Possible compensatory events in adult Down syndrome brain prior to the development of Alzheimer disease neuropathology: targets for nonpharmacological intervention.

Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology progressively with age but clinical signs of dementia are delayed by at least 10 years after the first signs of disease. Some individuals with DS do not develop dementia despite extensive AD neuropathology. Given the discordance between clinical decline and AD neuropathology, compensatory events may be of particular relevance for this group. Imaging studies using PET suggest compensatory increases in metabolic rate in vulnerable brain regions in DS prior to the development of dementia. Neurobiological studies of similarly aged DS autopsy cases provide further evidence of activation of plasticity mechanisms. Genes that are overexpressed in DS (APP, DSCAM, MNB/DYRK1A, and RCAN1) produce proteins critical for neuron and synapse growth, development and maintenance. We present the hypothesis that these genes may lead to developmental cognitive deficits but paradoxically with aging, may participate in molecular cascades supporting neuronal compensation. Enhancing or supporting compensatory mechanisms in aging individuals with DS may be beneficial as suggested by intervention studies in animal models. In combination, adults with DS may be a unique group of individuals well-suited for studies involving the manipulation or upregulation of compensatory responses as an approach to promote successful brain aging in the general population.

MMPI assessment of psychopathology in the adopted-away offspring of schizophrenics.

Previous studies completed in Denmark show a higher frequency of schizophrenia-related psychopathology in the adopted offspring of schizophrenics than in matched controls. This study adds a psychometric dimension to the earlier reports with an analysis of psychopathology in the adopted offspring of schizophrenics based on the Minnesota Multiphasic Personality Inventory (MMPI). A combination of MMPI criteria and interview-based diagnosis identifies 22% of the index cases and 6% of the control cases (P less than .01) as having a schizophrenia spectrum disorder. The findings support a genetic hypothesis, but the use of the MMPI does not fully clarify some issues raised in the earlier reports.

The dexamethasone suppression test and pituitary-adrenocortical function.

The dexamethasone suppression test (DST) as now commonly carried out in psychiatric settings yields "abnormal" results in many conditions including the healthy state. To determine whether the DST accurately identifies patients with physiologically meaningful increases in pituitary-adrenocortical activity, we compared DST results to baseline urinary cortisol level. Thirty-four psychiatric inpatients underwent a 24-hour urine collection and then a DST using 1 or 2 mg of dexamethasone. With the common 1-mg DST, 24-hour urinary cortisol levels in nonsuppressors and suppressors did not differ. With the 2-mg DST, however, nonsuppressors had significantly higher urinary cortisol levels than suppressors, and all nonsuppressors had urinary cortisol levels above the normal range. Thus, the 1-mg DST may not identify the heuristically important subgroup of psychiatric patients who have a pathophysiologically meaningful alteration in pituitary-adrenal regulation.

Extreme MMPI scores and the Research Diagnostic Criteria. Screening college men for psychopathology.

This study compares psychiatric evaluations made with the Minnesota Multiphasic Personality inventory (MMPI) to evaluations with a standard clinical interview and the Research Diagnostic Criteria (RDC). The purpose was to generate a nonhospitalized, previously undiagnosed sample of persons who had psychiatric difficulties or symptoms. Of 385 college male volunteers, 56 with scores at least 3 SD above the mean on at least one MMPI scale were chosen as an index group, and 27, with all MMPI scores within normal limits, as a control group. In the index group, 82% met the RDC for at least one diagnosis, whereas only 22% of the control sample met the RDC for any diagnosis. One index subject met the RDC for schizophrenia; 15 met the RDC for a major affective disorder. Some correspondence between specific MMPI profile code types and RDC diagnoses was evident. Thus, researchers can identify a range of psychopathology meeting the RDC by using MMPI screening in a nonhospital setting. Such a research sample, free from the possible artifacts of hospitalization, drug treatment, and diagnostic labeling, can be useful particularly in testing hypotheses concerning the biological correlates of psychopathology.

Psychiatric vulnerability, monoamine oxidase, and the average evoked potential.

College students in two separate studies had platelet monoamine oxidase (MAO) activity determinations and average evoked potential (AEP) measurements taken. On the basis of Minnesota Muliphasic Personality Inventory (MMPI) or Research Diagnostic Criteria (RDC) evaluations, psychopathology, particularly affective disorder, was found to be more prevalent among both persons with the combination of low MAO activity and AEP augmenting and those with high MAO activity and AEP reducing. The same pattern is apparent whether students were selected for extremely high or low MAO activity (study 1) or for elevated or normal MMPI scores (study 2). Some psychiatric patient groups also show this pattern. An interactive model of sensation-seeking and sensory inhibition is presented.

Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics.

We scanned 18 patients with schizophrenia who had never received neuroleptic medication and 20 age- and sex-matched controls by positron emission tomography with 18-F-fluorodeoxyglucose (fludeoxyglucose F 18) as a tracer of glucose metabolism. Subjects performed the Continuous Performance Test during 18-F-fluorodeoxyglucose uptake. Scan results were converted to metabolic rates, and computer algorithms were used to identify cortical regions. Previous reports of relative hypofrontality in schizophrenia were confirmed, indicating that this finding is not an artifact of previous treatment. Significantly reduced ratios of inferior and medial frontal regions to occipital cortex were found, together with diminished metabolism in the basal ganglia. This suggests the presence of a combined frontostriatal dysfunction in schizophrenia.

Smooth pursuit eye tracking impairment: relation to other 'markers' of schizophrenia and psychologic correlates.

Smooth pursuit eye tracking impairment has been observed in the major psychoses, particularly schizophrenia. To understand better the relationship of smooth pursuit disruption to personality dispositions linked to psychiatric syndromes and to two other "marker variables" associated with psychosis (low platelet monoamine oxidase [MAO] activity and poor performance on the continuous performance task [CPT]), we studied the psychologic, biochemical, and psychophysiologic correlates of impaired smooth pursuit tracking in two nonpsychiatric patient populations. One sample consisted of 67 volunteers screened for extreme values in a distribution of platelet MAO activities, and the second included 29 volunteers screened for extreme scores on the CPT. An aggregate of about 5% of both samples showed clearly dysfunctional smooth pursuit. Eye tracking dysfunction did not seem to be related to either MAO or CPT performance in either study. Both studies were consistent in showing that subjects with impaired smooth pursuit eye tracking had a psychologic profile characterized particularly by social introversion.

Attention dysfunction and psychopathology in college men.

Four hundred college men were screened on a measure of vigilance, the Continuous Performance Test (CPT). The individuals with good and poor attention (the upper and lower 5% of the CPT score distribution) were compared on multiple measures of psychiatric disturbance, cognition, and psycho-physiologic function. The attention dysfunction group (lower 5%) had a higher incidence of symptoms of hyperactivity both in childhood and as adults, but had no higher incidence of other psychopathology as assessed with either the Research Diagnostic Criteria or the Minnesota Multiphasic Personality Inventory. Cognitive differences between the lower and upper CPT groups, including differences on Wechsler Adult Intelligence Scale subtests, the Stroop test, reaction time, and evoked potentials, substantiated an attention dysfunction syndrome. Thus, attentional dysfunction in young adults seems more closely linked to hyperactivity than to current psychopathology.

Parallel compensatory and pathological events associated with tau pathology in middle aged individuals with Down syndrome.

Aged individuals with Down syndrome (DS) develop senile plaques and neurofibrillary tangles consistent with Alzheimer disease (AD). Prior to or in parallel with AD pathology, compensatory growth responses may occur. Immunohistochemistry and confocal microscopy studies in the hippocampus from 15 individuals ranging in age from 5 months to 67 years compared markers of normal and abnormal tau accumulation (phosphorylated tau [AT8, MC-1], tau-1, N-terminal tau) with the extent and location of neuronal growth marker immunoreactivity (BDNF, GAP-43, MAP-2). In middle age (30-40 years), prior to entorhinal neuron loss, the earliest tau accumulation occurred in the outer molecular layer (OML), which was consistent with both pathological and compensatory fetal tau expression. These events were followed at a later age, associated with entorhinal neuron loss, by an increase in GAP-43. Hilar neurons exhibiting a sprouting morphology were also noted. Age-dependent observations in the DS brain in the current study parallel hippocampal compensatory responses described in entorhinal cortex lesion studies in rodents. Thus, compensatory growth responses may occur in DS prior to extensive AD pathology and may be one mechanism underlying observations in PET studies of hypermetabolism in the entorhinal cortex of individuals with DS.

Isosafrole and schizophrenia-like psychosis.

A 19-year-old man developed a schizophrenia-like psychosis after ingesting isosafrole. His use of amphetamines and LSD failed to produce a similar syndrome. Isosafrole may provide another biochemical model for schizophrenia.

Paranoia and platelet MAO in normals and nonschizophrenic psychiatric groups.

The authors compared the correlation between platelet monoamine oxidase (MAO) activity and the Paranoia (Pa) scale of the Minnesota Multiphasic Personality Inventory in several groups. The data suggest that there is a positive association between high MAO activity and high scores on the Pa scale but only in samples with psychopathology.

Results of the dexamethasone suppression test in psychiatric patients with and without weight loss.

Rates of nonsuppression on the dexamethasone suppression test were compared in 32 psychiatric inpatients with reported weight loss and 32 psychiatric inpatients without weight loss who were matched for age, sex, and diagnosis. There was no significant difference in rate of nonsuppression.

PET and MRI of the thalamus in never-medicated patients with schizophrenia.

OBJECTIVE: This study reports the first paired measurements of glucose metabolism and size of thalamic regions in never-medicated schizophrenic patients using coregistered magnetic resonance imaging (MRI) templates. METHOD: Positron emission tomography with [18F]fluorodeoxyglucose and matching MRI scans were obtained in 20 never-medicated patients with schizophrenia and 15 normal volunteers. Methods for thalamic edge finding, statistical testing of shape differences with chi-square maps, and MRI localization of major thalamic subregions were developed. RESULTS: Patients with schizophrenia showed a diminished metabolic rate in the right thalamus, with a loss of the normal pattern of right greater than left asymmetry. Division into anterior/posterior segments revealed that the left anterior and right posterior showed the decrease. Differences were greater for metabolism in the weighted thalamic area (ratexarea) than for rate per unit area, a finding consistent with reported greater decreases in total neuron number than of neuron density in the thalami of schizophrenic patients. The area of the thalamus was smaller in the patients than in the volunteers, and this difference was greatest in the left anterior region. CONCLUSIONS: The reduced thalamic activity observed in this study lends further support to the concept of deficits in sensory filtering in schizophrenia.

A controlled trial of desipramine in 18 men with posttraumatic stress disorder.

Eighteen male U.S. veterans meeting DSM-III criteria for posttraumatic stress disorder (PTSD) completed a 4-week double-blind, crossover study comparing administration of 200 mg/day of desipramine with placebo. Response was measured by using the Beck Depression Inventory, the Hamilton Rating Scale for Depression, the Hamilton Rating Scale for Anxiety, and the Impact of Event Scale. Overall, the only apparent response to desipramine was in some symptoms of depression; there were no changes in anxiety and other PTSD symptoms.

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.

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.

Biological markers of affective disorders and posttraumatic stress disorder: a pilot study with desipramine.

Three biological markers of affective disorders and response to desipramine were used to study the relationship of posttraumatic stress disorder (PTSD) to affective illness. Blunted TRH response and decreased REM latency in eight patients with PTSD occurred at frequencies similar to those that have been found in patients with major affective disorder. Pretreatment Hamilton Rating Scale for Depression and Beck Depression Inventory scale scores were elevated; scores after 4 weeks' treatment with desipramine revealed significant (p less than .05 and p less than .005, respectively) improvement. These findings support a link between PTSD and affective illness.

Effects of clozapine, fluphenazine, and placebo on reaction time measures of attention and sensory dominance in schizophrenia.

Two reaction time (RT) paradigms were used to study clozapine's effects on sustained and selective attention compared to fluphenazine and placebo in 25 chronic schizophrenic patients. Sensory dominance was studied via simple and choice RTs to lights and tones, and on double-stimulus trials in which the two stimuli were presented simultaneously. Although 8 of the 25 patients could not perform the RT tasks when taking placebo, there were no effects of clozapine on simple or choice RT compared to placebo or fluphenazine. Subjects on all 3 treatments showed visual dominance: faster RT to lights than to tones on choice and double-stimulus trials. However, clozapine reduced this by means of a selective increase in RT to lights. Clozapine reduced failures to respond to the tone on double-stimulus trials. This was shown to be due to reductions in hallucinations. Clozapine does not generally improve attention, but it may increase the ability of schizophrenic persons to process nondominant or unattended stimuli possibly by increasing the efficiency of resource allocation. This may be partially mediated by a reduction in hallucinations.

Effect of attention on frontal distribution of delta activity and cerebral metabolic rate in schizophrenia.

15 patients with schizophrenia and nine normal volunteers had 32 channel topographic EEG recorded for spectral analysis during the uptake of 18-F-deoxyglucose (FDG) for positron emission tomography (PET). Both patients and controls performed the Continuous Performance Test, a visual vigilance task, during FDG uptake. EEG was also obtained during an initial pre-FDG resting period. Each EEG epoch was individually inspected for eye movement artifacts. Analysis confirmed increased delta activity in the frontal region of patients with schizophrenia in comparison to normal controls, and a significant correlation between increased frontal delta and relative reduction in frontal lobe metabolism among patients with schizophrenia. This finding of increased delta is consistent with PET, blood flow and topographic EEG studies of schizophrenia, suggesting reduced frontal activity.

Platelet monoamine oxidase activity and evoked response as predictors of anxiety and depression derived from the content analysis of speech.

Platelet MAO activity has been reported by several investigators to differentiate schizophrenia, schizophrenia related depressive disorders, alcoholism, unipolar and bipolar depression from normal controls. Evoked potentials likewise have differentiated schizophrenic and affective patients. However, the precise relationship between MAO activity, evoked potentials (EP), and psychiatric illness has not been clarified. A possible association between psychopathology and high MAO activity/EP reducing and low MAO activity/EP augmenting has been reported. Such a bidirectionality further confounds results. This study was undertaken to determine the association of psychopathological dimensions found in a group of subjects whose platelet MAO activity and evoked responses were obtained two years earlier. Utilizing the Gottschalk-Gleser verbal behavior scales of Anxiety, Depression, Social Alienation-Personal Disorganization and Cognitive Impairment a significant correlation was revealed between low platelet MAO activity and high Total Anxiety scale and Shame Anxiety subscale scores. Additionally, a significant correlation was demonstrated between reducing evoked potentials and elevated Death Anxiety, Somatic Concerns, and Total Death and Mutilation Depression subscales scores, combined and separately. Furthermore, a significant positive correlation was found between augmenting evoked potentials and Overt Hostility Outward scores. No significant correlations were demonstrated between platelet MAO activity or evoked potentials and Social Alienation-Personal Disorganization or Cognitive Impairment scores. These findings lend support to the position that biological markers may predict predispositions to anxiety and depression.