Remote assessment of the Penn computerised neurocognitive battery in individuals with 22q11.2 deletion syndrome.

BACKGROUND: Neurocognitive functioning is an integral phenotype of 22q11.2 deletion syndrome relating to severity of psychopathology and outcomes. A neurocognitive battery that could be administered remotely to assess multiple cognitive domains would be especially beneficial to research on rare genetic variants, where in-person assessment can be unavailable or burdensome. The current study compares in-person and remote assessments of the Penn computerised neurocognitive battery (CNB). METHODS: Participants (mean age = 17.82, SD = 6.94 years; 48% female) completed the CNB either in-person at a laboratory (n = 222) or remotely (n = 162). RESULTS: Results show that accuracy of CNB performance was equivalent across the two testing locations, while slight differences in speed were detected in 3 of the 11 tasks. CONCLUSIONS: These findings suggest that the CNB can be used in remote settings to assess multiple neurocognitive domains.

Common and dissociable regional cerebral blood flow differences associate with dimensions of psychopathology across categorical diagnoses.

The high comorbidity among neuropsychiatric disorders suggests a possible common neurobiological phenotype. Resting-state regional cerebral blood flow (CBF) can be measured noninvasively with magnetic resonance imaging (MRI) and abnormalities in regional CBF are present in many neuropsychiatric disorders. Regional CBF may also provide a useful biological marker across different types of psychopathology. To investigate CBF changes common across psychiatric disorders, we capitalized upon a sample of 1042 youths (ages 11-23 years) who completed cross-sectional imaging as part of the Philadelphia Neurodevelopmental Cohort. CBF at rest was quantified on a voxelwise basis using arterial spin labeled perfusion MRI at 3T. A dimensional measure of psychopathology was constructed using a bifactor model of item-level data from a psychiatric screening interview, which delineated four factors (fear, anxious-misery, psychosis and behavioral symptoms) plus a general factor: overall psychopathology. Overall psychopathology was associated with elevated perfusion in several regions including the right dorsal anterior cingulate cortex (ACC) and left rostral ACC. Furthermore, several clusters were associated with specific dimensions of psychopathology. Psychosis symptoms were related to reduced perfusion in the left frontal operculum and insula, whereas fear symptoms were associated with less perfusion in the right occipital/fusiform gyrus and left subgenual ACC. Follow-up functional connectivity analyses using resting-state functional MRI collected in the same participants revealed that overall psychopathology was associated with decreased connectivity between the dorsal ACC and bilateral caudate. Together, the results of this study demonstrate common and dissociable CBF abnormalities across neuropsychiatric disorders in youth.

Emergent, remitted and persistent psychosis-spectrum symptoms in 22q11.2 deletion syndrome.

Individuals with 22q11.2 deletion syndrome (22q11DS) are at markedly elevated risk for schizophrenia-related disorders. Stability, emergence, remission and persistence of psychosis-spectrum symptoms were investigated longitudinally. Demographic, clinical and cognitive predictors of psychosis were assessed. Prospective follow-up over 2.8 years was undertaken in 75 individuals with 22q11DS aged 8-35 years. Mood, anxiety, attention-deficit hyperactivity disorders and psychosis-spectrum symptoms were assessed with the Kiddie-Schedule for Affective Disorders and Schizophrenia and Scale of Prodromal Symptoms (SOPS). Four domains of cognition were evaluated with the Penn Computerized Neurocognitive Battery (executive functioning, memory, complex cognition and social cognition). Psychotic disorder or clinically significant SOPS-positive ratings were consistently absent in 35%, emergent in 13%, remitted in 22% and persistent in 31% of participants. Negative symptoms and functional impairment were found to be predictive of the emergence of positive psychosis-spectrum symptoms and to reflect ongoing deficits after remission of positive symptoms. Dysphoric mood and anxiety were predictive of emergent and persistent-positive psychosis-spectrum symptoms. Lower baseline global cognition and greater global cognitive decline were predictive of psychosis-spectrum outcomes but no particular cognitive domain stood out as being significantly more discriminating than others. Our findings suggest that negative symptoms, functioning and dysphoric mood are important predictors of psychosis risk in this population.

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.

Association between polygenic risk for schizophrenia, neurocognition and social cognition across development.

Breakthroughs in genomics have begun to unravel the genetic architecture of schizophrenia risk, providing methods for quantifying schizophrenia polygenic risk based on common genetic variants. Our objective in the current study was to understand the relationship between schizophrenia genetic risk variants and neurocognitive development in healthy individuals. We first used combined genomic and neurocognitive data from the Philadelphia Neurodevelopmental Cohort (4303 participants ages 8-21 years) to screen 26 neurocognitive phenotypes for their association with schizophrenia polygenic risk. Schizophrenia polygenic risk was estimated for each participant based on summary statistics from the most recent schizophrenia genome-wide association analysis (Psychiatric Genomics Consortium 2014). After correction for multiple comparisons, greater schizophrenia polygenic risk was significantly associated with reduced speed of emotion identification and verbal reasoning. These associations were significant by age 9 years and there was no evidence of interaction between schizophrenia polygenic risk and age on neurocognitive performance. We then looked at the association between schizophrenia polygenic risk and emotion identification speed in the Harvard/MGH Brain Genomics Superstruct Project sample (695 participants ages 18-35 years), where we replicated the association between schizophrenia polygenic risk and emotion identification speed. These analyses provide evidence for a replicable association between polygenic risk for schizophrenia and a specific aspect of social cognition. Our findings indicate that individual differences in genetic risk for schizophrenia are linked with the development of aspects of social cognition and potentially verbal reasoning, and that these associations emerge relatively early in development.

Characterizing social environment's association with neurocognition using census and crime data linked to the Philadelphia Neurodevelopmental Cohort.

BACKGROUND: The contribution of 'environment' has been investigated across diverse and multiple domains related to health. However, in the context of large-scale genomic studies the focus has been on obtaining individual-level endophenotypes with environment left for future decomposition. Geo-social research has indicated that environment-level variables can be reduced, and these composites can then be used with other variables as intuitive, precise representations of environment in research. METHOD: Using a large community sample (N = 9498) from the Philadelphia area, participant addresses were linked to 2010 census and crime data. These were then factor analyzed (exploratory factor analysis; EFA) to arrive at social and criminal dimensions of participants' environments. These were used to calculate environment-level scores, which were merged with individual-level variables. We estimated an exploratory multilevel structural equation model (MSEM) exploring associations among environment- and individual-level variables in diverse communities. RESULTS: The EFAs revealed that census data was best represented by two factors, one socioeconomic status and one household/language. Crime data was best represented by a single crime factor. The MSEM variables had good fit (e.g. comparative fit index = 0.98), and revealed that environment had the largest association with neurocognitive performance (ß = 0.41, p < 0.0005), followed by parent education (ß = 0.23, p < 0.0005). CONCLUSIONS: Environment-level variables can be combined to create factor scores or composites for use in larger statistical models. Our results are consistent with literature indicating that individual-level socio-demographic characteristics (e.g. race and gender) and aspects of familial social capital (e.g. parental education) have statistical relationships with neurocognitive performance.

Connectome-wide network analysis of youth with Psychosis-Spectrum symptoms.

Adults with psychotic disorders have dysconnectivity in critical brain networks, including the default mode (DM) and the cingulo-opercular (CO) networks. However, it is unknown whether such deficits are present in youth with less severe symptoms. We conducted a multivariate connectome-wide association study examining dysconnectivity with resting state functional magnetic resonance imaging in a population-based cohort of 188 youths aged 8-22 years with psychosis-spectrum (PS) symptoms and 204 typically developing (TD) comparators. We found evidence for multi-focal dysconnectivity in PS youths, implicating the bilateral anterior cingulate, frontal pole, medial temporal lobe, opercular cortex and right orbitofrontal cortex. Follow-up seed-based and network-level analyses demonstrated that these results were driven by hyper-connectivity among DM regions and diminished connectivity among CO regions, as well as diminished coupling between frontal and DM regions. Collectively, these results provide novel evidence for functional dysconnectivity in PS youths, which show marked correspondence to abnormalities reported in adults with established psychotic disorders.

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.

Psychiatric disorders in 22q11.2 deletion syndrome are prevalent but undertreated.

BACKGROUND: Chromosome 22q11.2 deletion syndrome (22q11DS) is a common genetic disorder with high rates of psychosis and other psychopathologies, but few studies discuss treatment. Our aim was to characterize the prevalence and treatment of major psychiatric illnesses in a well-characterized sample of individuals with 22q11DS. METHOD: This was a cross-sectional study of 112 individuals aged 8 to 45 years with a confirmed diagnosis of 22q11DS. Each participant was administered a modified Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS) and the Structured Interview for Prodromal Syndromes (SIPS). Phenotypes assessed were threshold and subthreshold psychosis, depression, mania, generalized and separation anxiety, obsessions/compulsions, inattention/hyperactivity and substance use. Histories of mental health care and current psychotropic treatment were obtained. RESULTS: Psychopathology was common, with 79% of individuals meeting diagnostic criteria for a disorder at the time of assessment. Diagnoses of psychosis were made in 11% of cases, attenuated positive symptom syndrome (APS) in 21%, and 47% experienced significant subthreshold symptoms. Peak occurrence of psychosis risk was during adolescence (62% of those aged 12-17 years). Criteria for a mood disorder were met by 14%, for anxiety disorder 34% and for attention deficit hyperactivity disorder (ADHD) 31%. Mental health care had been received by 63% of individuals in their lifetime, but only 40% continued therapy and 39% used psychotropics. Antipsychotics were used by 42% of participants with psychosis and none of the participants with APS. Half of those at risk for psychosis were receiving no mental health care. CONCLUSIONS: Psychopathology is common in 22q11DS but is not adequately treated or clinically followed. Particular attention should be paid to subthreshold psychotic symptoms, especially in adolescents.

Persistent infection with neurotropic herpes viruses and cognitive impairment.

BACKGROUND: Herpes virus infections can cause cognitive impairment during and after acute encephalitis. Although chronic, latent/persistent infection is considered to be relatively benign, some studies have documented cognitive impairment in exposed persons that is untraceable to encephalitis. These studies were conducted among schizophrenia (SZ) patients or older community dwellers, among whom it is difficult to control for the effects of co-morbid illness and medications. To determine whether the associations can be generalized to other groups, we examined a large sample of younger control individuals, SZ patients and their non-psychotic relatives (n=1852). Method Using multivariate models, cognitive performance was evaluated in relation to exposures to herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and cytomegalovirus (CMV), controlling for familial and diagnostic status and sociodemographic variables, including occupation and educational status. Composite cognitive measures were derived from nine cognitive domains using principal components of heritability (PCH). Exposure was indexed by antibodies to viral antigens. RESULTS: PCH1, the most heritable component of cognitive performance, declines with exposure to CMV or HSV-1 regardless of case/relative/control group status (p = 1.09 × 10-5 and 0.01 respectively), with stronger association with exposure to multiple herpes viruses (ß = -0.25, p = 7.28 × 10-10). There were no significant interactions between exposure and group status. CONCLUSIONS: Latent/persistent herpes virus infections can be associated with cognitive impairments regardless of other health status.

Heritability of functioning in families with schizophrenia in relation to neurocognition.

UNLABELLED: The role of daily functioning is an integral part of the schizophrenia (SZ) phenotype and deficits in this trait appear to be present in both affected persons and some unaffected relatives; hence we have examined its heritability in our cohort of African American schizophrenia families. There is now ample evidence that deficits in cognitive function can impact family members who are not themselves diagnosed with SZ; there is some, but less evidence that role function behaves likewise. We evaluate whether role function tends to "run in families" who were ascertained because they contain an African American proband diagnosed with SZ. METHODS: We analyzed heritability for selected traits related to daily function, employment, living situation, marital status, and Global Assessment Scale (GAS) score; modeling age, gender, along with neurocognition and diagnosis as covariates in a family based African-American sample (N=2488 individuals including 979 probands). RESULTS: Measures of role function were heritable in models including neurocognitive domains and factor analytically derived neurocognitive summary scores and demographics as covariates; the most heritable estimate was obtained from the current GAS scores (h2=0.72). Neurocognition was not a significant contributor to heritability of role function. CONCLUSIONS: Commonly assessed demographic and clinical indicators of functioning are heritable with a global rating of functioning being the most heritable. Measures of neurocognition had little impact on heritability of functioning overall. The family covariance for functioning, reflected in its heritability, supports the concept that interventions at the family level, such as evidenced-based family psychoeducation may be beneficial in schizophrenia.

Facial emotion recognition in adolescents with psychotic-like experiences: a school-based sample from the general population.

BACKGROUND: Psychotic symptoms, also termed psychotic-like experiences (PLEs) in the absence of psychotic disorder, are common in adolescents and are associated with increased risk of schizophrenia-spectrum illness in adulthood. At the same time, schizophrenia is associated with deficits in social cognition, with deficits particularly documented in facial emotion recognition (FER). However, little is known about the relationship between PLEs and FER abilities, with only one previous prospective study examining the association between these abilities in childhood and reported PLEs in adolescence. The current study was a cross-sectional investigation of the association between PLEs and FER in a sample of Irish adolescents. METHOD: The Adolescent Psychotic-Like Symptom Screener (APSS), a self-report measure of PLEs, and the Penn Emotion Recognition-40 Test (Penn ER-40), a measure of facial emotion recognition, were completed by 793 children aged 10-13 years. RESULTS: Children who reported PLEs performed significantly more poorly on FER (ß=-0.03, p=0.035). Recognition of sad faces was the major driver of effects, with children performing particularly poorly when identifying this expression (ß=-0.08, p=0.032). CONCLUSIONS: The current findings show that PLEs are associated with poorer FER. Further work is needed to elucidate causal relationships with implications for the design of future interventions for those at risk of developing psychosis.

Linkage analysis of schizophrenia in African-American families.

While many studies have sought a window into the genetics of schizophrenia, few have focused on African-American families. An exception is the Project among African-Americans to Explore Risks for Schizophrenia (PAARTNERS), which seeks to identify novel and known risk variation for schizophrenia by genetic analyses of African-American families. We report a linkage study of diagnostic status in 217 African-American families using the Illumina Linkage Panel. Due to assumed incomplete and time-dependent penetrance, we performed linkage analysis using two different treatments of diagnosis: (1) treating both affected and unaffected individuals as informative for linkage (using the program SIBPAL) and (2) treating only affected individuals as informative (using the program MERLIN). We also explore three definitions of affected status: narrowly defined schizophrenia; one broadened to include schizoaffective disorder; and another including all diagnoses indicating psychosis. Several regions show a decrease in the evidence for linkage as the definition broadens 8q22.1 (rs911, 99.26 cM; SIBPAL p-value [p] goes from 0.006 to 0.02), 16q24.3 (rs1006547, 130.48 cM; p from 0.00095 to 0.0085), and 20q13.2 (rs1022689, 81.73 cM; p from 0.00015 to 0.032). One region shows a substantial increase in evidence for linkage, 11p15.2 (rs722317, 24.27 cM; p from 0.0022 to 0.0000003); MERLIN results support the significance of the SIBPAL results (p=0.00001). Our linkage results overlap two broad, previously-reported linkage regions: 8p23.3-p12 found in studies sampling largely families of European ancestry; and 11p11.2-q22.3 reported by a study of African-American families. These results should prove quite useful for uncovering loci affecting risk for schizophrenia.

The misclassification of blinks as saccades: implications for investigations of eye movement dysfunction in schizophrenia.

It is important to have a simple. accurate method for recording eye movements. Of the two popular approaches commonly adopted, electro-oculography (EOG) and infrared oculography (IROG), IROG is often accepted as the more accurate, and it is the method that is currently used most frequently to examine eye movements in schizophrenia. This study investigated whether the misclassification of blinks as saccades affects saccade rates when the presence of a blink is determined using only IROG recordings of eye position. Both vertical electro-oculography (VEOG), which can be used to objectively identify blinks, and IROG were recorded while 17 schizophrenia patients and 19 healthy controls were presented with sinusoidal stimuli. Of the blinks identified with the VEOG for the total group of participants, a substantial number (37%) were misclassified as catch-up and anticipatory saccades when only the IROG was used. Furthermore, in the schizophrenia group, but not in the healthy control group, the use of the IROG led to a significant misclassification of blinks as anticipatory saccades. Therefore, when IROG alone is used to identify blinks, the misclassification of blinks as saccades is likely to introduce measurement error into estimates of saccade rates, particularly estimates of anticipatory saccade rates in schizophrenia patients.

Saccadic disinhibition in schizophrenia patients and their first-degree biological relatives. A parametric study of the effects of increasing inhibitory load.

Several studies have reported that patients with schizophrenia and their relatives perform poorly on antisaccade tasks and have suggested that this deficit represents saccadic disinhibition. If this proposition is correct, then varying task parameters that specifically increase the difficulty with which unwanted saccades can be inhibited should exacerbate deficits. Forty-two schizophrenia patients, 42 of their first-degree biological relatives, 21 psychotic affective disorder patients, and 38 nonpsychiatric comparison subjects were given fixation and antisaccade tasks. The introduction of distracters and the presence of visible fixation stimuli were parameters used to vary the difficulty in suppressing unwanted saccades (inhibitory load). It is known that the presence of a fixation stimulus at the time when a saccade must be inhibited results in fewer reflexive errors on antisaccade tasks. Performance on fixation tasks without (low load) vs with distracters (high load) and antisaccade tasks that had fixation stimuli still visible (low load) vs already extinguished (high load) at the time when the reflexive saccade must be inhibited was compared. The schizophrenia patients and their first-degree biological relatives showed evidence of increased saccadic disinhibition that was most pronounced during high inhibitory load conditions. These data indicate that dysfunctional inhibitory processes, at least in the oculomotor domain, are associated with the liability to schizophrenia. Results also suggest that this genetic liability may be related to dysfunctional prefrontal cortical areas that provide top-down inhibitory control over reflexive saccade generation.

Saccadic disinhibition in patients with acute and remitted schizophrenia and their first-degree biological relatives.

OBJECTIVE: Performance on measures of saccadic inhibition and control was investigated in a large family study of schizophrenia to evaluate the utility of using antisaccade task performance as an endophenotypic marker of genetic liability for schizophrenia. METHOD: Ninety-five patients with acute schizophrenia and 116 of their first-degree biological relatives, 13 schizophrenia patients whose illness was in full remission, 35 patients with acute psychotic affective disorder, and 109 nonpsychiatric comparison subjects were administered antisaccade and prosaccade tasks. RESULTS: Both schizophrenia patient groups had a greater number of errors on the antisaccade task than did the first-degree relatives and the affective disorder group, which both had more errors than the comparison subjects. Among the first-degree relatives of the probands with acute schizophrenia, relatives of poor-performing patients performed worse on the antisaccade task than relatives of patients with good performance. Reflexive errors were not likely the result of interfering psychotic symptoms, medication, or medication side effects. Although the schizophrenia patients demonstrated other signs of saccadic abnormalities, these problems, which were not observed in their relatives even though they had high antisaccade error rates, seem unlikely to account for the higher antisaccade error rate of the schizophrenia patients. CONCLUSIONS: These findings suggest that saccadic disinhibition is strongly associated with the genetic liability for schizophrenia.

Eye movement dysfunction in schizophrenia: a heritable characteristic for enhancing phenotype definition.

The occurrence of ocular motor dysfunction in schizophrenia patients and their first-degree biological relatives is remarkably consistent, suggesting that abnormal smooth pursuit and saccadic oculomotion are heritable characteristics that can be used to identify gene carriers for schizophrenia. Saccadic system dysfunction probably reflects a generalized deficit in prefrontal cortical functioning, rather than a specific deficit in saccade system functioning. Although abnormal smooth pursuit has also been associated with impaired frontal functioning, it is unclear whether these two types of dysfunction arise from the same neural pathology. Therefore, deviant smooth pursuit and saccadic oculomotion may constitute unrelated factors identifying two different types of genetic risk. Alternatively, they may derive from a single risk factor that causes (a) both types of deficits to be expressed together or (b) each type to be expressed separately as pleiotropic manifestations of the underlying genotype. Although a full complement of pursuit and saccade measures has not been examined together in family studies of schizophrenia, there is obvious value in determining how these measures relate to one another in schizophrenia families and whether they can be used in combination to enhance phenotype definition to facilitate the search for schizophrenia susceptibility genes.

Pathophysiology of congestive heart failure in ESRD.

Congestive heart failure (CHF) represents the inability of the heart to pump enough blood to meet tissue requirements for oxygen, resulting in a discrepancy between myocardial oxygen supply and demand. It can result from any clinical situation that alters myocardial performance, including end stage renal disease (ESRD). The purpose of this article is to describe the pathophysiology of CHF, major signs and symptoms, medical management, and nursing interventions in patients with ESRD.

Ethical issues in the elderly ESRD patient.

The fastest growing population group in the United States is the over 65 years old group. In 1985, 59% of all new patients to chronic dialysis were age 55 years or older. Quality of life has been a health care issue in the past and is more so now with decreasing health care resources. The rationing of health care resources has become an increasingly important issue in determining and defining the quality of life, especially for the chronically ill elderly. This article does not support either dialysis treatment or no dialysis treatment for the elderly, but assists readers to consider the implications to the health care system and the limited health care resources that are present. This bioethical dilemma will be with the health care system for years to come.