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Subtype-specific muscarinic cholinergic therapies in Alzheimer's disease
124S
Subtype specific cholinergic therapies
BIOL. PSYCHIATRY 1997;42:15-2975
brane phospholipid turnover is certainly consistent with neuronal necrosis or with neuronal atrophy (where there Is active loss of dendritic arbors and axons). However, selective neuronal loss without increased membrane tumover Is consistent with a process like neuronal apoptosis. Preliminary in-vivo ' H MRS studies In schizophrenia have revealed discrepant NAA and choline findings in the frontal lobes, temporal lobes. and hippocampi. Furthermore. recent pilot studies of both drug naive and medication with• drawn versus medicated schizophrenics have noted significant bilateral NAA reductions In the dorsolateral prefrontal cortex and hippocampus (Bertolino et al. 1995, 1996) suggesting that these reductions are Independent of drug effects. The objective of this study was to further characterize neuronal density as measured by N-acetylaspartate (NAA) and choline in the frontal lobes. anterior clngulate region, and hippocampi In schizophrenia using In-vivo proton magnetic resonance spectroscopic Imaging (' H MRSI). Methods: Thirty medicated. schizophrenic patients and 18 normal control SUbjects underwent' H MRSI using a Siemens Magnetom Vision MRIIMRS system. ' H MRSI was performed using a standard circUlarly polarized head coil. MRI scout views were used for PRESS volume localization. MP rage and double spin-echo MRI were also obtained for quantitative hippocampal voluming using In-house software. The 20 PRESS volume for the frontaVclngulate region was approximately 60 x 60 x 15 mm3 and the 20 PRESS volume for the hippocampal region was approximately 100 x 60 x 15 mm3 • Twenty four x 24 phase encoding steps and circular k-space sampling was used with a TR 1.8s. TE = 135 ms. MRSI data volumes were reconstructed using spectroscopic Imaging display software. Individual voxels (1.3 ml) were then selected in the frontal lobes. hippocampi, and anterior clngulate region using the higher resolution co-registered MR images. ' H spectra corresponding to these voxels were fit by NMR·1 curve filling software, and concentration estimates were obtained for the NAA. choline. and creatine spectral resonances. Results: Relative to controls, NAA values In the schizophrenic group were significantly lower In the left frontal region (p 0.0002), anterior clngulate region (p = 0.004), and hippocampi bilaterally (p = 0.002). Creatine was also elevated in the hippocampi of the schizophrenic group (p = 0.01). No significant group differences or Iaterallzed asymmetries In choline were noted. The patients with schizophrenia also demonstrated no significant differences from controls in MRI derived hippocampal volumes. NAA was not correlated with neuroleptic dosage or duration of illness. Conclusions: Decreased NAA suggests decreased neuronal density in the left frontal cortex, hippocampi. and anterior clngulate cortex In schizo• phrenics. The absence of elevated choline does not support a pathological process with exaggerated cell membrane phospholipid tumover such as neuronal atrophy or neuronal necrosis. Furthermore, decreased NAA in the absence of significant hippocampal volume reductions suggests that NAA may be a more sensitive marKer of neuronal loss than MRI derived volumetric methods.
Preliminary studies with this ligand Indicate that It Is possible to visualize 1he raphe nuclei in the brainstem of human subjects. Studies of this IiQand in major depression and the effects of treatment will be of Interest, although the ligand Is somewhat limited in the information It provides since it also binds to the dopamine transporter. Changes in serotonin transporter binding at the level of recurrent serotonin fibers and on the serotonergic neurons is not necessarily Informative about serotonergic function In the terminal fields. A third approach that we have pioneered Is the use of ,eF-deoxyg1ucose (,sFDG) to visualize regional brain metabolism In patients after challenge with a serotonergic agent such as fenfluramine. Fenfluramlne causes 1he release of serotonin and inhibits Its reuptake. Using this method, we have demonstrated a significant blunting of regional brain metabolic responses Ie) fenfluramine relative to placebo In depressed. untreated inpatients COlTlpared to healthy controls. What is not clear Is whether the changes obseIved .,.. due to diminution of releasable serotonin or due to downstream ef'fecls involving pyramidal cells or GABAergic Inhibitory intemeurons. Newer PET ligands for the 5-HT1A and 5-HT2A receptors. as well as for the serotonin transporter. have created the opportunity for more sophisticated PET studies of the serotonergic system In man. Application of these ligands to the study of major depression Is currently under way in a number of centers, and the results will be of enormous Interest to the field.
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41. Subtype specific cholinergic therapies• Effects on cognitive and non-cognitive symptoms in affective disorders
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References (1) Bertolino A, Nawroz S, Maney VS, et aI (1995). A specifIC anatomical pattern 01 neuronallmpalrmenl In echlzophrenla as assessed by multiallce 1H-MRSI. Proc Soc Magn Resen Annual Meeting 3: 1844. (2] Bertolino A. Callicott JH. Elman I, et al (1996) Proton magnetic resonance spectre• IICOPIc Imaging In drug free patients w~h schizophrenia: regional neuronal damage. BIoi Psychiatry 39: 634. (3) Ende G. Knowlton R. werKD. Mataon GB, WelnertIMI (199S). NM Ie a more sen• aitlve marker 01 hippocampal disease lIlan atrophy: evidence !hat NM Ie a neuronal marker. Proc ollhe Soc 01 Magn Reson Fourth Annual Meeting 3: 144.
140-61 ofPETuntreated studies of serotonerglc responslvity In the brain depressed patients J.J. Mann, S. Anjilvel, C.E. campbell. R.L Van Heertum, K.M. Malone. Department of Neuroscience, New York State Psychiatric Institute, and Department of Psychiatry. ColumbIa University. New York, NY, USA A major hypothesis regarding the pathogenesis of depressive Illness Is that there Is a deficiency of serotonergic transmission In key brain areas. It Is not clear whether this is due to a lack of serotonin available for neuronal release or whether this is due to sUbsensltivity of key serotonergic receptors. With the development of new approaches for In vivo imaging of the serotonergic system. It has become possible to more directly address this hypothesis. Studies of 5-hydroxytryptophan uptake using PET have suggested that there 18 reduced uptake in patients with major depression. This implies that a lack of precursor may contribute to reduced serotonerglc function. but technical details of Interpretation of these results limit confident conclusions. A second approach that has been employed is use of the SPECT ligand jJ-GIT.
141-1 I Subtype-specific muscarinic cholinergic therapies In Alzheimer's disease A.I. Levey. Department of Neurology, Emory University. Atlanta,
GA. US4
Impaired cholinergic transmission at muscarinic acetylcholine receptors (mAChR) In brain may contribute to the cognitive and behavioral 5YITlPtoms of Alzheimer's disease (AD). To clarify the roles of the rn1-m5 rnAChR subtypes In forebrain circuits mediating higher braln functions. ImrnunoIogic:ar studies were performed to Identify. localize. and determine alterations in the levels of Individual receptor proteins in brains from experirnental animaJs and postmortem AD and control cases. Methods: Subtype-specific antibodies were used In Irnmu~ studies at the light and electron microscopic level to precisely IocarIZe individual rnAChR proteins. and Immunoprecipitatlon studies were used 10 quantify each SUbtype. Results: All five rnAChRs are expressed in forebrain. with the m1, m2. and m4 receptor proteins most abundant in cortex. hippocampus, and basal ganglia. The subtypes each have distinct cellular and subcenutar localization. Electron microscopic studies In rat and monkey brain &uggest postsynaplic (m1) and presynaplic (m2. m4) functions InvoMng cholinergic modulation of glutamaterglc and GABAergic transmission. The subtypes are also differentially altered In postmortem brain samples from AD cases, With reductions In cortical and hippocampal m1 and m2 receptors, and Increases In m4 receptors. These alterations surprisingly appear to be due to changes In nonchollnergic structures. The molecular pharmacology and pathology of cholinergic synapses provides rationale for use of subtype-selective drugs to facilitate neurotransmission and provide more specific and effective treatments for the cognitive and behavioral symptoms of AD. Supported by NIH R01 NS30454.
141-21 Alzheimer's Cholinergic treatment of behavioral disturbances In disease J.L Cummings. Departments of Neurology and Psychiatry. UCLA School d Medicine. Los Angeles, California, USA Alzheimer's disease (AD) Is characterized by a marked cholinergic deficit as well as distinctive histologic changes such as neuritic plaques and neurofib• rillary tangles. Clinically, AD features progressive Impairment or m&rnory, language. visuospatlal skills, and executive functions. A diverse array of neuropsychiatric symptoms also occur in AD Including apathy, agitatiol\ Irritability. anxiety, depressive symptoms. purposeless motor behaviors, dis-
Subtype specific cholinergic therapies
BIOL. PSYCHIATRY 1997;42:15-2975
brane phospholipid turnover is certainly consistent with neuronal necrosis or with neuronal atrophy (where there Is active loss of dendritic arbors and axons). However, selective neuronal loss without increased membrane tumover Is consistent with a process like neuronal apoptosis. Preliminary in-vivo ' H MRS studies In schizophrenia have revealed discrepant NAA and choline findings in the frontal lobes, temporal lobes. and hippocampi. Furthermore. recent pilot studies of both drug naive and medication with• drawn versus medicated schizophrenics have noted significant bilateral NAA reductions In the dorsolateral prefrontal cortex and hippocampus (Bertolino et al. 1995, 1996) suggesting that these reductions are Independent of drug effects. The objective of this study was to further characterize neuronal density as measured by N-acetylaspartate (NAA) and choline in the frontal lobes. anterior clngulate region, and hippocampi In schizophrenia using In-vivo proton magnetic resonance spectroscopic Imaging (' H MRSI). Methods: Thirty medicated. schizophrenic patients and 18 normal control SUbjects underwent' H MRSI using a Siemens Magnetom Vision MRIIMRS system. ' H MRSI was performed using a standard circUlarly polarized head coil. MRI scout views were used for PRESS volume localization. MP rage and double spin-echo MRI were also obtained for quantitative hippocampal voluming using In-house software. The 20 PRESS volume for the frontaVclngulate region was approximately 60 x 60 x 15 mm3 and the 20 PRESS volume for the hippocampal region was approximately 100 x 60 x 15 mm3 • Twenty four x 24 phase encoding steps and circular k-space sampling was used with a TR 1.8s. TE = 135 ms. MRSI data volumes were reconstructed using spectroscopic Imaging display software. Individual voxels (1.3 ml) were then selected in the frontal lobes. hippocampi, and anterior clngulate region using the higher resolution co-registered MR images. ' H spectra corresponding to these voxels were fit by NMR·1 curve filling software, and concentration estimates were obtained for the NAA. choline. and creatine spectral resonances. Results: Relative to controls, NAA values In the schizophrenic group were significantly lower In the left frontal region (p 0.0002), anterior clngulate region (p = 0.004), and hippocampi bilaterally (p = 0.002). Creatine was also elevated in the hippocampi of the schizophrenic group (p = 0.01). No significant group differences or Iaterallzed asymmetries In choline were noted. The patients with schizophrenia also demonstrated no significant differences from controls in MRI derived hippocampal volumes. NAA was not correlated with neuroleptic dosage or duration of illness. Conclusions: Decreased NAA suggests decreased neuronal density in the left frontal cortex, hippocampi. and anterior clngulate cortex In schizo• phrenics. The absence of elevated choline does not support a pathological process with exaggerated cell membrane phospholipid tumover such as neuronal atrophy or neuronal necrosis. Furthermore, decreased NAA in the absence of significant hippocampal volume reductions suggests that NAA may be a more sensitive marKer of neuronal loss than MRI derived volumetric methods.
Preliminary studies with this ligand Indicate that It Is possible to visualize 1he raphe nuclei in the brainstem of human subjects. Studies of this IiQand in major depression and the effects of treatment will be of Interest, although the ligand Is somewhat limited in the information It provides since it also binds to the dopamine transporter. Changes in serotonin transporter binding at the level of recurrent serotonin fibers and on the serotonergic neurons is not necessarily Informative about serotonergic function In the terminal fields. A third approach that we have pioneered Is the use of ,eF-deoxyg1ucose (,sFDG) to visualize regional brain metabolism In patients after challenge with a serotonergic agent such as fenfluramine. Fenfluramlne causes 1he release of serotonin and inhibits Its reuptake. Using this method, we have demonstrated a significant blunting of regional brain metabolic responses Ie) fenfluramine relative to placebo In depressed. untreated inpatients COlTlpared to healthy controls. What is not clear Is whether the changes obseIved .,.. due to diminution of releasable serotonin or due to downstream ef'fecls involving pyramidal cells or GABAergic Inhibitory intemeurons. Newer PET ligands for the 5-HT1A and 5-HT2A receptors. as well as for the serotonin transporter. have created the opportunity for more sophisticated PET studies of the serotonergic system In man. Application of these ligands to the study of major depression Is currently under way in a number of centers, and the results will be of enormous Interest to the field.
=
41. Subtype specific cholinergic therapies• Effects on cognitive and non-cognitive symptoms in affective disorders
=
References (1) Bertolino A, Nawroz S, Maney VS, et aI (1995). A specifIC anatomical pattern 01 neuronallmpalrmenl In echlzophrenla as assessed by multiallce 1H-MRSI. Proc Soc Magn Resen Annual Meeting 3: 1844. (2] Bertolino A. Callicott JH. Elman I, et al (1996) Proton magnetic resonance spectre• IICOPIc Imaging In drug free patients w~h schizophrenia: regional neuronal damage. BIoi Psychiatry 39: 634. (3) Ende G. Knowlton R. werKD. Mataon GB, WelnertIMI (199S). NM Ie a more sen• aitlve marker 01 hippocampal disease lIlan atrophy: evidence !hat NM Ie a neuronal marker. Proc ollhe Soc 01 Magn Reson Fourth Annual Meeting 3: 144.
140-61 ofPETuntreated studies of serotonerglc responslvity In the brain depressed patients J.J. Mann, S. Anjilvel, C.E. campbell. R.L Van Heertum, K.M. Malone. Department of Neuroscience, New York State Psychiatric Institute, and Department of Psychiatry. ColumbIa University. New York, NY, USA A major hypothesis regarding the pathogenesis of depressive Illness Is that there Is a deficiency of serotonergic transmission In key brain areas. It Is not clear whether this is due to a lack of serotonin available for neuronal release or whether this is due to sUbsensltivity of key serotonergic receptors. With the development of new approaches for In vivo imaging of the serotonergic system. It has become possible to more directly address this hypothesis. Studies of 5-hydroxytryptophan uptake using PET have suggested that there 18 reduced uptake in patients with major depression. This implies that a lack of precursor may contribute to reduced serotonerglc function. but technical details of Interpretation of these results limit confident conclusions. A second approach that has been employed is use of the SPECT ligand jJ-GIT.
141-1 I Subtype-specific muscarinic cholinergic therapies In Alzheimer's disease A.I. Levey. Department of Neurology, Emory University. Atlanta,
GA. US4
Impaired cholinergic transmission at muscarinic acetylcholine receptors (mAChR) In brain may contribute to the cognitive and behavioral 5YITlPtoms of Alzheimer's disease (AD). To clarify the roles of the rn1-m5 rnAChR subtypes In forebrain circuits mediating higher braln functions. ImrnunoIogic:ar studies were performed to Identify. localize. and determine alterations in the levels of Individual receptor proteins in brains from experirnental animaJs and postmortem AD and control cases. Methods: Subtype-specific antibodies were used In Irnmu~ studies at the light and electron microscopic level to precisely IocarIZe individual rnAChR proteins. and Immunoprecipitatlon studies were used 10 quantify each SUbtype. Results: All five rnAChRs are expressed in forebrain. with the m1, m2. and m4 receptor proteins most abundant in cortex. hippocampus, and basal ganglia. The subtypes each have distinct cellular and subcenutar localization. Electron microscopic studies In rat and monkey brain &uggest postsynaplic (m1) and presynaplic (m2. m4) functions InvoMng cholinergic modulation of glutamaterglc and GABAergic transmission. The subtypes are also differentially altered In postmortem brain samples from AD cases, With reductions In cortical and hippocampal m1 and m2 receptors, and Increases In m4 receptors. These alterations surprisingly appear to be due to changes In nonchollnergic structures. The molecular pharmacology and pathology of cholinergic synapses provides rationale for use of subtype-selective drugs to facilitate neurotransmission and provide more specific and effective treatments for the cognitive and behavioral symptoms of AD. Supported by NIH R01 NS30454.
141-21 Alzheimer's Cholinergic treatment of behavioral disturbances In disease J.L Cummings. Departments of Neurology and Psychiatry. UCLA School d Medicine. Los Angeles, California, USA Alzheimer's disease (AD) Is characterized by a marked cholinergic deficit as well as distinctive histologic changes such as neuritic plaques and neurofib• rillary tangles. Clinically, AD features progressive Impairment or m&rnory, language. visuospatlal skills, and executive functions. A diverse array of neuropsychiatric symptoms also occur in AD Including apathy, agitatiol\ Irritability. anxiety, depressive symptoms. purposeless motor behaviors, dis-