Trajectories of behavior and social cognition in behavioral variant frontotemporal dementia and primary psychiatric disorders: A call for better operationalization of socioemotional changes.

BACKGROUND AND PURPOSE: Behavioral variant frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD), such as mood, psychotic, and autism spectrum disorders, share similar clinical characteristics of behavior and social cognition. Better understanding of clinical progression in bvFTD and PPD is essential for adequate disease monitoring and trial design. METHODS: In this longitudinal study (N = 89), patients with bvFTD and PPD with at least one follow-up assessment were included from the Social Brain Project of the Alzheimer Center Amsterdam. Behavioral change and social cognitive decline were assessed via informant-rated questionnaires (Cambridge Behavioral Inventory-Revised, Frontal Behavioral Inventory [FBI], Stereotypy Rating Inventory, Frontotemporal Dementia Rating Scale, Revised Self-Monitoring Scale [RSMS]-caregiver) and patient assessment (Ekman 60-Faces Test, RSMS-patient, Emotional Contagion Scale). Clinical trajectories (median = 1.4 years, interquartile range = 1.0-2.2) were examined using linear mixed models. In a subsample, associations with baseline serum neurofilament light (sNfL) were examined. RESULTS: At baseline, behavioral and social cognitive symptoms were similar between diagnosis groups, except for poorer emotion recognition in bvFTD. Over time, behavioral symptoms worsened in bvFTD, whereas most measures remained stable and the FBI improved in PPD. Regarding social cognition, emotion recognition and caregiver-reported socioemotional sensitivity worsened in bvFTD and remained stable in PPD. Patient-reported social cognitive measures did not change over time. Higher sNfL was associated with faster behavioral change. CONCLUSIONS: Trajectories of behavior and social cognition differentiate bvFTD from PPD, provided that social cognition is not patient-reported. Therefore, we stress the need to optimize longitudinal social cognitive assessment in bvFTD. sNfL may be a useful prognostic marker of behavioral progression in neuropsychiatric populations.

Decreased emotion recognition and reduced focus on facial hallmarks in behavioral variant frontotemporal dementia compared to primary psychiatric disorders and controls.

BACKGROUND AND PURPOSE: Early diagnosis of behavioral variant frontotemporal dementia (bvFTD) is challenging due to symptomatic overlap with primary psychiatric disorders (PPD). As emotion recognition deficits are early and key features of bvFTD, the aim was to explore processes driving social cognition deficits that may aid in the differentiation between bvFTD and PPD. METHODS: The total sample (N = 51) included 18 patients with bvFTD, 11 patients with PPD (mood, autism spectrum and psychotic disorders) and 22 controls from the Alzheimer Center Amsterdam of the Amsterdam UMC. Emotion recognition was assessed with the Ekman 60 Faces test, during which eye tracking metrics were collected in the first 5 s a face was presented. Group differences in dwell time on the total image as well as the circumscribed eyes area and mouth area were analysed using ANOVA, with post hoc comparisons. RESULTS: Patients with bvFTD scored lowest, patients with PPD scored intermediate and controls scored highest on emotion recognition. During facial processing, patients with bvFTD spent less dwell time on the total image than controls (mean difference 11.3%, F(2, 48) = 6.095, p = 0.004; bvFTD-controls p = 0.001, 95% confidence interval [CI] -892.64, -239.70). Dwell time on the eyes area did not differ between diagnostic groups, whilst patients with bvFTD spent less dwell time on the mouth area than PPD patients (mean difference 10.7%; F(2, 48) = 3.423, p = 0.041; bvFTD-PPD p = 0.022, 95% CI -986.38, -79.47) and controls (mean difference 7.8%; bvFTD-controls p = 0.043, 95% CI -765.91, -12.76). CONCLUSIONS: In bvFTD, decreased emotion recognition may be related to reduced focus on facial hallmarks. These findings suggest a valuable role for biometrics in social cognition assessment and the differentiation between bvFTD and PPD.

Metabolic syndrome rates in older patients with severe mental illness after five years of follow-up and the association with mortality.

OBJECTIVES: To establish the course of metabolic syndrome (MS) rates in older patients with severe mental illness (SMI) after 5-year follow-up and evaluate whether MS at baseline is associated with mortality or diabetes at follow-up. METHODS: Patients (>60 years of age) with SMI (N = 100) were included at a specialized mental health outpatient clinic. Metabolic parameters were collected from patients' medical files at baseline and after 5-year follow-up. RESULTS: Follow-up data were available of 98 patients (98%); nine patients had died. Parameters of MS were available of 76 patients; 34.2% were diagnosed with MS. This was not significantly different compared with baseline (46.1%). MS at baseline was not significantly associated with mortality or development of diabetes at follow-up. CONCLUSIONS: In older patients with SMI, the rates of MS may reach a plateau. Screening for MS in older patients treated at a specialized mental health outpatient clinic may generate attention for their somatic health and treatment for the components of MS that may in turn have a positive effect on their outcome. However, further research with larger sample sizes is needed in order to confirm these findings.

Screening for metabolic syndrome in older patients with severe mental illness.

OBJECTIVE: To evaluate metabolic screening of elderly patients with severe mental illness (SMI) in terms of newly detected metabolic abnormalities. METHODS: Prospective evaluation of the metabolic screening outcome data of 100 consecutive elderly outpatients with SMI, all with universal access to health services. We gathered data on previous diagnoses of hypertension, diabetes, and dyslipidemia and assessed metabolic syndrome parameters. The findings were compared with those from a group of 124 healthy elderly. RESULTS: In our patients with SMI (mean age: 69 years; 52% bipolar disorder, 48% schizophrenia), the frequency of metabolic syndrome was not higher compared with the healthy elderly. However, in 51% of the SMI sample, metabolic screening detected at least one metabolic abnormality in a patient with no prior history for that specific parameter. CONCLUSION: Implementing routine screening for metabolic syndrome in elderly patients with SMI may reveal substantial rates of previously undetected metabolic abnormalities.

Genetic factors underlie stability of obsessive-compulsive symptoms.

The contribution of genetic and environmental factors to the stability of obsessive-compulsive (OC) symptoms has not yet been established in adult population based samples. We obtained the Young Adult Self Report Obsessive-Compulsive Subscale in mono- and dizygotic twins from the population-based Netherlands Twin Register in 1991, 1995 and 1997 and the Padua Inventory Revised Abbreviated in 2002. Stability of OC symptoms was analyzed as a function of genetic and environmental components. Heritability of OC behavior was around 40% at each time-point, independent of the instrument used. OC behavior was moderately stable with correlations ranging between r = .2 (for 11-year intervals), .4 (for 4-5 year intervals) and .6 (for 2 year intervals). Genetic correlations across time were higher, varying between .4 and .9, indicating that the stability of OC symptoms is mainly due to stable genetic factors. This study showed a moderate heritability and stability for OC behavior in adults. Genetic stability across time is high.

An fMRI study in monozygotic twins discordant for obsessive-compulsive symptoms.

To examine neurobiological changes underlying obsessive-compulsive symptoms (OCS) we examined intrapair differences in behavior and fMRI brain activation in monozygotic twins discordant for OCS, using a Tower of London planning paradigm. Despite only mild evidence for impairment at the behavioral level, twins with OCS showed significantly decreased brain activation during planning in dorsolateral prefrontal cortex, thalamus pulvinar, and inferior parietal cortex. These findings are consistent with the hypothesis of disturbed cortico-striato-thalamo-cortical (CSTC) circuitry underlying OCS. In contrast to previous studies in patients with obsessive-compulsive disorder (OCD) we did not find robust evidence for reduced responsiveness in striatal brain regions. Together, these findings suggest that neurobiological mechanisms underlying OCS of environmental origin partly overlap with neurobiological changes in patients with OCD, where the disorder is likely caused by a combination of genetic and environmental influences. A difference between genetical and environmental etiologies may relate to the amount of reduced striatal responsiveness.

Heritability of obsessive-compulsive symptom dimensions.

Recent research has shown that obsessive-compulsive symptoms (OCS) differ remarkably among patients and can be divided into several symptom dimensions. OCS are influenced by genetic components, but it is unknown to what extent these symptom dimensions are heritable. The phenotypic heterogeneity also raises the question to what extent the symptom dimensions are influenced by specific or shared genetic factors. We studied a population sample of 1,383 female twins from the Virginia Twin Registry. OCS was measured by a questionnaire with 20 items from the Padua Inventory. After factor analysis, three reliable OC symptom dimensions were retained: Rumination, Contamination, and Checking. These OC dimensions were analyzed with multivariate genetic models to investigate both the overlap and uniqueness of genetic and environmental contributions underlying OC symptom dimensions. The multivariate common pathway model provided the best description of the data. All symptom dimensions share variation with a latent common factor, that is, OC behavior. Variation in this common factor was explained by both genes (36%) and environmental factors (64%). Only the Contamination dimension was influenced by specific genes and seemed to be a relatively independent dimension. The results suggest that a broad OC behavioral phenotype exists, influenced by both genes and nonshared environment. In addition, we found evidence for specific genetic and environmental factors underlying the Contamination dimension. Use of the Contamination dimension could therefore provide a powerful approach for the detection of genetic susceptibility loci that contribute to OCS.

Genetic and environmental contributions underlying stability in childhood obsessive-compulsive behavior.

BACKGROUND: Little is known about the stability of obsessive-compulsive (OC) behavior during childhood. The objective of this study is to determine the developmental stability of pediatric OC behavior and the genetic and environmental influences on stability in a large population-based twin sample. METHODS: Maternal and paternal ratings on the 8-item Obsessive Compulsive Scale of the Child Behavior Checklist (CBCL-OCS) on Dutch mono- and dizygotic twin pairs from 8083 families were collected at ages 7, 10, and 12 years. Using a longitudinal twin design, stability of OC behavior and genetic and environmental influences on stability were determined. Using cutoff criteria, persistent, resilient, and new onset cases were identified in this sample. RESULTS: OC behavior assessed by the CBCL-OCS showed a moderate stability with phenotypic correlations of around .50 for boys and for girls. Stability of OC behavior was influenced by genetic factors, by environmental factors shared by children growing up in the same family, and by non-shared environmental factors. Stability for OCS was lower when categorical data were analyzed than when quantitative definitions were used. CONCLUSIONS: OC behavior is moderately stable in childhood. Stability of OC behavior is influenced by genetic, shared, and non-shared environmental factors.

Twin studies on obsessive-compulsive disorder: a review.

Genetic factors have historically been thought of as important in the development of obsessive-compulsive disorder (OCD). For the estimation of the relative importance of genetic and environmental factors, twin studies are an obvious approach. Twin studies of OCD have a long history, starting in 1929. In this review, over 70 years of twin research of OCD is presented, using four different approaches that represent the steps in the twin research of OCD from past to present. These steps include (1) case-studies of twins with OCD from the old literature; (2) twin studies of OCD using Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria; (3) twin studies of OCD using a dimensional approach, comparing resemblances in monozygotic and dizygotic twins; and (4) twin studies of OCD using a dimensional approach, analyzing the data with Structural Equation Modeling. It is concluded that only the studies using the last method have convincingly shown that, in children, obsessive-compulsive (OC) symptoms are heritable, with genetic influences in the range of 45% to 65%. In adults, studies are suggestive for a genetic influence on OC symptoms, ranging from 27% to 47%, but a large twin study using a biometrical approach with continuous data is still needed to provide conclusive evidence. Strategies for future twin studies of OCD are discussed.

Environmental factors in obsessive-compulsive behavior: evidence from discordant and concordant monozygotic twins.

To investigate environmental factors that protect against or exacerbate obsessive-compulsive (OC) symptoms, we selected 25 monozygotic (MZ) twin pairs discordant, 17 MZ twin pairs concordant high and 34 MZ pairs concordant low on OC symptoms from a large longitudinal Dutch sample of adult twin pairs and their family members, applying stringent criteria for OC symptomatology. Data were collected on psychopathology, family structure, health, lifestyle, birth complications and life events. Unique environmental factors were studied using within-discordant MZ pair comparisons, whereas between-concordant MZ pair comparisons were used to study environmental factors that are shared by the twins of an MZ pair. The high-scoring MZ twins of the discordant group reported more life events (especially sexual abuse) than their low-scoring twin-siblings. The between-pair comparisons showed lower birth weight in the discordant MZ pairs than in the concordant MZ pairs. Further, the concordant high MZ pairs as well as their spouses had a lower educational level than the two other groups. On scale scores of anxious-depression, neuroticism, and somatic complaints, concordant high MZ pairs showed highest scores, and the discordant MZ pairs scored intermediate, except for neuroticism, on which the high-scoring twins of discordant MZ pairs were equal to the concordant high pairs. Discordance on psychological scale scores between the concordant MZ pairs was evident from 1991 onward, and within the discordant MZ pairs from 1997 onward, confirming previous reports of an association of early-onset OC symptoms with higher genetic load. Parent scores of OC symptoms and anxious-depression suggested intermediate genetic load in the discordant MZ group. In conclusion, this study reports on both unique and shared environmental factors associated with OC symptomatology. Whether these factors operate in addition to or in interaction with genetic disposition is to be elucidated in future studies.

Genetic and environmental contributions to self-report obsessive-compulsive symptoms in Dutch adolescents at ages 12, 14, and 16.

OBJECTIVE: To determine the contributions of genetic and environmental influences to variation in self-report of obsessive-compulsive (OC) symptoms in a population-based twin sample of adolescent boys and girls. METHOD: Self-report ratings on the eight-item Youth Self-Report Obsessive-Compulsive Scale were collected in Dutch mono- and dizygotic twin pairs who participated at age 12 (N = 746 twin pairs), 14 (N = 963 pairs), or 16 years (N = 1,070 pairs). Structural equation modeling was used to break down the variation in liability to OC symptoms into genetic and environmental components. RESULTS: At age 12, no difference in prevalence was found for OC symptoms in boys and girls. At ages 14 and 16, the prevalence was higher in girls. At all ages, genetic factors contributed significantly to variation on OC symptom liability; 27% at the age of 12,57% at the age of 14, and 54% at the age of 16. There were no sex differences in heritability. Only at age 12, environmental factors shared by children from the same family contributed significantly (16%) to individual differences in OC symptom scores. CONCLUSIONS: During adolescence, OC symptoms are influenced by genetic and nonshared environmental factors. Sex differences in prevalence, but not heritability, emerge in adolescence. At age 12, shared environmental factors are of importance, but their influence disappears at later ages. This is in line with earlier research at age 12 that used parental ratings of OC symptoms. Thus, between-family factors play a significant role in explaining individual differences in OC symptoms at this age.

Genetic and environmental influences on obsessive-compulsive symptoms in adults: a population-based twin-family study.

BACKGROUND: The contribution of genetic factors to obsessive-compulsive (OC) symptoms has not been examined using a large population-based sample of adults. Furthermore, the extent to which there are qualitative and quantitative differences in genetic architecture between men and women with OC symptoms has not been elucidated. METHOD: We obtained the Young Adult Self Report Obsessive-Compulsive Scale (YASR-OCS) from a group of 5893 monozygotic (MZ) and dizygotic (DZ) twins, and 1304 additional siblings from the population-based Netherlands Twin Register. Structural equation modelling was used to decompose the variation in OC behaviour into genetic and environmental components and analyse quantitative and qualitative sex differences. RESULTS: Familial resemblance was the same for DZ twins and non-twin siblings, which means that there was no evidence for a special twin environment. The same genetic risk factors for OC behaviour were expressed in men and women. Depending on the choice of fit index, we found small (39% for men and 50% for women) or no sex differences (47% for both men and women) in heritability. The remaining variance in liability was due to individual-specific environment. CONCLUSIONS: OC behaviour showed a moderate heritability. At most, small quantitative sex differences were found in the genetic architecture of OC behaviour, and no qualitative sex differences.