Greater metabolic rate decreases in hippocampal formation and proisocortex than in neocortex in Alzheimer's disease.

Neuropathological studies of Alzheimer's disease (AD) have found pathological changes in some cytoarchitectural regions and relative sparing in others. Positron emission tomography (PET) studies have also shown selective decreases in glucose metabolic rates but have generally focused on whole brain lobes or geometrically derived regions of interest. In this report, a template of Brodmann areas, derived from a whole brain histological section atlas, was used to analyze PET findings from 34 AD patients and 16 control subjects matched for age, sex, and educational level. AD patients had lowest glucose metabolic rates in limbic areas of the temporal lobe and other proisocortical areas higher rates in frontal lobe and unimodal association areas, and relative sparing of parietal/occipital lobes and motor/sensory cortices. Analysis of variance revealed larger effect sizes when AD and control subjects were compared on metabolic rate for cortical type than for lobe. These findings, which parallel neuropathological studies of regional distribution of neurofibrillary tangles in AD, suggest that vulnerability is greatest in cortical areas that are in closer synaptic contact with limbic areas.

Regional cerebral blood flow during the Wisconsin Card Sort Test in schizotypal personality disorder.

Regional cerebral blood flow (rCBF) was measured by single photon emission computed tomography in 10 patients with schizotypal personality disorder (SPD) and nine age- and sex-matched normal volunteers. Subjects performed both the Wisconsin Card Sort Test (WCST) and a control task, the Symbol Matching Test (SMT). Four-way analyses of variance were performed to assess relative rCBF of the prefrontal cortex and of the medial temporal region. Normal volunteers showed more marked activation in the precentral gyrus, while SPD patients showed greater activation in the middle frontal gyrus. Relative flow in the left prefrontal cortex was correlated with better WCST performance in normal volunteers. SPD patients, however, showed no such correlations in the left prefrontal cortex, but demonstrated correlations of good and bad performance with CBF in the right middle and inferior frontal gyrus, respectively. Thus, at least some SPD patients demonstrate abnormal patterns of prefrontal activation, perhaps as a compensation for dysfunction in other regions.

Ventricular volume and asymmetry in schizotypal personality disorder and schizophrenia assessed with magnetic resonance imaging.

Magnetic resonance imaging (MRI) was performed in 12 patients with schizotypal personality disorder (SPD), 11 patients with chronic schizophrenia, and 23 age- and sex-matched normal volunteers. MRI slices were acquired in the axial plane at 1.2-mm intervals, and the ventricles were traced on every other slice. The lateral ventricular system was divided into the anterior horn, temporal horn, and dorsal lateral ventricle. Schizophrenic patients had larger left anterior and temporal horns than the normal volunteers. Size of the left anterior and temporal horn in SPD patients was intermediate between those of normal volunteers and schizophrenic patients and differed significantly from schizophrenic patients. The left-minus-right difference was larger in schizophrenic patients than in normal volunteers or SPD patients. Thus, in their structural brain characteristics, as well as in their clinical symptomatology, SPD patients evidence, in attenuated form, abnormalities resembling those found in full-fledged schizophrenia. The findings suggest that decreased left hemispheric volume, in frontal and temporal regions, may characterize both psychotic and non-psychotic disorders of the schizophrenia spectrum.

Decreased anterior cingulate gyrus metabolic rate in schizophrenia.

OBJECTIVE: This study examined glucose metabolism in the anterior and posterior cingulate cortex in schizophrenia. METHOD: Fifty unmedicated male schizophrenic patients and 24 normal men were studied with positron emission tomography. RESULTS: Compared with the normal men, the schizophrenic patients had lower relative metabolic rates in the anterior cingulate and higher rates in the posterior cingulate. CONCLUSIONS: The findings suggest hypofunction in the anterior cingulate cortex in schizophrenia.

Effect of sertraline on regional metabolic rate in patients with affective disorder.

Seventeen patients with major affective disorder completed a 10-week, placebo-controlled, randomized trial of the serotonin reuptake inhibitor sertraline. Patients underwent positron emission tomography with 18F-deoxyglucose and were assessed with the Hamilton Depression Rating Scale at baseline and 10 weeks after treatment with sertraline or placebo. The middle frontal gyrus, an area previously characterized by decreased metabolic activity in depressive patients, showed relatively increased activity on both sides after sertraline when contrasted with temporal and some occipital areas. Sertraline was associated with a significantly increased relative metabolic rate in right parietal lobe and in left occipital area 19, and a decreased metabolic rate in right occipital area 18. Other areas that differed between controls and a larger cohort of 39 depressive patients--including medial frontal lobe, cingulate gyrus, and thalamus--also showed a normalization of metabolic rate after sertraline.

D-amphetamine challenge effects on Wisconsin Card Sort Test. Performance in schizotypal personality disorder.

The authors assessed the effects on Wisconsin Card Sort (WCST) performance and psychiatric symptoms of 30 mg d-amphetamine, a dopamine and norepinephrine agonist, vs placebo in nine patients with schizotypal personality disorder (SPD). Patients, particularly those who made more perseverative errors, demonstrated amphetamine-associated improvement on WCST performance. The data in this preliminary study suggest that some of the cognitive dysfunction present in SPD may improve with amphetamine challenge.

Cerebral metabolic activity correlates of subsyndromes in chronic schizophrenia.

Seventy-nine patients with schizophrenia and 47 healthy controls received positron-emission tomography (PET) with 18F-2-deoxyglucose uptake while executing the Continuous Performance Test (CPT). Patients had been off all psychoactive medication for at least four weeks. Patients' symptoms were assessed with the Brief Psychiatric Rating Scale and factor scale scores were obtained. These scores were used in cluster analysis to identify patients with predominantly delusional, negative, disorganized, and remitted symptoms. To address the interconnective nature of cerebral functioning, regions of interest were defined on the basis of the results of a factor analysis of metabolic rate in selected brain regions. This procedure identified six cortical and eight subcortical region of interest factors. Metabolic rate factor scale scores were compared between the patients' clusters and the healthy controls. The delusional cluster showed a significantly reduced hippocampal activity, while the negative symptoms cluster presented with a prominent hypofrontality and significantly increased left temporal cortex values. Concurrently, both clusters were associated with a decreased activity on the factor 'anterior cingulum and medial frontal gyrus'. The disorganized cluster was characterized by a significant overactivity in the parietal cortex and motor strip and a decreased activity in the corpus callosum. The subsyndromes of chronic schizophrenia are therefore characterized by deviant patterns of cerebral activity rather than deficits in a single location.

Correlational patterns of cerebral glucose metabolism in never-medicated schizophrenics.

We studied 18 never-mediated schizophrenic patients and 22 normal control subjects with 18F-deoxyglucose (FDG) positron emission tomography. Patients and controls performed the continuous performance test during FDG uptake. Cortical and subcortical structures comprising two circuits selected on the basis of several theoretical models of schizophrenia were examined. The correlation of glucose metabolic rate (GMR) for each structure in each circuit with connected structures was calculated and tested for two-tailed significance. Schizophrenics showed significantly different patterns of intercorrelations for both circuits. The largest difference was in the correlation of GMR in the anterior thalamus with the frontal cortex, a key element in the thalamo-cortical-striatal circuit suggested to be abnormal in some models of schizophrenia. Correlations of the frontal lobe with other regions were also more positive in normal controls than schizophrenics; controls had three correlational paths from the frontal cortex (to temporal cortex, ventral anterior thalamus, and dorsal medial thalamus) with significantly more positive correlations than schizophrenics perhaps consistent with other findings of frontal cortical dysfunction in schizophrenia. Normal controls also had both more significant positive and more significant negative correlations between the occipital cortex and other brain areas than schizophrenics. Correlations between homologous areas in the right and left hemispheres were prominent in both groups.

Gender differences in cortical glucose metabolism in Alzheimer's disease and normal aging.

Male Alzheimer's disease patients, studied with 18-fluoro-2-deoxyglucose positron emission tomography while performing a verbal memory test, showed a right-greater-than-left asymmetry of cortical metabolism that tended to be greater than that in healthy, age-matched control subjects. This asymmetry was absent in female patients, preliminarily suggesting a propensity for left hemispheric involvement in the Alzheimer's disease process in males.

Glucose metabolic correlates of continuous performance test performance in adults with a history of infantile autism, schizophrenics, and controls.

Twenty-five schizophrenic patients, fourteen adults with a history of infantile autism, and twenty normal controls performed a test of sustained attention, the degraded stimulus continuous performance test (CPT), during the 35 minute 18-fluoro-2-deoxyglucose uptake period preceding positron emission tomographic (PET) scan acquisition. This is the first analysis comparing correlations between glucose metabolic rate (GMR) for selected regions and CPT performance. CPT performance differed in controls and schizophrenics, but autistics did not differ from either group. In controls and schizophrenic patients, task performance correlated with GMR in medial superior frontal gyrus and lateral inferior temporal gyrus, suggesting that activation of those regions is important in the normal performance of the task and that damage to those regions, which also showed low GMR in schizophrenics, contributes to the attentional dysfunction in schizophrenia. Also, schizophrenics showed negative correlations of task performance with anterior cingulate activity suggesting that overactivity of that region, which is involved in mental effort and whose GMR was low in our larger study of schizophrenia, impairs task performance in schizophrenics. Autistic patients showed negative correlations of medial frontal cortical GMR with attentional performance, suggesting that neuronal inefficiency in that region may contribute to poor performance.

EEG delta, positron emission tomography, and memory deficit in Alzheimer's disease.

Quantitative scalp EEG from 32 channels and the cerebral glucose metabolic rate from the 32 underlying cortical positions as assessed by positron emission tomography (PET) with 18F-2-deoxyglucose (FDG) were obtained on 36 patients with mild to moderate senile dementia of the Alzheimer type and 17 age- and sex-matched normal control subjects. Subjects performed a verbal memory task during uptake of FDG. There were significant correlations between both delta amplitude and metabolic rate and memory performance during FDG uptake. Patients with Alzheimer's disease had significantly greater left temporal delta amplitude and lower glucose metabolic rates. Both EEG delta in microvolts and metabolic rate had similar diagnostic sensitivity, but PET had fewer false positives among normals. The left amygdala had the highest sensitivity and percent correct diagnosis of any brain area. Temporal lobe EEG delta activity showed higher correlations with hippocampal metabolic rate than metabolic rate directly under the electrode.

Structural and functional correlates of subsyndromes in chronic schizophrenia.

Recent psychopathological studies consistently identified a delusional, a negative, and a disorganized subsyndrome in chronic schizophrenia. The aim of our studies was to investigate the subsyndromes with respect to their underlying cerebral changes using computed tomography (CT) and positron emission tomography (PET). In a CT study 50 DSM III schizophrenics were subgrouped according to four factors identified by a factor analysis of BPRS ratings. This procedure identified three chronic clusters (delusional ideation, negative symptoms, and disorganization) and one cluster with a remitting course of the disorder. Both the negative and the delusional subsyndrome were associated with a widening of the frontal interhemispheric fissure. Disorganization was associated with neurological soft signs, an increased ventricle brain ratio, and width of the 3rd ventricle. The same subgrouping was applied in a 18F-deoxyglucose PET study of 79 neuroleptic free DSM III schizophrenic patients and 47 healthy controls. The delusional subsyndrome was associated with a decreased hippocampal function, while the negative subsyndrome showed a prominent hypofrontality and left temporal cortex changes. Both the delusional and the negative subsyndrome were associated with a decreased activity in the medial frontal gyrus in comparison to the other schizophrenic patients and the healthy controls. The disorganized subsyndrome was characterized by an overactivity in the parietal cortex and motor strip and a decreased activity in the corpus callosum. These findings support the differentiation of three subsyndromes in chronic schizophrenia. The subsyndromes seem to be characterized by deviant patterns of cerebral alterations, rather than deficits in a single location.

Patterns of cortical activity in schizophrenia.

Eighty-three patients with schizophrenia and 47 healthy controls received positron emission tomography (PET) with 18F-2-deoxyglucose uptake while they were executing the Continuous Performance Test (CPT). The entire cortex was divided into 16 regions of interest in each hemisphere, four in each lobe of the brain, and data from corresponding right and left hemispheric regions were averaged. Data from the schizophrenic patients were subjected to a factor analysis, which revealed five factors that explained 80% of the common variance. According to their content, the factors were identified and labelled 'parietal cortex and motor strip', 'associative areas', 'temporal cortex', 'hypofrontality' (which included midfrontal and occipital areas) and 'frontal cortex'. Hemispheric asymmetry was only confirmed for the temporal cortex. Factor weights obtained in the schizophrenic group were applied to the metabolic data of the healthy controls and factors scales computed. Schizophrenics were significantly more hypofrontal than the controls, with higher values on the 'parietal cortex and motor strip' factor and a trend towards higher values in the temporal cortex. A canonical discriminant analysis confirmed that the 'hypofrontality' and 'parietal cortex and motor strip' factors accurately separated the schizophrenic group from the healthy controls. Hemispheric asymmetry was only confirmed for the temporal lobe. Significantly higher factor scores for the left temporal lobe in schizophrenics than in normals were obtained when calculated for the right and left hemisphere separately. Taken together, our results confirm the importance of hypofrontality as a pattern of cortical metabolic rate and point to the potential importance of parietal and motor strip function in schizophrenia.

Cortical-striatal-thalamic circuits and brain glucose metabolic activity in 70 unmedicated male schizophrenic patients.

OBJECTIVE: The cortical-striatal-thalamic circuit modulates cognitive processing and thus may be involved in the cognitive dysfunction in schizophrenia. The imaging of metabolic rate in the structures making up this circuit could reveal the correlates of schizophrenia and its main symptoms. METHOD: Seventy male schizophrenic patients underwent [18F]-fluorodeoxyglucose positron emission tomography after a period of at least 4 weeks during which they had not received neuroleptic medication and were compared to 30 age-matched male normal comparison subjects. RESULTS: Analyses revealed decreased metabolism in medial frontal cortex, cingulate gyrus, medial temporal lobe, corpus callosum, and ventral caudate and increased metabolism in the left lateral temporal and occipital cortices in the schizophrenic cohort. Consistent with previous studies, the schizophrenic group had lower hypofrontality scores (ratios of lateral frontal to occipital metabolism) than did comparison subjects. The lateral frontal cortical metabolism of schizophrenic patients did not differ from that of comparison subjects, while occipital cortical metabolism was high, suggesting that lateral hypofrontality is due to abnormalities in occipital rather than lateral frontal activity. Hypofrontality was more prominent in medial than lateral frontal cortex. Brief Psychiatric Rating Scale (BPRS) scores, obtained for each schizophrenic patient on the scan day, were correlated with regional brain glucose metabolic rate. Medial frontal cortical and thalamic activity correlated negatively with total BPRS score and with positive and negative symptom scores. Lateral frontal cortical metabolism and hypofrontality scores did not significantly correlate with negative symptoms. Analyses of variance demonstrated a reduced right greater than left asymmetry in the schizophrenic patients for the lateral cortex as a whole, with simple interactions showing this effect specifically in temporal and frontal cortical regions. CONCLUSIONS: Low metabolic rates were confirmed in medial frontal cortical regions as well as in the basal ganglia, consistent with the importance of the cortical-striatal-thalamic pathways in schizophrenia. Loss of normal lateralization patterns was also observed on an exploratory basis. Correlations with negative symptoms and group differences were more prominent in medial than lateral frontal cortex, suggesting that medial regions may be more important in schizophrenic pathology.

Striatal metabolic rate and clinical response to neuroleptics in schizophrenia.

A low metabolic rate in the caudate nucleus and putamen in schizophrenic patients while they were not receiving medication was found to predict a favorable clinical response to haloperidol. Twenty-five patients (21 men and four women) entered a double-blind crossover trial of haloperidol and placebo; to our knowledge, this is the first such trial with positron emission tomography to be reported. Patients received either placebo or medication for the first 5 weeks, and they received the other treatment for the second 5 weeks. Positron emission tomographic scans were obtained at weeks 5 and 10. Patients with low relative metabolic rates in the caudate nucleus and putamen while they were receiving placebo were more likely to show decreases in their Brief Psychiatric Rating Scale scores with haloperidol treatment than individuals with normal or high metabolic rates. Among responders, haloperidol treatment had a "normalizing" effect on metabolic activity in the striatum, with the metabolic rate while they were receiving haloperidol being higher than that while they were receiving placebo. Nonresponders were more likely to show a worsening of hypofrontality while they were receiving medication and an absence of change in the striatum.

Adolescent developmental change in topography of EEG amplitude.

EEGs were recorded from 32 channels in 30 normal males, ages 16-22. Delta activity decreased throughout this age range. This decrease was greatest in the left frontal and temporal regions; no occipital lead showed this pattern. Relative EEG amplitude analysis, based on normalized maps, revealed decreases with age across alpha, delta, and theta bands with beta staying the same or increasing. These changes were greatest in the left temporal and left frontal regions. Taken together, these findings suggest that these cortical areas are maturing in the second decade of life. Both delta and theta showed significantly greater decreases with age in the left parietal region than in the right.

Regional glucose metabolic changes after learning a complex visuospatial/motor task: a positron emission tomographic study.

Regional cerebral glucose metabolic rate (GMR) quantified with positron emission tomography (PET) with 18-fluoro-2-deoxyglucose (FDG) was measured twice in 8 young men performing a complex visuospatial/motor task (the computer game Tetris), before and after practice. After 4-8 weeks of daily practice on Tetris, GMR in cortical surface regions decreased despite a more than 7-fold increase in performance. Subjects who improved their Tetris performance the most after practice showed the largest glucose metabolic decreases after practice in several areas. These results suggest that learning may result in decreased use of extraneous or inefficient brain areas. Changes in regional subcortical glucose metabolic rate with practice may reflect changes in cognitive strategy that are a part of the learning process.

Regional cerebral glucose metabolism and attention in adults with a history of childhood autism.

Sixteen high-functioning adults with a history of childhood autism and 26 normal control subjects underwent [18F]fluoro-2-deoxyglucose positron-emission tomography to assess regional cerebral glucose metabolic rate (GMR). Autistic patients had a left > right anterior rectal gyrus asymmetry, as opposed to the normal right > left asymmetry in that region. Patients also showed low GMR in the left posterior putamen and high GMR in the right posterior calcarine cortex. Brain regions with GMR > 3 SD from the normal mean were more prevalent in patients than in control subjects. This variable pattern of abnormal activity is consistent with heterogeneous neurophysiological etiology; group differences in striatum and cortex may represent a final common pathway.

Effects of oral dimethyl sulfoxide and dimethyl sulfone on murine autoimmune lymphoproliferative disease.

The results from several studies examining the effects of DMSO on autoimmune phenomena have been inconclusive, possibly because of differences in experimental models, treatment regimens and doses employed. In the present investigation, autoimmune strain MRL/lpr, C3H/lpr, and male BXSB mice were placed on a continuous treatment regimen with 3% DMSO or 3% DMSO2 in the drinking water, ad libitum, commencing at 1 to 2 months of age, before spontaneous disease development could be detected. This represented doses of 8-10 g/kg/day of DMSO and 6-8 g/kg/day of DMSO2. Both compounds were observed to extend the mean life span of MRL/lpr mice from 5 1/2 months to over 10 months of age. All strains showed decreased antinuclear antibody responses and significant diminution of lymphadenopathy, splenomegaly, and anemia development. Serum IgG levels and spleen IgM antibody plaque formation, however, did not differ from control values. There was no indication of involvement of systemic immunosuppressive or antiproliferative effects, and treated animals were observed to remain healthy and vigorous with no signs of toxicity. These results demonstrate that high doses of both DMSO and its major in vivo metabolite, DMSO2, provide significant protection against the development of murine autoimmune lymphoproliferative disease. Possible mechanisms of protection are discussed.