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Hypoxia and hyperventilation as models for cognitive deficiencies
0-21 Receptors and Second Messengers protected PC 12 cells against A,B-induced toxicity. Antioxidants reversed A,B-induced toxicity and A,B-induced arachidonic release. Protein kinase C activators (phorbol esther and l-oleyl-Zsacetyl-sn-glycercl), muscarinic receptor agonist carbachol and acethylcholinesterase inhibitor, tacrine attenuated A,B-induced toxicity in a dose response manner.
I0-20-81
Prospective Study of the Effect of APOE Genotype on Cognitive Performance in the Very Old
L. Altstiel 2 , R. Mohs I, D. Marin I, L. Lebow 3, X-P Yang I, M. Keddache I, D. Greenberg I. I Department of Psychiatry, The Mount Sinai School ofMedicine, NY, NY, USA.; 2 Lilly Research Laboratories, Indianapolis IN, USA.; 3 Jewish Home and Hospital for the Aged, NY, NY, USA. We have examined the relationships between APOE genotype, cognitive performance, and measures of behavior for over 1000 very old (mean age 85) individuals who reside in a nursing home (Jewish Home and Hospital for the Aged, New York, NY). The patients are unable to care for themselves due to illness, unsuitable home environment, or cognitive and/or behavioral problems. Most of the patients have multiple medical diagnoses (mean ICD9 diagnoses = 6) which preclude a NINCDS/ADRDA research diagnosis of Alzheimer's disease (AD). Our results demonstrate a strong correlation between APOE-E4 allele frequency and diminished cognitive performance as measured by the Mini-Mental Status Examination (MMSE). The relative risk of diminished cognitive performance is significantly influenced by APOE-E4 gene dosage. In these patients, APOE genotype was the strongest predictor of cognitive performance. These studies were prospective and there were no exclusionary criteria. In this population, APOE-E4 gene dosage did not increase the relative risk of cerebrovascular disease. However, the presence of an APOEE4 allele increased the relative risk of dementia among subjects with cerebrovascular disease. We have also examined the role of APOE genotype on the rate of cognitive decline in these patients. Our results suggest that subjects with an APOE-E4 allele have substantially lower MMSE scores at six month follow up than do those with no APOE-E4 alleles.
I0-20-91
Cognitive Process Produces Inactivated Serotonin
K. Kishitani. Department of Psychiatry, Yuki Hospital, Kanazawa, Japan i) a sentence statement of the study's specific objectives; Cognition or cognitive impairment have been concealed by anxiety or dementia which is often observed in ceruleal degeneration. ii) a brief statement of method; Cognitive process is complicated interaction of neurotransmitters and cannot be explained by one dimension. From a multi-associative consideration this would be a simultaneous and longitudinal feedback mechanism which regulates neurotransmission. iii) a summary of the results obtained; Why does the cognitive process produce inactivated serotonin? From the viewpoint of serotonin synthesis and synaptic transport, the cognitive process sends many impulses to the neuron increasing turnover of serotonin at the same time reuptaking serotonin and degrading serotonin by MAO. iv) a statement of the conclusion: In synaptic clefts there would be a small serotonin concentration and deficiency.
I0-20-10
1
HypOXia andHyperventilation as Models for Cognitive Deficiencies
E. Hogervorst, W. Riedel, M. Van Boxtel, P. Visser, P. Hameleers, S. Sey, J. Jolles. Dept. of Psychiatry and Neuropsychology, Maastricht University, The Netherlands In the present study we investigated if: normobaric hypoxia when compared to normoxia and baseline, and hypocapnic hyperventilation when compared to normocapnic hyperventilation and baseline, induce cognitive dysfunctions in a similar manner. These hypotheses were studied in 20 healthy volunteers, according to a cross-over, single-blind, orderbalanced design. Furthermore the influence of caffeine 230 mg according to a parallel groups, double-blind, placebo controlled design was studied.
145 The subjects inhaled hypoxic air (13.6% O2 , comparable to 3500 m altitude; Sa02 ± 85-87%) and normoxic air respectively, through a mask during 40 minutes. On a separate occasion, the subjects hyperventilated (end tidal C02 < 2.5 kPa) without (hypocapnia) or with additional CO 2 (normocapnia). In the latter condition they hyperventilated until normal end tidal levels were attained (± 5 kPa). Baseline measurements were carried out without the mask. Assessments included free recall and recognition memory measures of Rey's 15-word list, as well as speed and accuracy measures of search in short- term memory and choice RT. Heart rate was significantly elevated both during hypoxia and normoxia conditions relative to baseline. Delayed free recall of previously learned words was significantly deteriorated in caffeine treated subjects only, both under the influence of hypoxia and normoxia, and under the influence of hypocapnic- and normocapnic hyperventilation, when compared to their respective baseline performance. This surprising result seems to show that caffeine may exert detrimental effects on memory when subjects are physiologically challenged, i.e. aroused, in an unspecific manner.
I0·21 I Receptors and Second Messengers I 0-21-1 I Localization and Quantification of Serotonin-1 a, MRandGRmRNA in Human Hippocampus I.E LOpez, K.Y. Little, D.P. MacLaughlin, SJ. Watson. Mental Health Research Institute, University of Michigan, Ann Arbor, MJ The present study examined the distribution and quantification of serotonin (5-HT) la receptor mRNA, mineralocorticoid (MR) and glucocortiocid (GR) mRNA in the hippocampus of suicide victims using in situ hybridization with specific cRNA probes. The highest concentration of 5-HTla mRNA expression was observed in the granular layer ofthe dentate gyrus. A positive signal was also detected in the pyramidal cell layer of CA I, CA2 and CA3 subfields, although the mRNA levels were lower than in the dentate gyrus. No 5HTla mRNA was detected in the stratum oriens, radiatum or moleculare. We compared 5-HT I A mRNA levels in the hippocampus of suicide victims with a history of mood disorders and controls. We also studied the gene expression of glucocorticoid (GR) and mineralocorticoid (MR) receptors in the same brain area. GR and MR are believed to control HPA activity and we found them to be co-localized with 5-HT I A in the human hippocampus. Suicides and controls (n =6 per group) were matched for age and postmortem time. In addition, suicide victims were not taking chronic antidepressant medications at the time of death. To control for postmortem mRNA loss, receptor mRNA values were corrected by using p IB 15 mRNA. We found that suicide victims had lower 5-HT I A mRNA levels in all hippocampal subfields (CAl, CA2, CA3 and Dentate Gyrus). The decreases fluctuated from 31 % to 48% depending on the region, but they achieved significance only in the Dentate (p = 0.034). Suicide victims also showed a significant decrease in MR in the CA3 region (37%, p = 0.01). These changes in gene expression showed some specificity, since no significant changes were observed in the gene expression of GR. Although these results are consistent with the animal literature, they should be interpreted with caution due to the small number of subjects. We are currently increasing the number of subjects per group, and these results will be reported. The implications of our results for the pathophysiology of mood disorders will be discussed. Supported in part by a grant from the American Suicide Foundation and MHOII64-0IA2
10-21-21 Long-Term Changes Induced by Anti-Depressant Drugs in the Presynaptic Release Machinery M. Popoli, C. Vocaturo, J. Perez I, L. Buffa, G. Racagni. Center of Neuropharmacology, Dept. ofNeuropsychiatry, University of Milan, Italy; lIst. Scientifico HSR, Dept. of Neuropsychiatry, University of Milan, Italy A new component in the mechanism of action of antidepressants was found at presynaptic level. Long-term treatment with selective 5-HT or
I0-20-81
Prospective Study of the Effect of APOE Genotype on Cognitive Performance in the Very Old
L. Altstiel 2 , R. Mohs I, D. Marin I, L. Lebow 3, X-P Yang I, M. Keddache I, D. Greenberg I. I Department of Psychiatry, The Mount Sinai School ofMedicine, NY, NY, USA.; 2 Lilly Research Laboratories, Indianapolis IN, USA.; 3 Jewish Home and Hospital for the Aged, NY, NY, USA. We have examined the relationships between APOE genotype, cognitive performance, and measures of behavior for over 1000 very old (mean age 85) individuals who reside in a nursing home (Jewish Home and Hospital for the Aged, New York, NY). The patients are unable to care for themselves due to illness, unsuitable home environment, or cognitive and/or behavioral problems. Most of the patients have multiple medical diagnoses (mean ICD9 diagnoses = 6) which preclude a NINCDS/ADRDA research diagnosis of Alzheimer's disease (AD). Our results demonstrate a strong correlation between APOE-E4 allele frequency and diminished cognitive performance as measured by the Mini-Mental Status Examination (MMSE). The relative risk of diminished cognitive performance is significantly influenced by APOE-E4 gene dosage. In these patients, APOE genotype was the strongest predictor of cognitive performance. These studies were prospective and there were no exclusionary criteria. In this population, APOE-E4 gene dosage did not increase the relative risk of cerebrovascular disease. However, the presence of an APOEE4 allele increased the relative risk of dementia among subjects with cerebrovascular disease. We have also examined the role of APOE genotype on the rate of cognitive decline in these patients. Our results suggest that subjects with an APOE-E4 allele have substantially lower MMSE scores at six month follow up than do those with no APOE-E4 alleles.
I0-20-91
Cognitive Process Produces Inactivated Serotonin
K. Kishitani. Department of Psychiatry, Yuki Hospital, Kanazawa, Japan i) a sentence statement of the study's specific objectives; Cognition or cognitive impairment have been concealed by anxiety or dementia which is often observed in ceruleal degeneration. ii) a brief statement of method; Cognitive process is complicated interaction of neurotransmitters and cannot be explained by one dimension. From a multi-associative consideration this would be a simultaneous and longitudinal feedback mechanism which regulates neurotransmission. iii) a summary of the results obtained; Why does the cognitive process produce inactivated serotonin? From the viewpoint of serotonin synthesis and synaptic transport, the cognitive process sends many impulses to the neuron increasing turnover of serotonin at the same time reuptaking serotonin and degrading serotonin by MAO. iv) a statement of the conclusion: In synaptic clefts there would be a small serotonin concentration and deficiency.
I0-20-10
1
HypOXia andHyperventilation as Models for Cognitive Deficiencies
E. Hogervorst, W. Riedel, M. Van Boxtel, P. Visser, P. Hameleers, S. Sey, J. Jolles. Dept. of Psychiatry and Neuropsychology, Maastricht University, The Netherlands In the present study we investigated if: normobaric hypoxia when compared to normoxia and baseline, and hypocapnic hyperventilation when compared to normocapnic hyperventilation and baseline, induce cognitive dysfunctions in a similar manner. These hypotheses were studied in 20 healthy volunteers, according to a cross-over, single-blind, orderbalanced design. Furthermore the influence of caffeine 230 mg according to a parallel groups, double-blind, placebo controlled design was studied.
145 The subjects inhaled hypoxic air (13.6% O2 , comparable to 3500 m altitude; Sa02 ± 85-87%) and normoxic air respectively, through a mask during 40 minutes. On a separate occasion, the subjects hyperventilated (end tidal C02 < 2.5 kPa) without (hypocapnia) or with additional CO 2 (normocapnia). In the latter condition they hyperventilated until normal end tidal levels were attained (± 5 kPa). Baseline measurements were carried out without the mask. Assessments included free recall and recognition memory measures of Rey's 15-word list, as well as speed and accuracy measures of search in short- term memory and choice RT. Heart rate was significantly elevated both during hypoxia and normoxia conditions relative to baseline. Delayed free recall of previously learned words was significantly deteriorated in caffeine treated subjects only, both under the influence of hypoxia and normoxia, and under the influence of hypocapnic- and normocapnic hyperventilation, when compared to their respective baseline performance. This surprising result seems to show that caffeine may exert detrimental effects on memory when subjects are physiologically challenged, i.e. aroused, in an unspecific manner.
I0·21 I Receptors and Second Messengers I 0-21-1 I Localization and Quantification of Serotonin-1 a, MRandGRmRNA in Human Hippocampus I.E LOpez, K.Y. Little, D.P. MacLaughlin, SJ. Watson. Mental Health Research Institute, University of Michigan, Ann Arbor, MJ The present study examined the distribution and quantification of serotonin (5-HT) la receptor mRNA, mineralocorticoid (MR) and glucocortiocid (GR) mRNA in the hippocampus of suicide victims using in situ hybridization with specific cRNA probes. The highest concentration of 5-HTla mRNA expression was observed in the granular layer ofthe dentate gyrus. A positive signal was also detected in the pyramidal cell layer of CA I, CA2 and CA3 subfields, although the mRNA levels were lower than in the dentate gyrus. No 5HTla mRNA was detected in the stratum oriens, radiatum or moleculare. We compared 5-HT I A mRNA levels in the hippocampus of suicide victims with a history of mood disorders and controls. We also studied the gene expression of glucocorticoid (GR) and mineralocorticoid (MR) receptors in the same brain area. GR and MR are believed to control HPA activity and we found them to be co-localized with 5-HT I A in the human hippocampus. Suicides and controls (n =6 per group) were matched for age and postmortem time. In addition, suicide victims were not taking chronic antidepressant medications at the time of death. To control for postmortem mRNA loss, receptor mRNA values were corrected by using p IB 15 mRNA. We found that suicide victims had lower 5-HT I A mRNA levels in all hippocampal subfields (CAl, CA2, CA3 and Dentate Gyrus). The decreases fluctuated from 31 % to 48% depending on the region, but they achieved significance only in the Dentate (p = 0.034). Suicide victims also showed a significant decrease in MR in the CA3 region (37%, p = 0.01). These changes in gene expression showed some specificity, since no significant changes were observed in the gene expression of GR. Although these results are consistent with the animal literature, they should be interpreted with caution due to the small number of subjects. We are currently increasing the number of subjects per group, and these results will be reported. The implications of our results for the pathophysiology of mood disorders will be discussed. Supported in part by a grant from the American Suicide Foundation and MHOII64-0IA2
10-21-21 Long-Term Changes Induced by Anti-Depressant Drugs in the Presynaptic Release Machinery M. Popoli, C. Vocaturo, J. Perez I, L. Buffa, G. Racagni. Center of Neuropharmacology, Dept. ofNeuropsychiatry, University of Milan, Italy; lIst. Scientifico HSR, Dept. of Neuropsychiatry, University of Milan, Italy A new component in the mechanism of action of antidepressants was found at presynaptic level. Long-term treatment with selective 5-HT or