Unaffected First-degree Relatives Research Articles

Dorsolateral Prefrontal Cortex Activity is Impaired in Currently-Depressed Patients, But Intact in Individuals at High Risk: A Three-Group Functional MRI Study of Hot and Cold Cognition

Background: The neural mechanisms affecting risk for and resilience to depression are largely unknown. Modern neuropsychological models of depression posit that negatively biased emotional (hot) processing confers risk for depression, while preserved non-emotional (cold) cognition might promote resilience. However, few studies have compared neural responses during hot and cold cognitive tasks in samples at high-risk for depression and those currently experiencing a major depressive episode. Methods: We recruited 99 participants: 39 unmedicated currently-depressed patients, 30 unaffected first-degree relatives of depressed individuals, and 30 matched healthy controls with no first-degree relatives with depression. Primary analyses assessed neural activation on two functional magnetic resonance imaging tasks previously associated with depression: dorsolateral prefrontal cortex (DLPFC) responsivity during the N-back working memory task; and amygdala and subgenual anterior cingulate cortex (sgACC) responsivity during incidental emotional face processing. Outcomes: Depressed patients exhibited significantly attenuated working memory-related DLPFC activation, compared to both healthy volunteers and unaffected relatives; unaffected relatives did not differ from healthy volunteers. We did not observe a complementary pattern during emotion processing. Interpretation: These findings have important implications for understanding the neural mechanisms of risk and resilience in depression. Specifically, they are consistent with the proposal that preserved cold cognitive function may confer resilience to developing depression in at-risk individuals. However, this requires confirmation in longitudinal studies. Funding: This work was supported by the Brain and Behavior Research Foundation (grant number 20162) to JPR and a Brain Research Trust PhD studentship awarded to CLN. Conflict of Interest: JPR consults for Cambridge Cognition and Takeda Ltd. The other authors report no conflict of interest. Ethical Approval Statement: The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.

Caffeine Consumption in First-Degree Relatives of Essential Tremor Cases: Evidence of Dietary Modification Before Disease Onset

Background: Caffeine can exacerbate tremor. Reducing caffeine intake or switching to decaffeinated beverages can lessen tremor. Unaffected relatives of essential tremor (ET) cases often have mild, subclinical tremor. One question is whether the coffee and tea consumption pattern in these individuals differs from that of controls (Co). Methods: We ascertained the patterns of coffee and tea intake using a structured questionnaire, and compared the use in unaffected first-degree relatives of ET cases (FD-ET) to the use in age-matched Co. Three measures of relative caffeinated coffee + tea to decaffeinated coffee + tea were constructed. Caffeine index 1 = (cups of caffeinated coffee + tea) – (cups of decaffeinated coffee + tea) consumed on the day of evaluation. Caffeine index 2 = (cups of caffeinated coffee + tea) – (cups of decaffeinated coffee + tea) consumed in a typical month. The percentage of coffee and tea that was caffeinated in a typical month was also calculated. Results: There were 263 individuals (190 FD-ET, 73 Co). Caffeine index 1 in FD-ET was less than 1-half that of Co (p = 0.001). Caffeine index 2 was similarly lower in FD-ET than Co (p = 0.027). The percentage of coffee and tea that was caffeinated in a typical month was also significantly lower in FD-ET than Co (p = 0.018). Conclusion: The balance of caffeinated to decaffeinated beverages is different in FD-ET than Co. These data raise several intriguing questions. Among these is whether relatives of ET cases modify their caffeine consumption before disease onset.

A cross-sectional analysis of clinical evaluation in 35 individuals with mutations of the valosin-containing protein gene

Inclusion body myopathy (IBM) associated with Paget disease of the bone and frontotemporal dementia or IBMPFD is an autosomal dominant degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. We aim to establish a detailed clinical phenotype of VCP disease amongst 35 (28 affected individuals, 7 presymptomatic gene carriers) individuals versus 14 unaffected first-degree relatives in 14 families to establish useful biomarkers for IBMPFD and identify the most meaningful tests for monitoring disease progression in future clinical trials. Comprehensive studies included the Inclusion Body Myositis Functional Rating Scale (IBMFRS) and fatigue severity scale questionairres, strength measurements using the Manual Muscle Test with Medical Research Council (MRC) scales, hand-held dynamometry using the microFET and Biodex dynamometers, 6 minute walk test (6MWT), and pulmonary function studies. Strong correlation was observed between the IBMFRS and measurements of muscle strength with dynamometry and the other functional tests, indicating that it may be utilized in long-term follow-up assessments due to its relative simplicity. This cross-section study represents the most comprehensive evaluation of individuals with VCP disease to date and provides a useful guide for evaluating and possible monitoring of muscle weakness and pulmonary function progression in this unique cohort of individuals.

SH2B3 (lnk) Regulates Type 1 Diabetes Immune Phenotypes

Background: The type 1 diabetes (T1D)-associated risk gene SH2B Adaptor Protein 3 (SH2B3) encodes a phosphatase with specificity for Janus Kinase 2 (JAK2). We hypothesized that variations in SH2B3 would affect immune signaling pathways relevant to T1D autoimmunity. Here we report: 1) Occurrence of the SH2B3 risk variant among T1D patients, unaffected first-degree relatives and controls; 2) Prevalence of SH2B3 risk genotype in African Americans in the Southeastern U.S.; and 3) Alterations to immune composition associated with the SH2B3 risk variant. Approach and Results: 1) The University of Florida Diabetes Institute (UFDI) cohort (n=1946) was analyzed for genetic risk of T1D using a Taqman single nucleotide polymorphism (SNP) genotyping array with coverage of 32 SNPs. Two SNPs (rs3184504 and rs653178) corresponding to SH2B3 were in perfect linkage disequilibrium and will be described here as minor (T1D risk) or common variant. Among Caucasian subjects, the odds ratio (OR) for the minor variant among T1D subjects was 1.30 (1.06-1.59, p=1.42x10-2), similar to previous reports. Among African American subjects, the minor variant OR was elevated (2.93, 1.22-7.03, p=1.30x10-2), representing the most highly-associated non-HLA gene. Complete blood count (CBC, n=954) and flow cytometric human immunophenotyping (HIP, n=252) were performed on a subset of subjects. Individuals carrying the risk variant of SH2B3 had significantly more blood monocytes and neutrophils but similar numbers of lymphocytes compared to non-carriers. HIP revealed a significantly higher frequency of type 1 (CXCR3+) CD8+ T cells in subjects with the risk variant of SH2B3. Conclusions: The risk variant of SH2B3 is associated with both increased risk for T1D and seroconversion in Caucasian and African American subjects. Phenotypically, this element of T1D genetic risk presents as increased frequency of some myeloid cell populations and either expansion or polarization of CD8+ T cells bearing the canonical Th1 chemokine receptor CXCR3. Disclosure A. Camargo: None. D.J. Perry: None. T.M. Brusko: Stock/Shareholder; Self; OneVax, LLC. Advisory Panel; Self; Caladrius Biosciences, Inc.. Consultant; Self; Merck & Co., Inc., Sanofi-Aventis. M.A. Wallet: None.

Impaired planning in patients with obsessive-compulsive disorder and unaffected first-degree relatives: Evidence for a cognitive endophenotype

Patients with obsessive-compulsive disorder (OCD) show deficient planning capacity in the Tower of London (TOL) problem solving task. Preliminary evidence for similar deficits in unaffected first-degree relatives suggests that impaired planning may constitute an endophenotype of OCD. However, results on this issue are inconsistent, possibly owing to small sample sizes and variability in problem structure across TOL tasks. Here, we adopted a computerized version of the TOL task featuring a 2 × 2 factorial design (high/low search depth × full/partial tower goal state) and examined a well-characterized sample of n = 72 OCD patients, n = 76 unaffected first-degree relatives and n = 102 healthy comparison subjects. Both OCD patients and relatives exhibited significantly less accurate problem solving than controls. Search depth, goal hierarchy, or the number of minimum moves did not moderate these group differences. Medication, OCD symptoms, and depressive comorbidity did not affect TOL performance in patients, suggesting a state-independent effect. In conclusion, we found that OCD patients as well as unaffected first-degree relatives show deficient TOL performance across a range of task conditions, strongly supporting the role of impaired planning as an endophenotype of OCD, and contributing to the growing evidence for fronto-striatal dysfunctions in OCD.

Cerebral Imaging Markers of GBA and LRRK2 Related Parkinson's Disease and Their First-Degree Unaffected Relatives.

Cerebral atrophy has been detected in patients with Parkinson's disease (PD) both with and without dementia, however differentiation based on genetic status has thus far not yielded robust findings. We assessed cortical thickness and subcortical volumes in a cohort of PD patients and healthy controls carriers of the G2019S mutation in the LRRK2 gene and the common GBA mutations, in an attempt to determine whether genetic status influences structural indexes. Cortical thickness and subcortical volumes were computed and compared between six groups of participants; idiopathic PD, GBA-PD, LRRK2-PD, non-manifesting non-carriers (NMNC), GBA-non-manifesting carriers (NMC) and LRRK2-NMC utilizing the FreeSurfer software program. All participants were cognitively intact based on a computerized cognitive assessment battery. Fifty-seven idiopathic PD patients, 9 LRRK2-PD, 12 GBA-PD, 49 NMNC, 41 LRRK2-NMC and 14 GBA-NMC participated in this study. Lower volumes among patients with PD compared to unaffected participants were detected in bilateral hippocampus, nucleus accumbens, caudate, thalamus, putamen and amygdala and the right pallidum (p = 0.016). PD patients demonstrated lower cortical thickness indexes in a majority of regions assessed compared with non-manifesting participants. No differences in cortical thickness and subcortical volumes were detected within each of the groups of participants based on genetic status. Mutations in the GBA and LRRK2 genes are not important determinants of cortical thickness and subcortical volumes in both patients with PD and non-manifesting participants. PD is associated with a general reduction in cortical thickness and sub-cortical atrophy even in cognitively intact patients.

Variability of ecological executive function in children and adolescents genetically at high risk for schizophrenia: a latent class analysis.

Executive impairments have been observed both in patients with schizophrenia and in their unaffected first-degree relatives. Very few studies have investigated neurocognitive subgroups in unaffected first-degree relatives and in healthy participants using data-driven methods. The study included a high-risk group consisting of 100 unaffected young offspring and siblings of patients with schizophrenia and 198 healthy controls, all aged between 9 and 23years. Executive function, victimization, and emotional and behavioral problems of participants were assessed by a series of self-report scales. Neurocognitive subgroups were investigated using latent class analysis of executive function measures. Four neurocognitive clusters were identified: a good performance cluster, a good self-control cluster, a low self-control cluster, and a severe impairment cluster. Participants in severe impaired executive function cluster reported asignificantly higher level of victimization and had more prominent emotional and behavioral problems than the good performance cluster. Neurocognitive differences between high-risk young people and healthy controls were driven by individuals who have severe and global, rather than selective, executive deficits. Our results may provide clues to an explanation of the mechanisms behind executive impairments in young individuals at genetic risk and help to identify new targets for early interventions.

Schizotypy and smooth pursuit eye movements as potential endophenotypes of obsessive-compulsive disorder.

Patients with obsessive-compulsive disorder (OCD) show dysfunctions of the fronto-striatal circuitry, which imply corresponding oculomotor deficits including smooth pursuit eye movements (SPEM). However, evidence for a deficit in SPEM is inconclusive, with some studies reporting reduced velocity gain while others did not find any SPEM dysfunctions in OCD patients. Interestingly, psychosis-like traits have repeatedly been linked to both OCD and impaired SPEM. Here, we examined a large sample of n = 168 patients with OCD, n = 93 unaffected first-degree relatives and n = 171 healthy control subjects to investigate whether elevated levels of schizotypy and SPEM deficits represent potential endophenotypes of OCD. We applied a SPEM task with high demands on predictive pursuit that is more sensitive to assess executive dysfunctions than a standard task with continuous visual feedback, as episodes of target blanking put increased demands on basal ganglia and prefrontal involvement. Additionally, we examined the relation between schizotypy and SPEM performance in OCD patients and their relatives. Results indicate that OCD patients and unaffected relatives do not show deficient performance in either standard or predictive SPEM. Yet, both patients and relatives exhibited elevated levels of schizotypy, and schizotypy was significantly correlated with velocity gain during standard trials in unmedicated and depression-free OCD patients. These findings highlight the role of schizotypy as a candidate endophenotype of OCD and add to the growing evidence for predisposing personality traits in OCD. Furthermore, intact gain may represent a key characteristic that distinguishes the OCD and schizophrenia patient populations.

Sa1784 - Unaffected First-Degree Relatives of Patients with Inflammatory Bowel Disease have Altered Profiles of Inflammation-Related Proteins

Sa1784 - Unaffected First-Degree Relatives of Patients with Inflammatory Bowel Disease have Altered Profiles of Inflammation-Related Proteins

Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study

SummaryBackgroundGermline pathogenic variants in the E-cadherin gene (CDH1) are strongly associated with the development of hereditary diffuse gastric cancer. There is a paucity of data to guide risk assessment and management of families with hereditary diffuse gastric cancer that do not carry a CDH1 pathogenic variant, making it difficult to make informed decisions about surveillance and risk-reducing surgery. We aimed to identify new candidate genes associated with predisposition to hereditary diffuse gastric cancer in affected families without pathogenic CDH1 variants.MethodsWe did whole-exome sequencing on DNA extracted from the blood of 39 individuals (28 individuals diagnosed with hereditary diffuse gastric cancer and 11 unaffected first-degree relatives) in 22 families without pathogenic CDH1 variants. Genes with loss-of-function variants were prioritised using gene-interaction analysis to identify clusters of genes that could be involved in predisposition to hereditary diffuse gastric cancer.FindingsProtein-affecting germline variants were identified in probands from six families with hereditary diffuse gastric cancer; variants were found in genes known to predispose to cancer and in lesser-studied DNA repair genes. A frameshift deletion in PALB2 was found in one member of a family with a history of gastric and breast cancer. Two different MSH2 variants were identified in two unrelated affected individuals, including one frameshift insertion and one previously described start-codon loss. One family had a unique combination of variants in the DNA repair genes ATR and NBN. Two variants in the DNA repair gene RECQL5 were identified in two unrelated families: one missense variant and a splice-acceptor variant.InterpretationThe results of this study suggest a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants. We also identified new candidate genes associated with disease risk in these families.FundingUK Medical Research Council (Sackler programme), European Research Council under the European Union's Seventh Framework Programme (2007–13), National Institute for Health Research Cambridge Biomedical Research Centre, Experimental Cancer Medicine Centres, and Cancer Research UK.

Enhanced switching and familial susceptibility for psychosis.

IntroductionWorking Memory and Task‐Switching are essential components of cognitive control, which underlies many symptoms evident across multiple neuropsychiatric disorders, including psychotic and mood disorders. Vulnerability to these disorders has a substantial genetic component, suggesting that clinically unaffected first‐degree relatives may carry some vulnerability‐related traits. Converging evidence from animal and human studies demonstrates that dopamine transmission, striatal and frontal brain regions, and attention and switching behaviors are essential components of a multilevel circuit involved in salience, and disruptions in that circuit may lead to features of psychosis. Yet, it is possible that unaffected relatives may also possess characteristics that protect against development of illness. We hypothesized that reduced switch cost in a cued task‐switching task, may be a behavioral expression of this “resilience” phenotype that will be observable in unaffected relatives.MethodsWe tested a large community sample (n = 536) via the web, to assess different subcomponents of cognitive control, including task‐switching and working memory, as well as risk‐taking, among individuals who report having an affected relative with a psychotic or mood disorder.ResultsHealthy individuals with suspected genetic risk due to a self‐reported familial history of a psychotic disorder demonstrated better task‐switching performance compared to healthy people without a psychiatrically ill relative and those with a relative with a mood disorder. This result was specific to illness status and task domain, in that individuals with a personal history of depression or anxiety did not show improved task‐switching performance, and this improvement was selective to task‐switching and not seen in other putative cognitive control domains (working memory or risk taking).ConclusionsAlthough this study has limitations and independent replication is needed, these preliminary findings suggest a potential avenue for understanding susceptibility to these disorders by highlighting possible protective as well as vulnerability‐related aspects of risk phenotypes.

Distinct Associations of Motor Domains in Relatives of Schizophrenia Patients-Different Pathways to Motor Abnormalities in Schizophrenia?

Aberrant motor function is an integral part of schizophrenia. In fact, abnormalities are frequently found in patients, in populations at risk, and in unaffected relatives. Motor abnormalities are suspected to be relevant for the clinical outcome and could probably predict the conversion from at-risk individuals to schizophrenia. Furthermore, motor function has been argued as endophenotype of the disorder. Yet, which particular motor domain may classify as a potential endophenotype is unknown. We aimed to compare schizophrenia patients, unaffected first-degree relatives and healthy controls for different motor domains. We expected impairments in all domains in patients and in some domains in relatives. We included 43 schizophrenia patients, 34 unaffected first-degree relatives of schizophrenia patients, and 29 healthy control subjects, matched for age, gender, and education level. We compared motor function of four motor domains between the groups. The domains comprise neurological soft signs (NSS), abnormal involuntary movements (dyskinesia), Parkinsonism, and fine motor function including simple [finger tapping (FT)] and complex fine motor function, (i.e., dexterity as measured with the coin rotation test). Furthermore, we tested the association of motor function of the four domains with working memory, frontal lobe function, and nonverbal intelligence for each group separately using within-group bivariate correlations. Schizophrenia patients showed poorer motor function in all tested domains compared to healthy controls. First-degree relatives had intermediate ratings with aberrant function in two motor domains. In detail, relatives had significantly more NSS and performed poorer in the FT task than controls. In contrast, complex fine motor function was intact in relatives. Relatives did not differ from controls in dyskinesia or Parkinsonism severity. Taken together, schizophrenia patients have motor abnormalities in all tested domains. Thus, motor abnormalities are a key element of the disorder. Likewise, first-degree relatives presented motor deficits in two domains. A clear difference between relatives and healthy controls was found for NSS and FT. Thus, NSS and FT may be potential markers of vulnerability for schizophrenia. The lack of association between genetic risk and dyskinesia or Parkinsonism suggests distinct pathobiological mechanisms in the various motor abnormalities in schizophrenia.

The Effects of Parenteral K1 Administration in Pseudoxanthoma Elasticum Patients Versus Controls. A Pilot Study.

Pseudoxanthoma elasticum (PXE) is a rare disease caused by mutations in the ABCC6 gene. Vitamin K1 is involved in the posttranslational carboxylation of some proteins related to inhibition of the calcification process. Our aim was to investigate, in patients affected by PXE, baseline levels of vitamin K1-dependent proteins and -metabolites and whether parenteral administration of phytomenadione was effective in modulating their levels. We included eight PXE patients with typical clinical symptoms (skin, retina, and vascular calcification) and two ABCC6 causative mutations; 13 clinically unaffected first-degree patients' relatives (9 carrying one ABCC6 mutation and 4 non-carriers). We assessed urinary vitamin K1 metabolites and serum Glu- and Gla-OC, Gas6 and undercaboxylated prothrombin (PIVKA-II), at baseline and after 1 and 6 weeks after a single intramuscular injection of 10 mg vitamin K1. Comparison of PXE patients, heterozygous, and non-carriers revealed differences in baseline levels of serum MK-4 and of urinary vitamin K metabolites. The response to phytomenadione administration on vitamin K-dependent proteins was similar in all groups. The physiological axis between vitamin K1 and vitamin K-dependent proteins is preserved; however, differences in the concentration of vitamin K metabolites and of MK-4 suggest that vitamin K1 metabolism/catabolism could be altered in PXE patients.

F203. A META-ANALYSIS OF MINOR PHYSICAL ANOMALIES IN FIRST-DEGREE UNAFFECTED RELATIVES OF PATIENTS WITH SCHIZOPHRENIA

BackgroundNeurodevelopmental abnormalities are common in schizophrenia. Minor physical anomalies (MPAs) are associated with abnormalities in neural development. Previous studies clearly demonstrated that MPAs are significantly increased in schizophrenia. However, the available evidence in unaffected relatives of patients with schizophrenia is contradictory.MethodsA literature search was conducted between 1 JAN 1980 and SEP 2017 in PUBMED and SCOPUS. Random-effects model was used. Heterogeneity was tested with Q test and I2. The meta-analysis was conducted using OpenMetaAnalyst software.Results16 studies were included in the meta-analysis. MPAs were significantly more common unaffected first-degree relatives of patients with schizophrenia (d=0.56, CI=0.40–0.73, p<0.001). There was a significant heterogeneity in distribution of effect sizes (Q=42.2, p<0.001). The level of this heterogeneity was medium in range (I2=64 %). In meta-regression analyses, demographic variables were not significantly related with magnitude of the effect size.DiscussionMPAs are associated with risk of schizophrenia. However, the level of heterogeneity suggests that risk of psychosis is associated with neurodevelopmental abnormalities in some but not all individuals. Findings also emphasize that resilience factors might be protecting many neurodevelopmentally impaired relatives of schizophrenia against having a full-blown psychotic disorder.

S22. A TRANSDIAGNOSTIC NEUROANATOMICAL SIGNATURE OF PSYCHIATRIC ILLNESS

BackgroundDespite an increasing research and clinical focus on trans-diagnostic approaches to mental health, it remains unclear whether different diagnostic categories share a common neuronatomical basis. The current investigation sought to investigate whether a shared (trans-diagnostic) set of structural alterations characterized schizophrenia, depression, post-traumatic stress disorder and obsessive-compulsive disorder, and determine whether any such alterations reflected markers of psychiatric illness or pre-existing familial vulnerability.MethodsA total of 404 patients with a psychiatric diagnosis were recruited (psychosis, n=129; unipolar depression, n=92; post-traumatic stress disorder, n=91; obsessive compulsive disorder, n=92) alongside 201 healthy controls and 20 unaffected first-degree relatives. We collected structural Magnetic Resonance Imaging scans from each participant using the same 3.0 Tesla scanner and acquisition sequence, and tested for trans-diagnostic alterations using Voxel-Based Morphometry.ResultsWe report that the four psychiatric groups were all characterized by significantly greater gray matter volume in the bilateral putamen relative to healthy controls (right putamen: x=32 y=6 z=-2; z-score: 5.97; p-value<0.001 after FWE-correction; left putamen: x=-30 y=5 z=-7; z-score: 4.97; p-value=0.001 after FWE-correction). Furthermore, the volume of this region was positively correlated with severity of symptoms across groups, so that a higher gray matter volume in the putamen was associated with higher severity of symptoms (partial correlation: the results are age and gender corrected; right putamen: r=0.313, p<0.001; left putamen: =0.326, p<0.001). Bilateral putamen enlargement was also evident in unaffected relatives compared to healthy controls (right putamen: x=32 y=-6 z=2; t-value: 8.13, p-value<0.001 after FWE-correction; left putamen: x=-32 y=-8 z=2; z-score:9.39, p-value<0.001 after FWE-correction).DiscussionThese findings indicate that increased putamen volume may reflect a trans-diagnostic marker of underlying familial vulnerability to psychopathology. This raises the prospect that this region could be used to assess degree of familiar vulnerability to psychopathology above and beyond traditional diagnostic boundaries. Our investigation provides support to emerging conceptualisations of psychiatric illness, in which each disorder is best understood as a combination of diagnosis-specific features and a trans-diagnostic factor reflecting general psychopathology.

F73. COGNITIVE CLUSTERING IN SCHIZOPHRENIA PATIENTS, THEIR FIRST-DEGREE RELATIVES AND HEALTHY SUBJECTS IS ASSOCIATED WITH ANTERIOR CINGULATE CORTEX VOLUME

BackgroundCognitive impairments are a core feature in schizophrenia patients and are also observed in first-degree relatives of the schizophrenia patients. However, substantial variability in the impairments exists within and among schizophrenia patients, first-degree relatives and healthy controls. A cluster-analytic approach can group individuals based on profiles of traits and create more homogeneous groupings than predefined categories.MethodsHere, we investigated differences in the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery (six subscales) among 81 schizophrenia patients, 20 unaffected first-degree relatives and 25 healthy controls. To identify three homogeneous and meaningful cognitive groups regardless of categorical diagnoses (schizophrenia patients, first-degree relatives and healthy controls), cognitive clustering was performed using a k-means clustering analysis approach, and differences in the BACS subscales (verbal memory, digit sequencing, token motor, verbal fluency, symbol coding and Tower of London) among the cognitive cluster groups were investigated. Finally, the effects of diagnosis and cognition on brain volumes were examined.ResultsAs expected, there were significant differences in the five BACS subscales among the diagnostic groups (verbal memory, F2,123=20.6, P=1.90 × 10–8; digit sequencing, F2,123=8.0, P=5.65 × 10–4; token motor, F2,123=16.0, P=6.92 × 10–7; verbal fluency, F2,123=14.8, P=1.79 × 10–6 and symbol coding, F2,123=28.8, P=5.64 × 10–11). The cluster-analytic approach generated three meaningful subgroups: (i) neuropsychologically normal (Cluster 1, N=36), (ii) intermediate impaired (Cluster 2, N=60) and (iii) widespread impaired (Cluster 3, N=30). The cognitive subgroups were mainly affected by the clinical diagnosis (χ2=46.7, P=5.33 × 10-10), and significant differences in all BACS subscales among clusters were found (verbal memory, F2,123=64.1, P=8.49 × 10–20; digit sequencing, F2,123=35.7, P=5.89 × 10–13; token motor, F2,123=71.7, P=2.29 × 10–21; verbal fluency, F2,123=84.2, P=9.05 × 10–24; symbol coding, F2,123=115.6, P=5.70 × 10–29 and Tower of London, F2,123=6.9, P=1.43 × 10–3). The effects of the diagnosis (SCZ<FR<HC) and cognitive clusters (Clusters 3<2<1) on brain volumes overlapped in the frontal, temporal and limbic regions. Frontal and temporal volumes were mainly affected by the diagnosis, whereas the anterior cingulate cortex volumes were affected by the additive effects of diagnosis and cognition (FWE-corrected P<0.05, x, y, z=1.5, 40.5, 19.5, T=5.49).DiscussionWe investigated the cognitive heterogeneity and cognitive continuum among schizophrenia patients, first-degree relatives and healthy controls. The cognitive clustering approach without using clinical diagnoses successfully produced more homogeneous cognitive clusters: a neuropsychologically normal, an intermediately impaired and a globally impaired cognitive cluster. Clinical diagnoses (healthy controls, first-degree relatives and schizophrenia patients) were not evenly distributed into the three clusters; i.e., these clusters were mainly affected by clinical diagnoses. Both diagnoses and cognitive clusters were associated with decreased anterior cingulate cortex volumes. Our findings demonstrate a cognitive continuum among schizophrenia patients, first-degree relatives and healthy controls and support the hypothesis that cognitive impairments and the related anterior cingulate cortex volumes would be useful intermediate phenotypes in the pathophysiology of schizophrenia.

Clustering of Schizotypal Features in Unaffected First-Degree Relatives of Schizophrenia Patients.

Meehl conceptualized schizotypy as the phenotypic manifestations of a neural integrative defect resulting from a schizophrenia diathesis. The majority of schizotypy studies recruited subjects from the general population and revealed a multidimensional construct. This 2-phase investigation first examined the clustering of schizotypy in 194 unaffected relatives of schizophrenia patients using the Chapman Psychosis Proneness scales and then directly compared the cognitive profiles of negative schizotypal individuals and positive schizotypal individuals with schizophrenia patients and controls. In the first phase, cluster analysis categorized 194 unaffected relatives of schizophrenia patients into positive schizotypy (n = 33), negative schizotypy (n = 66), mixed schizotypy (n = 27), and low schizotypy (n = 64). Positive schizotypal participants showed more self-report pleasure experiences than negative schizotypal participants, replicating earlier cluster analytic findings. In the second phase, 27 negative schizotypal individuals, 18 positive schizotypal individuals, 19 schizophrenia patients, and 29 controls were recruited. Although the groups were matched in terms of age, gender, and IQ, they differed significantly in cognitive profiles. While schizophrenia patients exhibited the broadest cognitive impairments, negative schizotypal participants exhibited visual memory, working memory, and verbal fluency impairments, and positive schizotypal participants exhibited logical memory, visual memory, working memory, and theory-of-mind impairments. Among people with familial risk of schizophrenia, individuals exhibiting positive rather than negative schizotypal features resembled schizophrenia patients in cognitive profiles. Using the psychometric-familial method to identify schizotypy, our findings support the heterogeneity of schizotypy as well as the potential utility of the positive schizotypy dimension in genetically high-risk individuals to predict the risk of developing schizophrenia.

Unaffected first-degree relatives of essential tremor cases have more imbalance than age-matched control subjects

BackgroundEndophenotypes are measurable clinical characteristics that may be present in individuals with increased risk for disease (e.g., unaffected family members). Endophenotypes are useful; they may clarify diagnosis in genetic studies and foster the development of animal models. In recent years, problems with balance and mild gait ataxia have been associated with essential tremor (ET). We compared gait and balance of first-degree relatives of ET cases (FD-ET) to that of age-matched controls (Co). MethodsOne-hundred-ninety FD-ET and 68 Co, none of whom reported tremor or were diagnosed with ET, underwent a standardized assessment of gait and balance. ResultsFD-ET reported more near-falls in the past year (p = 0.015) and lower balance confidence according to the Activities of Balance Confidence (ABC-6) Scale (p = 0.03). The specific ABC-6 items for which FD-ET reported lower balance confidence than Co were being bumped into by people while walking (p = 0.006) and walking outside on icy sidewalks (p = 0.007). On videotaped neurological examination, FD-ET were able to stand in the tandem position for fewer seconds than were Co (p = 0.048). The differences between FD-ET and Co, although statistically significant, were clinically mild. ConclusionFD-ET reported more near-falls in the past year and a reduction in balance confidence; additionally, ability to maintain tandem stance was impaired compared to Co. These data suggest a more pervasive abnormality of cerebellar dysfunction than previously conceived, extending beyond ET cases themselves and manifesting in mild form in their unaffected family members.

Visual working memory encoding in schizophrenia and first-degree relatives: neurofunctional abnormalities and impaired consolidation.

Working memory (WM) deficits in schizophrenia (SCZ) have been linked to impairments in the encoding phase that are associated with aberrant neuronal functioning. Similar abnormalities have been observed in unaffected first-degree relatives (REL) and are thus discussed as candidate endophenotypes. The process of WM consolidation - i.e. the formation of durable WM representations - is assumed to be impaired in SCZ, but no study has investigated WM consolidation and neuronal correlates of visual WM encoding in REL before. We examined whole-brain activation during the encoding phase with an event-related functional magnetic resonance imaging study design in 25 SCZ subjects, 22 REL subjects, and 25 healthy controls. Subjects performed a visual masked change detection task that assessed WM performance and consolidation. SCZ showed deficient WM performance indicating an impairment consolidation process, accompanied by broad neuronal hypoactivation, most prominently in frontal brain regions, as well as increased activity of the anterior cingulate during the encoding phase. REL showed decreased neuronal activity in the middle and medial frontal gyrus and increased activity in the precentral gyrus and insula during encoding, but no significant behavioral deficits were observed. In respect of given consolidation times, REL showed a shift from decreased frontal activity at short time intervals to increased frontal activity at longer time intervals. Findings suggest WM consolidation may be slowed in REL so that the deployment of compensatory neuronal resources during encoding is needed to assure proper WM performance. This supports the view of WM-related neuronal dysfunctions as a potential endophenotypic marker.

P.3.010 - Imbalance in the deployment of neural resources during visual working memory encoding in schizophrenia as a possible intermediate phenotype

Visual working memory (VWM) deficits are a prominent impairment in patients with schizophrenia (SCZ) and are associated with an inefficient encoding process [1] and with neuronal dysfunctions [2]. Both behavioural and neurofunctional impairments can be observed in unaffected first-degree relatives of patients (REL) as well and are thus discussed as a possible intermediate phenotype of the disorder [3,4]. In this study we investigated the characteristics of WM encoding and its neural substrates in SCZ and REL to evaluate their potential role as an intermediate phenotype of the disorder. We examined n = 25 SCZ, n = 22 REL and n = 25 healthy control subjects (CON). All subjects underwent whole brain fMRI scans in a 3 Tesla MR system. During the fMRI scan, a VWM change-detection task was presented, which showed a sample array consisting of 3 red lines of different orientation that should be memorized. After a delay interval of either 100ms, 400ms or 800ms (SOA = stimulus onset asynchrony) a pattern mask was shown, followed by another delay period and a test array. The longer the delay interval until masking, the more durable the VWM representations were expected to be. Response accuracy served as an estimate of the grade of VWM encoding. The behavioural data was analyzed using a two-way univariate ANOVA with repeated measures and post hoc tests. For group statistics of the event-related fMRI data we conducted a random-effects GLM (RFX-GLM) and a subsequent ANOVA with 'group' as a between-subjects factor (3 levels) and 'SOA' as within-subjects factor (3 levels). For behavioural performance in the VWM task we found significant main effects of 'group' (p = 0.026) and 'SOA' (p = 0.013). The longer the SOA interval, the greater the response accuracy across groups (significant linear trend; p = 0.009). Response accuracy was significantly lower in SCZ compared to CON (p = 0.011) and REL (p = 0.041). We observed aberrant neural activation during VWM encoding for both SCZ and REL compared to CON: across SOA conditions SCZ showed widespread neural deactivation, including the DLPFC and precentral gyrus, as well as increased activity of the anterior cingulate. In REL, we observed a shift in neural activation in regard to the length of the SOA interval: at SOA 100 REL showed only decreased activity in the superior frontal gyrus and fusiform gyrus; at SOA 400 we observed decreased activity in the middle frontal gyrus and increased activity in the superior frontal gyrus; and at SOA 800 REL showed only increased activity in the inferior frontal gyrus. The findings indicate that impaired VWM in SCZ may emerge from an insufficient engagement of the functional WM network with concomitant anterior cingulate hyperactivity during encoding. In REL, the shift from decreased to increased activity might reflect a compensatory process: hypoactivity might point towards fundamental neural dysfunctions—at lighter processing demands local hyperactivity might ensure accurate VWM performance. Neural dysfunctions during VWM encoding should thus be considered as a candidate intermediate phenotype of SCZ.