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Biomedical subjects

R M Cohen

Publications and source records attributed to R M Cohen.

At least 109 records · Page 6Linked to original sources
PubMed1990

Cerebral glucose metabolic differences in patients with panic disorder.

Regional glucose metabolic rates were measured in patients with panic disorder during the performance of auditory discrimination. Those regions examined by Reiman and colleagues in their blood flow study of panic disorder [Nature 310:683 (1984)] were examined with a higher resolution positron emission tomography (PET) scanner and with the tracer [F-18]-2-fluoro-2-deoxyglucose (FDG). In contrast to the blood flow findings of Reiman et al., we did not find global gray metabolic differences between patients with panic disorder and normal controls. Consistent with the findings of Reiman et al. [Nature; Am J Psychiatry 143:469 (1986)], we found hippocampal region asymmetry. We also found metabolic decreases in the left inferior parietal lobule and in the anterior cingulate (trend), as well as an increase in the metabolic rate of the medial orbital frontal cortex (trend) of panic disorder patients. It is unclear whether the continuous performance task (CPT) enhanced or diminished findings that would have been noted in a study performed without task.

Acoustic Stimulation↗
PubMed1989

6-18F-L-dopa imaging of the dopamine neostriatal system in normal and clinically normal MPTP-treated rhesus monkeys.

Positron emission tomography following intravenous administration of 6-[18F]-L-fluorodopa was used to investigate the usefulness of PET for the assessment of normal and abnormal dopaminergic function. For this purpose, the incracerebral distribution of 6-[18F]-L-fluorodopa and its metabolites was evaluated in normal control and asymptomatic MPTP-treated rhesus monkeys. MPTP is a neurotoxic compound which destroys selectively the dapaminergic neurons of the nigrostriatal pathways in primates. The 18F accumulation was found to be significantly reduced in the striatum, putamen more than caudate, of the MPTP-treated animals compared to the normal controls. The 18F accumulation in dopamine-poor areas did not differ between the two groups. The ratios of striatum to dopamine-poor brain area were highly correlated to the concentrations of the dopamine metabolite, homovanillic acid, in the cerebrospinal fluid of the same animals. The findings are consistent with the hypothesis that "silent damage" to the dopaminergic nigral neurons may precede the onset of parkinsonism by many years and that PET scanner examination using 6-[18F]-L-fluorodopa may be useful in the detection of subtle dopaminergic dysfunctions as may exist in DA-related motor syndromes and neuropsychiatric disorders.

Animals↗
PubMed1989

Acute effects of high-dose thyrotropin releasing hormone infusions in Alzheimer's disease.

Thyrotropin releasing hormone (TRH) was administered intravenously to ten patients with Alzheimer's Disease (AD) in a high-dose paradigm, thought to maximize central nervous system effects and potentially produce facilitation of cholinergic function, a known property of the neuropeptide. Acute effects of TRH on behavioral, cognitive and physiologic measures were assessed after patients received 0.1 mg/kg TRH, 0.3 mg/kg TRH and placebo, the higher TRH dose and placebo being given in a randomized, double-blind fashion. Patients showed statistically significant increases in arousal and improvement in affect, as well as a modest improvement in semantic memory, all after receiving the higher TRH dose. Both TRH doses produced transient rises in systolic blood pressure, with no effect on diastolic blood pressure, heart rate or temperature. This study suggests that high-dose TRH can be safely administered to AD patients and is neurobehaviorally active; further studies are needed to determine the extent and mechanism of the cognitive and psychobiological properties of this peptide in AD and other neuropsychiatric disorders.

Aged↗
PubMed1989

Low-dose oral lorazepam administration in Alzheimer subjects and age-matched controls.

Ten patients with Alzheimer's disease and ten age-matched normal controls were studied in a double-blind, placebo-controlled acute trial of 1 mg PO lorazepam to test the effects of low-dose benzodiazepine on memory and behavior in a mostly older population. Cognitive effects differed somewhat between Alzheimer patients and normal controls, with Alzheimer patients revealing predominantly "attentional" impairments and age-matched controls showing possible "disinhibition." Specifically, Alzheimer patients made more omission errors on a continuous performance task, whereas controls made more commission and intrusion errors with lorazepam versus placebo. This low dose of lorazepam (1 mg), which was associated with mild but statistically significant sedation in both groups, also produced no significant decrease in recent memory or in access to semantic memory. These cognitive findings contrast markedly to the reported effects of scopolamine on recent memory; therefore, supporting the idea that cholinergic interruption has a more specific effect on human memory and on learning than that of low-dose benzodiazepines. Further studies with a wider dose range of benzodiazepines are necessary to evaluate the possibility of differential sensitivity between Alzheimer patients and normal elderly controls.

Administration, Oral↗
PubMed1989

Cerebral glucose metabolic rates in obsessive compulsive disorder.

Brain metabolism was measured with positron emission tomography and [18F] 2-fluoro-2-deoxyglucose in normal subjects and in patients with obsessive compulsive disorder (OCD) while they performed a continuous auditory discrimination task designed to evaluate the functional localization of sustained attention. Data on 8 nondepressed patients with OCD were compared with 30 normal volunteers. We observed significantly higher normalized regional metabolism both in the right orbital frontal cortex (p = 0.002, two-tailed t test) and in the left anterior orbital frontal cortex (p = 0.017, one-tailed t test) and in patients with OCD as compared to normal controls. We observed no normalized glucose metabolic differences in basal ganglia structures in patients with OCD as compared to our normal controls. There were no statistical differences in global glucose metabolic values between the OCD and the control group. Our findings are consistent with the findings of Baxter et al. (Arch Gen Psychiatry 44:211-218, 1987). Regions in the parietal cortex also appear to show differences in this preliminary study.

Adult↗
PubMed1989

Evidence for common alterations in cerebral glucose metabolism in major affective disorders and schizophrenia.

Regional glucose metabolic rates were measured in affectively disordered patients during the performance of auditory discrimination. Those regions previously observed as abnormal in schizophrenia were examined to see if similar alterations might be associated with affective disorder. The abnormalities observed in the mid-prefrontal cortex, an area that appears to be an important biologic determinant of the sustained attention required of subjects in this task, are similar to those previously observed in schizophrenia. Moreover, the abnormalities do not appear to relate directly to symptomatology or the subject's performance. The authors discuss the possibility that this abnormality may reflect dysfunction in the integrating component of the attention network critical for the maintenance of goal-directed behavior and thus represent a psychosis vulnerability factor in some patients.

Acoustic Stimulation↗
PubMed1989

Quality control procedure for 6-[18F]fluoro-L-DOPA: a presynaptic PET imaging ligand for brain dopamine neurons.

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 interpretation of clinical PET imaging results. The assurance of such quality control would enable comparisons of 6-[18F]-DOPA/PET data obtained from various medical centers using different radiopharmaceutical procedures.

Brain↗
PubMed1989

Reversal of brain metabolic abnormalities following treatment of AIDS dementia complex with 3'-azido-2',3'-dideoxythymidine (AZT, zidovudine): a PET-FDG study.

Brain glucose metabolism was evaluated in four patients with acquired immunodeficiency syndrome (AIDS) dementia complex using [18F]fluorodeoxyglucose (FDG) and positron emission tomography (PET) scans at the beginning of therapy with 3'-azido-2',3'-dideoxythymidine (AZT, zidovudine), and later in the course of therapy. In two patients, baseline, large focal cortical abnormalities of glucose utilization were reversed during the course of therapy. In the other two patients, the initial PET study did not reveal pronounced focal alterations, while the post-treatment scans showed markedly increased cortical glucose metabolism. The improved cortical glucose utilization was accompanied in all patients by immunologic and neurologic improvement. PET-FDG studies can detect cortical metabolic abnormalities associated with AIDS dementia complex, and may be used to monitor the metabolic improvement in response to AZT treatment.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Role of serotonergic input in the down-regulation of beta-adrenoceptors following long-term clorgyline treatment.

Administration of the selective monoamine oxidase (MAO) type A-inhibiting antidepressant clorgyline (1 mg/kg per day) to rats for 21 days caused a significant decrease in cortical [3H]dihydroalprenolol binding. Selective lesioning of central serotonergic axons by 5,7-dihydroxytryptamine (5,7-DHT; confirmed by the presence of the serotonin syndrome in response to a 40 mg/kg dose of 5-hydroxytryptophan (5-HTP) or inhibition of 5-HT synthesis by parachlorophenylalanine (PCPA) caused significant 5-HT and 5-HIAA depletions in the cortex without much effect on NE and DA concentrations, but did not have any significant effect on beta-adrenoceptor density, and furthermore failed to attenuate clorgyline-induced decreases in beta-adrenoceptor density. Clorgyline treatment partially antagonized 5-HT depletion by the 5,7-DHT lesion or PCPA treatment. These findings suggest that due to their ability to raise 5-HT concentrations, MAO-inhibiting antidepressants may be a better alternative than the tricyclics in treating depressed patients with reduced 5-HT if down-regulation of beta-adrenoceptors is critical for antidepressant efficacy.

5,7-Dihydroxytryptamine↗
PubMed1988

Blockade of in vivo binding of 125I-labeled 3-iodobenzamide (IBZM) to dopamine receptors by D2 antagonist and agonist.

The in vivo binding of [125I]3-iodobenzamide (IBZM), a substituted benzamide, to DA receptor binding sites in the caudate nucleus, nucleus accumbens, and olfactory tubercle was investigated by using ex vivo autoradiography. The in vivo binding of IBZM seems to be selective to D2 dopamine receptors, since the binding was blocked by pretreatment of animals with D2 agonist LY-171555 or antagonist YM-09151-2. Furthermore, in vitro binding assays in striatal membranes confirmed that IBZM binding was highly selective to D2 sites. Thus, IBZM, when labeled with 123I (T1/2: 13h; 159 kev), could be a potential ligand for imaging D2 dopamine receptors by single photon emission computerized tomography procedures.

Animals↗
PubMed1988

Multiple-dose arecoline infusions in Alzheimer's disease.

Twelve patients with dementia of the Alzheimer type received two-hour infusions of placebo and the muscarinic cholinergic agonist arecoline hydrobromide at rates of 1, 2, and 4 mg/h in a double-blind, randomized fashion. These infusions resulted in dose-dependent physiologic and neuroendocrine effects consistent with central cholinergic stimulation. Infusions were generally well tolerated. No statistically significant improvement in performance on most cognitive tasks assessing knowledge memory and episodic learning and memory was observed at any dose, although marginal improvement in picture recognition ability and in ratings of word-finding were observed at the lower doses. Psychomotor activation and slightly improved affect were reliably observed at the lower doses, whereas increasing psychomotor retardation was observed at the highest dose. The data support a role for central cholinergic modulation of some aspects of cognition, behavior, and affect in this population. The apparent greater behavioral sensitivity of patients with Alzheimer's disease in comparison with subject populations previously studied, as well as the altered dose responsiveness, merit further study in relationship to normal aging.

Aged↗
PubMed1988

The effects of acute scopolamine in geriatric depression.

In an intensive multidrug, multidose study, nine elderly depressed patients were administered 0.1, 0.25, and 0.5 mg of scopolamine hydrobromide, 1 mg of oral lorazepam, and placebo in a double-blind investigation aimed at assessing the status of the central cholinergic nervous system in geriatric depression. Significant cognitive and behavioral effects of scopolamine were observed only at the high dose (0.5 mg), while lower doses and lorazepam showed no significant differences from placebo. Cognitive deficits caused by scopolamine were in the areas of new learning, access to semantic memory, vigilance, and continuous performance. Behavioral effects consisted of activation, restlessness, and anxiety, but there was no significant effect on depressed mood. These results suggest that elderly depressed patients with mild to moderate cognitive impairment seem to be more similar to previously studied elderly controls rather than to patients with Alzheimer's disease in their reaction to short-term cholinergic blockade, and suggest that the cognitive and mood changes often seen in geriatric depression may involve factors other than disturbed muscarinic cholinergic mechanisms.

Aged↗
PubMed1988

In vitro binding properties and autoradiographic imaging of 3-iodobenzamide ([125I]-IBZM): a potential imaging ligand for D-2 dopamine receptors in SPECT.

The in vitro binding properties of the [125I] labeled benzamide (S(-)-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-hydroxy-3-iodo-6-methoxy- benzamide, IBZM) were determined in bovine and mouse caudate membrane homogenates and by autoradiography of mouse brain slices. [125I]-IBZM binding is saturable and reversible with a Bmax of 373 +/- 51 fmol/mg protein and a Kd of 3.1 +/- 0.62 nM (mean +/- SD, Scatchard analyses) and 0.56 nM as calculated by association and dissociation time constants. In competition experiments, Ki values for the D-2 antagonists YM-09151-2 and spiperone are 4 orders of magnitude lower than the Ki value for the D-1 antagonist SCH-23390 and S(-)-IBZM is ten-fold more potent than R(+)-IBZM. [125I]-IBZM has a low affinity for serotonin S-2 and for alpha receptors. Therefore, it is a highly selective ligand for dopamine D-2 receptors. Autoradiographic images of brain sections incubated with [125I]-IBZM show the dopamine D-2 receptors of the striatum, nucleus accumbens and olfactory tubercle with a high ratio of specific to nonspecific binding. Thus, S(-)-IBZM, when labeled with [123I], may be useful for in vivo imaging of dopamine D-2 receptors by single photon emission computerized tomography (SPECT).

Animals↗
PubMed1988

The effect of neuroleptics on dysfunction in a prefrontal substrate of sustained attention in schizophrenia.

Regional brain metabolism was measured in patients with schizophrenia during the performance of auditory discrimination to evaluate the effect of neuroleptic medication on the middle prefrontal cortex, an area that appears to be an important biological determinant of the sustained attention required of subjects in this task. While unmedicated patients with schizophrenia have lower than "normal" metabolic rates in this cortical area that are unrelated to performance, patients receiving neuroleptics appear to have this metabolic deficit attenuated with higher metabolism in this area associated with greater accuracy of performance. This change occurs in the context of differential neuroleptic effects on the cortical regions of the frontal cortex, increased metabolism in the basal ganglia, thalamus and temporal lobes, and no apparent effect in the parietal and occipital cortices. The findings suggest that only part of the abnormality in the prefrontal cortex determination of sustained attention in schizophrenia is sensitive to neuroleptic treatment.

Adult↗
PubMed1988

From syndrome to illness: delineating the pathophysiology of schizophrenia with PET.

The Section on Clinical Brain Imaging of the Laboratory of Cerebral Metabolism has been engaged in studying regional brain metabolism by positron emission tomography (PET) to establish the pathophysiology of schizophrenia. Recent studies have revealed that the fluorodeoxyglucose (FDG) PET methodology can be applied successfully to determine the anatomical substrata of directed attention. In normal controls, the metabolic rate in the middle prefrontal cortex, measured during the ongoing performance of auditory discrimination, is associated with their accuracy of performance. In unmedicated patients with schizophrenia, even those who performed as well as normals, the metabolic rate in the mid-prefrontal cortex was found to be significantly lower than normal. Further, this decreased metabolic rate was unrelated to performance. In medicated patients with schizophrenia, at least part of the metabolic deficit remains, but this deficit appears to be performance-related. These findings suggest several conclusions. The mid-prefrontal cortex and its dopamine neurotransmitter pathway input are important biological determinants of sustained attention. Two types of prefrontal metabolic deficits may contribute to dysfunctional goal-directed behavior and, more speculatively, vulnerability to psychosis in some patients with schizophrenia. One deficit is sensitive to neuroleptics, and thus presumably to a change in the balance of regional brain dopamine input. A second deficit is unaffected by neurolpetic treatment.

Brain↗
PubMed1988

High-dose naloxone in older normal subjects: implications for Alzheimer's disease.

The behavioral and cognitive effects of naloxone HCl, in doses of 5 micrograms/kg, 0.1 mg/kg, and 2.0 mg/kg administered as an IV bolus, were assessed in a double-blind, placebo-controlled, randomized study of eight normal subjects ranging in age from 44 to 74 years (mean 63). Naloxone produced mild behavioral effects with slight cognitive impairment after the 2.0 mg/kg dose only. The threshold, dose dependency, characteristics, and magnitude of these behavioral effects were similar to what has previously been reported in young normal subjects, but markedly different from those observed in patients with dementia of the Alzheimer type (DAT) matched in age to the current study sample. These data suggest that the metabolic fate of naloxone is not substantially affected by age within the range studied. The findings of this study provide further support for a role for endogenous opiate systems in the modulation of behavior and cognition, and suggest that the unusual behavioral sensitivity of patients with DAT to naloxone cannot be accounted for by the effect of age.

Adult↗