fMRI connectivity as a biomarker of antipsychotic treatment response: A systematic review.

BACKGROUND: Antipsychotic drugs are the first-choice therapy for psychotic episodes, but antipsychotic treatment response (AP-R) is unpredictable and only becomes clear after weeks of therapy. A biomarker for AP-R is currently unavailable. We reviewed the evidence for the hypothesis that functional magnetic resonance imaging functional connectivity (fMRI-FC) is a predictor of AP-R or could serve as a biomarker for AP-R in psychosis. METHOD: A systematic review of longitudinal fMRI studies examining the predictive performance and relationship between FC and AP-R was performed following PRISMA guidelines. Technical and clinical aspects were critically assessed for the retrieved studies. We addressed three questions: Q1) is baseline fMRI-FC related to subsequent AP-R; Q2) is AP-R related to a change in fMRI-FC; and Q3) can baseline fMRI-FC predict subsequent AP-R? RESULTS: In total, 28 articles were included. Most studies were of good quality. fMRI-FC analysis pipelines included seed-based-, independent component- / canonical correlation analysis, network-based statistics, and graph-theoretical approaches. We found high heterogeneity in methodological approaches and results. For Q1 (N = 17) and Q2 (N = 18), the most consistent evidence was found for FC between the striatum and ventral attention network as a potential biomarker of AP-R. For Q3 (N = 9) accuracy's varied form 50 till 93%, and prediction models were based on FC between various brain regions. CONCLUSION: The current fMRI-FC literature on AP-R is hampered by heterogeneity of methodological approaches. Methodological uniformity and further improvement of the reliability and validity of fMRI connectivity analysis is needed before fMRI-FC analysis can have a place in clinical applications of antipsychotic treatment.

Clonal Elimination of the Pathogenic Allele as Diagnostic Pitfall in SAMD9L-Associated Neuropathy.

BACKGROUND: Heterozygous gain-of-function variants in SAMD9L are associated with ataxia-pancytopenia syndrome (ATXPC) and monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1). Association with peripheral neuropathy has rarely been described. METHODS: Whole-exome sequencing (WES) from DNA extracted from peripheral blood was performed in a 10-year-old female presenting with demyelinating neuropathy, her similarly affected mother and the unaffected maternal grandparents. In addition to evaluation of single nucleotide variants, thorough work-up of copy number and exome-wide variant allele frequency data was performed. RESULTS: Combined analysis of the mother's and daughter's duo-exome data and analysis of the mother's and her parents' trio-exome data initially failed to detect a disease-associated variant. More detailed analysis revealed a copy number neutral loss of heterozygosity of 7q in the mother and led to reanalysis of the exome data for respective sequence variants. Here, a previously reported likely pathogenic variant in the SAMD9L gene on chromosome 7q (NM_152703.5:c.2956C>T; p.(Arg986Cys)) was identified that was not detected with standard filter settings because of a low percentage in blood cells (13%). The variant also showed up in the daughter at 32%, a proportion well below the expected 50%, which in each case can be explained by clonal selection processes in the blood due to this SAMD9L variant. CONCLUSION: The report highlights the specific pitfalls of molecular genetic analysis of SAMD9L and, furthermore, shows that gain-of-function variants in this gene can lead to a clinical picture associated with the leading symptom of peripheral neuropathy. Due to clonal hematopoietic selection, displacement of the mutant allele occurred, making diagnosis difficult.

The neurobiological characterization of distinct cognitive subtypes in early-phase schizophrenia-spectrum disorders.

INTRODUCTION: Cognitive deficits are present in some, but not all patients with schizophrenia-spectrum disorders (SSD). We and others have demonstrated three cognitive clusters: cognitively intact patients, patients with deficits in a few domains and those with global cognitive deficits. This study aimed to identify cognitive subtypes of early-phase SSD with matched controls as a reference group, and evaluated cognitive subgroups regarding clinical and brain volumetric measures. METHODS: Eighty-six early-phase SSD patients were included. Hierarchical cluster analysis was conducted using global performance on the Brief Assessment of Cognition in Schizophrenia (BACS). Cognitive subgroups were subsequently related to clinical and brain volumetric measures (cortical, subcortical and cortical thickness) using ANCOVA. RESULTS: Three distinct cognitive clusters emerged: relative to controls we found one cluster of patients with preserved cognition (n = 25), one moderately impaired cluster (n = 38) and one severely impaired cluster (n = 23). Cognitive subgroups were characterized by differences in volume of the left postcentral gyrus, left middle caudal frontal gyrus and left insula, while differences in cortical thickness were predominantly found in fronto-parietal regions. No differences were demonstrated in subcortical brain volume. DISCUSSION: Current results replicate the existence of three distinct cognitive subgroups including one relatively large group with preserved cognitive function. Cognitive subgroups were characterized by differences in cortical regional brain volume and cortical thickness, suggesting associations with cortical, but not subcortical development and cognitive functioning such as attention, executive functions and speed of processing.

Auditory verbal hallucinations and childhood trauma subtypes across the psychosis continuum: a cluster analysis.

Introduction: A strong link between voice-hearing experience and childhood trauma has been established. The aim of this study was to identify whether there were unique clusters of childhood trauma subtypes in a sample across the clinical spectrum of auditory verbal hallucinations (AVH) and to examine clinical and phenomenological features across these clusters.Methods: Combining two independent international datasets (the Netherlands and Australia), childhood trauma subtypes were examined using hierarchical cluster analysis. Clinical and phenomenological characteristics were compared across emerging clusters using MANOVA and chi-squared analyses.Results: The total sample (n = 413) included 166 clinical individuals with a psychotic disorder and AVH, 122 non-clinical individuals with AVH and 125 non-clinical individuals without AVH. Three clusters emerged: (1) low trauma (n = 299); (2) emotion-focused trauma (n = 71); (3) multi-trauma (n = 43). The three clusters differed significantly on their AVH ratings of amount of negative content, with trend-level effects for loudness, degree of negative content and degree of experienced distress. Furthermore, perceptions of voices being malevolent, benevolent and resistance towards voices differed significantly.Conclusion: The data revealed different types of childhood trauma had different relationships between clinical and phenomenological features of voice-hearing experiences. Thus, implicating different mechanistic pathways and a need for tailored treatment approaches.

Human genomics of the humoral immune response against polyomaviruses.

Human polyomaviruses are widespread in humans and can cause severe disease in immunocompromised individuals. To identify human genetic determinants of the humoral immune response against polyomaviruses, we performed genome-wide association studies and meta-analyses of qualitative and quantitative immunoglobulin G responses against BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), Merkel cellpolyomavirus (MCPyV), WU polyomavirus (WUPyV), and human polyomavirus 6 (HPyV6) in 15,660 individuals of European ancestry from three independent studies. We observed significant associations for all tested viruses: JCPyV, HPyV6, and MCPyV associated with human leukocyte antigen class II variation, BKPyV and JCPyV with variants in FUT2, responsible for secretor status, MCPyV with variants in STING1, involved in interferon induction, and WUPyV with a functional variant in MUC1, previously associated with risk for gastric cancer. These results provide insights into the genetic control of a family of very prevalent human viruses, highlighting genes and pathways that play a modulating role in human humoral immunity.

Language in schizophrenia: relation with diagnosis, symptomatology and white matter tracts.

Language deviations are a core symptom of schizophrenia. With the advances in computational linguistics, language can be easily assessed in exact and reproducible measures. This study investigated how language characteristics relate to schizophrenia diagnosis, symptom, severity and integrity of the white matter language tracts in patients with schizophrenia and healthy controls. Spontaneous speech was recorded and diffusion tensor imaging was performed in 26 schizophrenia patients and 22 controls. We were able to classify both groups with a sensitivity of 89% and a specificity of 82%, based on mean length of utterance and clauses per utterance. Language disturbances were associated with negative symptom severity. Computational language measures predicted language tract integrity in patients (adjusted R2 = 0.467) and controls (adjusted R2 = 0.483). Quantitative language analyses have both clinical and biological validity, offer a simple, helpful marker of both severity and underlying pathology, and provide a promising tool for schizophrenia research and clinical practice.

No association between anti-thyroidperoxidase antibodies and bipolar disorder: a study in the Dutch Bipolar Cohort and a meta-analysis.

BACKGROUND: Thyroid autoimmunity has been associated with bipolar disorder (BD). However, results from previous studies on the seroprevalence of anti-thyroid peroxidase antibodies (TPO-abs) in BD are inconsistent. OBJECTIVES: The aim of the present study is to investigate whether the seroprevalence and titer levels of TPO-abs are related to BD. METHOD: TPO-abs were measured in plasma samples of 760 patients with bipolar disorder, 261 first-degree relatives and 363 controls by enzyme-linked immunosorbent assay (ELISA). To address methodological limitations of previous studies, we assessed clinical characteristics with several (self-reported) questionnaires to investigate whether TPO-abs positivity is related to particular clinical subgroups of BD patients. We performed an additional meta-analysis of seroprevalences of TPO-abs in BD patients including data from present and previous studies. RESULTS: Seroprevalence or titer levels of TPO-abs did not significantly differ between patients with BD, their first-degree relatives, and controls. In BD patients, the prevalence of TPO-abs was unrelated to specific clinical factors, including lithium use. Our meta-analysis of twelve studies showed an overall odds ratio of 1.3 (CI 95 %: 0.7-2.3; p = 0.30), reaffirming the absence of an association of BD with TPO-abs. CONCLUSIONS: In the largest study of TPO-abs in BD to date, our findings indicate that TPO-abs are not associated with (the risk for) bipolar disorder.

Biallelic CSGALNACT1-mutations cause a mild skeletal dysplasia.

Genetic causes of skeletal disorders are manifold and affect, among others, enzymes of bone and connective tissue synthesis pathways. We present a twelve-year-old boy with a mild skeletal dysplasia, hypermobility of joints and axial malalignment of lower limbs and feet. Exome sequencing revealed a biallelic loss of function mutation in CSGALNACT1, which encodes chondroitin sulfate N-acetylgalactosaminyltransferase 1 and plays a major role in the chondroitin sulfate chain biosynthesis and therefore in the synthesis of glycosaminoglycans. Recently, the first case of a pediatric patient with a mild skeletal dysplasia due to a compound heterozygous large intragenic deletion and a damaging missense variant in CSGALNACT1 was reported. We here identify a second case and the first juvenile patient with a homozygous frameshift variant in CSGALNACT1 which corroborates its role in mild and non-progressive skeletal dysplasia with joint laxity.

Auditory hallucinations, top-down processing and language perception: a general population study.

BACKGROUND: Studies investigating the underlying mechanisms of hallucinations in patients with schizophrenia suggest that an imbalance in top-down expectations v. bottom-up processing underlies these errors in perception. This study evaluates this hypothesis by testing if individuals drawn from the general population who have had auditory hallucinations (AH) have more misperceptions in auditory language perception than those who have never hallucinated. METHODS: We used an online survey to determine the presence of hallucinations. Participants filled out the Questionnaire for Psychotic Experiences and participated in an auditory verbal recognition task to assess both correct perceptions (hits) and misperceptions (false alarms). A hearing test was performed to screen for hearing problems. RESULTS: A total of 5115 individuals from the general Dutch population participated in this study. Participants who reported AH in the week preceding the test had a higher false alarm rate in their auditory perception compared with those without such (recent) experiences. The more recent the AH were experienced, the more mistakes participants made. While the presence of verbal AH (AVH) was predictive for false alarm rate in auditory language perception, the presence of non-verbal or visual hallucinations were not. CONCLUSIONS: The presence of AVH predicted false alarm rate in auditory language perception, whereas the presence of non-verbal auditory or visual hallucinations was not, suggesting that enhanced top-down processing does not transfer across modalities. More false alarms were observed in participants who reported more recent AVHs. This is in line with models of enhanced influence of top-down expectations in persons who hallucinate.

Genome-wide association study results for educational attainment aid in identifying genetic heterogeneity of schizophrenia.

Higher educational attainment (EA) is negatively associated with schizophrenia (SZ). However, recent studies found a positive genetic correlation between EA and SZ. We investigate possible causes of this counterintuitive finding using genome-wide association study results for EA and SZ (N = 443,581) and a replication cohort (1169 controls; 1067 cases) with deeply phenotyped SZ patients. We find strong genetic dependence between EA and SZ that cannot be explained by chance, linkage disequilibrium, or assortative mating. Instead, several genes seem to have pleiotropic effects on EA and SZ, but without a clear pattern of sign concordance. Using EA as a proxy phenotype, we isolate FOXO6 and SLITRK1 as novel candidate genes for SZ. Our results reveal that current SZ diagnoses aggregate over at least two disease subtypes: one part resembles high intelligence and bipolar disorder (BIP), while the other part is a cognitive disorder that is independent of BIP.

Clinical use of semantic space models in psychiatry and neurology: A systematic review and meta-analysis.

Verbal communication disorders are a hallmark of many neurological and psychiatric illnesses. Recent developments in computational analysis provide objective characterizations of these language abnormalities. We conducted a meta-analysis assessing semantic space models as a diagnostic or prognostic tool in psychiatric or neurological disorders. Diagnostic test accuracy analyses revealed reasonable sensitivity and specificity and high overall efficacy in differentiating between patients and controls (n=1680: Hedges' g =.73, p=.001). Analyses of full sentences (Hedges' g =.95 p <.0001) revealed a higher efficacy than single words (Hedges' g = .51, p <.0001). Specifically, models examining psychotic patients (Hedges' g =.96, p=.003) and those with autism (Hedges' g = .84, p <.0001) were highly effective. Our results show semantic space models are effective as a diagnostic tool in a variety of psychiatric and neurological disorders. The field is still exploratory in nature; techniques differ and models are only used to distinguish patients from healthy controls so far. Future research should aim to distinguish between disorders and perhaps explore newer semantic space tools like word2vec.

OTTO: a new strategy to extract mental disease-relevant combinations of GWAS hits from individuals.

Despite high heritability of schizophrenia, genome-wide association studies (GWAS) have not yet revealed distinct combinations of single-nucleotide polymorphisms (SNPs), relevant for mental disease-related, quantifiable behavioral phenotypes. Here we propose an individual-based model to use genome-wide significant markers for extracting first genetic signatures of such behavioral continua. 'OTTO' (old Germanic=heritage) marks an individual characterized by a prominent phenotype and a particular load of phenotype-associated risk SNPs derived from GWAS that likely contributed to the development of his personal mental illness. This load of risk SNPs is shared by a small squad of 'similars' scattered under the genetically and phenotypically extremely heterogeneous umbrella of a schizophrenia end point diagnosis and to a variable degree also by healthy subjects. In a discovery sample of >1000 deeply phenotyped schizophrenia patients and several independent replication samples, including the general population, a gradual increase in the severity of 'OTTO's phenotype' expression is observed with an increasing share of 'OTTO's risk SNPs', as exemplified here by autistic and affective phenotypes. These data suggest a model in which the genetic contribution to dimensional behavioral traits can be extracted from combinations of GWAS SNPs derived from individuals with prominent phenotypes. Even though still in the 'model phase' owing to a world-wide lack of sufficiently powered, deeply phenotyped replication samples, the OTTO approach constitutes a conceptually novel strategy to delineate biological subcategories of mental diseases starting from GWAS findings and individual subjects.

Auditory hallucinations across the lifespan: a systematic review and meta-analysis.

BACKGROUND: Auditory Hallucinations (AH) are nowadays regarded as symptoms following a continuum; from a (transient) phenomenon in healthy individuals on one end to a symptom of (psychiatric) illnesses at the other. An accumulating number of epidemiological studies focused on the prevalence of AH in the general population, but results vary widely. The current meta-analysis aims to synthesize existing evidence on lifetime prevalence of AH across the lifespan. METHODS: We conducted a quantitative review and meta-analysis according to PRISMA guidelines. Studies were combined to calculate a mean lifetime general population AH prevalence rate. Moreover, prevalences were calculated for four age groups: children (5-12 years), adolescents (13-17 years), adults (18-60 years) and elderly (⩾60 years). RESULTS: We retrieved 25 study samples including 84 711 participants. Mean lifetime prevalence rate of AH was 9.6% (95% CI 6.7-13.6%). The mean lifetime prevalence was similar in children (12.7%) and adolescents (12.4%), but these two groups differed significantly from the adults (5.8%) and the elderly (4.5%). Significant heterogeneity indicated that there is still dispersion in true prevalence rates between studies, even within the different age categories. CONCLUSIONS: Current meta-analysis shows that AH are quite common (up to one in ten individuals) in the general population during lifetime, with children and adolescents reporting these experiences significantly more often compared with adults and elderly. Large follow-up studies on the longitudinal course of AH are needed to reveal associated risk and resilience factors.

Sexual dimorphism of AMBRA1-related autistic features in human and mouse.

Ambra1 is linked to autophagy and neurodevelopment. Heterozygous Ambra1 deficiency induces autism-like behavior in a sexually dimorphic manner. Extraordinarily, autistic features are seen in female mice only, combined with stronger Ambra1 protein reduction in brain compared to males. However, significance of AMBRA1 for autistic phenotypes in humans and, apart from behavior, for other autism-typical features, namely early brain enlargement or increased seizure propensity, has remained unexplored. Here we show in two independent human samples that a single normal AMBRA1 genotype, the intronic SNP rs3802890-AA, is associated with autistic features in women, who also display lower AMBRA1 mRNA expression in peripheral blood mononuclear cells relative to female GG carriers. Located within a non-coding RNA, likely relevant for mRNA and protein interaction, rs3802890 (A versus G allele) may affect its stability through modification of folding, as predicted by in silico analysis. Searching for further autism-relevant characteristics in Ambra1+/- mice, we observe reduced interest of female but not male mutants regarding pheromone signals of the respective other gender in the social intellicage set-up. Moreover, altered pentylentetrazol-induced seizure propensity, an in vivo readout of neuronal excitation-inhibition dysbalance, becomes obvious exclusively in female mutants. Magnetic resonance imaging reveals mild prepubertal brain enlargement in both genders, uncoupling enhanced brain dimensions from the primarily female expression of all other autistic phenotypes investigated here. These data support a role of AMBRA1/Ambra1 partial loss-of-function genotypes for female autistic traits. Moreover, they suggest Ambra1 heterozygous mice as a novel multifaceted and construct-valid genetic mouse model for female autism.

Recent Advances in Imprinting Disorders.

Imprinting disorders (ImpDis) are a group of currently 12 congenital diseases with common underlying (epi)genetic etiologies and overlapping clinical features affecting growth, development and metabolism. In the last years it has emerged that ImpDis are characterized by the same types of mutations and epimutations, i.e. uniparental disomies, copy number variations, epimutations, and point mutations. Each ImpDis is associated with a specific imprinted locus, but the same imprinted region can be involved in different ImpDis. Additionally, even the same aberrant methylation patterns are observed in different phenotypes. As some ImpDis share clinical features, clinical diagnosis is difficult in some cases. The advances in molecular and clinical diagnosis of ImpDis help to circumvent these issues, and they are accompanied by an increasing understanding of the pathomechanism behind them. As these mechanisms have important roles for the etiology of other common conditions, the results in ImpDis research have a wider effect beyond the borders of ImpDis. For patients and their families, the growing knowledge contributes to a more directed genetic counseling of the families and personalized therapeutic approaches.

Maternal uniparental disomy of chromosome 16 [upd(16)mat]: clinical features are rather caused by (hidden) trisomy 16 mosaicism than by upd(16)mat itself.

Maternal uniparental disomy of chromosome 16 [upd(16)mat] as the result of trisomy 16 is one of the most frequently reported uniparental disomies in humans, but a consistent phenotype is not obvious. Particularly, it is difficult to discriminate between features resulting from upd(16)mat and mosaic trisomy 16. By evaluating literature data (n = 74) and three own cases we aimed to determine whether the clinical features are due to upd(16)mat or to trisomy 16 mosaicism. While in single cases the clinical symptoms were caused by homozygosity of autosomal recessive mutations on chromosome 16, it turned out that clinical features in upd(16)mat are caused by (hidden) trisomy 16 mosaicism and a specific chromosome 16-associated imprinting disorder does not exist. In trisomy 16/upd(16)mat pregnancies, the management should be based on the ultrasound results and on the clinical course of the pregnancy. In fact, mosaic trisomy 16 pregnancies require a close monitoring because of the higher risk for hypertensive disorders. Postnatal testing for upd(16)mat should be considered in case of homozygosity for an autosomal-recessive mutation, in individuals carrying chromosome 16 aberrations and in phenotypes comprising features of the trisomy 16/upd(16)mat spectrum. Finally, upd(16)mat probably represents a bioindicator for a hidden trisomy 16 mosaicism.