The Role of the N-Methyl-D-Aspartate Receptors in Social Behavior in Rodents

The appropriate display of social behaviors is essential for the well-being, reproductive success and survival of an individual. Deficits in social behavior are associated with impaired N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission. In this review, we describe recent studies using genetically modified mice and pharmacological approaches which link the impaired functioning of the NMDA receptors, especially of the receptor subunits GluN1, GluN2A and GluN2B, to abnormal social behavior. This abnormal social behavior is expressed as impaired social interaction and communication, deficits in social memory, deficits in sexual and maternal behavior, as well as abnormal or heightened aggression. We also describe the positive effects of pharmacological stimulation of the NMDA receptors on these social deficits. Indeed, pharmacological stimulation of the glycine-binding site either by direct stimulation or by elevating the synaptic glycine levels represents a promising strategy for the normalization of genetically-induced, pharmacologically-induced or innate deficits in social behavior. We emphasize on the importance of future studies investigating the role of subunit-selective NMDA receptor ligands on different types of social behavior to provide a better understanding of the underlying mechanisms, which might support the development of selective tools for the optimized treatment of disorders associated with social deficits

Sphingomyelin Synthases in Neuropsychiatric Health and Disease

Sphingomyelin synthases (SMS) catalyze the conversion of ceramide and phosphatidylcholine to sphingomyelin and diacylglycerol and are thus crucial for the balance between synthesis and degradation of these structural and bioactive molecules. SMS thereby play an essential role in sphingolipid metabolism, cell signaling, proliferation and differentiation processes. Although tremendous progress has been made toward understanding the involvement of SMS in physiological and pathological processes, literature in the area of neuropsychiatry is still limited. In this review, we summarize the main features of SMS as well as the current methodologies and tools used for their study and provide an overview of SMS in the central nervous system and their implications in neurological as well as psychiatric disorders. This way, we aim at establishing a basis for future mechanistic as well as clinical investigations on SMS in neuropsychiatric health and diseases

Gustav Nikolaus Specht (1860–1940) : Sein Einfluss auf die Nosologie Kraepelins und Annäherungen an seine Position im Nationalsozialismus

Hinführung Gustav Specht steht am Anfang der Erlanger Universitätspsychiatrie. 80 Jahre nach seinem Tod untersucht der vorliegende Artikel insbesondere die Rolle Spechts bei der von Kraepelin ausgehenden psychopathologisch-nosologischen Diskussion. Trotz spärlicher Datenlage unternehmen die Autoren erstmals eine Annäherung an Spechts Positionen innerhalb der nationalsozialistischen Psychiatrie. Methode Relevantes archivalisches Material sowie Primär- und Sekundärliteratur wurden ausgewertet. Ergebnisse Specht wurde 1897 zum außerplanmäßigen Professor und 1903 zum ersten Ordinarius für Psychiatrie in Erlangen ernannt. Specht arbeitete die Bedeutung des manischen Elementes in der Paranoia heraus. Specht ergänzte den sog. „exogenen Reaktionstypus“ Bonhoeffers 1913 um die depressiven Zustandsbilder; er selbst war – bei fremddiagnostischem Verdacht auf zyklothymes Temperament – zweimalig exogen reaktiv depressiv erkrankt. Diskussion Durch seine Forschungsarbeiten zum pathologischen Affekt in der chronischen Paranoia beeinflusste Specht die zeitgenössische psychopathologische Diskussion nachhaltig. Spechts Perspektivenwechsel in puncto „Erbgesundheit“ lässt sich interpretieren als Anpassung an das NS-Regime. Schlussfolgerung Das Werk Gustav Spechts kann u. a. dazu anregen, einen interdisziplinären psychopathologischen Diskurs zu kultivieren

Cerebrospinal Fluid Tau, p-Tau 181 and Amyloid-beta(38/40/42) in Frontotemporal Dementias and Primary Progressive Aphasias

Background/Aims: We determined cerebrospinal fluid (CSF) concentrations of amyloid-beta(A beta)(1-38), A beta(1-40), A beta(1-42), total tau and phospho-tau (p-tau) in order to study their differential expression in frontotemporal dementia (FTD, n = 25) and primary progressive aphasia (PPA, n = 12) as compared to Alzheimer's dementia (AD, n = 25) and nondemented controls (n = 20). Methods: Commercially available ELISA and electrochemiluminescence methods were applied. Results: High CSF p-tau and low ratios of A beta(1-42)/A beta(1-40) and A beta(1-42)/A beta(1-38), respectively, were specific for AD. CSF A beta(1-38) was reduced in FTD as compared to each of the other diagnostic groups, including PPA. CSF tau and p-tau levels were elevated in PPA as compared to FTD. Conclusion: This is the first detailed report on biomarker patterns in PPA, indicating distinct CSF biomarker patterns in FTD and PPA as major subgroups of frontotemporal lobar degeneration. The diagnostic and pathophysiological implications of our results warrant further studies on larger and neuropathologically diagnosed patient populations. Copyright (C) 2010 S. Karger AG, Base

Development of Comorbid Depression after Social Fear Conditioning in Mice and Its Effects on Brain Sphingolipid Metabolism

Currently, there are no animal models for studying both specific social fear and social fear with comorbidities. Here, we investigated whether social fear conditioning (SFC), an animal model with face, predictive and construct validity for social anxiety disorder (SAD), leads to the development of comorbidities at a later stage over the course of the disease and how this affects the brain sphingolipid metabolism. SFC altered both the emotional behavior and the brain sphingolipid metabolism in a time-point-dependent manner. While social fear was not accompanied by changes in non-social anxiety-like and depressive-like behavior for at least two to three weeks, a comorbid depressive-like behavior developed five weeks after SFC. These different pathologies were accompanied by different alterations in the brain sphingolipid metabolism. Specific social fear was accompanied by increased activity of ceramidases in the ventral hippocampus and ventral mesencephalon and by small changes in sphingolipid levels in the dorsal hippocampus. Social fear with comorbid depression, however, altered the activity of sphingomyelinases and ceramidases as well as the sphingolipid levels and sphingolipid ratios in most of the investigated brain regions. This suggests that changes in the brain sphingolipid metabolism might be related to the short- and long-term pathophysiology of SAD

Basic Human Body Dimensions Relate to Alcohol Dependence and Predict Hospital Readmission

Alcohol dependence is a severe mental illness and there is a need for more effective preventive and therapeutic strategies. Translational research suggests that intrauterine sex hormone exposure modulates the risk and course of alcohol dependence during adulthood. During development, sex hormones permanently shape sexually dimorphic body dimensions. Thus, these dimensions may provide insight into sex hormone organization. Here, we compared body measurements (absolute, relative to, and residualized on height) between 200 alcohol-dependent in-patients and 240 age-matched healthy control subjects and investigated how these measurements associate with the patients’ prospective 12- and 24-month outcome. The results show that alcohol dependence is related to lower absolute, relative, and residualized body measurements for height and weight, head circumference, bitragion head arc, lip-chin distance, hip, thigh, and calf circumference, and foot length and breadth. In male alcohol-dependent in-patients, higher risk, shorter latency, and more alcohol-related readmissions were predicted by higher absolute, relative, and residualized thigh and calf circumferences. The second-to-fourth finger length ratio, a putative proxy for prenatal sex hormone organization, was not convincingly correlated with the body dimensions, suggesting that the results represent pubertal (or later) effects. The study’s findings have implications for further research. The body measurements’ high accessibility may facilitate the future transition into clinical settings

Cerebrospinal fluid Aβ42/40 corresponds better than Aβ42 to amyloid PET in Alzheimer’s disease

Background: Decreased concentrations of amyloid-β 1-42 (Aβ(42)) in cerebrospinal fluid (CSF) and increased retention of Aβ tracers in the brain on positron emission tomography (PET) are considered the earliest biomarkers of Alzheimer’s disease (AD). However, a proportion of cases show discrepancies between the results of the two biomarker modalities which may reflect inter-individual differences in Aβ metabolism. The CSF Aβ(42/40) ratio seems to be a more accurate biomarker of clinical AD than CSF Aβ(42) alone. Objective: We tested whether CSF Aβ(42) alone or the Aβ(42/40) ratio corresponds better with amyloid PET status and analyzed the distribution of cases with discordant CSF-PET results. Methods: CSF obtained from a mixed cohort (n = 200) of cognitively normal and abnormal research participants who had undergone amyloid PET within 12 months (n = 150 PET-negative, n = 50 PET-positive according to a previously published cut-off) was assayed for Aβ(42) and Aβ(40) using two recently developed immunoassays. Optimal CSF cut-offs for amyloid positivity were calculated, and concordance was tested by comparison of the areas under receiver operating characteristic (ROC) curves (AUC) and McNemar’s test for paired proportions. Results: CSF Aβ(42/40) corresponded better than Aβ(42) with PET results, with a larger proportion of concordant cases (89.4% versus 74.9%, respectively, p < 0.0001) and a larger AUC (0.936 versus 0.814, respectively, p < 0.0001) associated with the ratio. For both CSF biomarkers, the percentage of CSF-abnormal/PET-normal cases was larger than that of CSF-normal/PET-abnormal cases. Conclusion: The CSF Aβ(42/40) ratio is superior to Aβ(42) alone as a marker of amyloid-positivity by PET. We hypothesize that this increase in performance reflects the ratio compensating for general between-individual variations in CSF total Aβ

The Erlangen Test of Activities of Daily Living: first results on reliability and validity of a short performance test to measure fundamental activities of daily living in dementia patients

Background: In the absence of an easily applicable performance test for making valid measurements of fundamental activities of daily living (ADL) in dementia patients, this study reports the development of an ADL performance test which constitutes both a reliable and a valid measurement of the relevant autonomous areas of everyday activities for dementia patients. Methods: The Erlangen Test of Activities of Daily Living (E-ADL-Test) consists of five items: pouring a drink, cutting a piece of bread, opening a small cupboard, washing hands and tying a bow. Each test item underwent standardized evaluation on a scale of 0 to 6. To determine retest reliability each assessment was repeated at two-weekly intervals. The Global Deterioration Scale, Mini-mental State Examination (MMSE) and Nurses' Observations Scale for Geriatric Patients (NOSGER) were used to assess construct validity. Spearman's rank correlation coefficient was applied. Forty-six patients (42 women and 4 men) with clinically diagnosed dementia, who were resident in nursing homes, took part in the validation study. Their average age was 86. Results: The E-ADL-Test revealed good inter-individual differentiation ability, particularly in cases of moderate to severe dementia. Cronbach's α was 0.77, retest reliability 0.73. The correlation coefficients were −0.47 with GDS, 0.60 with NOSGER and 0.72 with MMSE. Conclusions: The E-ADL-Test is a suitable performance test for measuring activities of daily living as it is easy to use, reliable, valid and well accepte

Neuroanatomical Correlates of Intelligence in Healthy Young Adults: The Role of Basal Ganglia Volume

Background: In neuropsychiatric diseases with basal ganglia involvement, higher cognitive functions are often impaired. In this exploratory study, we examined healthy young adults to gain detailed insight into the relationship between basal ganglia volume and cognitive abilities under non-pathological conditions. Methodology/Principal Findings: We investigated 137 healthy adults that were between the ages of 21 and 35 years with similar educational backgrounds. Magnetic resonance imaging (MRI) was performed, and volumes of basal ganglia nuclei in both hemispheres were calculated using FreeSurfer software. The cognitive assessment consisted of verbal, numeric and figural aspects of intelligence for either the fluid or the crystallised intelligence factor using the intelligence test Intelligenz-Struktur- Test (I-S-T 2000 R). Our data revealed significant correlations of the caudate nucleus and pallidum volumes with figural and numeric aspects of intelligence, but not with verbal intelligence. Interestingly, figural intelligence associations were dependent on sex and intelligence factor;in females, the pallidum volumes were correlated with crystallised figural intelligence (r=0.372, p=0.01),whereas in males, the caudate volumes were correlated with fluid figural intelligence (r=0.507, p=0.01). Numeric intelligence was correlated with right-lateralised caudate nucleus volumes for both females and males, but only for crystallised intelligence (r=0.306, p=0.04 and r=0.459, p=0.04, respectively). The associations were not mediated by prefrontal cortical subfield volumes when controlling with partial correlation analyses. Conclusions/Significance: The findings of our exploratory analysis indicate that figural and numeric intelligence aspects, but not verbal aspects, are strongly associated with basal ganglia volumes. Unlike numeric intelligence, the type of figural intelligence appears to be related to distinct basal ganglia nuclei in a sex-specific manner. Subcortical brain structures thus may contribute substantially to cognitive performance