Journal of molecular psychiatry最新文献

The aim of this review is to propose a Unified Theory of Alzheimer's disease (UTAD) that integrates all key behavioural, genetic and environmental risk factors in a causal chain of etiological and pathogenetic events. It is based on three concepts that emanate from human's evolutionary history: (1) The grandmother-hypothesis (GMH), which explains human longevity due to an evolutionary advantage in reproduction by trans-generational transfer of acquired knowledge. Consequently it is argued that mental health at old-age must be the default pathway of humans' genetic program and not development of AD. (2) Therefore, mechanism like neuronal rejuvenation (NRJ) and adult hippocampal neurogenesis (AHN) that still function efficiently even at old age provide the required lifelong ability to memorize personal experiences important for survival. Cumulative evidence from a multitude of experimental and epidemiological studies indicate that behavioural and environmental risk factors, which impair productive AHN, result in reduced episodic memory performance and in reduced psychological resilience. This leads to avoidance of novelty, dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis and cortisol hypersecretion, which drives key pathogenic mechanisms of AD like the accumulation and oligomerization of synaptotoxic amyloid beta, chronic neuroinflammation and neuronal insulin resistance. (3) By applying to AHN the law of the minimum (LOM), which defines the basic requirements of biological growth processes, the UTAD explains why and how different lifestyle deficiencies initiate the AD process by impairing AHN and causing dysregulation of the HPA-axis, and how environmental and genetic risk factors such as toxins or ApoE4, respectively, turn into disease accelerators under these unnatural conditions. Consequently, the UTAD provides a rational strategy for the prevention of mental decline and a system-biological approach for the causal treatment of AD, which might even be curative if the systemic intervention is initiated early enough in the disease process. Hence an individualized system-biological treatment of patients with early AD is proposed as a test for the validity of UTAD and outlined in this review.

Background: Recent genetic association studies have linked the cadherin-based adherens junction protein alpha-T-catenin (αT-cat, CTNNA3) with the development of autism. Where αT-cat is expressed in the brain, and how its loss could contribute to this disorder, are entirely unknown.

Methods: We used the αT-cat knockout mouse to examine the localization of αT-cat in the brain, and we used histology and immunofluorescence analysis to examine the neurobiological consequences of its loss.

Results: We found that αT-cat comprises the ependymal cell junctions of the ventricles of the brain, and its loss led to compensatory upregulation of αE-cat expression. Notably, αT-cat was not detected within the choroid plexus, which relies on cell junction components common to typical epithelial cells. While αT-cat was not detected in neurons of the cerebral cortex, it was abundantly detected within neuronal structures of the molecular layer of the cerebellum. Although αT-cat loss led to no overt differences in cerebral or cerebellar structure, RNA-sequencing analysis from wild type versus knockout cerebella identified a number of disease-relevant signaling pathways associated with αT-cat loss, such as GABA-A receptor activation.

Conclusions: These findings raise the possibility that the genetic associations between αT-cat and autism may be due to ependymal and cerebellar defects, and highlight the potential importance of a seemingly redundant adherens junction component to a neurological disorder.

Background: A spontaneous de novo mutation is a new mutation appeared in a child that neither the parent carries. Recent studies suggest that recurrent de novo loss-of-function mutations identified in patients with sporadic autism spectrum disorder (ASD) play a key role in the etiology of the disorder. POGZ is one of the most recurrently mutated genes in ASD patients. Our laboratory and other groups have recently found that POGZ has at least 18 independent de novo possible loss-of-function mutations. Despite the apparent importance, these mutations have never previously been assessed via functional analysis.

Methods: Using wild-type, the Q1042R-mutated, and R1008X-mutated POGZ, we performed DNA-binding experiments for proteins that used the CENP-B box sequence in vitro. Data were statistically analyzed by one-way ANOVA followed by Tukey-Kramer post hoc tests.

Results: This study reveals that ASD-associated de novo mutations (Q1042R and R1008X) in the POGZ disrupt its DNA-binding activity.

Conclusions: Here, we report the first functional characterization of de novo POGZ mutations identified in sporadic ASD cases. These findings provide important insights into the cellular basis of ASD.

Background: Caregivers like family members or other relatives are central and provide not only practical help and personal care but also give emotional support, and they are suffering from plenty of challengeable tasks. These, eventually, cast out family caregivers into multidimensional problems prominently for mental distress like depression, anxiety, sleep problem and somatic disorder which are followed by physiologic changes and impaired health habits that ultimately lead to illness and possibly to death. Numerous studies demonstrate that mental distress of caregivers are two times compared to general populations. Despite it was not uncommon to observe manifestations of caregivers' mental distress, yet there was no study on this area. Therefore, this study was intended to assess the prevalence of mental distress and associated factors among the caregivers of persons with severe mental illness in the out patients unit of Amanuel Hospital, Ethiopia.

Methods: Institutional based cross sectional study was conducted from May 1 to 31, 2013 at Amanuel Hospital, Addis Ababa, Ethiopia. Systematic random sampling technique with "k" interval of 13 was employed to withdraw a total of 423 participants from study population. Five psychiatric nurses carried out interview by using standardized and validated Self Reported Questionnaire (SRQ 20). Descriptive statistics, binary and multivariate logistic regression analysis were conducted.

Results: This study revealed that the overall prevalence of mental distress was found to be 221(56.7 %). The factors like missed social support, two or more times admission of patient, care giving for psychotic patient, being farmer and being female were found to be predictors for mental distress of caregivers with this [AOR 95 % CI = 9.523(5.002, 18.132)], 3.293(1.474, 3.3560), 2.007(1.109, 3.634), 2.245(1.129, 4.463) and 3.170(1.843, 5.454)] respectively.

Conclusions: In this respect the study observed that there was a higher level of mental distress experienced by caregivers of patients with severe mental illness in Amanuel Hospital, and social support are strongly associated with mental distress besides to other variables. Effectively planned interventions have to be targeted at alleviating mental distress and actions like on-going psycho-education and mutual support that could expand social support should be implemented in Amanuel hospital health service delivery system.

Background: The education system in Germany is beginning to witness a sea change, lately, owing to the country's ratification of the United Nation's Convention on the Rights of Persons with Disabilities. The enactment is aiming at making provision for special education teachers to share the same teaching platform and institution with other teachers for teaching children from all backgrounds, irrespective of their needs. While promoting the benefits of collaborative teaching, this provision would also effectively establish role demarcation among teachers. However, the level of participation and adaptiveness displayed by individual teachers would play a major role in determining the success or failure of the intended collaborative framework. Collaboration also becomes challenging due to the level of stress involved in the teaching profession. The fact that only 65 % of teachers in Germany reach retirement age while still in service, primarily due to psychiatric illness, has posed questions on adopting the collaborative framework for teachers from diverse backgrounds. In other words, it can be stated that the process of collaborating with teachers from different professional backgrounds and with varying levels of skills will potentially lead to further stress. The stress-related psychological states, developed through the collaborative processes, might affect the biological stress-response systems of the participating teachers. With stress-response contributing directly to the pathogenesis of stress-related diseases and disorders in the long term, it would be important to contain the ripple effect of collaborative framework that the enactment intends to establish between SEN (special educational needs) teachers and others.

Methods: In addition to impacting the long-term health of teachers, the collaborative framework is also suggestive of having similar effects on students studying special education (SEN students). A study was conducted to examine the stress levels associated with the collaborative framework. An expression in terms of two (group affiliation) × 2 (measurement time) between subjects design was implemented to examine the effects of an Acceptance and Commitment Training on the subjective tension of a sample (N = 68) of SEN students. The sample was split into an intervention and a control group (IG and CG). The effects of the training on collaborative competence were examined using the Chi-square test. Questionnaire and role plays were used to assess the collaborative competence and the subjective tension.

Results: The participants had significant stress levels and displayed an uncooperative attitude during the initial assessment. However, these results reversed after the Acceptance and Commitment Training. Significant decrease in stress levels and improved cooperation were evident among the participants in the intervention group, as opposed to the participants of the cont

Background: DNA methylation differences between monozygotic twins discordant for schizophrenia have been previously reported. However, the origin of methylation differences between monozygotic twins discordant for schizophrenia is not clear. The findings here argue that all DNA methylation differences may not necessarily represent the cause of the disease; rather some may result from the effect of antipsychotics.

Methods: Methylation differences in rat brain regions and also in two pairs of unrelated monozygotic twins discordant for schizophrenia have been studied using genome-wide DNA methylation arrays at Arraystar Inc. (Rockville, Maryland, USA). The identified gene promoters showing significant alterations to DNA methylation were then further characterized using ingenuity pathway analysis (Ingenuity System Inc, CA, USA).

Results: Pathway analysis of the most significant gene promoter hyper/hypomethylation revealed a significant enrichment of DNA methylation changes in biological networks and pathways directly relevant to neural development and psychiatric disorders. These included HIPPO signaling (p = 3.93E-03) and MAPK signaling (p = 4.27E-03) pathways involving hypermethylated genes in schizophrenia-affected patients as compared to their unaffected co-twins. Also, a number of significant pathways and networks involving genes with hypomethylated gene promoters have been identified. These included CREB signaling in neurons (p = 1.53E-02), Dopamine-DARPP32 feedback in cAMP signaling (p = 7.43E-03) and Ephrin receptors (p = 1.13E-02). Further, there was significant enrichment for pathways involved in nervous system development and function (p = 1.71E-03-4.28E-02).

Conclusion: The findings highlight the significance of antipsychotic drugs on DNA methylation in schizophrenia patients. The unique pathways affected by DNA methylation in the two pairs of monozygotic twins suggest that patient-specific pathways are responsible for the disease; suggesting that patient-specific treatment strategies may be necessary in treating the disorder. The study reflects the need for developing personalized medicine approaches that take into consideration epigenetic variations between patients.

Background: The spontaneously hypertensive rat (SHR) has been used to model changes in the central nervous system associated with cognitive-related disorders. Recent human and animal studies indicate a possible relationship between cognitive deficits, insulin resistance and hypertension. We aimed to investigate whether cognitively impaired SHRs develop central and/or peripheral insulin resistance and how their cognitive performance is influenced by the animal's sex and age as well as strains used for comparison (Wistar and Wistar-Kyoto/WKY).

Methods: Three and seven-month-old SHR, Wistar, and WKY rats were studied for their cognitive performance using Morris Water Maze (MWM) and Passive Avoidance tests (PAT). Plasma glucose and insulin were obtained after oral glucose tolerance tests. Cerebral cortex, hippocampus, and striatum status of insulin-receptor (IR) β-subunit and glycogen synthase kinase-3β (GSK3β) and their phosphorylated forms were obtained via ELISA.

Results: SHRs performed poorly in MWM and PAT in comparison to both control strains but more pronouncedly compared to WKY. Females performed poorer than males and 7-month-old SHRs had poorer MWM performance than 3-month-old ones. Although plasma glucose levels remained unchanged, plasma insulin levels were significantly increased in the glucose tolerance test in 7-month-old SHRs. SHRs demonstrated reduced expression and increased activity of IRβ-subunit in cerebral cortex, hippocampus, and striatum with different regional changes in phospho/total GSK3β ratio, as compared to WKYs.

Conclusion: Results indicate that cognitive deficits in SHRs are accompanied by both central and peripheral insulin dysfunction, thus allowing for the speculation that SHRs might additionally be considered as a model of insulin resistance-induced type of dementia.

In the last decade evidence has accumulated that suggests that the cerebellum is involved not only in motor but also in behavioral and cognitive functions. A myriad of anatomical, clinical and imaging studies support that assumption. The lengthened survival of patients with cerebellar tumors has also brought an increased awareness of neurocognitive deficits to the neurooncological community. Although evidence from neurosurgical case series exists that clearly demonstrates that patients afflicted from posterior fossa tumors are at high risk for long-term cognitive or adaptive deficits, there is still a lack of systematic translational review on this issue. Accordingly a systematic review was conducted to summarize the impact of cerebellar lesions on behavior and cognition. The findings and clinical implications are discussed in the light of the recent advances in neuroimaging techniques.

Agomelatine is an antidepressant with a unique mechanism of action. Since its marketing in 2009, concerns have been raised regarding its potential to induce liver injury. The authors therefore address the need to comprehensively evaluate the potential risk posed by agomelatine of inducing liver injury by reviewing data from published and unpublished clinical trials in both the pre- and postmarketing settings, as well as data from non-interventional studies, pharmacovigilance database reviews and one case report. Recommendations for clinicians are also provided. In this review, agomelatine was found to be associated with higher rates of liver injury than both placebo and the four active comparator antidepressants used in the clinical trials for agomelatine, with rates as high as 4.6% for agomelatine compared to 2.1% for placebo, 1.4% for escitalopram, 0.6% for paroxetine, 0.4% for fluoxetine, and 0% for sertraline. The review also provides evidence for the existence of a positive relationship between agomelatine dose and liver injury. Furthermore, rates of liver injury were found to be lower in non-interventional studies. Findings from pharmacovigilance database reviews and one case report also highlight the risk of agomelatine-induced liver injury. As agomelatine does pose a risk of liver injury, clinicians must carefully monitor liver function throughout treatment. However, agomelatine's unique mechanism of action and favourable safety profile render it a valuable treatment option. A quantitative analysis of agomelatine-induced liver injury is lacking in the literature and would be welcomed.

Pathologies of central nervous system (CNS) functions are involved in prevalent conditions such as Alzheimer's disease, depression, and Parkinson's disease. Notable pathologies include dysfunctions of circadian rhythm, central metabolism, cardiovascular function, central stress responses, and movement mediated by the basal ganglia. Although evidence suggests exercise may benefit these conditions, the neurobiological mechanisms of exercise in specific brain regions involved in these important CNS functions have yet to be clarified. Here we review murine evidence about the effects of exercise on discrete brain regions involved in important CNS functions. Exercise effects on circadian rhythm, central metabolism, cardiovascular function, stress responses in the brain stem and hypothalamic pituitary axis, and movement are examined. The databases Pubmed, Web of Science, and Embase were searched for articles investigating regional brain adaptations to exercise. Brain regions examined included the brain stem, hypothalamus, and basal ganglia. We found evidence of multiple regional adaptations to both forced and voluntary exercise. Exercise can induce molecular adaptations in neuronal function in many instances. Taken together, these findings suggest that the regional physiological adaptations that occur with exercise could constitute a promising field for elucidating molecular and cellular mechanisms of recovery in psychiatric and neurological health conditions.