Spontaneous recovery of memory functions in an untreated case of anti NMDAR encephalitis – a reason to maintain hope

Objective: Anti N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disorder that was only fully discovered recently and neuropsychological outcome data remains sparse. We present the case of BA, a 19-year-old male, which illustrates the cognitive outcome in an untreated case over a time period of over 2½ years.Method: We conducted three cognitive assessments, including tests of memory and executive functioning, over this time period and considered the evidence for reliable change in memory function using the Wechsler Advanced Clinical Solutions (ACS) serial assessment package.Results: Our findings revealed mild memory problems 6 months post-discharge with, at best, static and potentially declining memory functioning at follow-up assessment 12 months post-discharge. However, the results of testing at 30 months post-discharge revealed significant improvements in immediate and delayed memory index performances.Conclusions: Our report of a case of anti-NMDAR encephalitis provides evidence for spontaneous improvements in memory functioning occurring more than 2 years after initial assessment and also demonstrates both the utility and potential limitations of the ACS serial assessment software when used in a relatively typical clinical assessment situation.     

Vascular perfusion differs in two distinct PDGFRβ-positive zones within the ischemic core of male mice 2 weeks following photothrombotic stroke

Stroke therapy has largely focused on preventing damage and encouraging repair outside the ischemic core, as the core is considered irreparable. Recently, several studies have suggested endogenous responses within the core are important for limiting the spread of damage and enhancing recovery, but the role of blood flow and capillary pericytes in this process is unknown. Using the Rose Bengal photothrombotic model of stroke, we illustrate blood vessels are present in the ischemic core and peri-lesional regions 2 weeks post stroke in male mice. A FITC-albumin gel cast of the vasculature revealed perfusion of these vessels, suggesting cerebral blood flow (CBF) may be partially present, without vascular leakage. The length of these vessels is significantly reduced compared to uninjured regions, but the average width is greater, suggesting they are either larger vessels that survived the initial injury, smaller vessels that have expanded in size (i.e., arteriogenesis), or that neovascularization begins with larger vessels. Concurrently, we observed an increase in platelet-derived growth factor receptor beta (PDGFRβ, a marker of pericytes) expression within the ischemic core in two distinct patterns, one which resembles pericyte-derived fibrotic scarring at the edge of the core, and one which is vessel associated and may represent blood vessel recovery. We find little evidence for dividing cells on these intralesional blood vessels 2 weeks post stroke. Our study provides evidence flow is present in PDGFRβ-positive vessels in the ischemic core 2 weeks post stroke. We hypothesize intralesional CBF is important for limiting injury and for encouraging endogenous repair following cerebral ischemia.     

Measures of anxiety, sensorimotor function, and memory in male and female mGluR4⁻/⁻ mice

Metabotropic glutamate receptors (mGluRs) are coupled to second messenger pathways via G proteins and modulate synaptic transmission. Of the eight different types of mGluRs (mGluR1-mGluR8), mGluR4, mGluR6, mGluR7, and mGluR8 are members of group III. Group III receptors are generally located presynaptically, where they regulate neurotransmitter release. Because of their role in modulating neurotransmission, mGluRs are attractive targets for therapies aimed at treating anxiety disorders. Previously we showed that the mGluR4-selective allosteric agonist VU 0155041 reduces anxiety-like behavior in wild-type male mice. Here, we explore the role of mGluR4 in adult (6-month old) and middle-aged (12-month old) male and female mice lacking this receptor. Compared to age- and sex-matched wild-type mice, middle-aged mGluR4^−/− male mice showed increased measures of anxiety in the open field and elevated zero maze and impaired sensorimotor function on the rotarod. These changes were not seen in adult 6-month-old male mice. In contrast to the male mice, mGluR4^−/− female mice showed reduced measures of anxiety in the open field and elevated zero maze and enhanced rotarod performance. During the hidden platform training sessions of the water maze, mGluR4^−/− mice swam farther away from the platform than wild-type mice at 6, but not at 12, months of age. mGluR4^−/− mice also showed enhanced amygdala-dependent cued fear conditioning. No genotype differences were seen in hippocampus-dependent contextual fear conditioning. These data indicate that effects of mGluR4 on sensorimotor function and measures of anxiety, but not cued fear conditioning, are critically modulated by sex and age.     

Knockdown of phospholipase C-β1 in the medial prefrontal cortex of male mice impairs working memory among multiple schizophrenia endophenotypes

Background

Decreased expression of phospholipase C-β1 (PLC-β1) has been observed in the brains of patients with schizophrenia, but, to our knowledge, no studies have shown a possible association between this altered PLC-β1 expression and the pathogenesis of schizophrenia. Although PLC-β1-null (PLC-β1^−/−) mice exhibit multiple endophenotypes of schizophrenia, it remains unclear how regional decreases in PLC-β1 expression in the brain contribute to specific behavioural defects.

Methods

We selectively knocked down PLC-β1 in the medial prefrontal cortex (mPFC) using a small hairpin RNA strategy in mice.

Results

Silencing PLC-β1 in the mPFC resulted in working memory deficits, as assayed using the delayed non-match-to-sample T-maze task. Notably, however, other schizophrenia- related behaviours observed in PLC-β1^−/− mice, including phenotypes related to locomotor activity, sociability and sensorimotor gating, were normal in PLC-β1 knockdown mice.

Limitations

Phenotypes of PLC-β1 knockdown mice, such as locomotion, anxiety and sensorimotor gating, have already been published in our previous studies. Further, the neural mechanisms underlying the working memory deficit in mice may be different from those in human schizophrenia.

Conclusion

These results indicate that PLC-β1 signalling in the mPFC is required for working memory. Importantly, these results support the notion that the decrease in PLC-β1 expression in the brains of patients with schizophrenia is a pathogenically relevant molecular marker of the disorder.     

Distribution of two isozymes of 5α-reductase in the brains of adult male and female green anole lizards

The 5α-reductase (5αR) enzyme converts testosterone to 5α-dihydrotestosterone. This local metabolism within the brain is important for the full expression of male sexual behavior in many species, including green anole lizards. Two isozymes of 5αR exist and little is known about their specific distributions. We conducted in situ hybridization for both isozymes in intact male and female green anole brains during the breeding (BS) and non-breeding (NBS) seasons. 5αR1 mRNA was only detected in the brainstem, while 5αR2 was expressed in specific areas throughout the brain. As our primary interest was evaluating the potential role of 5αR in forebrain regulation of reproductive behavior, we quantified 5αR2 expression in the preoptic area, amygdala (AMY), and ventromedial hypothalamus (VMH). More 5αR2 cells were detected during the NBS than BS in the AMY, and the density of these cells was greater in females than males. In the VMH, the right side contained more 5αR2 cells than the left, an effect driven by a lateralized increase in the NBS. These data expand understanding of the distribution and potential roles of both isozymes in the adult brain, and differences in expression patterns between mammals and birds suggest that they may have been co-opted for different functions later in evolution.     

Chronic models of the preclinical and early clinical stages of Parkinson’s disease in mice

Degradation of the dopaminergic nigrostriatal system is a central process of the pathogenesis of Parkinson’s disease, which is a chronic neurodegenerative disorder. A specific feature of the disease is longterm asymptomatic progress over decades, which occurs due to the functioning of compensatory processes in the brain. Specific motor symptoms appear after substantial lesion of the nigrostriatal system and depletion of compensatory reserves. At this stage, traditional treatment of patients has low efficiency. In the present study, we developed new neurotoxic models of the maximally prolonged preclinical stage and early clinical stage of Parkinson’s disease in mice and performed a thorough evaluation of motor behavior and the morphofunctional state of the nigrostriatal system in these animals. Further comparative study of these models will help to identify: (a) specific peripheral biomarkers of each stage as a basis for the development of the early preclinical diagnostics of Parkinson’s disease; (b) the mechanisms of neuroplasticity that are responsible for asymptomatic progress of the disease; (c) molecular triggers of impaired motor behavior during the transition from the preclinical stage to the clinical stage.     

Behavioral disturbances in adult mice following neonatal virus infection or kynurenine treatment – Role of brain kynurenic acid

Exposure to infections in early life is considered a risk-factor for developing schizophrenia. Recently we reported that a neonatal CNS infection with influenza A virus in mice resulted in a transient induction of the brain kynurenine pathway, and subsequent behavioral disturbances in immune-deficient adult mice. The aim of the present study was to investigate a potential role in this regard of kynurenic acid (KYNA), an endogenous antagonist at the glycine site of the N-methyl-d-aspartic acid (NMDA) receptor and at the cholinergic α7 nicotinic receptor. C57BL/6 mice were injected i.p. with neurotropic influenza A/WSN/33 virus (2400 plaque-forming units) at postnatal day (P) 3 or with l-kynurenine (2 × 200 mg/kg/day) at P7–16. In mice neonatally treated with l-kynurenine prepulse inhibition of the acoustic startle, anxiety, and learning and memory were also assessed. Neonatally infected mice showed enhanced sensitivity to d-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as adults. Neonatally l-kynurenine treated mice showed enhanced sensitivity to d-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as well as mild impairments in prepulse inhibition and memory. Also, d-amphetamine tended to potentiate dopamine release in the striatum in kynurenine-treated mice. These long-lasting behavioral and neurochemical alterations suggest that the kynurenine pathway can link early-life infection with the development of neuropsychiatric disturbances in adulthood.     

Prevalence and trajectory of psychopathology among child and adolescent survivors of disasters: a systematic review of epidemiological studies across 1987–2011

Aims

The goal of this paper was to systematically review evidence on (1) the potential magnitude of the psychopathological impacts of community-wide disasters on child and adolescent survivors, and (2) the long-term course or trajectory of disaster-induced psychopathology among children and adolescents.

Methods

The PubMed/MEDLINE and PsycINFO databases were searched from their respective inception through December 2011. All of the resulting epidemiological studies of child and adolescent survivors following community-wide disasters were examined.

Results

Sixty cross-sectional studies and 25 longitudinal or long-term follow-up studies were identified. The estimated rates of posttraumatic stress disorder (PTSD) and depression among child and adolescent survivors varied greatly across the included studies, ranging from 1.0 to 95 % and 1.6 to 81 %, respectively, while the reported rates of diagnosable PTSD according to the DSM-IV criteria and diagnosable depression ranged from 1.0 to 60 % and 1.6 to 33 %, respectively. The long-term courses of psychopathology among youthful survivors were summarized. Methodological issues with those studies were discussed.

Conclusions

The empirical findings summarized in this review highlight the importance of psychosocial intervention at early postdisaster stages for child and adolescent survivors. The methodological flaws revealed by this review indicate the need for continued attempts to better understand the epidemiology and trajectory of psychopathological problems among youthful survivors.     

Comparative evaluation of Tissue factor and Thrombomodulin activity changes during normal and idiopathic early and late foetal loss: the cause of hypercoagulability?

Various components of the coagulation and fibrinolytic pathways are involved in normal embryonic implantation, trophoblast invasion, placentation, and recurrent miscarriages are characterized by defective placentation and microthrombi in the placental vasculature. Although recurrent miscarriage is a heterogeneous condition the relationship between abnormalities in the haemostatic pathways and pregnancy outcome is increasingly recognized. The challenge we face is how to discriminate between women who are destined to miscarry from those whose pregnancy will be successful. Considering the crucial role of thrombomodulin and tissue factor in coagulation and in embryonic development, we have performed a study using specific assays for thrombomodulin, tissue factor activity and procoagulant phospholipids in association with other parameters in 30 early (under 12 weeks) and 32 late (over 22 weeks) pregnancy loss women and compared them with 62 normal pregnancy women and 35 non-pregnant women. Plasma levels of tissue factor activity, thrombomodulin activity, and procoagulant phospholipids were significantly higher in patients than in control subjects. In addition the tissue factor activity/free tissue factor pathway inhibitor ratio was higher in patients than in controls. Interestingly, patients with late pregnancy loss had higher tissue factor activity/free tissue factor pathway inhibitor ratios than patients with early pregnancy loss. The combinations of these different parameters reveal an increase in procoagulant activity which could be secondary to endothelial damage or coagulation activation and then are involved in the pathogenesis of pregnancy loss. Their simultaneous measurement of these activities might provide a new tool to assess the prognosis of pregnancy loss.     

Neuroprotective and neurodegenerative effects of the chronic expression of tumor necrosis factor α in the nigrostriatal dopaminergic circuit of adult mice

Tumor necrosis factor (TNF)-α, a pro-inflammatory cytokine, has been implicated in both neuronal death and survival in Parkinson's disease (PD). The substantia nigra (SN), a CNS region affected in PD, is particularly susceptible to inflammatory insults and possesses the highest density of microglial cells, but the effects of inflammation and in particular TNF-α on neuronal survival in this region remains controversial. Using adenoviral vectors, the CRE/loxP system and hypomorphic mice, we achieved chronic expression of two levels of TNF-α in the SN of adult mice. Chronic low expression of TNF-α levels reduced the nigrostriatal neurodegeneration mediated by intrastriatal 6-hydroxydopamine administration. Protective effects of low TNF-α level could be mediated by TNF-R1, GDNF, and IGF-1 in the SN and SOD activity in the striatum (ST). On the contrary, chronic expression of high levels of TNF-α induced progressive neuronal loss (63% at 20 days and 75% at 100 days). This effect was accompanied by gliosis and an inflammatory infiltrate composed almost exclusively by monocytes/macrophages. The finding that chronic high TNF-α had a slow and progressive neurodegenerative effect in the SN provides an animal model of PD mediated by the chronic expression of a single cytokine. In addition, it supports the view that cytokines are not detrimental or beneficial by themselves, i.e., their level and time of expression among other factors can determine its final effect on CNS damage or protection. These data support the view that new anti-parkinsonian treatments based on anti-inflammatory therapies should consider these dual effects of cytokines on their design.     

Physical recovery in anorexia nervosa: is this the sole purpose of a child and adolescent medical-psychiatric unit?

Patients with anorexia nervosa are discharged from inpatient medical psychiatric wards on achievement of their target weight ("physical recovery") or even earlier. However, recent studies have consistently revealed that a very high percentage relapse, usually within a year. We hypothesized that the more rapid pace of physical compared with psychological recovery in anorexia nervosa creates a gap or interim stage when inpatients are particularly vulnerable. This phase has its own identifiable characteristics and prognostic value. To counter this problem, we formulated a treatment model where patients in the "physical recovery" stage participate in a follow-up program within the inpatient unit itself concomitant with individual psychotherapy at the outpatient community service. The program helps to preserve the strong therapeutic alliance established during hospitalization and to maintain the patient's base of security against the loss of the "anorectic solution." The program provides a full range of services--inpatient, day-treatment and follow-up, adapting itself to the changing needs of the patient. It has been in effect in our unit for three years, and the rate of relapse has decreased dramatically. Further controlled studies are needed to confirm these findings.     

Expression pattern of the cannabinoid receptor genes in the frontal cortex of mood disorder patients and mice selectively bred for high and low fear

Although the endocannabinoid system (ECS) has been implicated in brain development and various psychiatric disorders, precise mechanisms of the ECS on mood and anxiety disorders remain unclear. Here, we have investigated developmental and disease-related expression pattern of the cannabinoid receptor 1 (CB1) and the cannabinoid receptor 2 (CB2) genes in the dorsolateral prefrontal cortex (PFC) of humans. Using mice selectively bred for high and low fear, we further investigated potential association between fear memory and the cannabinoid receptor expression in the brain. The CB1, not the CB2, mRNA levels in the PFC gradually decrease during postnatal development ranging in age from birth to 50 years (r2 > 0.6 & adj. p < 0.05). The CB1 levels in the PFC of major depression patients were higher when compared to the age-matched controls (adj. p < 0.05). In mice, the CB1, not the CB2, levels in the PFC were positively correlated with freezing behavior in classical fear conditioning (p < 0.05). These results suggest that the CB1 in the PFC may play a significant role in regulating mood and anxiety symptoms. Our study demonstrates the advantage of utilizing data from postmortem brain tissue and a mouse model of fear to enhance our understanding of the role of the cannabinoid receptors in mood and anxiety disorders.     

Treatment of adult patients with schizophrenia and complex mental health needs – A national clinical guideline

Background and aim: The Danish Health and Medicines Authority assembled a group of experts to develop a national clinical guideline for patients with schizophrenia and complex mental health needs. Within this context, ten explicit review questions were formulated, covering several identified key issues. Methods: Systematic literature searches were performed stepwise for each review question to identify relevant guidelines, systematic reviews/meta-analyses, and randomized controlled trials. The quality of the body of evidence for each review question was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Clinical recommendations were developed on the basis of the evidence, assessment of the risk-benefit ratio, and perceived patient preferences. Results: Based on the identified evidence, a guideline development group (GDG) recommended that the following interventions should be offered routinely: antipsychotic maintenance therapy, family intervention and assertive community treatment. The following interventions should be considered: long-acting injectable antipsychotics, neurocognitive training, social cognitive training, cognitive behavioural therapy for persistent positive and/or negative symptoms, and the combination of cognitive behavioural therapy and motivational interviewing for cannabis and/or central stimulant abuse. SSRI or SNRI add-on treatment for persistent negative symptoms should be used only cautiously. Where no evidence was available, the GDG agreed on a good practice recommendation. Conclusions: The implementation of this guideline in daily clinical practice can facilitate good treatment outcomes within the population of patients with schizophrenia and complex mental health needs. The guideline does not cover all available interventions and should be used in conjunction with other relevant guidelines.     

Neutralization of interleukin-1β reduces cerebral edema and tissue loss and improves late cognitive outcome following traumatic brain injury in mice

Increasing evidence suggests that interleukin-1β (IL-1β) is a key mediator of the inflammatory response following traumatic brain injury (TBI). Recently, we showed that intracerebroventricular administration of an IL-1β-neutralizing antibody was neuroprotective following TBI in mice. In the present study, an anti-IL-1β antibody or control antibody was administered intraperitoneally following controlled cortical injury (CCI) TBI or sham injury in 105 mice and we extended our histological, immunological and behavioral analysis. First, we demonstrated that the treatment antibody reached target brain regions of brain-injured animals in high concentrations (> 11 nm) remaining up to 8 days post-TBI. At 48 h post-injury, the anti-IL-1β treatment attenuated the TBI-induced hemispheric edema (P < 0.05) but not the memory deficits evaluated using the Morris water maze (MWM). Neutralization of IL-1β did not influence the TBI-induced increases (P < 0.05) in the gene expression of the Ccl3 and Ccr2 chemokines, IL-6 or Gfap. Up to 20 days post-injury, neutralization of IL-1β was associated with improved visuospatial learning in the MWM, reduced loss of hemispheric tissue and attenuation of the microglial activation caused by TBI (P < 0.05). Motor function using the rotarod and cylinder tests was not affected by the anti-IL-1β treatment. Our results suggest an important negative role for IL-1β in TBI. The improved histological and behavioral outcome following anti-IL-1β treatment also implies that further exploration of IL-1β-neutralizing compounds as a treatment option for TBI patients is warranted.     

Delayed treatment of 6-Bromoindirubin-3′-oxime stimulates neurogenesis and functional recovery after focal ischemic stroke in mice

Glycogen synthase kinase 3β (GSK3β) was originally identified as a regulator for glycogen metabolism and is now an important therapeutic target for a variety of brain disorders including neurodegenerative diseases due to it's pivotal role in cellular metabolism, proliferation and differentiation. In the development of stroke therapies focusing on tissue repair and functional recovery, promoting neurogenesis is a main approach in regenerative medicine. In the present investigation, we explored the effects of a GSK3β specific inhibitor, 6-Bromoindirubin-3′-oxime (BIO), on regenerative activities of neuroblasts in the subventricular zone (SVZ) and functional recovery after focal cerebral ischemia. Adult C57/BL mice were subjected to occlusion of distal branches of middle cerebral artery (MCA) supplying the sensorimotor barrel cortex. Three days later, BIO (8.5 μg/kg, i.p.) was administered every 2 days until sacrificed at 14 or 21 days after stroke. The BIO treatment significantly increased generation of neuroblasts labeled with BrdU and BrdU/doublecortin (DCX) in the SVZ. Comparing to vehicle controls, increased number of neuroblasts migrated to the peri-infarct region where they differentiate into mature neurons. Along with the elevated BDNF expression at the peri-infarct area, the number of newly formed neurons was significantly increased. BIO treatment significantly enhanced sensorimotor functional recovery after the focal ischemia. It is suggested that the GSK3 signaling may be a potential therapeutic target for regenerative treatment after ischemic stroke.