Glutamate imaging (GluCEST) reveals lower brain GluCEST contrast in patients on the psychosis spectrum.

Psychosis commonly develops in adolescence or early adulthood. Youths at clinical high risk (CHR) for psychosis exhibit similar, subtle symptoms to those with schizophrenia (SZ). Malfunctioning neurotransmitter systems, such as glutamate, are implicated in the disease progression of psychosis. Yet, in vivo imaging techniques for measuring glutamate across the cortex are limited. Here, we use a novel 7 Tesla MRI glutamate imaging technique (GluCEST) to estimate changes in glutamate levels across cortical and subcortical regions in young healthy individuals and ones on the psychosis spectrum. Individuals on the psychosis spectrum (PS; n=19) and healthy young individuals (HC; n=17) underwent MRI imaging at 3 and 7 T. At 7 T, a single slice GluCEST technique was used to estimate in vivo glutamate. GluCEST contrast was compared within and across the subcortex, frontal, parietal and occipital lobes. Subcortical (χ2 (1)=4.65, P=0.031) and lobular (χ2 (1)=5.17, P=0.023) GluCEST contrast levels were lower in PS compared with HC. Abnormal GluCEST contrast levels were evident in both CHR (n=14) and SZ (n=5) subjects, and correlated differentially, across regions, with clinical symptoms. Our findings describe a pattern of abnormal brain neurochemistry early in the course of psychosis. Specifically, CHR and young SZ exhibit diffuse abnormalities in GluCEST contrast attributable to a major contribution from glutamate. We suggest that neurochemical profiles of GluCEST contrast across cortex and subcortex may be considered markers of early psychosis. GluCEST methodology thus shows promise to further elucidate the progression of the psychosis disease state.

Neurocognitive development in 22q11.2 deletion syndrome: comparison with youth having developmental delay and medical comorbidities.

The 22q11.2 deletion syndrome (22q11DS) presents with medical and neuropsychiatric manifestations including neurocognitive deficits. Quantitative neurobehavioral measures linked to brain circuitry can help elucidate genetic mechanisms contributing to deficits. To establish the neurocognitive profile and neurocognitive 'growth charts', we compared cross-sectionally 137 individuals with 22q11DS ages 8-21 to 439 demographically matched non-deleted individuals with developmental delay (DD) and medical comorbidities and 443 typically developing (TD) participants. We administered a computerized neurocognitive battery that measures performance accuracy and speed in executive, episodic memory, complex cognition, social cognition and sensorimotor domains. The accuracy performance profile of 22q11DS showed greater impairment than DD, who were impaired relative to TD. Deficits in 22q11DS were most pronounced for face memory and social cognition, followed by complex cognition. Performance speed was similar for 22q11DS and DD, but 22q11DS individuals were differentially slower in face memory and emotion identification. The growth chart, comparing neurocognitive age based on performance relative to chronological age, indicated that 22q11DS participants lagged behind both groups from the earliest age assessed. The lag ranged from less than 1 year to over 3 years depending on chronological age and neurocognitive domain. The greatest developmental lag across the age range was for social cognition and complex cognition, with the smallest for episodic memory and sensorimotor speed, where lags were similar to DD. The results suggest that 22q11.2 microdeletion confers specific vulnerability that may underlie brain circuitry associated with deficits in several neuropsychiatric disorders, and therefore help identify potential targets and developmental epochs optimal for intervention.

[99mTc]TRODAT-1 SPECT imaging correlates with odor identification in early Parkinson disease.

BACKGROUND: In vivo imaging of the dopamine transporter with [99mTc]TRODAT-1 (TRODAT) and olfactory testing have both been proposed as potential biomarkers in Parkinson disease (PD). OBJECTIVE: To evaluate the relationship between TRODAT SPECT imaging, odor identification skills, and motor function in patients with early PD. METHODS: Twenty-four patients with a clinical diagnosis of early-stage PD (mean Hoehn & Yahr stage = 1.4) underwent TRODAT imaging, Unified PD Rating Scale (UPDRS) ratings of motor function, and administration of the University of Pennsylvania Smell Identification Test (UPSIT). Brain images were obtained using a standardized processing protocol and specific uptake ratios for striatal regions of interest were calculated. Partial correlations between the imaging indices, disease duration, UPSIT scores, and UPDRS motor scores were then calculated. RESULTS: UPSIT scores were correlated with TRODAT uptake in the striatum as a whole (r = 0.66, p = 0.001). The putamen showed the strongest correlation with the UPSIT (r = 0.74; p < 0.001). The correlation between dopamine transporter density in the caudate and UPSIT was moderate (r = 0.36, p = 0.11), but was not significant. CONCLUSIONS: Olfactory function is highly correlated with dopamine transporter imaging abnormalities in early Parkinson disease (PD). Further studies are warranted to determine whether changes over time in these two measures are also correlated in early PD.

Computerized neurocognitive scanning: I. Methodology and validation in healthy people.

Neuropsychological testing batteries are applied in neurobehavioral evaluations of brain disorders, including neuropsychiatric populations. They are lengthy, require expert administrators and professional scorers, and are prone to data handling errors. We describe a brief computerized neurocognitive "scan" that assesses similar domains with adequate reliability. The scan and a traditional battery were administered to a sample of 92 healthy individuals (44 men, 48 women) in a counterbalanced order. Both approaches showed a significant "sex-typical" gradient, with women outperforming men in verbal memory relative to spatial tasks. Both methods also yielded similar profiles of sex differences, with the additional computerized measure of face memory showing better performance in women. Age effects were evident for both methods, but the computerized scan isolated the effects to speed rather than accuracy. Therefore, the computerized scan has favorable reliability and construct validity and can be applied efficiently to study healthy variability related to age and gender.

Computerized neurocognitive scanning: II. The profile of schizophrenia.

Cognitive dysfunction in schizophrenia is well established with neuropsychological batteries, which have assessed multiple domains indicating diffuse deficits especially in processing related to frontotemporal systems. Two studies are reported examining the feasibility of the computerized neurocognitive scan to assess differential deficits in schizophrenia. In Study 1, we tested 53 patients and 71 controls with the traditional and computerized assessments counterbalanced in order. Both showed comparable generalized impairment in schizophrenia with differential deficits in executive functions and memory. The profile was replicated in Study 2 in a new sample of 68 patients and 37 controls, receiving only the computerized scan. The combined sample showed robust correlations between performance on both speed and accuracy measures of the neurocognitive scan and clinical variables, including premorbid adjustment, onset age, illness duration, quality of life, and severity of negative symptoms. These correlations were higher and more prevalent in women than men, who showed correlations predominantly for speed rather than accuracy. Neuroleptic exposure was associated with poorer performance only for speed of memory processing, and in men, this association was seen only for typical neuroleptics. We conclude that the computerized neurocognitive scan can be applied reliably in people with schizophrenia, yielding data that support its construct and criterion validity.

Dysregulation of olfactory receptor neuron lineage in schizophrenia.

BACKGROUND: Growing evidence implicates abnormal neurodevelopment in schizophrenia. While neuron birth and differentiation is largely completed by the end of gestation, the olfactory epithelium (OE) is a unique part of the central nervous system that undergoes regeneration throughout life, thus offering an opportunity to investigate cellular and molecular events of neurogenesis and development postmortem. We hypothesized that OE neurons exhibit deviant progress through neurodevelopment in schizophrenia characterized by an increase in immature neurons. METHODS: Olfactory epithelium was removed at autopsy from 13 prospectively assessed elderly subjects who had schizophrenia and 10 nonpsychiatric control subjects. Sections were immunolabeled with antibodies that distinguish OE neurons in different stages of development, including basal cells (low-affinity nerve growth factor receptor, p75NGFR), postmitotic immature neurons (growth-associated protein 43 [GAP43]), and mature olfactory receptor neurons (olfactory marker protein). Absolute and relative densities of each cell type were determined. RESULTS: We observed a significantly lower density of p75NGFR basal cells (37%) in schizophrenia and increases in GAP43 + postmitotic immature neurons (316%) and ratios of GAP43 + postmitotic immature neurons to p75NGFR + cells (665%) and olfactory marker protein + mature neurons to p75NGFR + basal cells (328%). Neuroleptic-free schizophrenia subjects exhibited the highest GAP43 + postmitotic immature neuron values. CONCLUSIONS: Abnormal densities and ratios of OE neurons at different stages of development indicate dysregulation of OE neuronal lineage in schizophrenia. This could be because of intrinsic factors controlling differentiation or an inability to gain trophic support from axonal targets in the olfactory bulb. While caution is necessary in extrapolating developmental findings in mature OE to early brain development, similarities in molecular events suggest that such studies may be instructive.

Effectiveness of an attention- and memory-training program on neuropsychological deficits in schizophrenia.

The effect of two cognitive remediation procedures developed for closed head injury, Attention Process Training (APT) and Prospective Memory Training (PROMT), on neuropsychological deficits in schizophrenia was investigated. Six patients with schizophrenia, varying in baseline intellectual function and symptoms, were studied; three in a remediation condition and three in a nonremediated control condition. Results were evaluated individually for each of the three treated patients. Two of three remediation-treated subjects showed marked improvement on tests of sustained and divided attention. Untreated patients showed little evidence of change in neuropsychological test performance across a similar time interval, when tested on a subset of the measures administered to remediation-treated patients. The results of this study are discussed with a view toward future studies using larger sample sizes with homogeneous subject populations.

Cognitive impairment and functional status in elderly institutionalized patients with schizophrenia.

OBJECTIVE: The relationship of cognitive impairment to functional status in older adults with schizophrenia was investigated. PATIENTS: Ninety-three psychiatric inpatients with schizophrenia between the ages of 65 and 88 years. Two subsets of this sample, consisting of 48 and 24 patients, were studied with a greater number of assessment instruments. MEASURES: The Mini-Mental State Examination (MMSE) was used for brief assessment of overall cognitive functioning, and the Psychogeriatric Dependency Rating Scale (PGDRS) was administered to assess functional status. The cognitive test battery from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) and/or an expanded neuropsychological battery, was given to a subset of the patients. RESULTS: In the overall sample, patients with greater global cognitive impairment had higher levels of rated impairment on the individual items that comprised the Orientation and Physical, but not Behavior, subscales of the PGDRS. Furthermore, in the two subsamples, specific neuropsychological measures of problem-solving, word list learning, naming and constructional praxis were related to overall measures of outcome. CONCLUSIONS: Neuropsychological deficit and psychosocial outcome are multi-dimensional entities that relate to one another in complex ways.

Olfactory dysfunction in schizophrenia and temporal lobe epilepsy.

BACKGROUND: Schizophrenia and mesial temporal lobe epilepsy (TLE) represent two common brain disorders that share dysfunction of temporo-limbic neural substrates. OBJECTIVE: We evaluated whether patients with schizophrenia exhibited olfactory performance more similar to right or left temporal lobe epilepsy patients. METHODS: Odor identification ability and detection threshold sensitivity were measured in 40 patients with schizophrenia, 14 patients with right- and 18 patients with left-temporal lobe epilepsy (TLE) patients, and 25 healthy controls. Odor identification was assessed with the University of Pennsylvania Smell Identification Test (UPSIT) and odor detection threshold sensitivity with a single-staircase procedure using the stimulant phenyl ethyl alcohol (PEA). RESULTS: Relative to controls, only patients with schizophrenia and right TLE exhibited significant impairment in UPSIT performance. Left TLE patients and controls performed comparably on the UPSIT. Detection threshold sensitivity to PEA did not differ significantly among the four groups. CONCLUSIONS: These data suggest a greater reliance of olfactory processing on right hemisphere structures and are also consistent with recent neuroimaging studies that have implicated aberrant processing of olfactory information in right hemispheric brain regions in schizophrenia.

Olfactory-evoked regional cerebral blood flow in Alzheimer's disease.

Olfaction is impaired in Alzheimer's disease (AD). It was hypothesized that AD would reduce olfactory-evoked perfusion in mesial temporal olfactory (piriform) cortex, where neuropathology begins. Seven AD patients and 8 elderly controls (ECs) underwent olfactory threshold and identification tests and olfactory stimulation during positron emission tomography. Odor identification was impaired in AD, but threshold was not. Olfactory stimulation in ECs activated right and left piriform areas and right anterior ventral temporal cortex. AD patients had less activation in right piriform and anterior ventral temporal cortex but not in the left piriform area. Although orbital cortex did not activate in ECs, there was a significant between-groups difference in this area. Right piriform activation correlated with odor identification. Impaired odor identification likely reflects sensory cortex dysfunction rather than cognitive impairment. Given olfactory bulb projections to the mesial temporal lobe, olfactory stimulation during functional imaging might detect early dysfunction in this region.

Comparison of the standard and structured interview guide for the Hamilton Depression Rating Scale in depressed geriatric inpatients.

The interrater reliability of the standard Hamilton Depression Rating Scale (Ham-D) and a structured interview guide for the Ham-D (the SIGH-D) were compared in a sample of 20 elderly inpatients with major depression. Each patient was independently interviewed by four raters; two used the standard 24-item Ham-D, and the other two used a 24-item modified version of the Structured Interview Guide for the Ham-D. Systematic counterbalancing of raters and scales and a stringent evaluation schedule were used to counter position effects, spontaneous symptom change, or diurnal variation. The modified SIGH-D produced uniformly higher item- and summary-scale reliabilities than the unstructured Ham-D.

Controlled and automatic processing during animal word list generation in schizophrenia.

Controlled and automatic aspects of semantic-associative functioning in schizophrenia were investigated by evaluating performance on animal word list generation (WLG). Responses from control (n = 47) and patient (n = 38) participants were subjected to multidimensional scaling (MDS), cluster analysis (CA), and indices on the basis of number of shared attributes (SA) between consecutive responses. Patient MDS results accounted for less variance and contained more error than control data. CA results yielded fewer and less clear animal-response subgroups among patients yet demonstrated intact associations among strongly related exemplars. The SA indices revealed better clustering and more effective switching among response clusters in controls than patients. Results suggest that animal WLG in schizophrenia is compromised both by aberrant automatic semantic-associative network activation and by controlled processes such as search, access, and selection. This pattern is consistent with prominent frontotemporal pathology evident in the disorder.

Approaches to cognitive remediation of neuropsychological deficits in schizophrenia: a review and meta-analysis.

A review and critique of the literature pertaining to the use of cognitive remediation techniques in patients with schizophrenia is presented. The review is organized into three sections, according to the neuropsychological deficit targeted for remediation: 1) executive-function, 2) attention, and 3) memory. With regards to executive-function, despite an initial report suggesting that Wisconsin Card Sorting Test performance cannot be remediated, subsequent studies suggest that performance can be improved on a variety of dependent measures including perseverative errors, categories achieved, and conceptual level responses. These observations were confirmed by a meta-analytic investigation that revealed large mean effects sizes (d+ = 0.96) for these studies. Effect sizes were homogenous across discrepant remediation strategies and dependent measures. With regards to attention, serial scanning can be improved with instruction and reinforcement, whereas there is mixed evidence suggesting that practice-based attention drills can improve performance on measures of sustained attention in schizophrenia. With regards to memory, relatively simple semantic and affective elaborate encoding strategies elevates verbal list-learning memory in patients with schizophrenia to levels consistent with controls. A similar encoding procedure, combined with vigilance training, produces substantial improvement in social cue recognition. Avenues for future research are discussed.

Ten-year follow-up survey of clinical neuropsychologists: part I. Practices and beliefs.

A 21-item questionnaire previously used to survey practices and beliefs of clinical neuropsychologists (Sweet & Moberg, 1990; Sweet, Moberg, & Westergaard, 1996) was mailed in February 1999 to all ABPP Diplomates in clinical neuropsychology and a larger sample of randomly selected non-ABPP members of Division 40 (Clinical Neuropsychology) of the American Psychological Association. Results were compared with data previously collected in 1989 and 1994. Across 10 years there have been some persistent differences between neuropsychologists based on board certification status. These differences include degree of involvement in neuropsychological practice and forensic practice, involvement in research and teaching, frequency of subscribing to or regularly reading a variety of relevant journals, employment settings, use of assistants, and use of projective assessment. There are also a number of areas of shared belief and common practice. These important areas of agreement are unrelated to board certification status and are interpreted as signs of cohesiveness and maturity in the continuing evolution of the subspecialty. Shared beliefs and common practices include: appropriate field of training, type of degree, assessment philosophy, most types of information to be gathered in evaluations, and time spent per assessment. In general, the use of assistants is correlated significantly with the number of evaluations performed per month. Although sometimes viewed as exclusively providing assessment, the majority of neuropsychologists are also involved in treating patients with brain dysfunction. Survey data appear useful in characterizing and monitoring professional status and trends of clinical neuropsychology.

Reduced olfactory bulb volume in patients with schizophrenia.

OBJECTIVE: The authors' goal in this study was to compare the size of olfactory bulbs of patients with schizophrenia and those of healthy subjects. METHOD: Magnetic resonance imaging scans of olfactory bulbs were obtained from 26 patients with schizophrenia and 22 healthy comparison subjects. A reliable region of interest procedure was used to measure olfactory bulb volume. RESULTS: Patients exhibited 23% smaller bilateral bulb volume than comparison subjects, independent of acute clinical, demographic, or treatment measures. Bulb volume correlated with odor detection sensitivity in healthy subjects but not in patients with schizophrenia. CONCLUSIONS: Patients with schizophrenia exhibit structural olfactory deficits as well as functional olfactory deficits. The olfactory system may be a model system in which to study the neurobiology of the disorder.

Ten-year follow-up survey of clinical neuropsychologists: part II. Private practice and economics.

Analyses of a 10-year follow-up survey of clinical neuropsychologists demonstrated significant changes in employment settings away from institutions, placing a clear majority of the field in private practice settings in 1999 (Sweet, Moberg, & Suchy, 2000). The present paper compares characteristics of practices and beliefs of clinical neuropsychologists who work in institutions versus private practice, using data from 1989, 1994, and 1999. Previous survey data had not been analyzed along the dimension of work setting. Among the significant findings are differences in age, referral sources, hours per week engaged in specific professional activities (clinical, neuropsychological, forensic, supervisory, research, teaching), ages of patients, type and frequency of data gathered in assessments, hours spent per evaluation, use of an assistant to gather data, and journal subscriptions. Economic changes within the last 5 years have had a differential impact for the two groups in terms of yearly income and hourly reimbursement. However, approximately half of the neuropsychologists in both groups have increased hours performing clinical work, hours performing administrative duties, and patient load to compensate for economic changes in the last 5 years. Decreases in clinical research and teaching activities are apparent in both groups, but in different amounts.

Olfactory dysfunction in schizophrenia: a qualitative and quantitative review.

Olfactory dysfunction in patients with schizophrenia has been a topic of increasing interest, with deficits in odor identification, detection threshold sensitivity, discrimination, and memory being reported. Despite increasing knowledge, controversy has existed about possible differential deficits among olfactory tests as well as the influences of gender, smoking, and medication status on olfactory measures. To help elucidate some of this controversy, we conducted a qualitative and quantitative (meta-analytic) review of the English language literature on olfaction in schizophrenia. Moderator variables such as gender, medication status, and smoking history were also examined. Results indicated that substantial olfactory deficits, across all domains, are observed in patients with schizophrenia. No differential deficits were observed across domains of odor identification, detection threshold sensitivity, discrimination, and memory. The influences of gender, medication status, and smoking on effect sizes were not significant across studies. This supports the hypothesis of primary dysfunction in the olfactory system that is regulated by brain regions where structural and functional abnormalities have also been reported in neuroimaging studies.

Parallel loss of presynaptic and postsynaptic dopamine markers in normal aging.

Aging of the human brain is associated with a decline in dopamine (DA) function, generally interpreted as reflecting DA cell loss. Positron emission tomography studies revealed that in healthy individuals, the age-related losses in DA transporters (presynaptic marker) were associated with losses in D2 receptors (postsynaptic marker) rather than with increases as is known to occur with DA cell loss. This association was specific for DA synaptic markers, because they were not correlated with striatal metabolism. Furthermore, the association was independent of age, suggesting that a common mechanism regulates the expression of receptors and transporters irrespective of age.

Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals.

OBJECTIVE: Although it is documented that brain dopamine activity declines with age, the functional significance of this is not known. This study assessed the relation between measures of brain dopamine activity and indexes of motor and cognitive function in healthy individuals. METHOD: Thirty healthy volunteers aged 24-86 years were studied with positron emission tomography and [11C]raclopride to assess dopamine D2 receptors. All subjects underwent a neuropsychological test battery that included tasks found to be sensitive to dopamine alterations in patients with neurodegenerative disease and control tasks. RESULTS: Transfer of [11C]raclopride from plasma to brain in the striatum and cerebellum was not affected by age. In contrast, D2 receptor availability in the caudate and putamen declined with age. Correlations between D2 receptors and neuropsychological test performance were strongest for the motor task (Finger Tapping Test) and were also significant for most tasks involving frontal brain regions, including measures of abstraction and mental flexibility (Wisconsin Card Sorting Test) and attention and response inhibition (Stroop Color-Word Test, interference score). These relationships remained significant after control for age effects. CONCLUSIONS: Age-related decreases in brain dopamine activity are associated with a decline in motor function and may also contribute to impaired performance on tasks that involve frontal brain regions. Interventions that enhance dopamine activity may improve performance and quality of life for the elderly. The fact that correlations remained significant after age effects were partialed out suggests that dopamine activity may influence motor and cognitive performance irrespective of age.