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The elevation of plasma beta-endorphin levels in major depression.
Day-time plasma beta-endorphin/beta-lipotrophic hormone (beta-ENDO/beta-LPH), ACTH and cortisol have been determined in 26 patients with major depression and 25 controls. beta-ENDO/beta-LPH and cortisol were significantly elevated in patients, while ACTH was not. Cortisol levels were significantly negatively correlated with age in controls as were beta-ENDO/beta-LPH and ACTH. In patients, by contrast, cortisol levels were positively, albeit not significantly, related to age. Peptide levels were not related to age in the patient group. Instead, beta-ENDO/beta-LPH was negatively correlated with clinical ratings of symptom severity in patients and positively associated with an acute psychosocial precipitant. The findings cast further light on beta-ENDO/beta-LPH as a measure of hypothalamic-pituitary over activity in depressive illness. A negative association with symptom severity suggests that beta-ENDO/beta-LPH responses are, like those of ACTH, down-regulated in the course of depressive illness.
Selecting controls for schizophrenia research studies: the use of the National Adult Reading Test (NART) is a measure of premorbid ability.
The National Adult Reading Test (NART) has achieved popularity as a measure of pre-morbid intellectual ability, based on the premises that pronunciation of irregular words is unaffected in many clinical disorders and that performance is highly correlated with general intellectual ability. Recently, schizophrenia research studies have begun to appear in the literature, where the NART has been used to estimate pre-morbid ability. However, this use has preceded the basic required demonstration that, in fact, NART performance is unaffected by the schizophrenic process. In the present study, NART performance was compared across three groups; 20 acutely ill unmedicated DSM-IIIR schizophrenics, 10 other unmedicated acute psychotics, and 20 control subjects. When demographic variability between the groups was controlled for, there were no group differences in terms of NART performance. NART performance was not correlated with Brief Psychiatric Rating Scale scores, and in all three groups, no significant differences emerged when demographically predicted intelligence quotients were compared with NART estimated intelligence quotients. NART performance (predicted on the basis of demographic variables) was not significantly different from observed NART performance in any of the three experimental groups. However, within the sample with schizophrenia, NART estimated pre-morbid IQ was significantly higher than currently measured intellectual abilities. These results suggest that the National Adult Reading Test provides a reasonable estimate of pre-morbid ability in acutely ill, unmedicated schizophrenic patients.
Mortality and causes of death in idiopathic Parkinson's disease: results from the Aberdeen whole population study.
Two hundred and forty-nine patients with Parkinson's disease previously examined by Mutch et al 1,2 were followed up three and a half years after the original study. Cognitive impairment, age, some postural signs and symptoms of Parkinson's disease and high scores on the Hoehn and Yahr scale predicted premature death. Patients were more likely to die from respiratory infections than controls. Respiratory diseases as cause of death recorded on the death certificate were not related to kyphosis, posture scores or Hoehn and Yahr scores before death. The hypothesis is advanced that death of respiratory causes might be associated with signs of general autonomic dysregulation.
Statistical parametric mapping of (99m)Tc-HMPAO-SPECT images for the diagnosis of Alzheimer's disease: normalizing to cerebellar tracer uptake.
BACKGROUND: For a quantitative comparison of images obtained during (99m)Tc-hexamethylpropylene amine oxime (HMPAO) single-photon emission computed tomography (SPECT), brain activity values are usually normalized to a reference region. In studies of Alzheimer-type dementia (ATD), the cerebellum is often used as a reference region, assuming that it is spared any major pathological involvement. Statistical parametric mapping (SPM) may enhance the evaluation of SPECT scans in ATD patients. However, current SPM software only allows scaling to average whole brain activity (i.e., global normalization). The aim of this study was to develop an easily applied, objective, and reproducible method for determining average cerebellar tracer uptake so that images can be scaled specifically to cerebellar activity prior to the performance of SPM analysis. We also investigated whether cerebellar normalization increases the sensitivity and specificity of SPM analysis of ATD patients compared with global normalization. METHODS: Image files were taken from a parallel study investigating the use of SPECT as a diagnostic tool for early onset of ATD. Two methods for determining cerebellar activity were developed: one manually, using templates, the other automated, using specified coordinates entered into a Matlab routine. Group comparison of ATD patients versus controls (= healthy volunteers and depressed patients) was performed on a voxel-by-voxel basis using SPM 96 on Windows 95. Receiver operator characteristics (ROC) were computed for 20 student raters examining patient and control scans with and without single-subject SPMs. RESULTS: The reduction of cerebral blood flow in the group of ATD patients appeared 1.7 times greater in spatial extent when the tracer uptake was normalized to cerebellum rather than to average whole brain activity. Computing the reverse contrast (reductions in the control group compared with ATD patients) produced clusters of significance in globally normalized images which were not manifest after normalizing to cerebellum. This is consistent with the notion that the cerebellum is spared in ATD. Analysis of the area under the ROC curve showed that cerebellar-normalized SPM produced significantly improved accuracy over perfusion scans alone. CONCLUSION: An easily applied, objective, reproducible method was developed for normalizing images to cerebellum prior to the performance of SPM analysis. Cerebellar normalization produced more extensive abnormalities in SPM analyses of ATD patients than global normalization. Furthermore, cerebellar normalization produced marginally more accurate diagnostic results in single-scan SPM analysis of ATD patients than did global normalization.
Clinical and psychometric correlates of dopamine D2 binding in depression.
BACKGROUND: Single photon emission tomography (SPET) with the dopamine D2/3 ligand 123I-IBZM gives a semi-quantitative estimate of dopamine binding. In depressed patients, we predicted evidence of reduced function, i.e. increased binding, particularly in more retarded patients. METHODS: Fifteen depressed patients with major depressive illness and 15 healthy, age- and sex- matched volunteerS were examined with a clinical and neuropsychological test battery and high resolution IBZM-SPET. Estimates for specific binding were computed by averaging striatum to whole slice or frontal uptake ratios over 8-10 scans acquired from 70 min after tracer injection. RESULTS: Using whole slice as reference, left striatal uptake ratios did not significantly differ for patients from controls. Right ratios were significantly higher in patients than controls (P = 0.03). There were significant correlations between IBZM binding in left and right striatum and measures of reaction time and verbal fluency. CONCLUSIONS: Increased IBZM binding in striatum probably reflects reduced dopamine function, whether due to reduced release of dopamine, or secondary up-regulation of receptors. The observed abnormalities may be trait or state related, an issue that needs to be addressed with longitudinal study designs. The possible role of medication as a confounding variable requires further exploration.
Temporal lobe abnormalities in dementia and depression: a study using high resolution single photon emission tomography and magnetic resonance imaging.
OBJECTIVES: Perfusion SPECT and MRI were used to test the hypothesis that late onset depression is associated with brain abnormalities. METHODS: Forty depressed patients (DSM-III-R major depressive episode, not demented at two year follow up) were recruited who were either drug free, or on a stable dose of antidepressants for at least three weeks, as well as 22 demented patients (DSM-IIIR and NINCDS/ADRDA criteria for probable Alzheimer's disease). Patients were imaged at rest with a high resolution single slice 12 detector head scanner (SME-Neuro 900) and the cerebral perfusion marker 99mTc-exametazime (HM-PAO). Temporal lobe templates were fitted with brains pitched by 20 degrees-30 degrees. A subgroup of 41 patients (22 depressed) were also scanned using a Siemens Magnetron 1.0 Tesla magnetic resonance imager, using a FLAIR imaging sequence for the assessment of white matter hyperintensities, and a Turbo FLASH sequence for the measurement of medial temporal lobe width. RESULTS: Demented patients showed reduced perfusion, particularly in the left temporoparietal cortex. In these regions of interest, patients with late onset depression tended to have perfusion values intermediate between patients with early onset depression and demented patients. Differences in changes in white matter between demented and early and late onset depressive patients did not reach conventional levels of significance. Temporal lobe width differed between demented and depressed patients, but not between early and late onset depressed patients. Perfusion and temporal lobe width were not associated, but reductions of perfusion were associated with periventricular white matter changes. Mini mental state examination scores were associated with temporal perfusion in demented patients and with changes in deep white matter in depressed patients. Finally, severity of depressive symptoms was associated with decreased perfusion in frontotemporal and basal ganglia regions of interest. CONCLUSION: A cumulative effect of duration of illness on regional cerebral perfusion could not be confirmed. Late onset depression may show more abnormalities of deep white matter and of left temporoparietal perfusion than early onset depression, but the underlying pathology remains to be established.
Alzheimer's disease in adults with Down's syndrome: the relationship between regional cerebral blood flow equivalents and dementia.
Twenty adult patients suffering from Down's syndrome (DS) were recruited from hospitals and the community, together with 14 age- and sex-matched controls of normal intelligence. Dementia was diagnosed in patients using a structured psychiatric and physical examination as well as a carer interview and case notes. All patients and controls were imaged using single photon emission computerized tomography with 99mTc-exametazime. Four patients were clinically demented and all of them showed regional cerebral blood flow (rCBF) changes commonly found in patients with Alzheimer's disease, namely bilateral temporo-parietal deficits. These changes were also observed in about half of the patients without clinical evidence of dementia, but in none of the healthy controls. Across the group of patients, temporo-parietal rCBF deficits were associated with evidence of deterioration, but not with advancing age.
Estimating pre-morbid intellectual ability in the Alcoholic Korsakoff syndrome.
The National Adult Reading Test (NART) is widely used in clinical and research settings to estimate pre-morbid intellectual levels. The validity of the NART in estimating premorbid ability in Alcoholic Korsakoff Syndrome (AKS) is examined in the present study. Twenty AKS subjects were compared with 40 healthy controls. The validity of the NART as a pre-morbid measure in AKS was examined using four methods. AKS subjects made more NART errors than controls, had lower NART predicted IQ than demographically predicted IQ, made more NART errors than predicted by demographic variables and demonstrated NART performance which correlated with degree of memory impairment. It is concluded that NART performance is detrimentally affected by the AKS and that estimating pre-morbid intellectual level in Korsakoff's psychosis using the NART may be invalid. Furthermore, it is postulated that the impaired ability to pronounce correctly irregular words in AKS may reflect a failure in cognitive 'error checking' which may represent a consequence of frontal lobe dysfunction.
Altered cerebral perfusion measured by SPECT in relatives of patients with schizophrenia. Correlations with memory and P300.
BACKGROUND: Genetic studies in schizophrenia are hampered by the complex heterogeneous clinical phenotype. Biological variables identified as trait markers of risk could clarify the mode of inheritance, define clinical subgroups and provide clues about aetiology. AIMS: To use single photon emission computed tomography (SPECT) to compare brain perfusion maps in patients with schizophrenia (n = 19), their asymptomatic 'high-risk' relatives (n = 36) and control subjects (n = 34) and to examine the relationships between imaging, memory and P300 event-related potential. METHOD: SPECT, memory tests and P300 recording were carried out. RESULTS: In the patients with schizophrenia and their relatives, perfusion was reduced in left inferior prefrontal and anterior cingulate cortex and increased bilaterally in a subcortical region. Perfusion significantly correlated with verbal memory and P300 amplitude in left inferior prefrontal cortex and with P300 latency in anterior cingulate cortex. CONCLUSIONS: Medication- and symptom-free relatives had altered regional perfusion intermediate between subjects with schizophrenia and controls. Impaired perfusion, verbal memory and P300 appear to be related traits associated with an increased risk of illness.
Limbic dysfunction in schizophrenia and mania. A study using 18F-labelled fluorodeoxyglucose and positron emission tomography.
BACKGROUND: Diagnostic classes (derived from CATEGO) can be correlated with regional brain metabolism in patients with major psychiatric disorders. METHOD: Seventeen patients with schizophrenia, 15 with mania, 10 with depression and 10 healthy Volunteers were examined with positron emission tomography (PET) and 18F-labelled fluorodeoxyglucose, as a marker for glucose metabolism. The number of possible comparisons of regions of interest was reduced by principal-components analysis, and differences in factor scores were determined between diagnostic groups. RESULTS: Four independent factors, representing distributed brain systems, emerged: an anterior-posterior (1), a left-right temporal (2), a temporofrontal (3), and a mediofrontal (4) system, of which (1), (2) and (3) were abnormal in schizophrenia, (1) and (2) in mania, and (1) in depression. CONCLUSIONS: Abnormal patterns of metabolism could be detected, in decreasing order, in schizophrenia, mania and depression. Some of these abnormalities are likely to be due to medication, but others will be associated with structural or functional abnormalities of the frontolimbic system in the diagnostic groups.
Uptake of 99mTc-exametazime shown by single photon emission computerized tomography in obsessive-compulsive disorder compared with major depression and normal controls.
Twelve patients with obsessive-compulsive disorder (OCD) were investigated at rest using single photon emission computerized tomography with 99mTc-exametazime. The uptake of 99mTc-exametazime was expressed relative to calcarine/occipital cortex. Patients were matched for drug treatment with 12 patients with a major depressive episode and the patient groups were compared with a control group. Significant bilateral decreases in tracer uptake were confined to basal ganglia in the OCD group. There was a paradoxical positive correlation between anxiety ratings and tracer uptake to basal ganglia in the OCD group. The findings confirm that the functional topography of OCD implicates altered function in the basal ganglia.
P300 and smooth eye pursuit: concordance of abnormalities and relation to clinical features in DSM-III schizophrenia.
Twenty-five DSM-III-diagnosed schizophrenics and 37 normal and age-matched controls were examined using an oddball paradigm for the generation of P300 and smooth eye-pursuit tasks. Results were compared between groups and related to clinical characteristics, including a family history of psychiatric illness. Group differences were found for P300 amplitudes, latencies and eye-tracking. A family history of psychiatric illness was associated with normal eye-tracking in patients. Small P300 amplitudes alone and in combination with long P300 latencies were associated with a family history in controls.
Neuroticism as a predictor of mood change: the effects of tryptophan depletion.
BACKGROUND: Acute tryptophan depletion (ATD) results in a transient lowering of mood in patients recovered from depression and in healthy volunteers with a family history of affective disorders. The personality trait of neuroticism is strongly associated with depression. AIMS: To assess whether neuroticism predicts mood change in response to ATD in healthy volunteers. METHOD: Healthy volunteers who scored at the top and bottom fifth percentiles of neuroticism scores (17 and 15 respectively) were selected. In a double-blind, crossover study they received a tryptophan-free or a control drink. Mood and cognition were assessed. RESULTS: Neuroticism did not predict the amount of mood change following ATD but did moderate performance on the verbal fluency test. A family history of affective disorder (n=5) predicted mood change but not cognitive function following ATD. CONCLUSIONS: Neuroticism moderates aspects of cognitive function, but in this study it was not strongly related with mood change via serotonin.
Stimulation of the noradrenergic system enhances and blockade reduces memory for emotional material in man.
BACKGROUND: It is clearly established that emotional events tend to be remembered particularly vividly. The neurobiological substrates of this phenomenon are poorly understood. Recently, the noradrenergic system has been implicated in that beta blockade has been shown to reduce significantly the delayed recall of emotional material with matched neutral material being unaffected. METHODS: In the present study, 36 healthy young adults were randomly allocated to receive either yohimbine, which stimulates central noradrenergic activity, metoprolol which blocks noradrenergic activity, or matched placebo. The three groups were well matched. All capsules were taken orally, prior to viewing a narrated 11 slide show described a boy being involved in an accident. RESULTS: Yohimbine significantly elevated, and metoprolol reduced mean heart rate during the slide show relative to placebo, thus confirming the efficacy of the pharmacological manipulation. One week later, in a surprise' test, memory for the slide show was tested. As predicted, yohimbine-treated subjects recalled significantly more and metoprolol subjects fewer slides relative to placebo. This result was confirmed via analysis of multiple-choice recognition memory scores. CONCLUSIONS: We conclude that stimulation of the noradrenergic system results in the enhancement and blockade in a reduction of recall and recognition of emotional material in man.
Laterality of visuo-spatial attention in acute and chronic schizophrenia, major depression and in healthy controls.
Previous studies have suggested that schizophrenia is characterized by an asymmetry of visuo-spatial attention, in particular that acute unmedicated schizophrenics demonstrate relative inattention to right hemispace, whereas chronically medicated patients demonstrate the opposite pattern. In the present study, 30 unmedicated schizophrenic patients, 32 chronically medicated schizophrenic patients, 30 patients suffering from major depression and 60 healthy controls were assessed using two measures of hemispatial attentional neglect, namely letter and star cancellation. The results demonstrated that the chronic schizophrenic group made more total omissions for star cancellation (in both right and left hemispace), but that there was no difference between the groups in terms of omission asymmetry for either letter or star cancellation.
Correlation of regional cerebral blood flow equivalents measured by single photon emission computerized tomography with P300 latency and eye movement abnormality in schizophrenia.
Single photon emission tomography with the intravenous blood flow marker 99mTc-exametazime was carried out in 14 acutely ill drug-free schizophrenic patients from whom P300 event-related potential, smooth eye pursuit eye tracking and verbal fluency were measured within a few days of scanning. Smooth pursuit eye movement abnormality correlated significantly with abnormal tracer uptake in superior pre-frontal cortex on the right and left and inferior pre-frontal cortex on the left. Abnormal eye movement was also associated with higher tracer uptake in left anterior cingulate and left posterior cingulate. P300 latency was significantly correlated with higher tracer uptake in left superior pre-frontal and left parietal regions. Verbal fluency performance was negatively correlated with tracer uptake in left frontal region. Eye tracking abnormality in schizophrenia is associated with bilateral frontal lobe disturbance and P300 latency increase with left-sided frontal and temporoparietal dysfunction. There was, however, a significant inverse relation between eye tracking abnormalities and abnormal perfusion in the left anterior cingulate region.
Effects of fluvoxamine treatment on cognitive functioning in the alcoholic Korsakoff syndrome.
Eight patients suffering from the alcoholic Korsakoff syndrome (AKS) were entered in a double-blind cross-over trial of fluvoxamine 200 mg per day for 4 weeks versus matched placebo for 4 weeks. At the end of each phase, patients were assessed using a detailed neuropsychological test battery. Verbal fluency performance was significantly impaired following fluvoxamine treatment. No significant differences emerged on any of the other cognitive test measures when fluvoxamine was compared with placebo. However, two of the patients developed a major depressive episode while receiving fluvoxamine.
PASAT performance and the pattern of uptake of 99mTc-exametazime in brain estimated with single photon emission tomography.
The effect of the paced auditory serial addition test (PASAT) on the regional uptake of 99mTc-exametazime was determined by single photon emission computed tomography. Twenty insulin-treated diabetic outpatients were scanned at rest and during the performance of the PASAT task using split-dose injection of tracer. When resting and activation scans were compared there were significant decreases in tracer uptake in the right anterior cingulate and left posterior cingulate areas during PASAT activation. The findings are compared with previous studies which had implicated the anterior cingulate area in the mechanisms of attention in humans and other animals. The potentially confounding role of anxiety during attentional tasks is discussed.
Proactive interference and the neuropsychology of schizophrenia.
Gray, Felden, Rawlins, Hemsley & Smith (1991) have proposed a theoretical model of the neuropsychology of schizophrenia. A major feature of this model is that it is a weakening of the influences of memories of previous input on current perception/learning which is basic to the phenomenon of acute schizophrenia. In the present study, proactive interference (PI) was used as a paradigm to test this hypothesis. PI occurs when new learning is diminished as a consequence of previously learned material. According to our reading of the Gray et al. (1991) model, acutely ill unmedicated patients with schizophrenia should demonstrate reduced PI relative to controls. Ten acutely ill unmedicated patients with schizophrenia, 20 patients suffering from major depressive disorder, and 20 healthy controls were assessed using a PI paradigm. No significant differences in PI emerged between the groups. The results do not support this specific feature of the neuropsychological model of acute schizophrenia proposed by Gray et al. (1991).