Schizophrenia in the Spectrum of Gene–Stress Interactions: The FKBP5 Example

Many studies have demonstrated that genotype (G) interacts with adverse life experiences (E) to produce individual differences in vulnerability and resilience to mental disorders, including schizophrenia. Genetic susceptibility to stress and the timing of the environmental exposure(s) are relevant for these interactions and represent common risk factors. We take the example of the FKBP5 gene to illustrate G × E interactions that predict pleiotropic psychiatric outcomes, including schizophrenia.     

Emotion and Theory of Mind in Schizophrenia—Investigating the Role of the Cerebellum

Social cognitive dysfunction, including deficits in facial emotion recognition and theory of mind, is a core feature of schizophrenia and more strongly predicts functional outcome than neurocognition alone. Although traditionally considered to play an important role in motor coordination, the cerebellum has been suggested to play a role in emotion processing and theory of mind, and also shows structural and functional abnormalities in schizophrenia. The aim of this systematic review was to investigate the specific role of the cerebellum in emotion and theory of mind deficits in schizophrenia using previously published functional neuroimaging studies. PubMed and PsycINFO were used to search for all functional neuroimaging studies reporting altered cerebellum activity in schizophrenia patients during emotion processing or theory of mind tasks, published until December 2014. Overall, 14 functional neuroimaging studies were retrieved. Most emotion studies reported lower cerebellum activity in schizophrenia patients relative to healthy controls. In contrast, the theory of mind studies reported mixed findings. Altered activity was observed across several posterior cerebellar regions involved in emotion and cognition. Weaker cerebellum activity in schizophrenia patients relative to healthy controls during emotion processing may contribute to blunted affect and reduced ability to recognise emotion in others. This research could be expanded by examining the relationship between cerebellum function, symptomatology and behaviour, and examining cerebellum functional connectivity in patients during emotion and theory of mind tasks.     

Does a Person’s Autism Play a Role in Their Interactions with Police: The Perceptions of Autistic Adults and Parent/Carers

This study aimed to describe the impact that autistic characteristics (core features of autism and co-occurring conditions) have on interactions with police. Twelve autistic adults and 19 parent/carers were interviewed about interactions with police in the past 5 years. Using content analysis, it was found that in most (92.3%) interactions, autistic characteristics were described as having a role in the police interaction, either as a causal factor or more commonly by affecting the conduct of the interaction. In the latter case, the impact was associated with negative perceptions of the interaction. By sampling a more representative group across age, gender, functional abilities and context, this study provides insight into factors that underlie many autistic individual’s reported dissatisfaction with police interactions.

     

Insight in Schizophrenia: Involvement of Self-Reflection Networks?

Background: An association between social disadvantage and established psychosis is well documented in the literature, but there remains a lack of data on the social circumstances of patients before they became ill. We investigated whether social disadvantage at, and prior to, first contact with psychiatric services, is associated with psychosis. Method: We collected information on social disadvantage in childhood and adulthood from 278 cases presenting with their first episode of psychosis to the South London and Maudsley National Health Service Foundation Trust and from 226 controls recruited from the local population. Three markers of childhood social disadvantage and 3 markers of disadvantage in adulthood were analyzed. Results: Long term separation from, and death of, a parent before the age of 17 years were both strongly associated with a 2- to 3-fold-increased odds of psychosis. Cases were also significantly more likely to report 2 or more markers of adult social disadvantage than healthy controls (OR = 9.03) at the time of the first presentation with psychosis, independent of a number of confounders. When we repeated these analyses for long-standing adult social disadvantage, we found that the strength of the association decreased but still remained significant for 1 year (OR = 5.67) and 5 years (OR = 2.57) prior to the first contact. Conclusions: Social disadvantage indexes exposure to factors operating prior to onset that increase the risk of psychosis, both during childhood and adulthood.Key words: schizophrenia, social disadvantage, unemploy ment, separation, loss, environmentA rich body of literature has consistently reported an association between loss of a parent in childhood either by death or separation and increased risk of depression in adulthood.^1–3 Social disadvantage in childhood has also been related to substance abuse, poor physical health in adult life, and poor outcome in schizophrenia.⁴ A recent meta-analysis including 36 studies found evidence that childhood adversity is substantially associated with an increased risk for psychosis and suggested that studies should focus on differentiating adversity types.⁵ Special attention has been given to social inequality at birth and the parental socioeconomic situation of people who develop psychosis^6–8; but there are still unanswered questions. As a marker of social disadvantage in childhood we focused on long-term separation from, or death of, one or both parents; only a few studies have specifically examined these associations.^9,10 Both studies found that each marker of childhood disadvantage or loss was associated with a 2- to 3-fold-increased odds of psychosis. No studies have looked at family arrangements before the age of 17 yet.Individuals with established psychotic disorders often experience marked social disadvantage in adult life; they are more likely to live alone,¹¹ be unemployed,¹² and have few close relationships.¹³ However, it is unclear whether these are a consequence of the illness or whether they antedate the illness and if the latter, whether they contribute to its onset. Unfortunately, there is a lack of data on the social circumstances of psychotic patients before they became ill and only a few studies have tried systematically to investigate this. A Danish study of 5341 patients showed that schizophrenia is associated with poor social achievement long before the first admission.¹⁴ Morgan et al investigated the relationship between psychosis and a number of current and long-term indicators of adult social disadvantage in 390 cases with a first episode of psychosis and 391 healthy controls drawn from the UK-based AESOP study; all current and long-term indicators (eg, unemployment, living alone, and social housing) were associated with increased odds of psychosis.¹⁵ In this article, our focus is on social disadvantage (1) in childhood, (2) at 5 years and 1 year prior to first presentation to psychiatric services, and (3) at first presentation with psychosis and the association of any disadvantage with psychosis.     

Emerging Adults’ Stress and Health: The Role of Parent Behaviors and Cognitions

Although parent behaviors and cognitions are important for stress/health outcomes throughout development, little research examines whether cognitions mediate the relationship between parent behaviors and stress/health outcomes. As a result, the current study examined the reports of 160 emerging adults regarding their mothers’ and fathers’ behaviors (via the Parental Bonding Instrument and Alabama Parenting Questionnaire), their cognitions (via the Stress Appraisal Measure, Negative Mood Regulation Scale, Life Orientation Test-Revised, General Self-Efficacy Scale, and Ruminative Response Scale-Abbreviated), and their stress/health outcomes (via the Perceived Stress Scale and Short-Form Health Survey). Results of this study suggested that emerging adults’ cognitions partially mediated the relationship between their mothers’ behaviors and their stress/health outcomes and fully mediated the relationship between their fathers’ behaviors and their stress/health outcomes. Future research should examine parent behaviors as important distal variables in emerging adults’ stress/health outcomes but should examine cognitions as more salient, immediate predictors of their stress/health outcomes.     

The Dopamine Hypothesis of Schizophrenia: Version III��The Final Common Pathway

The dopamine hypothesis of schizophrenia has been one of the most enduring ideas in psychiatry. Initially, the emphasis was on a role of hyperdopaminergia in the etiology of schizophrenia (version I), but it was subsequently reconceptualized to specify subcortical hyperdopaminergia with prefrontal hypodopaminergia (version II). However, these hypotheses focused too narrowly on dopamine itself, conflated psychosis and schizophrenia, and predated advances in the genetics, molecular biology, and imaging research in schizophrenia. Since version II, there have been over 6700 articles about dopamine and schizophrenia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence, findings on environmental risk factors, research into the extended phenotype, and animal studies. We synthesize this evidence into a new dopamine hypothesis of schizophrenia—version III: the final common pathway. This hypothesis seeks to be comprehensive in providing a framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function. It explains how a complex array of pathological, positron emission tomography, magnetic resonance imaging, and other findings, such as frontotemporal structural and functional abnormalities and cognitive impairments, may converge neurochemically to cause psychosis through aberrant salience and lead to a diagnosis of schizophrenia. The hypothesis has one major implication for treatment approaches. Current treatments are acting downstream of the critical neurotransmitter abnormality. Future drug development and research into etiopathogenesis should focus on identifying and manipulating the upstream factors that converge on the dopaminergic funnel point.     

Cognitive Impairment in Schizophrenia: Interplay of BDNF and Childhood Trauma? A Review of Literature

Cognitive impairment is a core feature of schizophrenia. These deficits can also serve as an endophenotype for the illness in genetic studies. There is evidence that suggests that cognition can be considered a reasonable target for intervention in both schizophrenia and bipolar disorder. One of the most studied genetic phenotypes for psychosis is brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. BDNF has an established role in neuronal development and cell survival in response to stress and is abnormally expressed in schizophrenia. Studies have shown that childhood trauma is associated with poor prognosis of schizophrenic patients. BDNF-Val66Met polymorphism has been shown to moderate the impact of childhood adversity on later expression of affective symptoms, suggesting the possibility of gene environment interactions. Considering the recent advances of neuroscience an up to date review of relevant literature is warranted in this field. This article reviews the current literature available regarding associations between the Val66Met polymorphism, childhood trauma and cognitive dysfunction in schizophrenia.     

The Role of Cholesterol in α-Synuclein and Lewy Body Pathology in GBA1 Parkinson's Disease

Parkinson's disease (PD) is a progressive neurodegenerative disease where dopaminergic neurons in the substantia nigra are lost, resulting in a decrease in striatal dopamine and, consequently, motor control. Dopaminergic degeneration is associated with the appearance of Lewy bodies, which contain membrane structures and proteins, including α-synuclein (α-Syn), in surviving neurons. PD displays a multifactorial pathology and develops from interactions between multiple elements, such as age, environmental conditions, and genetics. Mutations in the GBA1 gene represent one of the major genetic risk factors for PD. This gene encodes an essential lysosomal enzyme called β-glucocerebrosidase (GCase), which is responsible for degrading the glycolipid glucocerebroside into glucose and ceramide. GCase can generate glucosylated cholesterol via transglucosylation and can also degrade the sterol glucoside. Although the molecular mechanisms that predispose an individual to neurodegeneration remain unknown, the role of cholesterol in PD pathology deserves consideration. Disturbed cellular cholesterol metabolism, as reflected by accumulation of lysosomal cholesterol in GBA1-associated PD cellular models, could contribute to changes in lipid rafts, which are necessary for synaptic localization and vesicle cycling and modulation of synaptic integrity. α-Syn has been implicated in the regulation of neuronal cholesterol, and cholesterol facilitates interactions between α-Syn oligomers. In this review, we integrate the results of previous studies and describe the cholesterol landscape in cellular homeostasis and neuronal function. We discuss its implication in α-Syn and Lewy body pathophysiological mechanisms underlying PD, focusing on the role of GCase and cholesterol. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society     

The “Liquid Biopsy”: the Role of Circulating DNA and RNA in Central Nervous System Tumors

The detection of tumor-derived circulating nucleic acids in patients with cancer, known as the “liquid biopsy,” has expanded from use in plasma to other bodily fluids in an increasing number of malignancies. Circulating nucleic acids could be of particular use in central nervous system tumors as biopsy carries a 5-7 % risk of major morbidity. This application presents unique challenges that have limited the use of cell-free DNA and RNA in the diagnosis and monitoring of CNS tumors. Recent work suggests that cerebrospinal fluid may be a useful source of CNS tumor-derived circulating nucleic acids. In this review, we discuss the available data and future outlook on the use of the liquid biopsy for CNS tumors.