Schizophrenia and frontotemporal dementia: Shared causation?

Abstract

The relationship between specific genes and particular diseases in neuropsychiatry is unclear, and newer studies focus on shared domains of neurobiological and cognitive pathology across different disorders. This paper reviews the evidence for an association between schizophrenia and frontotemporal dementia, including symptom similarity, familial co-morbidity, and neuroanatomical changes. Genetic as well as epigenetic findings from both schizophrenia and frontotemporal dementia are also discussed. As a result, we introduce the hypothesis of a shared susceptibility for certain subgroups of schizophrenia and frontotemporal dementia. This common causation may involve the same gene(s) at different stages of life: early in schizophrenia and late in frontotemporal dementia. Additionally, we provide a rationale for future research that should emphasize both genetic and cognitive parallels between certain forms of schizophrenia and frontotemporal dementia in a synergistic, coordinated way, placing both in the context of aberrant lateralization patterns.     

Schizophrenia and beta-thalassemia: a genetic link?

This report of two cases in which schizophrenia and beta-thalassemia occurred simultaneously in several family members may suggest that a genetic link exists between these two disorders. A known genetic disease (beta-thalassemia) could help confirm the presence, on the short arm of chromosome 11, of a genetic susceptibility factor for schizophrenia.     

Schizophrenia and frontal cortex: where does it fail?

Schizophrenia is characterized by cognitive, social, and emotional impairments and by psychotic symptoms. Neuroimaging studies have reported abnormalities within the prefrontal cortex and it has been hypothesized that schizophrenia results from poor or miswired anatomical/functional connections. We have compared the functional connectivity within the frontal cortex in control and schizophrenic subjects during the realization of a Continuous Performance Task. The connectivity pattern within the frontal cortex was uncovered by the analysis of the correlation matrix computed from the fMRI time series in frontal areas for 14 schizophrenic patients and 14 control subjects. In control subjects, the right dorsolateral prefrontal cortex (DLFCr) activity correlated i) positively with the left dorsolateral prefrontal cortex and the posterior part of the supplementary motor area, ii) negatively with the medial and anterior/inferior part of the frontal cortex. In the schizophrenic group, these relations were abolished or strongly lowered. The negative relation between the DLFCr and the medial frontal cortex has been proposed to play a key role in setting a harmonious balance between the direction of attention to the external world and the expression of the individual believes and self-referential activities, and therefore, the impaired relation of right DLFCr with other frontal areas could explain a distorted perception of external world in relation with internal motivations.     

An Association of Elevated Serum Gonadotropin Concentrations and Alzheimer Disease?

Alzheimer disease affects almost 4 million Americans and costs $65 billion annually. The disease is more common in women than in men, and studies suggest that oestrogen may have a protective effect. Oestrogen replacement lowers circulating concentrations of gonadotropins. When gonadotropins are added to rat granulosa cells in culture, the number of low density lipoprotein (LDL) receptors and the rate of uptake of low density lipoprotein increases. Many proteins found in Alzheimer disease plaques are ligands for low density lipoprotein receptors (LDLR) on central nervous system (CNS) neurones. This study evaluated whether gonadotropins may be associated with Alzheimer disease. Circulating concentrations of follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels in 40 male residents of long-term care facilities with the primary diagnosis of dementia were compared to 29 age-matched controls. Serum concentrations of FSH and LH were significantly higher in dementia patients. We speculate they may play an aetiologic role in the deposition of abnormal proteins, particularly those associated with low density lipoprotein receptors, in CNS neurones.     

Schizophrenia: an epigenetic puzzle?

Developments in molecular biology over the past three decades have led to an increasing awareness of the importance of epigenetic phenomena in a variety of genome functions. Epigenetic aspects of complex multifactorial diseases including schizophrenia, however, have not been investigated sufficiently. Various facets of epigenetics are reevaluated through their putative relevance to four theories of schizophrenia: neurodevelopmental, dopamine dysfunction, viral, and genetic anticipation with unstable DNA. The heuristic value of the epigenetic model of schizophrenia arises from the possibility of integration of a wide variety of empirical data into a new theoretical framework. It can be hypothesized that in addition to pathological effects of DNA structural mutations and environmental factors, inherited and acquired epigenetic defects, or epimutations, may be of etiological importance in schizophrenia. In addition, the epigenetic model may lead to experiments investigating the molecular substrates of genetic-environmental interactions.     

Schizophrenia Genetics: Where Next?

The purpose of this invited review is to summarize the state of genetic research into the etiology of schizophrenia (SCZ) and to consider options for progress. The fundamental uncertainty in SCZ genetics has always been the nature of the beast, the underlying genetic architecture. If this were known, studies using the appropriate technologies and sample sizes could be designed with an excellent chance of producing high-confidence results. Until recently, few pertinent data were available, and the field necessarily relied on speculation. However, for the first time in the complex and frustrating history of inquiry into the genetics of SCZ, we now have empirical data about the genetic basis of SCZ that implicate specific loci and that can be used to plan the next steps forward.     

Dopamine Genes and Schizophrenia: Case Closed or Evidence Pending?

The dopamine hypothesis of schizophrenia (SZ) has motivated a large number of genetic association studies but few if any dopaminergic (DA) polymorphisms are accepted as credible risk factors at present. To evaluate whether dopamine-related genes have been investigated adequately, we surveyed public genetic databases and published SZ association studies with regard to 14 conventional DA genes and 7 selected dopamine-interacting proteins. We estimate that 325 polymorphisms would be required to evaluate the impact of common variation on SZ risk among Caucasian samples. To date, 98 polymorphisms have been analyzed in published association studies. We estimate that only 19 of these variations have been evaluated in samples with at least 50% power to detect an association of the effect size commonly found in genetically complex disorders. While it is possible that DA genes do not harbor genetic risk factors for SZ, our review suggests that satisfactory conclusions for most genes cannot be drawn at present. Whole-genome association studies have begun to fill this void, but additional analyses are likely to be needed. Recommendations for future association studies include analysis of adequately powered samples, judiciously selected polymorphisms, multiple ethnic groups, and concurrent evaluation of function at associated single-nucleotide polymorphisms.     

Schizophrenia and quality of life: how important are symptoms and functioning?

Objective  

the relationship between Quality of life (QoL) and global functioning and symptoms in outpatients with Schizophrenia     

Schizophrenia and Crime: How Predictable Are Charges,Convictions and Violence?

The schizophrenia-crime relationship was studied in 151 research participants meeting DSM-IV criteria for schizophrenia or schizoaffective disorder and with histories positive or negative for criminal charges, convictions and offences involving violence. These crime-related variables were regressed on a block of nine predictors reflecting non-specific illness context (e.g. demographic, social) and a block of 14 predictors reflecting specific illness content (e.g. symptoms). Context variables predicted charges, with unique contributions from employment status, education and substance use. Further significant validity was provided by content-related predictors including symptoms (paranoia, depression, low energy), but not cognitive performance (verbal and non-verbal ability, working memory, processing speed, verbal memory, word fluency, inhibition, practical cognition). In contrast, neither convictions nor violence were predicted by illness context or content variables. These results suggest that specific contextual and intrinsic aspects of schizophrenic illness make interaction with law enforcement and therefore criminal charges more likely.     

Association Between BDNF Val66Met Polymorphism and Cognitive Performance in Antipsychotic-Na?ve Patients with Schizophrenia

Cognitive impairment is one of the core symptoms in schizophrenia, which reflects the neurodevelopmental deficits in the etiology of this disease. Brain-derived neurotrophic factor (BDNF) plays an important role in various neurodevelopmental processes. Growing evidence has shown that BDNF may be involved in the etiology of schizophrenia. The aim of this study was to examine the association of the BDNF Val66Met polymorphism with cognition in patients with schizophrenia. Various neuropsychological tests including the Wechsler Adult Intelligence Scale-Revised, the Wechsler Memory Scale-Revised, and the Wisconsin Card Sorting Test (WCST) were employed in a sample of 112 antipsychotic-na?ve patients with schizophrenia and 63 healthy controls. We examined the Val66Met polymorphism in the 112 patients and 394 controls. Among the patients, cognition was compared between Met allele carriers and non-Met allele carriers. A wide range of cognitive deficits were demonstrated in the schizophrenic patients, compared with the controls (Ps?相似文献   

How Prevalent Are Anxiety Disorders in Schizophrenia? A Meta-Analysis and Critical Review on a Significant Association

Objective: The presence of anxiety disorders (AD) in schizophrenia (SZ) is attracting increasing interest. However, published studies have yielded very broad variations in prevalence rates across studies. The current meta-analysis sought to (1) investigate the prevalence of co-occurring AD in SZ by reporting pooled prevalence rates and (2) identify potential sources of variations in reported rates that could guide our efforts to identify and treat these co-occurring disorders in patients with SZ. Methods: We performed a systematic search of studies reporting prevalence of AD in SZ and related psychotic disorders. Mean prevalence rates and 95% confidence intervals (CIs) were first computed for each disorder. We then examined the impact of potential moderators related to patient sampling or to AD assessment methods on these rates. Results: Fifty-two eligible studies were identified. Pooled prevalence rates and CIs were 12.1% (7.0%–17.1%) for obsessive-compulsive disorders, 14.9% (8.1%–21.8%) for social phobia, 10.9% (2.9%–18.8%) for generalized AD, 9.8% (4.3%–15.4%) for panic disorders, and 12.4% (4.0%–20.8%) for post-traumatic stress disorders. For all disorders, we found significant heterogeneity in rates across studies. This heterogeneity could at least partially be explained by the effect of moderator variables related to patient characteristics or assessment methods. Conclusions: AD are highly prevalent in SZ, but important variations in rates are observed between studies. This meta-analysis highlights several factors that affect risk for, or detection of AD in SZ, and could, thus, have an important impact on treatment and outcome of SZ patients.     

Schizophrenia: still Kraepelin's dementia praecox?

Asking whether E. Kraepelin's early dementia praecox and disease concepts (1896) are still valid today, we condensed his early theory into four theses: 1) schizophrenia is a disease entity, distinguishable from affective psychosis. 2) It is caused by a specific neuropathology. 3) It usually manifests itself in adolescence or early adulthood. 4) Underlying schizophrenia is a progressive disease process that leads to defects and dementia. Having tested whether Kraepelin's dementia praecox and modern schizophrenia are actually comparable, we studied 1) how schizophrenia and depression are linked or separable in terms of symptoms, risk factors and illness course from onset until five years after first treatment contact. The analyses are based on a population-based sample of 130 first admissions because of schizophrenia, 130 age- and sex-matched first admissions because of unipolar depressive disorder and 130 "healthy" population controls from the study area. 2) Results will be presented that, though not very specific, confirm Kraepelin's farsighted hypothesis of a neuropathological basis of the disorder. In this context it will be discussed whether the brain changes are developmental or degenerative in origin. 3) The distribution of age of onset extends far into old age. In a sample of 1109 consecutive first admissions because of nonaffective psychosis from the total age range it was shown that age-dependent developmental factors modify certain components of symptomatology linearly and significantly. The main risk factors, too, significantly change with age. 4) Long-term course was examined in three studies of epidemiologically recruited first-episode samples: Study 1 included five cross sections over 5 years, Study 2 was a prospective pre-post-comparison over 12 years supplemented by a retrospective assessment of the illness course (IRAOS) and Study 3 encompassed 10 cross sections over fifteen years. Finally, the disease concept of schizophrenia, as it presents itself in the light of current knowledge, will be outlined and compared with Kraepelin's earlier and later view of the disorder.     

Epstein-Barr Virus and MS:Causality or Association?

The search for the aetiology of multiple sclerosis (MS) has led to many theories over the years. It has become clear, however, that MS is complex and multifactorial, involving many interlacing mechanisms, many of which appear to be playing a role in the causation and evolution of the disease. In the large part for epidemiological reasons, an infectious aetiology has always been a prime suspect in this search. Although many agents have been examined over the years, the Epstein-Barr virus (EBV) has re-emerged as a candidate pathogen, based to a large degree on sero-epidemiological evidence, and on the knowledge of the effects this virus is capable of producing in other situations.