Unaffected First-degree Relatives Research Articles

Social and non-social reward learning reduced and related to a familial vulnerability in schizophrenia spectrum disorders

Patients with a disorder in the schizophrenia spectrum (SZ) demonstrate impairments in reward learning. A reduced sensitivity to social reward may impede social beyond non-social reward learning mechanisms. The aim of the current study was to investigate social and non-social reward learning in SZ by means of two interactive game-theoretical investment paradigms. Unaffected first-degree relatives of patients were included to examine whether (social) reward-learning impairments are part of a familial vulnerability of SZ. We included 50 patients with a SZ disorder, 20 unaffected first-degree relatives of patients and 49 healthy controls. The trust game (social) and the lottery game (non-social) were used, consisting of 20 game trials each. The game paradigms were programmed to increase the likelihood of higher repayments in response to increased investments. Multilevel regression analyses were used to examine learning over trials in both contexts. The results showed that controls learned equally well in social and non-social contexts, as reflected in an increase of investments over game rounds in both paradigms. In contrast, patients and relatives showed reduced reward learning, regardless of its social or non-social nature, reflected by flatter or decreasing slopes over game rounds in both paradigms. The findings suggest that patients and relatives have a general reduced sensitivity to reward, which appears to reflect a familial vulnerability rather than illness related mechanisms. Results indicate that reward learning may be an important marker for the familial risk to SZ.

Resting-state Functional Connectivity between Dorsolateral Prefrontal Cortex and Left Temporal Language-related Region in Unaffected First-degree Relatives of Schizophrenia Patients

According to the large body of literature data, patients with schizophrenia demonstrate altered (decreased) functional connectivity (FC) between the brain regions involved in executive functions and language (in particular, dorsolateral prefrontal cortex (DLPFC) and left temporal regions). However, the analysis of similar FC in the genetic risk group has not been done, although such data are significant for studying the neurobiological markers of schizophrenia, linked to the genetic architecture of the disorder (its traits or so-called endophenotypes). The aim of this study was to investigate whether FC between the DLPFC and left temporal language-related region was altered in unaffected first-degree relatives of patients with schizophrenia. First-degree unaffected relatives of patients with schizophrenia (12 subjects) and healthy individuals without family history of mental disorders (13 subjects) underwent resting-state functional magnetic resonance imaging at 3T Philips scanner. The FC between the regions of interest (left/right DLPFC, on the one hand, and left temporal region, on the other hand) was compared between groups as well as indexes of Verbal fluency and the Scale of Prodromal Symptoms (SOPS). As compared to controls, the relatives of patients with schizophrenia were characterized by increased FC between the left DLPFC and left temporal language-related region, although they did not differ in the other indexes, and there were no correlations between the indexes and FC. The findings might reflect some compensatory functional processes in unaffected first-degree relatives of schizophrenic patients.

Amygdala functional connectivity in major depression - disentangling markers of pathology, risk and resilience.

Limbic-cortical imbalance is an established model for the neurobiology of major depressive disorder (MDD), but imaging genetics studies have been contradicting regarding potential risk and resilience mechanisms. Here, we re-assessed previously reported limbic-cortical alterations between MDD relatives and controls in combination with a newly acquired sample of MDD patients and controls, to disentangle pathology, risk, and resilience. We analyzed functional magnetic resonance imaging data and negative affectivity (NA) of MDD patients (n = 48), unaffected first-degree relatives of MDD patients (n = 49) and controls (n = 109) who performed a faces matching task. Brain response and task-dependent amygdala functional connectivity (FC) were compared between groups and assessed for associations with NA. Groups did not differ in task-related brain activation but activation in the superior frontal gyrus (SFG) was inversely correlated with NA in patients and controls. Pathology was associated with task-independent decreases of amygdala FC with regions of the default mode network (DMN) and decreased amygdala FC with the medial frontal gyrus during faces matching, potentially reflecting a task-independent DMN predominance and a limbic-cortical disintegration during faces processing in MDD. Risk was associated with task-independent decreases of amygdala-FC with fronto-parietal regions and reduced faces-associated amygdala-fusiform gyrus FC. Resilience corresponded to task-independent increases in amygdala FC with the perigenual anterior cingulate cortex (pgACC) and increased FC between amygdala, pgACC, and SFG during faces matching. Our results encourage a refinement of the limbic-cortical imbalance model of depression. The validity of proposed risk and resilience markers needs to be tested in prospective studies. Further limitations are discussed.

Temporal discrimination threshold and blink reflex recovery cycle in cervical dystonia – two sides of the same coin?

IntroductionElevated temporal discrimination thresholds (TDT) have been found in cervical dystonia (CD) and unaffected first-degree relatives, indicating autosomal dominant inheritance with reduced penetrance, serving as an endophenotype and being indicative of abnormal inhibitory processing within the brainstem-basal ganglia circuits. The blink reflex R2 recovery cycle (BRRC) is also a measure of excitability of brainstem-basal ganglia circuits, and inconsistent findings are reported in CD. The aim was to investigate TDT and BRRC in CD and evaluate its reliability as an endophenotype. Methods29 patients with isolated cervical dystonia (mean age: 56.1 ± 14.3, female n = 18) and 29 age- and gender-matched healthy controls (mean age: 56.0 ± 14.2, female n = 18) were evaluated using a TDT-paradigm, performed as previously described by testing visual, tactile and visual-tactile temporal discrimination thresholds, and the BRRC, investigated with electrical and air puff stimulation. ResultsMean visual-tactile (p = 0.001) and visual TDTs (p = 0.015) differed between CD and controls; tactile TDTs revealed no group differences (p = 0.232). No between group differences were found for BRRC using either electrical or air puff stimulation (p = 0.117). There was no correlation between the elevation of TDTs and the degree of BRRC-inhibition in CD. ConclusionOur findings support the hypothesis that the TDT is an endophenotype in CD. BRRC testing did not demonstrate disinhibition of brainstem-basal ganglia circuits in CD. In contrast to TDT, the BRRC seems not to represent an endophenotype in cervical dystonia.

MACHINE LEARNING IN PSYCHIATRIC GENOMICS: INTEGRATING MULTIPLE LEVELS OF ANALYSIS THROUGH DEEP NETWORK MODELS

Schizophrenia patients (SCZ) display widespread cognitive deficits that are strongly associated with functional outcomes. Cognitive impairments occur along a genetic continuum among SCZ, their unaffected first-degree relatives (FRs) and healthy controls (HCs). Although SCZ impairs the premorbid intelligence quotient (IQ) and causes a subsequent intelligence decline (ID), a decrease in present IQ from the premorbid level, it remains unclear when during the illness course these impairments develop. Differences in premorbid and present IQ and ID were investigated among 125 SCZ, 61 FRs and 107 HCs, using analysis of covariance and a paired t-test. Furthermore, these subjects were classified into preserved and deteriorated IQ groups based on the degree of ID, and we investigated which factors contribute to this classification. We found significant differences in premorbid and present IQ among the diagnostic groups. Compared with HCs, SCZ and FRs displayed lower premorbid and present IQ. There was no significant difference in premorbid IQ between SCZ and FRs, but SCZ had a significantly lower present IQ than FRs. Only SCZ showed a significant ID. As most FRs and HCs did not display an ID, there were fewer subjects with deteriorated IQ among FRs and HCs than among SCZ. Subjects with preserved IQ showed higher educational attainment than those with deteriorated IQ among SCZ and FRs. These findings suggest that the impairment of premorbid IQ and the ID in SCZ become evident before and around the time of onset, respectively, and different pathophysiological mechanisms might be related to these impairments.

Risk Model Assessment in Early-Onset and Adult-Onset Schizophrenia Using Neurological Soft Signs.

Age at onset is one of the most important clinical features of schizophrenia that could indicate greater genetic loadings. Neurological soft signs (NSS) are considered as a potential endophenotype for schizophrenia. However, the association between NSS and different age-onset schizophrenia still remains unclear. We aimed to compare risk model in patients with early-onset schizophrenia (EOS) and adult-onset schizophrenia (AOS) with NSS. This study included 262 schizophrenia patients, 177 unaffected first-degree relatives and 243 healthy controls. We estimated the discriminant abilities of NSS models for early-onset schizophrenia (onset age < 20) and adult-onset schizophrenia (onset age ≥ 20) using three data mining methods: artificial neural networks (ANN), decision trees (DT) and logistic regression (LR). We then assessed the magnitude of NSS performance in EOS and AOS families. For the four NSS subscales, the NSS performance were greater in EOS and AOS families compared with healthy individuals. More interestingly, there were significant differences found between patients’ families and control group in the four subscales of NSS. These findings support the potential for neurodevelopmental markers to be used as schizophrenia vulnerability indicators. The NSS models had higher discriminant abilities for EOS than for AOS. NSS were more accurate in distinguishing EOS patients from healthy controls compared to AOS patients. Our results support the neurodevelopmental hypothesis that EOS has poorer performance of NSS than AOS. Hence, poorer NSS performance may be imply trait-related NSS feature in EOS.

Impaired theory of mind in unaffected first-degree relatives of patients with anorexia nervosa.

Previous studies have shown theory of mind (ToM) is affected in patients with anorexia nervosa (AN). There has also been growing interest in the study of endophenotypes in psychiatric disorders, since they allow better understanding of genetic mechanisms underlying different conditions, making them potential targets for future treatment. The goal of this study was to investigate whether ToM inefficiencies observed in patients with AN, are shared by unaffected first-degree relatives. Performance on two ToM tasks (Reading the Mind in the Eyes and Faux Pas Test) were compared in 17 unaffected first-degree relatives of AN patients and in 17 healthy individuals matched for age and level of education. Depression, anxiety, obsessive compulsive, and eating disorder symptoms were also assessed and correlated with ToM and clinical/demographic variables. Significant differences between groups were observed in all ToM tasks, with relatives of AN patients showing poorer performance. ToM assessment did not correlate with any clinical or demographic variable. The preliminary results of this study suggest unaffected first-degree relatives of AN patients display similar patterns of difficulty in ToM as reported previously for AN patients, supporting the hypothesis that ToM inefficiencies are a familial trait in this condition.

Whole-Exome Sequencing of Adult and Pediatric Cohorts of the Rare Vascular Disorder Systemic Capillary Leak Syndrome.

Systemic capillary leak syndrome (SCLS) is a rare disorder that presents with episodes of hypovolemic shock. The extent to which genetic abnormalities contribute to SCLS is unknown. We identified pediatric and adult cohorts with characteristic clinical courses. We sought to describe the clinical characteristics of both cohorts, identify a possible genetic contribution to SCLS, and demonstrate that whole-exome sequencing (WES) may be conducted by critical care providers. Prospective observational study of WES of nine adult and eight pediatric SCLS patients and available unaffected first-degree relatives. Tertiary children's hospitals and referral research laboratory. Children and adults with SCLS. None. Patients and available first-degree relatives underwent WES. Data were analyzed for rare homozygous, biallelic, de novo, and heterozygous variants with allelic enrichment and metabolic pathway analyses. Children with SCLS presented at a younger age with episodes similar to those experienced by adults. All patients and available relatives underwent satisfactory WES. No overlapping gene variants or metabolic pathways were identified across all SCLS patients. Multiple candidate genes with homozygous or biallelic mutations were identified in individual subjects with SCLS. There was no significant enrichment of genes with rare heterozygous variants. The clinical characteristics of children and adults with SCLS are similar. We did not identify a uniform germline exomic genetic etiology for SCLS. WES identified several candidate genes in individual patients for future research. WES is a viable way for critical care providers to investigate the etiology of diseases with presumed genetic contributions.

Association of elevated serumfree light chains with chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

Chronic lymphocytic leukemia (CLL) and its precursor, monoclonal B-cell lymphocytosis (MBL), are heritable. Serumfree light-chain (sFLC) measures are a prognostic factor for CLL, but their role in susceptibility to CLL is not clear. We investigated differences between sFLC measurements in pre-treatment serum from five groups to inform the association of sFLC with familial and sporadic CLL: (1) familial CLL (n = 154), (2) sporadic CLL (n = 302), (3) familial MBL (n = 87), (4) unaffected first-degree relatives from CLL/MBL families (n = 263), and (5) reference population (n = 15,396). The percent of individuals having elevated monoclonal and polyclonal sFLCs was compared using age-stratified and age- and sex-adjusted logistic regression models. In age groups >50 years, monoclonal sFLC elevations were increased in sporadic and familial CLL cases compared to the reference population (p’s < 0.05). However, there were no statistically significant differences in sFLC monoclonal or polyclonal elevations between familial and sporadic CLL cases (p’s > 0.05). Unaffected relatives and MBL cases from CLL/MBL families, ages >60 years, showed elevated monoclonal sFLC, compared to the reference population (p’s < 0.05). This is the first study to demonstrate monoclonal sFLC elevations in CLL cases compared to controls. Monoclonal sFLC levels may provide additional risk information in relatives of CLL probands.

Impairment in the goal-directed corticostriatal learning system as a biomarker for obsessive-compulsive disorder.

Compulsive behaviors in obsessive-compulsive disorder (OCD) have been related to impairment within the associative cortical-striatal system connecting the caudate and prefrontal cortex that underlies consciously-controlled goal-directed learning and behavior. However, little is known whether this impairment may serve as a biomarker for vulnerability to OCD. Using resting-state functional magnetic resonance imaging (fMRI), we employed Granger causality analysis (GCA) to measure effective connectivity (EC) in previously validated striatal sub-regions, including the caudate, putamen, and the nucleus accumbens, in 35 OCD patients, 35 unaffected first-degree relatives and 35 matched healthy controls. Both OCD patients and their first-degree relatives showed greater EC than controls between the left caudate and the orbital frontal cortex (OFC). Both OCD patients and their first-degree relatives showed lower EC than controls between the left caudate and lateral prefrontal cortex. These results are consistent with findings from task-related fMRI studies which found impairment in the goal-directed system in OCD patients. The same changes in EC were present in both OCD patients and their unaffected first-degree relatives suggest that impairment in the goal-directed learning system may be a biomarker for OCD.

Visual memory dysfunction as a neurocognitive endophenotype in bipolar disorder patients and their unaffected relatives. Evidence from a 5-year follow-up Valencia study.

BackgroundScarce research has focused on Visual Memory (VM) deficits as a possible neurocognitive endophenotype of bipolar disorder (BD). The main aim of this longitudinal, family study with healthy controls was to explore whether VM dysfunction represents a neurocognitive endophenotype of BD. MethodsAssessment of VM by Rey–Osterrieth Complex Figure Test (ROCF) was carried out on a sample of 317 subjects, including 140 patients with BD, 60 unaffected first-degree relatives (BD-Rel), and 117 genetically-unrelated healthy controls (HC), on three occasions over a 5-year period (T1, T2, and T3). BD-Rel group scores were analyzed only at T1 and T2. ResultsPerformance of BD patients was significantly worse than the HC group (p < 0.01). Performance of BD-Rel was also significantly different from HC scores at T1 (p < 0.01) and T2 (p = 0.05), and showed an intermediate profile between the BD and HC groups. Only among BD patients, there were significant differences according to sex, with females performing worse than males (p = 0.03). Regarding other variables, education represented significant differences only in average scores of BD-Rel group (p = 0.01). LimitationsImportant attrition in BD-Rel group over time was detected, which precluded analysis at T3. ConclusionsBD patients show significant deficits in VM that remain stable over time, even after controlling sociodemographic and clinical variables. Unaffected relatives also show stable deficits in VM. Accordingly, the deficit in VM could be considered a potential endophenotype of BD, which in turn may be useful as a predictor of the evolution of the disease. Further studies are needed to confirm these findings.

Characterizing Brain Network Topology in Cervical Dystonia Patients and Unaffected Relatives via Graph Theory.

Cervical Dystonia (CD) is a neurological movement disorder characterized by intermittent muscle contractions in the head and neck. The pathophysiology and neural networks underpinning this condition are incompletely understood. There is increasing evidence that isolated focal dystonias are due to network-wide functional alterations. An abnormal temporal discrimination threshold (TDT) is believed to be a mediational endophenotype due to its prevalence in unaffected first-degree relatives as well as patients. However the neural correlates linking abnormal TDT and CD remain poorly understood. Probing changes in large-scale network topology via graph theory with resting state fMRI data from relatives and patients may provide further insight into the pathophysiology of CD. In this study, resting state fMRI data were acquired and analyzed from 16 CD patients with abnormal TDT, 32 unaffected first degree relatives (16 with normal TDT and 16 with abnormal TDT) and 16 healthy controls. Graph theory metrics demonstrating network topology were extracted. The results indicate large-scale functional reorganization of networks in relatives (with abnormal TDT) along with a manifestation of topological aberrations similar to patients.

Polygenic effects of schizophrenia on hippocampal grey matter volume and hippocampus-medial prefrontal cortex functional connectivity.

Schizophrenia is a complex mental disorder with high heritability and polygenic inheritance. Multimodal neuroimaging studies have also indicated that abnormalities of brain structure and function are a plausible neurobiological characterisation of schizophrenia. However, the polygenic effects of schizophrenia on these imaging endophenotypes have not yet been fully elucidated. To investigate the effects of polygenic risk for schizophrenia on the brain grey matter volume and functional connectivity, which are disrupted in schizophrenia. Genomic and neuroimaging data from a large sample of Han Chinese patients with schizophrenia (N = 509) and healthy controls (N = 502) were included in this study. We examined grey matter volume and functional connectivity via structural and functional magnetic resonance imaging, respectively. Using the data from a recent meta-analysis of a genome-wide association study that comprised a large number of Chinese people, we calculated a polygenic risk score (PGRS) for each participant. The imaging genetic analysis revealed that the individual PGRS showed a significantly negative correlation with the hippocampal grey matter volume and hippocampus-medial prefrontal cortex functional connectivity, both of which were lower in the people with schizophrenia than in the controls. We also found that the observed neuroimaging measures showed weak but similar changes in unaffected first-degree relatives of patients with schizophrenia. These findings suggested that genetically influenced brain grey matter volume and functional connectivity may provide important clues for understanding the pathological mechanisms of schizophrenia and for the early diagnosis of schizophrenia.

Machine learning identifies unaffected first-degree relatives with functional network patterns and cognitive impairment similar to those of schizophrenia patients.

Schizophrenia (SCZ) patients and their unaffected first-degree relatives (FDRs) share similar functional neuroanatomy. However, it remains largely unknown to what extent unaffected FDRs with functional neuroanatomy patterns similar to patients can be identified at an individual level. In this study, we used a multivariate pattern classification method to learn informative large-scale functional networks (FNs) and build classifiers to distinguish 32 patients from 30 healthy controls and to classify 34 FDRs as with or without FNs similar to patients. Four informative FNs-the cerebellum, default mode network (DMN), ventral frontotemporal network, and posterior DMN with parahippocampal gyrus-were identified based on a training cohort and pattern classifiers built upon these FNs achieved a correct classification rate of 83.9% (sensitivity 87.5%, specificity 80.0%, and area under the receiver operating characteristic curve [AUC] 0.914) estimated based on leave-one-out cross-validation for the training cohort and a correct classification rate of 77.5% (sensitivity 72.5%, specificity 82.5%, and AUC 0.811) for an independent validation cohort. The classification scores of the FDRs and patients were negatively correlated with their measures of cognitive function. FDRs identified by the classifiers as having SCZ patterns were similar to the patients, but significantly different from the controls and FDRs with normal patterns in terms of their cognitive measures. These results demonstrate that the pattern classifiers built upon the informative FNs can serve as biomarkers for quantifying brain alterations in SCZ and help to identify FDRs with FN patterns and cognitive impairment similar to those of SCZ patients.

Neurological soft signs and neurocognitive deficits in remitted patients with schizophrenia, their first-degree unaffected relatives, and healthy controls.

Neurological soft signs (NSS) and neurocognitive deficits (ND) are highly prevalent in schizophrenia, and have been separately proposed as candidate endophenotypes of schizophrenia. However, few relevant studies focus on remitted patients with schizophrenia (RP) and integrate NSS and ND as a composite endophenotype. This study aimed to explore the NSS and ND and examine the comparative relationship between them in RP, their first-degree unaffected relatives (FDR), and healthy controls, furthermore, to seek potential endophenotypes subitems of NSS and ND and create a composite endophenotype. 86 RP, 86 FDR, and 86 healthy controls were included. NSS and ND were independently assessed with Cambridge Neurological Inventory and MATRICSTM Consensus Cognitive Battery. RP had more NSS and ND than FDR in all subitems except disinhibition, information processing speed, working memory, and visual memory. Similarly, FDR presented poorer performance than controls in all subscales except disinhibition, sensory integration, working memory, and visual memory. Six subitems of NSS and ND met the criteria of endophenotype and the three groups were most accurately classified (71.2%) with these subitems working as a composite endophenotype. Moreover, information processing speed, attention, and social cognition were associated with sensory integration in RP and FDR. These findings add evidences that certain subitems of NSS and ND might be the endophenotypes of schizophrenia and integrating these endophenotypes may prove useful in identifying schizophrenia and high-risk individuals. Furthermore, sensory integration and specific cognitive domains covary, hence suggesting an overlap of compromised underlying neural systems.

Characterizing neurocognitive markers of familial risk for depression using multi-modal imaging, behavioral and self-report measures

BackgroundMajor depressive disorder (MDD) is associated with poorer behavioral performance in domains of working memory and associated cognitive systems for cognitive control and attention. Functional neuroimaging studies show altered functioning in MDD in frontal executive control circuits implicated in these cognitive processes. It is not yet known whether poor cognitive performance involving these circuits is part of the familial risk for MDD, and we addressed this issue using a multi-modal imaging, behavioral and self-report approach in unaffected first-degree relatives of parent probands with MDD. Methods72 unaffected adult first-degree relatives of probands with MDD (mean age 30.5 ± 13.4 years) with and 66 case-wise matched non-relative controls underwent functional magnetic resonance imaging during performance of ‘n-back’ working memory task, a Go/No-go task assessing cognitive control and an Auditory Oddball test of selective attention. Groups were compared on imaging data analyzed voxel wise with a focus on dorsolateral prefrontal cortex, anterior cingulate cortex and insula regions of interest, and on corresponding behavioral accuracy and reaction time data. Symptoms were assessed using self-report scales. ResultsRelatives were distinguished by comparatively decreased activation in the left dorsolateral prefrontal cortex (DLPFC) during updating of working memory. Behaviorally, relatives also showed more errors of omission during working memory updating. DLPFC hypo-activation was associated with greater depressive symptom severity. ConclusionsDeficits in cognitive processing may be part of the profile of familial risk for depression, preceding illness onset, specifically in the domain of working memory.

Olfactory Identification in 7-Year-Old Children with Familial High Risk of Schizophrenia or Bipolar Disorder - The Danish High Risk and Resilience Study VIA 7

Background: Olfactory identification deficits are present in individuals with schizophrenia and their unaffected first-degree relatives, while deficits are less pronounced in individuals with bipolar disorder. We hypothesized that children with familial high-risk for schizophrenia (FHR-SZ) show olfactory identification deficits compared to population-based controls (PBC), and that children with familial high-risk for bipolar disorder (FHR-BP) perform intermediate. Furthermore, we investigated potential relationships with psychopathology, cognition, and home environment. Methods: Olfactory identification was assessed at age 7 in 184 children with FHR-SZ, 106 children with FHR-BD, and 186 PBC with the Brief Smell Identification Test (BSIT). BSIT total score and the proportion of children scoring below pre-defined cut-off scores were the outcomes. Potential relationships with psychopathological, cognitive, and home environmental variables were conducted using hierarchical and logistic multiple regression analyses. Outcomes: ANOVA revealed no between-group differences in olfactory identification. Chi-square test of independence showed a significant greater proportion of boys with FHR-SZ than population-based boys with an abnormal olfactory identification (p<0·05). Regression analyses of all children showed significant positive associations of olfactory identification with girls, social responsiveness, and working memory. Less social responsiveness predicted abnormal olfactory identification in boys with FHR-SZ. Interpretation: Abnormal olfactory identification is more frequent in 7-year-old boys with FHR-SZ than in matched low-risk boys and is linked to a deficit of social responsiveness. This supports the idea that olfactory and social dysfunction share a common pathophysiological and perhaps neurobiological pathway in schizophrenia. Funding Statement: Mental Health Services of the Capital Region of Denmark, Aarhus University, and the Lundbeck Foundation Initiative for Integrative Psychiatric Research. Declaration of Interests: All authors confirmed to have no conflicts of interest. Ethics Approval Statement: The project was approved by The Danish Data Protection Agency. The study procedures were aligned with the guidelines of the National Committee for Health Research Ethics, although formal ethical approval was not required due to its observational design.

Metabolic profile in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives

ObjectiveThe prevalence of metabolic syndrome and insulin resistance is twice as high in patients with bipolar disorder compared with the general population, and possibly associated with a disabling illness trajectory of bipolar disorder, an increased risk of cardiovascular disease and premature death. Despite these detrimental effects, the prevalence of metabolic syndrome and insulin resistance in patients newly diagnosed with bipolar disorder and their unaffected first-degree relatives is largely unknown.MethodsIn a cross-sectional study of 206 patients with newly diagnosed bipolar disorder, 50 of their unaffected first-degree relatives and 109 healthy age- and sex-matched individuals, we compared the prevalence of metabolic syndrome and insulin resistance (HOMA-IR). In patients with bipolar disorder, we further investigated illness and medication variables associated with the metabolic syndrome and insulin resistance.ResultsHigher rates of metabolic syndrome (odds ratio = 3.529, 95% CI 1.378–9.041, P = 0.009) and levels of insulin resistance (B = 1.203, 95% CI 1.059–1.367, P = 0.005) were found in patients newly diagnosed with bipolar disorder, but not in their unaffected first-degree relatives compared with matched healthy individuals (data adjusted for sex and age). Most patients with bipolar disorder (94.7%) were diagnosed within the preceding 2 years, and the average illness duration, defined as time from first mood episode, was 10 years.ConclusionOur findings of elevated prevalence of metabolic syndrome and insulin resistance in patients with newly diagnosed bipolar disorder highlight the importance of screening for these conditions at an early stage to employ adequate and early care reducing the risk of cardiovascular disease and premature death.

Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients.

BackgroundAutoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs) of patients, who exhibit increased future risk for the same disease.MethodsSamples (n = 1321) from disease-specific autoantibody-positive (aAb+) systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D) patients; and unaffected aAb+ and autoantibody-negative (aAb–) SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS) were calculated.FindingsAlternative autoimmunity occurred in SLE patients (56%) and FDRs (57·4%), RA patients (32·6%) and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR] 2·44) and expanded (OR 3·27) autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs.InterpretationAutoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE) and organ-specific (T1D) autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies.FundNIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.

Intelligence decline between present and premorbid IQ in schizophrenia: Schizophrenia Non-Affected Relative Project (SNARP)

Schizophrenia patients (SCZ) display widespread cognitive deficits that are strongly associated with functional outcomes. Cognitive impairments occur along a genetic continuum among SCZ, their unaffected first-degree relatives (FRs) and healthy controls (HCs). Although SCZ impairs the premorbid intelligence quotient (IQ) and causes a subsequent intelligence decline (ID), a decrease in present IQ from the premorbid level, it remains unclear when during the illness course these impairments develop. Differences in premorbid and present IQ and ID were investigated among 125 SCZ, 61 FRs and 107 HCs, using analysis of covariance and a paired t-test. Furthermore, these subjects were classified into preserved and deteriorated IQ groups based on the degree of ID, and we investigated which factors contribute to this classification. We found significant differences in premorbid and present IQ among the diagnostic groups. Compared with HCs, SCZ and FRs displayed lower premorbid and present IQ. There was no significant difference in premorbid IQ between SCZ and FRs, but SCZ had a significantly lower present IQ than FRs. Only SCZ showed a significant ID. As most FRs and HCs did not display an ID, there were fewer subjects with deteriorated IQ among FRs and HCs than among SCZ. Subjects with preserved IQ showed higher educational attainment than those with deteriorated IQ among SCZ and FRs. These findings suggest that the impairment of premorbid IQ and the ID in SCZ become evident before and around the time of onset, respectively, and different pathophysiological mechanisms might be related to these impairments.