff

Publications and source records attributed to I Alafuzoff.

At least 55 records · Page 3Linked to original sources
PubMed1994

A comparison of multiplex and simplex families with Alzheimer's disease/senile dementia of Alzheimer type within a well defined population.

A study was made on 150 clinically demented patients presenting at autopsy at Umeå University Hospital in Sweden. In 90 of the cases dementia was considered to be primary in nature and of these forty six per cent (41 cases), fulfilled both the clinical and histopathological criteria for the diagnosis of Alzheimer's disease/Senile dementia of Alzheimer type (AD/SDAT). The families of these 41 AD/SDAT cases were then studied, and a family history obtained through interviews with multiple family informants and from civil and medical records. Additional diseased family members suffering from progressive dementia (multiplex families) were observed in 12 probands out of 41 (29%). Multiplex families exhibited similar clinical and histopathological characteristics as simplex families containing a single affected individual. The secondary cases in the multiplex families exhibited similar demographic and clinical characteristics as the probands. 39% of the multiplex and 14% of the simplex cases had an early age of onset of the disease, that was under 65 years. The overall prevalence of progressive dementia disorders in the 41 families was 5.9%. The prevalence of a progressive dementia disorder was 11% in the multiplex families (14% for the early onset cases) and 3.5% in the simplex families (2% for the early onset cases). The prevalence of progressive dementia disorder for family members who had passed the mean age of the onset of the disease for their family, was 45% for multiplex and 18% for simplex families. Furthermore the incidence rate for dementia was significantly higher (p < 0.005) in multiplex families (5.5 per 1,000 person years) when compared to simplex families (2.5 per 1,000 person years). No differences could be seen in parental age at birth of the diseased when comparing the two sets of families. However in multiplex families the duration of the disease was significantly (p < 0.025) shorter, in subjects with parental age at birth over 35 years compared to those with a parental age under 35 years. The multiplex families contained significantly (p < 0.025) larger sibships; and showed a significantly lower age of onset for the disease (p < 0.001), and a significantly longer duration of disease (p < 0.05) compared to the simplex families. A significant intra familial correlation of age at disease onset was observed in both sets of the families.

Age of Onset↗
PubMed1994

A retrospective analysis of clinical diagnoses and autopsy findings in 3,042 cases during two different time periods.

The accuracy of clinical diagnoses was determined and compared between the two periods of time 1977 to 1978 and 1987 to 1988 based on the analysis of 3,042 autopsies at Huddinge University Hospital. The discrepancy rates were calculated by counting the number of missed or incompletely diagnosed major diseases and their complications. Moreover, sensitivity, specificity, and clinical accuracy for positive and negative diagnoses also were calculated for all cases of acute myocardial infarction and malignant tumors. The autopsy rate decreased from 80% to 39%. The autopsy successfully addressed the clinical questions in 97% of the cases. The selection of the cases possibly could explain the significant 5% increase in the proportion of clinically undetected major underlying diseases. The discrepancy rate was higher among the older patients. There were no significant changes in the diagnosis of cardiovascular diseases apart from thrombosis of the mesenteric artery, which more than doubled. The proportion of infectious diseases increased significantly from 27% to 32%. The number of cases with clinically missed tuberculosis was twice as high in the 1987 to 1988 period as in the 1977 to 1978 period and there was a marked increase in fungal and viral infections. There was no significant change in the clinical diagnosis of malignant tumors between the two periods. Approximately 15% of all major cancers were not diagnosed before autopsy; half of these tumors were lethal. We conclude that the role of the autopsy has not diminished in spite of advanced diagnostic methods and it remains an effective tool in the assessment of medical care.

Adolescent↗
PubMed1993

Intracranial infusion of purified nerve growth factor to an Alzheimer patient: the first attempt of a possible future treatment strategy.

We report on the clinical outcome of a first case of intracranial infusion of nerve growth factor (NGF) to an Alzheimer patient. The therapeutic attempt is based on animal research showing that NGF stimulates central cholinergic neurons of the type known to be lost during the development of Alzheimer's disease (AD). Furthermore, our own previous clinical experience of infusing NGF to support the survival of intracranially transplanted adrenal chromaffin cells to Parkinsonian patients indicate this approach to be technically possible and safe and clinically of significant potential. Our first case was a 69-year-old woman, with symptoms of dementia since 8 years. Intraventricular infusion of 6.6 mg NGF over three months resulted in a marked transient increase in uptake and binding of [11C]nicotine in frontal and temporal cortex and a persistent increase in cortical blood flow as measured by PET as well as progressive decreases of slow wave EEG activity. After one month of NGF infusion, tests of verbal episodic memory were improved whereas other cognitive tests were not. No adverse effects of the NGF infusion were found. The results of this single case indicate that NGF may counteract cholinergic deficits in AD, and suggest that further clinical trials of NGF infusion in AD are warranted.

Aged↗
PubMed1993

Coupling of muscarinic receptors to GTP proteins in postmortem human brain--alterations in Alzheimer's disease.

The coupling of muscarinic agonist receptors to guanine nucleotide-binding (G) proteins was investigated in the frontal, temporal cortices and thalamus of control and Alzheimer brains by using carbachol in competition experiments with [3H]QNB. In the presence of GppNHp, the carbachol/[3H]QNB competition binding data showed a 6-fold increase in the high-affinity muscarinic agonist coefficient (Ki high) in the thalami of control brains and a significantly increased proportion of low-affinity agonist binding sites (Bmax low) in the temporal cortices of control brains, while no significant effect of GppNHp was observed in Alzheimer brains. The results suggest a disturbance of the muscarinic receptor-G protein coupling in Alzheimer's disease.

Aged↗
PubMed1993

Clinical diagnostic accuracy audited by autopsy in a university hospital in two eras.

A retrospective analysis of 3042 autopsies was carried out to determine and compare the discrepancy rates between clinical and autopsy diagnoses as well as the sensitivity and specificity of clinical diagnostics in 10 diseases in 1977/78 and 1987/88. The autopsy rate decreased from 80% to 39%, which might explain the increased discrepancy rate from 22% to 27% regarding the diagnoses of major, principal diseases. The accuracy of clinical diagnostics seemed to improve during the period for some of the diseases (pulmonary embolism, peptic ulcer, infectious carditis, peritonitis), while it worsened for others (acute myocardial infarction, thrombosis of the mesenteric artery, ruptured aortic aneurysm, tuberculosis) or remained unchanged (cirrhosis of the liver, malignant tumours regarded as a whole group). The findings underline the importance of autopsies and their cumulative studies in assessing the accuracy and providing data for the determination of necessary fallibility of clinical diagnostics.

Adolescent↗
PubMed1993

The selection for post-mortem examination: a retrospective analysis of 74 deceased surgical cases.

The factors which could influence the selection of cases for post-mortem examination were analysed during a 6-month period. The variables studied included the age and sex of the patients, the length of terminal hospitalization, the principal disease, the certainty of the clinical diagnostics and the extent of the clinical investigation. Both clinical and autopsy records were reviewed. Seventy-four patients died at the Department of Surgery during this period of whom 50 (68% autopsy rate) were autopsied. The autopsy rate was influenced by (a) the length of the terminal hospitalization, (b) the diagnosis of the principal disease and, to a certain degree, (c) the extent of the clinical investigation. Thus, patients who were hospitalized for a shorter period, had no clinically diagnosed malignant tumours and were not investigated with more sophisticated methods were more frequently autopsied. The discrepancy rate between principal clinical and post-mortem diagnoses was 28% and was not influenced by the use of modern investigative methods.

Aged↗
PubMed1993

How to run a brain bank: potentials and pitfalls in the use of human post-mortem brain material in research.

Brain banks for neurological diseases serve as a link between the clinician, the neuropathologist and the basic scientist who require brain tissue samples from patients who have undergone a thorough clinical investigation and whose brains have been subjected to detailed neuropathological analysis. In order to provide research groups with post-mortem brain tissue from patients who show clinical signs of dementia such as Alzheimer's disease (AD), senile dementia of Alzheimer type (SDAT), vascular dementia including multi-infarct dementia (MID) and mixed dementia, a brain bank was established at Huddinge University Hospital at the end of 1988. The brain bank provides either rapidly or slowly frozen tissue samples, tissue samples fixed in formalin (short/long fixation time), cerebrospinal fluid (CSF), and blood samples. Average postmortem times are from 3-47 hours. The information available on the cases includes the clinical diagnosis, the premortem clinical investigation with behavioral observations, psychometric and neuropsychological test data, premortem medication, cause of death, agonal state, pH in brain and CSF, and the general anatomic and neuropathologic assessments leading to the final diagnosis.

Autopsy↗
PubMed1992

Characterization of muscarinic receptor subtypes in Alzheimer and control brain cortices by selective muscarinic antagonists.

Subtypes of muscarinic receptors were characterized in the frontal cortices of control and Alzheimer brains, with labelled quinuclidinyl benzilate [3H]QNB and the unlabelled muscarinic antagonists pirenzepine, AF-DX 116, hexahydro-sila-diphenidol (HHSiD), para-fluoro-hexahydro-sila-diphenidol (p-F-HHSiD) and himbacine. High and low affinity sites were observed for both pirenzepine and AF-DX 116 in human control frontal cortices. The majority (76%) of the pirenzepine binding sites showed high affinity to the muscarinic receptors (M1), while the rest of the binding sites had an affinity that was 40 times less. AF-DX 116 displayed two sets of binding sites where the high affinity AF-DX 116 (M2) sites constituted 27%, while the low affinity AF-DX 116 (non-M2 site) was 73%. A single class of binding sites was observed for HHSiD, p-F-HHSiD and himbacine in human frontal cortices. HHSiD showed an affinity in the frontal cortices that was comparable to that of the pirenzepine high affinity binding (M1) sites. The affinity of p-F-HHSiD was three times lower than that of HHSiD but similar to himbacine. A significant increase in the affinity (+ 40%) as well as in the Bmax (+ 99%) value was observed for the pirenzepine high affinity binding sites (M1) in the frontal cortices of Alzheimer brains compared to controls. Similarly, a significant increase was observed in the Bmax value (+ 60%) for the AF-DX 116 low affinity binding sites (non-M2), while no change was found for the high affinity binding sites (M2).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Nicotinic and muscarinic subtypes in the human brain: changes with aging and dementia.

Different effects of normal aging on muscarinic and nicotinic receptor subtypes were observed in postmortem brain tissue from different regions of the human brain. A significant decrease in M1 and M2 receptors was found in cerebral cortex, while the M1 and especially the M2 receptors increased with age in the thalamus. A similar pattern of changes was also observed when using (-)3H-nicotine as ligand for nicotinic receptors in the cortex and thalamus. No significant changes in nicotinic receptor binding were observed with age in the cortex or thalamus when using 3H-acetylcholine as ligand. Nicotinic and muscarinic receptors in the brain are not equally affected in dementia disorders. A marked loss of high affinity nicotinic receptors was observed in cortical tissue from patients with Alzheimer's disease and with multi-infarct dementia (MID). The muscarinic receptors were (both M1 and M2) increased in Alzheimer cortical tissue while they were decreased in MID.

Adolescent↗
PubMed1992

Neurotransmitter-mediated inhibition of post-mortem human brain adenylyl cyclase.

The effects of a range of neurotransmitter agonists showing selectivity for receptor types inhibitorily coupled to adenylyl cyclase were compared in membrane preparations of hippocampus, frontal cortex and caudate nucleus/striatum from previously frozen post-mortem human and rat brain. Agonists were tested against basal and forskolin stimulated activities, forskolin being a potent activator of the catalytic sub-unit of the enzyme. Of those agonists tested, only somatostatin (100 microM) and neuropeptide Y (10 microM) gave consistent inhibitions of basal and forskolin stimulated enzyme activities in all three regions of both human and rat brain. Somatostatin-mediated inhibition of human brain adenylyl cyclase was reduced in the absence of GTP and in the presence of the guanine nucleotide partial agonist, guanosine 5'-O-thiodiposphate, consistent with a G-protein-linked receptor. No such GTP-dependence was found for the neuropeptide Y-mediated adenylyl cyclase inhibition. GTP-dependent somatostatin mediated inhibitions of human brain adenylyl cyclase activity were of highest magnitude in the thalamus, intermediate magnitude in the hippocampus and caudate nucleus and lowest magnitude in the frontal cortex. It is concluded that of a range of neurotransmitter receptor agonists tested, only somatostatin gives robust, GTP-dependent responses that are reproducible enough to be used with post-mortem tissue for the comparison of receptor function in human brain disorders.

Adenylyl Cyclase Inhibitors↗
PubMed1992

Nerve growth factor affects 11C-nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patient (case report).

Based on animal research suggesting that nerve growth factor (NGF) can stimulate central cholinergic neurons, the known losses of cholinergic innervation of the cortices in Alzheimer's disease (AD), and our experience of infusing NGF to support adrenal grafts in parkinsonian patients, we have initiated clinical trials of NGF infusions into the brain of patients with AD. Here we report a follow-up of our first case, a 69-year-old woman, with symptoms of dementia since 8 years. Intraventricular infusion of 6.6 mg NGF during three months resulted in a marked transient increase in uptake and binding of 11C-nicotine in frontal and temporal cortex and a persistent increase in cortical blood flow as measured by PET as well as progressive decreases of slow wave EEG activity. After one month of NGF, tests of verbal episodic memory were improved whereas other cognitive tests were not. No adverse effects could be ascribed to the NGF infusion. Taken together, the results of this case study indicate that NGF may counteract cholinergic deficits in AD, and suggest that further clinical trials of NGF infusion in AD are warranted.

Aged↗
PubMed1992

Brain gamma-aminobutyrate aminotransferase (GABA-T) and monoamine oxidase (MAO) in patients with Alzheimer's disease.

Activities of Gamma-aminobutyrate aminotransferase (GABA-T) and Monoamine oxidase (MAO)-A and -B were estimated in postmortem brains from 6 control subjects without psychiatric or neurologic disorders and 8 histopathologically verified cases of patients with Alzheimer's disease and senile dementia of Alzheimer type (AD/SDAT). The enzyme activities were examined in four cortical brain regions, three nuclei in the basal ganglia, thalamus and white matter. GABA-T activities in the cortical regions (frontal, parietal, occipital and temporal cortices) and nucleus caudatus were significantly lowered in the AD/SDAT patients. The MAO-A activities were significantly increased in the occipital cortex, caudate nucleus, thalamus and white matter in the AD/SDAT patients. No significant differences were found in the other regions (frontal cortex, parietal cortex, temporal cortex, putamen and globus pallidus). The MAO-B activities in three cortical regions (frontal, parietal and occipital cortices), thalamus and white matter were significantly increased in the AD/SDAT patients, whereas no difference was apparent in the other regions. The changed activities could not be correlated with age or postmortem time. The present results are the first describing decreased GABA-T activities as well as increased MAO-A activities in brain from patients with AD/SDAT, while the results with MAO-B support previous findings. A possible connection was found between the order of magnitude of the changes in enzyme activities and the severity of the disease.

4-Aminobutyrate Transaminase↗
PubMed1992

Lipid composition in different regions of the brain in Alzheimer's disease/senile dementia of Alzheimer's type.

The lipid compositions of 10 different brain regions from patients affected by Alzheimer's disease/senile dementia of Alzheimer's type were analyzed. The total phospholipid amount decreased somewhat in nucleus caudatus and in white matter. The cortical areas that are morphologically affected by Alzheimer's disease, i.e., frontal and temporal cortex and the hippocampus, showed elevated contents of lipid solvent-extractable phosphatidylinositol. Sphingomyelin content was decreased in regions rich in myelin. There was a 20-50% decrease in dolichol amount in all investigated parts of the brain, but no change was seen in the polyisoprenoid pattern. Levels of alpha-unsaturated polyprenes were decreased in Alzheimer brains. Dolichyl-phosphate content increased in most regions, up to 100%. In both control and Alzheimer tissue almost all of the dolichyl-phosphate was covalently bound, apparently through glycosylation. Cholesterol amounts were highly variable but mostly unchanged, whereas ubiquinone concentrations increased by 30-100% in most regions in brains affected by Alzheimer's disease. These results demonstrate that both phospholipids and neutral lipids are modified in brains affected by Alzheimer's disease/senile dementia of Alzheimer's type.

Aged↗
PubMed1992

Adenylyl cyclase activity in postmortem human brain: evidence of altered G protein mediation in Alzheimer's disease.

The effects of agonal status, postmortem delay, and age on human brain adenylyl cyclase activity were determined in membrane preparations of frontal cortex from a series of 18 nondemented subjects who had died with no history of neurological or psychiatric disease. Basal and guanosine 5'-O-(3-thiotriphosphate)-, aluminum fluoride-, and forskolin-stimulated enzyme activities were not significantly reduced over an interval from death to postmortem of between 3 and 37 h and were also not significantly different between individuals dying with a long terminal phase of an illness and those dying suddenly. Basal and aluminum fluoride-stimulated enzyme activities showed a negative correlation with increasing age of the individual. In subsequent experiments, basal and guanosine 5'-O-(3-thiotriphosphate)-, aluminum fluoride-, and forskolin-stimulated enzyme activities were compared in five brain regions from a series of eight Alzheimer's disease and seven matched nondemented control subjects. No significant differences were observed between the groups for either basal activity or activities in response to forskolin stimulation of the catalytic subunit of the enzyme. In contrast, enzyme activities in response to stimulation with guanosine 5'-O-(3-thiotriphosphate) and aluminum fluoride were significantly reduced in preparations of neocortex and cerebellum from the Alzheimer's disease cases compared with the nondemented controls. Lower guanosine 5'-O-(3-thiotriphosphate)-, but not aluminum fluoride-, stimulated activity was also observed in preparations of frontal cortex from a group of four disease controls compared with nondemented control values. The disease control group, which contained Parkinson's disease and progressive supranuclear palsy patients, showed increased forskolin-stimulated activity compared with both the nondemented control and the Alzheimer's disease groups. These findings indicate a widespread impairment of G protein-stimulated adenylyl cyclase activity in Alzheimer's disease brain, which occurs in the absence of altered enzyme catalytic activity and which is unlikely to be the result of non-disease-related factors associated with the nature of terminal illness of individuals.

Adenylyl Cyclases↗
PubMed1991

Preservation of 5-hydroxytryptamine1A receptor-G protein interactions in the cerebral cortex of patients with Alzheimer's disease.

The coupling of 5-hydroxytryptamine1A (5-HT1A) receptors to guanine nucleotide binding (G) proteins was investigated in membranes prepared from frontal and parietal cortices of control and Alzheimer's disease brains by characterising the effect of guanosine 5'-[beta gamma-imido]diphosphate (Gpp[NH]p) on [3H]8-hydroxy-2-(di-n-propylamino)-tetralin ([3H]8-OH-DPAT) binding parameters. In the absence of guanine nucleotides, [3H]8-OH-DPAT bound to a single high affinity binding site in all membrane types. The number of [3H]8-OH-DPAT binding sites was significantly decreased in the parietal cortex of Alzheimer's disease samples compared with controls, whereas in the frontal cortex the number of binding sites remained unchanged. Gpp[NH]p reduced the [3H]8-OH-DPAT binding affinity and the number of binding sites to the same degree in both regions in control and Alzheimer's disease cases. [3H]8-OH-DPAT binding was inhibited in a concentration dependent manner with an IC50 value of approximately 1 microM in all cases. These results suggest that the 5-HT1A receptor-G protein complex is functionally intact in these regions in Alzheimer's disease brain.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Coupling of human brain cerebral cortical alpha 2-adrenoceptors to GTP-binding proteins in Alzheimer's disease.

The coupling of alpha 2-adrenoceptors to guanine nucleotide binding G-proteins was investigated in cerebral cortical membranes from control and Alzheimer's disease brain by characterizing the effects of MnCl2 and Gpp[NH]p on [3H]clonidine binding. The manganese induced elevation of [3H]clonidine binding was apparent in both control and Alzheimer's disease samples and the effect showed no significant difference between the two groups in the frontal cortex. However, the MnCl2 concentration dependence curves for control and Alzheimer's disease samples were significantly different from one another in the temporal cortex, whereas the pattern of stimulation by MnCl2 remained the same. The guanine nucleotide analogue, Gpp[NH]p inhibited [3H]clonidine binding in a concentration-dependent manner, the profiles of inhibition showing no significant differences between control and Alzheimer's disease samples. Analysis of the effect of Gpp[NH]p on [3H]clonidine saturation binding curves showed no significant differences between control and Alzheimer's disease samples in either frontal (Kd = 9.68 +/- 1.38, 9.1 +/- 2.6 nM; Bmax = 40.23 +/- 4.33, 44.3 +/- 9.4 fmol/mg, control and Alzheimer's disease values, respectively), or temporal (Kd = 11.61 +/- 4.04, 5.38 +/- 2.5 nM; Bmax = 52.0 +/- 14.0, 31.07 +/- 8.00 fmol/mg control and Alzheimer's disease values, respectively) cortices.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Alzheimer beta/A4 amyloid precursor protein in human brain: aging-associated increases in holoprotein and in a proteolytic fragment.

Alzheimer beta/A4 amyloid precursor protein (APP) has been suggested to play a central role in the pathogenesis of Alzheimer disease. We have measured the content of different species of APP holoprotein and carboxyl-terminal fragments in human brains from young individuals, nondemented aged individuals, and aged individuals with Alzheimer disease. By using an antibody directed against the cytoplasmic domain of APP, five species were resolved. Three of these, of molecular masses 106, 113, and 133 kDa, represent presumptive immature and mature isoforms of APP holoprotein. Two smaller proteins, of molecular masses 15 and 19 kDa, represent presumptive proteolytic carboxyl-terminal fragments of APP. The 133-, 113-, 106-, and 15-kDa species were found in both grey and white matter, whereas the 19-kDa species was found only in grey matter. Total APP immunoreactivity (sum of all five species) and the levels of the 113-, 106-, and 15-kDa species were not significantly different in brain samples from young individuals, nondemented aged individuals, and aged individuals with Alzheimer disease. In contrast, the levels of the 133- and 19-kDa species increased 2- to 3-fold with age. A correlation was observed between the levels of the 133- and 19-kDa species, suggesting a possible precursor-product relationship. The size of the 19-kDa fragment indicated that it might have an intact beta/A4 domain and therefore be amyloidogenic. The age-dependent increase either in a mature APP isoform and/or in a putative amyloidogenic fragment could explain why Alzheimer disease is associated with advanced age.

Adolescent↗