Robert Cohen - Academia.edu (original) (raw)
Papers by Robert Cohen
Mammalian Genome, 2001
How allelic diversity affects neural mechanisms to produce behavioral variation is largely unknow... more How allelic diversity affects neural mechanisms to produce behavioral variation is largely unknown. The elevated plus maze, consisting of open and closed arms, has been used as a model of behavioral variation in rodent exploration. Under dim illumination the nature of the sensory stimuli that influence arm choice is uncertain. Two inbred mouse strains, A/J (Tyr c /Tyr c , the albino phenotype, mutation in tyrosinase) with a strong preference for closed arm entry, and CBA/J (Pdeb rdl /Pdeb rdl , the retinal degeneration phenotype, mutation in the -subunit of rod cGMP phosphodiesterase), with a weak preference for open arm entry, were studied under varying light. Because behavioral differences persist under red light, variation in light perception is not likely to fully account for variation in arm choice. To identify genetic factors influencing arm choice (100 × Open arm entries/Total arm entries) quantitative trait loci analyses (QTL) were performed on (A/J × CBA/J)F 2 mice. Two QTLs, one of which includes PDEB, were identified on Chr 5 (LOD > 10) and account for > 30% of the behavioral variation in arm preference. Tyr (Chr 7, 44 cM) was linked to closed arm entries but not arm preference, and is unlikely to be acting through a direct effect on light perception, because A/J arm entries were not affected by red light and there was no interaction with PDEB in the (A/J × CBA/J)F 2 mice. Whether the candidate QTLs on Chr 5 affect arm choice through an effect on light perception is unknown, but phenotypic differences between F 2 mice with retinal degeneration and CBA/J mice and F 2 mice with albinism and A/J mice suggest that factors other than light sensitivity contribute to arm preference in these two strains.
Archives of General Psychiatry, 1982
\s=b\Motor performance and cognitive function were examined in depressed patients and controls. I... more \s=b\Motor performance and cognitive function were examined in depressed patients and controls. Increasing severity of depression was strongly associated with decrements in performance in both motor and memory tasks. Greatest depressionrelated impairment was found on those cognitive and motor tasks that required sustained effort. We discuss these results in terms of a generalized deficit in the central motivational state of depressed individuals.
Frontiers in Neuroscience, Jun 16, 2020
Alzheimer's disease (AD) is a progressive neurodegenerative disease resulting in cognitive declin... more Alzheimer's disease (AD) is a progressive neurodegenerative disease resulting in cognitive decline. A unique rat model, TgF344-AD, recapitulates pathological hallmarks of AD. We used a longitudinal design to address the timing of expression of behavioral phenotypes in male and female TgF344-AD rats. In both sexes, we confirmed an agedependent buildup of amyloid-β. In the open field, female, but not male, TgF344-AD rats were hypoactive at 6 and 12 months of age but at 18 months the two genotypes were similar in levels of activity response. Both male and female TgF344-AD rats had a deficit in performance on a learning and memory task. Male TgF344-AD, but not female, rats had evidence of hyposmia regardless of age. Rest-activity rhythms followed the typical active/inactive phase in all rats regardless of genotype or age. In males, home cage activity was similar across age and genotype; in females, regardless of genotype animals were less active as they aged. These changes highlight some behavioral markers of disease in the rat model. Early markers of disease may be important in early diagnosis and assessment of efficacy when treatment becomes available.
Pharmacology and Functional Regulation of Dopaminergic Neurons, 1988
Hippocampus, 2018
Alzheimer's disease (AD) is a neurodegenerative disease that disproportionately impacts memory an... more Alzheimer's disease (AD) is a neurodegenerative disease that disproportionately impacts memory and the hippocampus. However, it is unclear how AD pathology influences the activity of surviving neurons in the hippocampus to contribute to the memory symptoms in AD. One wellunderstood connection between spatial memory and neuronal activity in healthy brains is the activity of place cells, neurons in the hippocampus that fire preferentially in a specific location of a given environment (the place field of the place cell). In the present study, place cells were recorded from the hippocampus in a recently-developed rat model of AD (Tg-F344 AD) at an age (12-20 months) at which the AD rats showed marked spatial memory deficits. Place cells in the CA2 and CA3 pyramidal regions of the hippocampus in AD rats showed sharply reduced spatial fidelity relative to wild-type (WT) rats. In contrast, spiking activity of place cells recorded in region CA1 in AD rats showed good spatial fidelity that was similar to CA1 place cells in WT rats. Oral administration of the M 1 muscarinic acetylcholine receptor agonist VU0364572 impacted place cell firing rates in CA1 and CA2/3 hippocampal regions but did not improve the spatial fidelity of CA2/3 hippocampal place cells in AD rats. The results indicated that, to the extent the spatial memory impairment in AD rats was attributable to hippocampal dysfunction, the memory impairment was more attributable to dysfunction in hippocampal regions CA2 and CA3 rather than CA1.
Neuropsychopharmacology, 1994
This study used positron-emission tomography to examine cerebral metabolic rates of glucose (CMRG... more This study used positron-emission tomography to examine cerebral metabolic rates of glucose (CMRG) in 17 patients with DSM III-R diagnoses of personality disorder. Within the group of 17 personality disorder patients, there was a significant inverse correlation between a life history of aggressive impulse difficulties and regional CMRG in the frontal cortex of the transaxial plane approximately 40 mm above the canthomeatal line (CML) (r =-.56, P = 0.17). Diagnostic groups included antisocial (n = 6), borderline (n = 6), dependent (n = 2), and narcissistic (n = 3).
Journal of Cerebral Blood Flow & Metabolism, 1987
Journal of Cerebral Blood Flow & Metabolism, 1985
This article describes a method for partitioning metabolic variability found in positron emission... more This article describes a method for partitioning metabolic variability found in positron emission tomography/[18F]fluorodeoxyglucose studies. For the 15 subjects examined, 74.8% of the total metabolic variability could be ascribed to individual differences in global metabolic rate, whereas 15.8% of the total variability was consistent regional variation or pattern across subjects. Subsequently, the method of Q-component analysis is described for the identification of strong- and weak-pattern subjects. In addition, a standardization procedure that amplifies the observed pattern by removing systematic individual differences is described. Finally, the implications of these findings and methods for future and clinical studies are discussed.
JAMA, 2003
HILE THE EXACT BIOLOGIcal cascade associated with Alzheimer disease (AD) is only partially unders... more HILE THE EXACT BIOLOGIcal cascade associated with Alzheimer disease (AD) is only partially understood, many potential biomarkers of this disease process are known. 1 Two of the most obvious candidates are -amyloid 1-42 and tau proteins, as they are intimately related to the pathognomonic features of amyloid plaques and neurofibrillary tangles in the AD brain. 2,3 Multiple previous studies have reported decreases in cerebrospinal fluid (CSF) measures of -amyloid. 4-7 Similarly, CSF measures of tau have routinely showed considerable elevations of this peptide in AD cases worldwide. 7-12 Some authors have reported that these 2 measures alone can accurately differentiate clinically diagnosed AD cases from controls more than 85% of the time. 7,13 Studies of CSF in AD patients have used widely varying methods and nomenclature for assessing and describ-Author Affiliations are listed at the end of this article.
Investigative Opthalmology & Visual Science, 2014
Brain Imaging and Behavior, 2010
![Research paper thumbnail of Quality control procedure for 6-[18F]fluoro-L-DOPA: a presynaptic PET imaging ligand for brain dopamine neurons](https://attachments.academia-assets.com/109119139/thumbnails/1.jpg)
](Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1989
The goal of the current study was to establish a quality control procedure for clinical use of 6-... more The goal of the current study was to establish a quality control procedure for clinical use of 6-[18F]fluoro-L-DOPA (6-[18F]-DOPA) as a selective presynaptic positron emission tomographic (PET) imaging ligand for brain dopamine neurons. A high performance liquid chromatographic procedure using a 5-mu C-18 reverse phase column and ion-pairing mobile phase was used for the quantification of 6-[18F]-DOPA. The radiochemical purity of 6-[18F]-DOPA was measured by 18F radioactivity in HPLC fractions while the chemical purity was determined by an amperometric electrochemical detector with a sensitivity of 25 pg. Quality control of eight consecutive batches of highly purified 6-[18F]-DOPA sample used in a pre-clinical trial revealed that the chemical and/or radiochemical purity of the PET imaging ligand, 6-[18F]-DOPA was greater than 97 +/- 0.5% with a specific activity of 365 +/- 31 mCi/mmol. The knowledge and assurance of radiochemical purity of PET ligands are essential for the interpret...
Annals of Neurology, 2005
Nicotinic acetylcholine receptors (nAChRs) have close interactions with the dopaminergic system a... more Nicotinic acetylcholine receptors (nAChRs) have close interactions with the dopaminergic system and play critical roles in cognitive function. nAChRs were imaged in 10 non-demented Parkinson's disease (PD) patients and 15 age-matched healthy subjects using a single photon emission computed tomography ligand [ 123 I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine. Using an arterial input function, we measured the total distribution volume (V; specific plus non-displaceable) as well as the delivery (K 1). PD showed a widespread significant decrease (∼10%) of V in both cortical and subcortical regions without a significant change in K 1. These results indicate the importance of extending the study to demented patients.
Journal of Alzheimer's disease : JAD, 2013
The rapidly rising prevalence and cost of Alzheimer's disease in recent decades has made the ... more The rapidly rising prevalence and cost of Alzheimer's disease in recent decades has made the imaging of amyloid-β deposits the focus of intense research. Several amyloid imaging probes with purported specificity for amyloid-β plaques are currently at various stages of FDA approval. However, a number of factors appear to preclude these probes from clinical utilization. As the available "amyloid specific" positron emission tomography imaging probes have failed to demonstrate diagnostic value and have shown limited utility for monitoring therapeutic interventions in humans, a debate on their significance has emerged. The aim of this review is to identify and discuss critically the scientific issues contributing to the extensive inconsistencies reported in the literature on their purported in vivo amyloid specificity and potential utilization in patients.
Psychopharmacology, 1981
8 mg of naloxone were administered IV to 14 normal volunteers in a placebo-controlled, double-bli... more 8 mg of naloxone were administered IV to 14 normal volunteers in a placebo-controlled, double-blind experiment. Plasma levels offl-endorphin, cortisol, prolactin, growth hormone, HVA and MHPG were determined before and 45 min after administration. Naloxone elicited significant increases in cortisol and MHPG but did not change plasma levels of the other compounds. In an additional experiment on two subjects, 20 mg of naloxone caused elevations offl-endorphin as well as of cortisol. This parallel increase indicates that the linkage between the secretion of fi-endorphin and ACTH/cortisol may be dose-dependent. The increase in MHPG is in agreement with the hypothesized association of noradrenergic hyperactivity and opiate withdrawal.
Neuropsychopharmacology, 1998
The regional cerebral metabolic rates of 19 male medicationwithdrawn schizophrenic patients were ... more The regional cerebral metabolic rates of 19 male medicationwithdrawn schizophrenic patients were determined by positron emission tomography (PET) while performing an auditory discrimination task (CPT). Regardless of the accuracy of their CPT performance, the schizophrenic patients had lower metabolic rates in their prefrontal cortex and higher rates in their posterior putamen compared to 41 healthy males. Abnormally low right anterior midprefrontal cortex metabolic rates predicted better clinical response while high basal ganglia rates and low mid-cingulate rates predicted poor treatment response to neuroleptics. The findings imply that the sustained attention pathway and its distributed network of brain structures are likely to play an important role in the expression of psychotic symptoms and the mediation of their response to antipsychotics.
Journal of Cerebral Blood Flow & Metabolism, 1993
Two consecutive measurements of resting CBF were carried out in normal volunteers (n = 25) using ... more Two consecutive measurements of resting CBF were carried out in normal volunteers (n = 25) using H215O positron emission tomography. Absolute whole-brain blood flow (WBBF; ml 100 g−1 min−1, mean ± SD) for the first (40.3 ± 6.4) and second (39.3 ± 6.5) measurements was not significantly different (mean % difference 2.3 ± 8.7). Analysis of regions of interest showed no significant differences in absolute regional CBF (rCBF) and normalized (rCBF/WBBF) rCBF. Left-right differences were also not significant. These data demonstrate the reproducibility of resting CBF measurements in normal humans.
British Journal of Pharmacology, 1987
Administration of the 5-HTIB receptor agonist m-chlorophenylpiperazine (m-CPP) to rats produces d... more Administration of the 5-HTIB receptor agonist m-chlorophenylpiperazine (m-CPP) to rats produces dose-dependent decreases in locomotor activity and food intake. 2 The locomotor suppressant effect of m-CPP was inhibited by the 5-hydroxytryptaminergic antagonist, metergoline, but not by phentolamine, propranolol, clonidine, or haloperidol. 3 The locomotor suppressant effects of m-CPP were enhanced following long-term (but not shortterm) treatment with imipramine, possibly reflecting the postulated development of a functional supersensitivity of 5-HTIB receptors mediating locomotion during longer-term antidepressant drug treatment. 4 The food intake suppressant effects of m-CPP were enhanced following both short (3-5 days) and longer-term (21 days) treatment with imipramine. Rapidly developing 5-hydroxytryptamine uptake inhibition may be responsible for this change, or it may represent an earlier adaptive change in the 5-HTIB receptors mediating food intake compared to more complexly modulated motor responses.
Biological Psychiatry, 1992
Phencyclidine (PCP) intoxication can mimic the positive and negative symptoms of schizophrenia. P... more Phencyclidine (PCP) intoxication can mimic the positive and negative symptoms of schizophrenia. PCP blocks the NMDA glutamate channel, decreasing corticostriatal activation. The basal ganglia modulates the relay of sensory information to the cortex. This striatothalamocortical loop is hypothesized to be involved in schizophrenia and PCP intoxication. We measured FDG PET metabolism and EEG ot following photic sensory driving in six chronic PCP users. The photic driving stimulus was administered at 2.38 c/sec, 4.54 c/sec, and 8.33 c/sec. High basal ganglia FDG metabolism was related to decreased frontal, parietal, and occipital photic driving ot power (r =-0.067 to-0.93). High thalamic FDG metabolism was similarly related to decreased photic driving ot (r =-0.33 to-0.7). These data are consistent with a PCP effect on subcortical •netabolism which may have resulted in the abnormal relay of sensory information to the cortex reflected by a decreased a pc,,ver.
Clinical Pediatrics, 1996
Background. Lesch-Nyhan disease is a rare, devastating, X-linked recessive disorder of purine syn... more Background. Lesch-Nyhan disease is a rare, devastating, X-linked recessive disorder of purine synthesis. Patients present with hyperuricemia, choreoathetosis, dystonia, and aggressive and self-injurious behavior. Although the genetic and biochemical abnormalities have been identified, the causes of the neuropsychiatric syndrome remain unclear. Methods. We used positron-emission tomography to measure presynaptic accumulation of fluorodopa F 18 tracer in the dopaminergic regions of the brains of 12 patients with Lesch-Nyhan disease (age, 10 to 20 years) and 15 healthy controls (age, 12 to 23). The results were expressed as ratios of specific to nonspecific radioactive counts. A low ratio indicates decreased dopa decarboxylase activity and dopamine storage. Results. The fluorodopa F 18 ratio was significantly lower in the putamen (31 percent of control values), cau-date nucleus (39 percent), frontal cortex (44 percent), and ventral tegmental complex (substantia nigra and ventral tegmentum; 57 percent) in the patients with Lesch-Nyhan disease than in the controls. Uptake of the tracer was abnormally low even in the youngest patients tested, and there was no overlap in the values between patients and controls. Conclusions. Patients with Lesch-Nyhan disease have abnormally few dopaminergic nerve terminals and cell bodies. The abnormality involves all dopaminergic pathways and is not restricted to the basal ganglia. These dopaminergic deficits are pervasive and appear to be developmental in origin, which suggests that they contribute to the characteristic neuropsychiatric manifestations of the disease.
Mammalian Genome, 2001
How allelic diversity affects neural mechanisms to produce behavioral variation is largely unknow... more How allelic diversity affects neural mechanisms to produce behavioral variation is largely unknown. The elevated plus maze, consisting of open and closed arms, has been used as a model of behavioral variation in rodent exploration. Under dim illumination the nature of the sensory stimuli that influence arm choice is uncertain. Two inbred mouse strains, A/J (Tyr c /Tyr c , the albino phenotype, mutation in tyrosinase) with a strong preference for closed arm entry, and CBA/J (Pdeb rdl /Pdeb rdl , the retinal degeneration phenotype, mutation in the -subunit of rod cGMP phosphodiesterase), with a weak preference for open arm entry, were studied under varying light. Because behavioral differences persist under red light, variation in light perception is not likely to fully account for variation in arm choice. To identify genetic factors influencing arm choice (100 × Open arm entries/Total arm entries) quantitative trait loci analyses (QTL) were performed on (A/J × CBA/J)F 2 mice. Two QTLs, one of which includes PDEB, were identified on Chr 5 (LOD > 10) and account for > 30% of the behavioral variation in arm preference. Tyr (Chr 7, 44 cM) was linked to closed arm entries but not arm preference, and is unlikely to be acting through a direct effect on light perception, because A/J arm entries were not affected by red light and there was no interaction with PDEB in the (A/J × CBA/J)F 2 mice. Whether the candidate QTLs on Chr 5 affect arm choice through an effect on light perception is unknown, but phenotypic differences between F 2 mice with retinal degeneration and CBA/J mice and F 2 mice with albinism and A/J mice suggest that factors other than light sensitivity contribute to arm preference in these two strains.
Archives of General Psychiatry, 1982
\s=b\Motor performance and cognitive function were examined in depressed patients and controls. I... more \s=b\Motor performance and cognitive function were examined in depressed patients and controls. Increasing severity of depression was strongly associated with decrements in performance in both motor and memory tasks. Greatest depressionrelated impairment was found on those cognitive and motor tasks that required sustained effort. We discuss these results in terms of a generalized deficit in the central motivational state of depressed individuals.
Frontiers in Neuroscience, Jun 16, 2020
Alzheimer's disease (AD) is a progressive neurodegenerative disease resulting in cognitive declin... more Alzheimer's disease (AD) is a progressive neurodegenerative disease resulting in cognitive decline. A unique rat model, TgF344-AD, recapitulates pathological hallmarks of AD. We used a longitudinal design to address the timing of expression of behavioral phenotypes in male and female TgF344-AD rats. In both sexes, we confirmed an agedependent buildup of amyloid-β. In the open field, female, but not male, TgF344-AD rats were hypoactive at 6 and 12 months of age but at 18 months the two genotypes were similar in levels of activity response. Both male and female TgF344-AD rats had a deficit in performance on a learning and memory task. Male TgF344-AD, but not female, rats had evidence of hyposmia regardless of age. Rest-activity rhythms followed the typical active/inactive phase in all rats regardless of genotype or age. In males, home cage activity was similar across age and genotype; in females, regardless of genotype animals were less active as they aged. These changes highlight some behavioral markers of disease in the rat model. Early markers of disease may be important in early diagnosis and assessment of efficacy when treatment becomes available.
Pharmacology and Functional Regulation of Dopaminergic Neurons, 1988
Hippocampus, 2018
Alzheimer's disease (AD) is a neurodegenerative disease that disproportionately impacts memory an... more Alzheimer's disease (AD) is a neurodegenerative disease that disproportionately impacts memory and the hippocampus. However, it is unclear how AD pathology influences the activity of surviving neurons in the hippocampus to contribute to the memory symptoms in AD. One wellunderstood connection between spatial memory and neuronal activity in healthy brains is the activity of place cells, neurons in the hippocampus that fire preferentially in a specific location of a given environment (the place field of the place cell). In the present study, place cells were recorded from the hippocampus in a recently-developed rat model of AD (Tg-F344 AD) at an age (12-20 months) at which the AD rats showed marked spatial memory deficits. Place cells in the CA2 and CA3 pyramidal regions of the hippocampus in AD rats showed sharply reduced spatial fidelity relative to wild-type (WT) rats. In contrast, spiking activity of place cells recorded in region CA1 in AD rats showed good spatial fidelity that was similar to CA1 place cells in WT rats. Oral administration of the M 1 muscarinic acetylcholine receptor agonist VU0364572 impacted place cell firing rates in CA1 and CA2/3 hippocampal regions but did not improve the spatial fidelity of CA2/3 hippocampal place cells in AD rats. The results indicated that, to the extent the spatial memory impairment in AD rats was attributable to hippocampal dysfunction, the memory impairment was more attributable to dysfunction in hippocampal regions CA2 and CA3 rather than CA1.
Neuropsychopharmacology, 1994
This study used positron-emission tomography to examine cerebral metabolic rates of glucose (CMRG... more This study used positron-emission tomography to examine cerebral metabolic rates of glucose (CMRG) in 17 patients with DSM III-R diagnoses of personality disorder. Within the group of 17 personality disorder patients, there was a significant inverse correlation between a life history of aggressive impulse difficulties and regional CMRG in the frontal cortex of the transaxial plane approximately 40 mm above the canthomeatal line (CML) (r =-.56, P = 0.17). Diagnostic groups included antisocial (n = 6), borderline (n = 6), dependent (n = 2), and narcissistic (n = 3).
Journal of Cerebral Blood Flow & Metabolism, 1987
Journal of Cerebral Blood Flow & Metabolism, 1985
This article describes a method for partitioning metabolic variability found in positron emission... more This article describes a method for partitioning metabolic variability found in positron emission tomography/[18F]fluorodeoxyglucose studies. For the 15 subjects examined, 74.8% of the total metabolic variability could be ascribed to individual differences in global metabolic rate, whereas 15.8% of the total variability was consistent regional variation or pattern across subjects. Subsequently, the method of Q-component analysis is described for the identification of strong- and weak-pattern subjects. In addition, a standardization procedure that amplifies the observed pattern by removing systematic individual differences is described. Finally, the implications of these findings and methods for future and clinical studies are discussed.
JAMA, 2003
HILE THE EXACT BIOLOGIcal cascade associated with Alzheimer disease (AD) is only partially unders... more HILE THE EXACT BIOLOGIcal cascade associated with Alzheimer disease (AD) is only partially understood, many potential biomarkers of this disease process are known. 1 Two of the most obvious candidates are -amyloid 1-42 and tau proteins, as they are intimately related to the pathognomonic features of amyloid plaques and neurofibrillary tangles in the AD brain. 2,3 Multiple previous studies have reported decreases in cerebrospinal fluid (CSF) measures of -amyloid. 4-7 Similarly, CSF measures of tau have routinely showed considerable elevations of this peptide in AD cases worldwide. 7-12 Some authors have reported that these 2 measures alone can accurately differentiate clinically diagnosed AD cases from controls more than 85% of the time. 7,13 Studies of CSF in AD patients have used widely varying methods and nomenclature for assessing and describ-Author Affiliations are listed at the end of this article.
Investigative Opthalmology & Visual Science, 2014
Brain Imaging and Behavior, 2010
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1989
The goal of the current study was to establish a quality control procedure for clinical use of 6-... more The goal of the current study was to establish a quality control procedure for clinical use of 6-[18F]fluoro-L-DOPA (6-[18F]-DOPA) as a selective presynaptic positron emission tomographic (PET) imaging ligand for brain dopamine neurons. A high performance liquid chromatographic procedure using a 5-mu C-18 reverse phase column and ion-pairing mobile phase was used for the quantification of 6-[18F]-DOPA. The radiochemical purity of 6-[18F]-DOPA was measured by 18F radioactivity in HPLC fractions while the chemical purity was determined by an amperometric electrochemical detector with a sensitivity of 25 pg. Quality control of eight consecutive batches of highly purified 6-[18F]-DOPA sample used in a pre-clinical trial revealed that the chemical and/or radiochemical purity of the PET imaging ligand, 6-[18F]-DOPA was greater than 97 +/- 0.5% with a specific activity of 365 +/- 31 mCi/mmol. The knowledge and assurance of radiochemical purity of PET ligands are essential for the interpret...
Annals of Neurology, 2005
Nicotinic acetylcholine receptors (nAChRs) have close interactions with the dopaminergic system a... more Nicotinic acetylcholine receptors (nAChRs) have close interactions with the dopaminergic system and play critical roles in cognitive function. nAChRs were imaged in 10 non-demented Parkinson's disease (PD) patients and 15 age-matched healthy subjects using a single photon emission computed tomography ligand [ 123 I]5-iodo-3-[2(S)-2-azetidinylmethoxy]pyridine. Using an arterial input function, we measured the total distribution volume (V; specific plus non-displaceable) as well as the delivery (K 1). PD showed a widespread significant decrease (∼10%) of V in both cortical and subcortical regions without a significant change in K 1. These results indicate the importance of extending the study to demented patients.
Journal of Alzheimer's disease : JAD, 2013
The rapidly rising prevalence and cost of Alzheimer's disease in recent decades has made the ... more The rapidly rising prevalence and cost of Alzheimer's disease in recent decades has made the imaging of amyloid-β deposits the focus of intense research. Several amyloid imaging probes with purported specificity for amyloid-β plaques are currently at various stages of FDA approval. However, a number of factors appear to preclude these probes from clinical utilization. As the available "amyloid specific" positron emission tomography imaging probes have failed to demonstrate diagnostic value and have shown limited utility for monitoring therapeutic interventions in humans, a debate on their significance has emerged. The aim of this review is to identify and discuss critically the scientific issues contributing to the extensive inconsistencies reported in the literature on their purported in vivo amyloid specificity and potential utilization in patients.
Psychopharmacology, 1981
8 mg of naloxone were administered IV to 14 normal volunteers in a placebo-controlled, double-bli... more 8 mg of naloxone were administered IV to 14 normal volunteers in a placebo-controlled, double-blind experiment. Plasma levels offl-endorphin, cortisol, prolactin, growth hormone, HVA and MHPG were determined before and 45 min after administration. Naloxone elicited significant increases in cortisol and MHPG but did not change plasma levels of the other compounds. In an additional experiment on two subjects, 20 mg of naloxone caused elevations offl-endorphin as well as of cortisol. This parallel increase indicates that the linkage between the secretion of fi-endorphin and ACTH/cortisol may be dose-dependent. The increase in MHPG is in agreement with the hypothesized association of noradrenergic hyperactivity and opiate withdrawal.
Neuropsychopharmacology, 1998
The regional cerebral metabolic rates of 19 male medicationwithdrawn schizophrenic patients were ... more The regional cerebral metabolic rates of 19 male medicationwithdrawn schizophrenic patients were determined by positron emission tomography (PET) while performing an auditory discrimination task (CPT). Regardless of the accuracy of their CPT performance, the schizophrenic patients had lower metabolic rates in their prefrontal cortex and higher rates in their posterior putamen compared to 41 healthy males. Abnormally low right anterior midprefrontal cortex metabolic rates predicted better clinical response while high basal ganglia rates and low mid-cingulate rates predicted poor treatment response to neuroleptics. The findings imply that the sustained attention pathway and its distributed network of brain structures are likely to play an important role in the expression of psychotic symptoms and the mediation of their response to antipsychotics.
Journal of Cerebral Blood Flow & Metabolism, 1993
Two consecutive measurements of resting CBF were carried out in normal volunteers (n = 25) using ... more Two consecutive measurements of resting CBF were carried out in normal volunteers (n = 25) using H215O positron emission tomography. Absolute whole-brain blood flow (WBBF; ml 100 g−1 min−1, mean ± SD) for the first (40.3 ± 6.4) and second (39.3 ± 6.5) measurements was not significantly different (mean % difference 2.3 ± 8.7). Analysis of regions of interest showed no significant differences in absolute regional CBF (rCBF) and normalized (rCBF/WBBF) rCBF. Left-right differences were also not significant. These data demonstrate the reproducibility of resting CBF measurements in normal humans.
British Journal of Pharmacology, 1987
Administration of the 5-HTIB receptor agonist m-chlorophenylpiperazine (m-CPP) to rats produces d... more Administration of the 5-HTIB receptor agonist m-chlorophenylpiperazine (m-CPP) to rats produces dose-dependent decreases in locomotor activity and food intake. 2 The locomotor suppressant effect of m-CPP was inhibited by the 5-hydroxytryptaminergic antagonist, metergoline, but not by phentolamine, propranolol, clonidine, or haloperidol. 3 The locomotor suppressant effects of m-CPP were enhanced following long-term (but not shortterm) treatment with imipramine, possibly reflecting the postulated development of a functional supersensitivity of 5-HTIB receptors mediating locomotion during longer-term antidepressant drug treatment. 4 The food intake suppressant effects of m-CPP were enhanced following both short (3-5 days) and longer-term (21 days) treatment with imipramine. Rapidly developing 5-hydroxytryptamine uptake inhibition may be responsible for this change, or it may represent an earlier adaptive change in the 5-HTIB receptors mediating food intake compared to more complexly modulated motor responses.
Biological Psychiatry, 1992
Phencyclidine (PCP) intoxication can mimic the positive and negative symptoms of schizophrenia. P... more Phencyclidine (PCP) intoxication can mimic the positive and negative symptoms of schizophrenia. PCP blocks the NMDA glutamate channel, decreasing corticostriatal activation. The basal ganglia modulates the relay of sensory information to the cortex. This striatothalamocortical loop is hypothesized to be involved in schizophrenia and PCP intoxication. We measured FDG PET metabolism and EEG ot following photic sensory driving in six chronic PCP users. The photic driving stimulus was administered at 2.38 c/sec, 4.54 c/sec, and 8.33 c/sec. High basal ganglia FDG metabolism was related to decreased frontal, parietal, and occipital photic driving ot power (r =-0.067 to-0.93). High thalamic FDG metabolism was similarly related to decreased photic driving ot (r =-0.33 to-0.7). These data are consistent with a PCP effect on subcortical •netabolism which may have resulted in the abnormal relay of sensory information to the cortex reflected by a decreased a pc,,ver.
Clinical Pediatrics, 1996
Background. Lesch-Nyhan disease is a rare, devastating, X-linked recessive disorder of purine syn... more Background. Lesch-Nyhan disease is a rare, devastating, X-linked recessive disorder of purine synthesis. Patients present with hyperuricemia, choreoathetosis, dystonia, and aggressive and self-injurious behavior. Although the genetic and biochemical abnormalities have been identified, the causes of the neuropsychiatric syndrome remain unclear. Methods. We used positron-emission tomography to measure presynaptic accumulation of fluorodopa F 18 tracer in the dopaminergic regions of the brains of 12 patients with Lesch-Nyhan disease (age, 10 to 20 years) and 15 healthy controls (age, 12 to 23). The results were expressed as ratios of specific to nonspecific radioactive counts. A low ratio indicates decreased dopa decarboxylase activity and dopamine storage. Results. The fluorodopa F 18 ratio was significantly lower in the putamen (31 percent of control values), cau-date nucleus (39 percent), frontal cortex (44 percent), and ventral tegmental complex (substantia nigra and ventral tegmentum; 57 percent) in the patients with Lesch-Nyhan disease than in the controls. Uptake of the tracer was abnormally low even in the youngest patients tested, and there was no overlap in the values between patients and controls. Conclusions. Patients with Lesch-Nyhan disease have abnormally few dopaminergic nerve terminals and cell bodies. The abnormality involves all dopaminergic pathways and is not restricted to the basal ganglia. These dopaminergic deficits are pervasive and appear to be developmental in origin, which suggests that they contribute to the characteristic neuropsychiatric manifestations of the disease.