- Email: [email protected]
Cortisol secretion and ad progression
122A
Dementia
BIOL PSYCH'-,TRY 1991;29:43A- 185A
168 PROTON (IH) NMR STUDIES OF AMINO ACIDS IN ALZHEIMER'S DISEASE BRAIN W.E. Klunk, M.D., Ph.D., K. Panchalingam, Ph.D., R.J. McClure, Ph.D., J.W. Pettegrew, M.D. Western Psychiatric Institute and Clinic, Pittsburgh, PA 15213. Previous .~tp NMR studies have shown alterations in membrane phosphulipid and energy metabolism in Alzheimer's disease (AD) brain. Since only phosphorus-containing metabolites can be studied with this method, we have begun to examine water-soluble (perchloric acid) and lipid-soluble (Folch) extracts by ~H NMR spectroscopy. ~H NMR spectroscopy has the advantage of being able to assess many more metabolites since .,dmost all compounds of interest will contain some protons. Extracts of eight brains with autopsy° verified AD and four age-matched control brains have been studied. The IH NMR resonances of these extracts have been largely identified by one- and two-dimensional IH NMR spectroscopy and pH conditions have been optimized for separating resonances of interest. These include the putative neuronal marker, Nacetyl-aspartate (NAA), glutamate, glutamine, GABA, taurine, and aspartate. NAA decreases in AD as the numbers of senile plaques increase, supporting a role for NAA as an in vitro and in vivo neuronal marker. Glutamate and glutamine increase with the number of senile plaques, suggesting that the relative amount of excitatory neurotransmitter per neuron ~reases as AD progresses. These relative changes may be more important than absolute changes and may play a role in neuronal death in AD. These in vitro studies will lay a foundation for future studies of AD by in vivo ~H NMR spectroscopy.
169 A STUDY ON THE MASS LESION EFFECT OF SENILE PLAQUES Manuel F. Casanova, M.D., Kunimasa Arima, M.D., Joel E. Kleinman, M.D., Ph.D. NIMH Neuroscience Center at St. Elizabeths, Washington. D.C. 20032. Ever since the turn of the century multiple studies have suggested that clinical deterioration in Alzheimer's disease (AD) is accompanied by a gradual increase in both the size and n,imbers of senile plaques (SPs). In the present study we investigated whether the "'mass effect" of SPs aifertoi the morphometry of adjacent neurons. For this purpose pyramidal cells from the hippocampus of eight AD patien!~. IO schizophrenic (SC) patients, and five cognitively impaired non-AD non-SC control patients were studied with a computerized image analysis system. Software routines allowed for the calculation of cell shape, area and disarray. An X-Y plotter quantitated the number of SPs and neurofibrillary tangles (NFTs) per corpus ammonis subfield. Our results indicated no significant differences between groups for measurements of neuronal size, disarray or shape. Contrary to previous reports, no evidence of pyramidal cell disarray was noted in schizophrenic patients. Our results suggest that SPs behave as inert structures with no evidence of mass effect on their surrounding neurons.
POSTER SESSION DEMENTIA F r i d a y , M a y 10, 1 : 0 0 - 6 : 0 0 PM
PonchartrainA
170 CORTISOL SECRETION AND AD PROGRESSION Myron F. Weiner, M.D. Southwestern Medical School, 5323 Harry Hines Blvd., Dallas, TX 75235.
Dementia
BIOL PSYCHIATRY 1991:29:43A- |85A
! 23A
We attempied to determine if a relationship exists between cortisol secretion and AD p r o ~ s s i o n . We studied subjects diagnosed as probable AD by NINCDS criteria. Subjects were tested at 0 and 12 ~ s with the Alzheimer's Disease Assessment Scale (ADAS). In addition to determin/ng veno~.~ [CORT| at 1200 hr, an Afternoon Cortisol Test (ACT) (.~ [CORTI of venous samples drawn Q 20 min between I 3 ~ and 1600h) was performed to estimate average 24h [CORTI. As of ! 1/30/90, 8 subjects had completed the study. Their mean age was 7 ! years (range = 59-84); and their mean duration of illness, 3.5 years ( ~ g e !-8). Time 0 ADAS scores (.~ ___ SD = 23.58 _ 8°55) suggested miki to moderate cognitive i m p a i ~ t . There was no relationship between age or duration of illness and time 0 ADAS, ACT, or 1200 or 1300h [CORT]. When the sample of 8 subjects was divided into two groups {SAME/IMPROVED n = 5, ~ A ADAS = - 7.25; WORSE, n = 3, .~ A ADAS = + 7.33), there was no difference in .~ ACT, but higher .~ [CORTI ! 200h (15.15 v 1 i.59 'g/dL) and [CORT1 ! 300h ( 14.08 v ! 0.98 ~.g/dL at time 0 were associated with the WORSE group. [CORTI 1200h and 1300h were lower at 12 months (but ne t. as low as SAME' IMPROVED) than at time 0, suggesting that higher |CORT| is not a simp|e concomitant of v,of~cmng disease, but may predict worse outcome.
171 EFFECTS OF CHRONIC IDAZOXAN ON COGNITIVE
PERFORMANCE Karon Dawkins, M.D., Herbert Weingartner, Ph.D., Husseini Magi, M.D., Fred Grossman, D.O., William Z. Potter, M.D., Ph.D. Section on Clinical Pharmacology, ETB, National Institute of Mental Health, Bethesda, MD 20892. We demonstrated dose-dependent alterations in a variety of biochemical, neuroendocrine, and cognitive ~easures by intravenous alprazolam (IV APZ), including deficits in cognitive tasks. Based on precl~cal evidence suggesting that idazoxan (IDX), an ct, antagonist, enhances memory retrieval, we designed a study to explore interactions of the GABA/NE systems using cognitive performance. Healthy vol~teers were given IV APE (0.2 mg/kg) at baseline and following 17 days of oral IDX ( 120 rag/day). T e s ~ g of effort demanding learning (BuschkeL recall (vigilance), and implicit memory (fragmented pictures) was conducted in four conditions: baseline, after IV APZ, after IDX, and IV APZ on IDX. Preliminary results reveal an attenuation of APZ-induced deficits in the Buschke test. These results suggest either that chronic IDX may enhance effort demanding learning and/or interfere with specific BDZ-induced cognitive deficits, supporting the concept of behaviorally significant interactions of the NE/GABA systems.
172 THYROTROPIN-RELEASING HORMONE EFFECTS ON
MONOAMINES AND COGNITION IN HUMANS S. E. Molchan, M.D., R. A. Martinez, M.D., B. Vitiello, M.D., H. J. Weingartner, Ph.D., and T. Sunderland, M.D. Laboratory. of Clinical Science, NIMH, Bethesda, MD 20892. The brain tripeptide thyrotropin-releasing hormone (TRH) has been shown to facilitate cholinergic neurotransmission, and, as predicted, has been shown to reverse or attenuate the cognitive i m p ~ e n t caused by the central anticholinergic drug scopolamine in human ano animal studies. TRH is also known to stimulate neurotransmitter systems other than the cholinergic, including the noradrenergic and doparmnergic systems. This has led to questions as to whether the ability of TRH to improve cognitive performance in cholinergically compromised systems such as the scopolamine model, septohippocampal-lesioned animals, and Alzheimer's disease are nonspecific, and not due solely to facilitation of the cholinergic system. Indices of cholinergic neurotransmission cannot be measured peripherally, but there are studies showing that peripheral measures of monoamines or monoamine metabolites reflect central levels to some degree. In this study, I2 young normal controls (mean age = 26.9 +_ 7.9 years) were given scopolamine (0.5 mg IV) foIIowed by TRH (0.5 mg/kg IV). Blood samples were taken at baseline and immediately before and after cognitive testing on each study day for measurement of plasma norepinephfine, 3-methoxy-4-hydroxy-phenylglycol (MHPG),
Dementia
BIOL PSYCH'-,TRY 1991;29:43A- 185A
168 PROTON (IH) NMR STUDIES OF AMINO ACIDS IN ALZHEIMER'S DISEASE BRAIN W.E. Klunk, M.D., Ph.D., K. Panchalingam, Ph.D., R.J. McClure, Ph.D., J.W. Pettegrew, M.D. Western Psychiatric Institute and Clinic, Pittsburgh, PA 15213. Previous .~tp NMR studies have shown alterations in membrane phosphulipid and energy metabolism in Alzheimer's disease (AD) brain. Since only phosphorus-containing metabolites can be studied with this method, we have begun to examine water-soluble (perchloric acid) and lipid-soluble (Folch) extracts by ~H NMR spectroscopy. ~H NMR spectroscopy has the advantage of being able to assess many more metabolites since .,dmost all compounds of interest will contain some protons. Extracts of eight brains with autopsy° verified AD and four age-matched control brains have been studied. The IH NMR resonances of these extracts have been largely identified by one- and two-dimensional IH NMR spectroscopy and pH conditions have been optimized for separating resonances of interest. These include the putative neuronal marker, Nacetyl-aspartate (NAA), glutamate, glutamine, GABA, taurine, and aspartate. NAA decreases in AD as the numbers of senile plaques increase, supporting a role for NAA as an in vitro and in vivo neuronal marker. Glutamate and glutamine increase with the number of senile plaques, suggesting that the relative amount of excitatory neurotransmitter per neuron ~reases as AD progresses. These relative changes may be more important than absolute changes and may play a role in neuronal death in AD. These in vitro studies will lay a foundation for future studies of AD by in vivo ~H NMR spectroscopy.
169 A STUDY ON THE MASS LESION EFFECT OF SENILE PLAQUES Manuel F. Casanova, M.D., Kunimasa Arima, M.D., Joel E. Kleinman, M.D., Ph.D. NIMH Neuroscience Center at St. Elizabeths, Washington. D.C. 20032. Ever since the turn of the century multiple studies have suggested that clinical deterioration in Alzheimer's disease (AD) is accompanied by a gradual increase in both the size and n,imbers of senile plaques (SPs). In the present study we investigated whether the "'mass effect" of SPs aifertoi the morphometry of adjacent neurons. For this purpose pyramidal cells from the hippocampus of eight AD patien!~. IO schizophrenic (SC) patients, and five cognitively impaired non-AD non-SC control patients were studied with a computerized image analysis system. Software routines allowed for the calculation of cell shape, area and disarray. An X-Y plotter quantitated the number of SPs and neurofibrillary tangles (NFTs) per corpus ammonis subfield. Our results indicated no significant differences between groups for measurements of neuronal size, disarray or shape. Contrary to previous reports, no evidence of pyramidal cell disarray was noted in schizophrenic patients. Our results suggest that SPs behave as inert structures with no evidence of mass effect on their surrounding neurons.
POSTER SESSION DEMENTIA F r i d a y , M a y 10, 1 : 0 0 - 6 : 0 0 PM
PonchartrainA
170 CORTISOL SECRETION AND AD PROGRESSION Myron F. Weiner, M.D. Southwestern Medical School, 5323 Harry Hines Blvd., Dallas, TX 75235.
Dementia
BIOL PSYCHIATRY 1991:29:43A- |85A
! 23A
We attempied to determine if a relationship exists between cortisol secretion and AD p r o ~ s s i o n . We studied subjects diagnosed as probable AD by NINCDS criteria. Subjects were tested at 0 and 12 ~ s with the Alzheimer's Disease Assessment Scale (ADAS). In addition to determin/ng veno~.~ [CORT| at 1200 hr, an Afternoon Cortisol Test (ACT) (.~ [CORTI of venous samples drawn Q 20 min between I 3 ~ and 1600h) was performed to estimate average 24h [CORTI. As of ! 1/30/90, 8 subjects had completed the study. Their mean age was 7 ! years (range = 59-84); and their mean duration of illness, 3.5 years ( ~ g e !-8). Time 0 ADAS scores (.~ ___ SD = 23.58 _ 8°55) suggested miki to moderate cognitive i m p a i ~ t . There was no relationship between age or duration of illness and time 0 ADAS, ACT, or 1200 or 1300h [CORT]. When the sample of 8 subjects was divided into two groups {SAME/IMPROVED n = 5, ~ A ADAS = - 7.25; WORSE, n = 3, .~ A ADAS = + 7.33), there was no difference in .~ ACT, but higher .~ [CORTI ! 200h (15.15 v 1 i.59 'g/dL) and [CORT1 ! 300h ( 14.08 v ! 0.98 ~.g/dL at time 0 were associated with the WORSE group. [CORTI 1200h and 1300h were lower at 12 months (but ne t. as low as SAME' IMPROVED) than at time 0, suggesting that higher |CORT| is not a simp|e concomitant of v,of~cmng disease, but may predict worse outcome.
171 EFFECTS OF CHRONIC IDAZOXAN ON COGNITIVE
PERFORMANCE Karon Dawkins, M.D., Herbert Weingartner, Ph.D., Husseini Magi, M.D., Fred Grossman, D.O., William Z. Potter, M.D., Ph.D. Section on Clinical Pharmacology, ETB, National Institute of Mental Health, Bethesda, MD 20892. We demonstrated dose-dependent alterations in a variety of biochemical, neuroendocrine, and cognitive ~easures by intravenous alprazolam (IV APZ), including deficits in cognitive tasks. Based on precl~cal evidence suggesting that idazoxan (IDX), an ct, antagonist, enhances memory retrieval, we designed a study to explore interactions of the GABA/NE systems using cognitive performance. Healthy vol~teers were given IV APE (0.2 mg/kg) at baseline and following 17 days of oral IDX ( 120 rag/day). T e s ~ g of effort demanding learning (BuschkeL recall (vigilance), and implicit memory (fragmented pictures) was conducted in four conditions: baseline, after IV APZ, after IDX, and IV APZ on IDX. Preliminary results reveal an attenuation of APZ-induced deficits in the Buschke test. These results suggest either that chronic IDX may enhance effort demanding learning and/or interfere with specific BDZ-induced cognitive deficits, supporting the concept of behaviorally significant interactions of the NE/GABA systems.
172 THYROTROPIN-RELEASING HORMONE EFFECTS ON
MONOAMINES AND COGNITION IN HUMANS S. E. Molchan, M.D., R. A. Martinez, M.D., B. Vitiello, M.D., H. J. Weingartner, Ph.D., and T. Sunderland, M.D. Laboratory. of Clinical Science, NIMH, Bethesda, MD 20892. The brain tripeptide thyrotropin-releasing hormone (TRH) has been shown to facilitate cholinergic neurotransmission, and, as predicted, has been shown to reverse or attenuate the cognitive i m p ~ e n t caused by the central anticholinergic drug scopolamine in human ano animal studies. TRH is also known to stimulate neurotransmitter systems other than the cholinergic, including the noradrenergic and doparmnergic systems. This has led to questions as to whether the ability of TRH to improve cognitive performance in cholinergically compromised systems such as the scopolamine model, septohippocampal-lesioned animals, and Alzheimer's disease are nonspecific, and not due solely to facilitation of the cholinergic system. Indices of cholinergic neurotransmission cannot be measured peripherally, but there are studies showing that peripheral measures of monoamines or monoamine metabolites reflect central levels to some degree. In this study, I2 young normal controls (mean age = 26.9 +_ 7.9 years) were given scopolamine (0.5 mg IV) foIIowed by TRH (0.5 mg/kg IV). Blood samples were taken at baseline and immediately before and after cognitive testing on each study day for measurement of plasma norepinephfine, 3-methoxy-4-hydroxy-phenylglycol (MHPG),