Showing papers by "Michael Wagner published in 2012"

Glucose metabolism, gray matter structure, and memory decline in subjective memory impairment

Abstract: Objective: To identify biological evidence for Alzheimer disease (AD) in individuals with subjective memory impairment (SMI) and unimpaired cognitive performance and to investigate the longitudinal cognitive course in these subjects. Method: [ 18 F]fluoro-2-deoxyglucose PET (FDG-PET) and structural MRI were acquired in 31 subjects with SMI and 56 controls. Cognitive follow-up testing was performed (average follow-up time: 35 months). Differences in baseline brain imaging data and in memory decline were assessed between both groups. Associations of memory decline with brain imaging data were tested. Results: The SMI group showed hypometabolism in the right precuneus and hypermetabolism in the right medial temporal lobe. Gray matter volume was reduced in the right hippocampus in the SMI group. At follow-up, subjects with SMI showed a poorer performance than controls on measures of episodic memory. Longitudinal memory decline in the SMI group was associated with reduced glucose metabolism in the right precuneus at baseline. Conclusion: The cross-sectional difference in 2 independent neuroimaging modalities indicates early AD pathology in SMI. The poorer memory performance at follow-up and the association of reduced longitudinal memory performance with hypometabolism in the precuneus at baseline support the concept of SMI as the earliest manifestation of AD.

Preventing progression to first-episode psychosis in early initial prodromal states

Abstract: Background Young people with self-experienced cognitive thought and perception deficits (basic symptoms) may present with an early initial prodromal state (EIPS) of psychosis in which most of the disability and neurobiological deficits of schizophrenia have not yet occurred. Aims To investigate the effects of an integrated psychological intervention (IPI), combining individual cognitive–behavioural therapy, group skills training, cognitive remediation and multifamily psychoeducation, on the prevention of psychosis in the EIPS. Method A randomised controlled, multicentre, parallel group trial of 12 months of IPI v. supportive counselling (trial registration number: [NCT00204087][1]). Primary outcome was progression to psychosis at 12- and 24-month follow-up. Results A total of 128 help-seeking out-patients in an EIPS were randomised. Integrated psychological intervention was superior to supportive counselling in preventing progression to psychosis at 12-month follow-up (3.2% v . 16.9%; P = 0.008) and at 24-month follow-up (6.3% v . 20.0%; P = 0.019). Conclusions Integrated psychological intervention appears effective in delaying the onset of psychosis over a 24-month time period in people in an EIPS. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00204087&atom=%2Fbjprcpsych%2F200%2F1%2F22.atom

Biomarker validation of a cued recall memory deficit in prodromal Alzheimer disease

Abstract: Objective: To compare cued recall measures with other memory and nonmemory tests regarding their association with a biomarker profile indicative of Alzheimer disease (AD) in CSF among patients with mild cognitive impairment (MCI) Methods: Data were obtained by the German Dementia Competence Network A total of 185 memory clinic patients fulfilling broad criteria for MCI (1 SD deficit in memory tests or in nonmemory tests) were assessed with an extended neuropsychological battery, which included the Free and Cued Selective Reminding Test (FCSRT), the word list learning task from the Consortium to Establish a Registry for Alzheimer9s Disease neuropsychological battery (CERAD-NP), and the Logical Memory (LM) paragraph recall test from the Wechsler Memory Scale–Revised CSF was obtained from all patients Results: A total of 74 out of 185 subjects with MCI (40%) had a CSF profile consistent with AD (Aβ 1-42 /tau ratio; CSF AD+ group) FCSRT measures reflecting both free and cued recall discriminated best between CSF AD+ and CSF AD− patients, and significantly improved CSF AD classification accuracy, as compared with CERAD delayed recall and LM delayed recall Conclusions: Cued recall deficits are most closely associated with CSF biomarkers indicative of AD in subjects with MCI This novel finding complements results from prospective clinical studies and provides further empirical support for cued recall as a specific indicator of prodromal AD, in line with recently proposed research criteria

Thermo-Induced Self-Assembly of Responsive Poly(DMAEMA‑b‑DEGMA) Block Copolymers into Multi- and Unilamellar Vesicles

Abstract: A series of thermoresponsive diblock copolymers of poly[2-(dimethylamino)ethyl methacrylate-block-di(ethyleneglycol) methyl ether methacrylate], poly(DMAEMA-b-DEGMA), were synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerizations. The series consist of diblock and quasi diblock copolymers. Sequential monomer addition was used for the quasi diblock copolymer synthesis and the macro-chain transfer approach was utilized for the block copolymer synthesis. The focus of this contribution is the controlled variation of the ratios of DMAEMA to DEGMA in the copolymer composition, resulting in a systematic polymer library. One of the investigated block copolymer systems showed double lower critical solution temperature (LCST) behavior in water and was further investigated. The phase transitions of this block copolymer were studied in aqueous solutions by turbidimetry, dynamic light scattering (DLS), variable temperature proton nuclear magnetic resonance (1H NMR) spectroscopy, zeta poten...

Glucose metabolism, gray matter structure and memory decline in subjective memory impairment

Abstract: OBJECTIVE To identify biological evidence for Alzheimer disease (AD) in individuals with subjective memory impairment (SMI) and unimpaired cognitive performance and to investigate the longitudinal cognitive course in these subjects. METHOD [¹⁸F]fluoro-2-deoxyglucose PET (FDG-PET) and structural MRI were acquired in 31 subjects with SMI and 56 controls. Cognitive follow-up testing was performed (average follow-up time: 35 months). Differences in baseline brain imaging data and in memory decline were assessed between both groups. Associations of memory decline with brain imaging data were tested. RESULTS The SMI group showed hypometabolism in the right precuneus and hypermetabolism in the right medial temporal lobe. Gray matter volume was reduced in the right hippocampus in the SMI group. At follow-up, subjects with SMI showed a poorer performance than controls on measures of episodic memory. Longitudinal memory decline in the SMI group was associated with reduced glucose metabolism in the right precuneus at baseline. CONCLUSION The cross-sectional difference in 2 independent neuroimaging modalities indicates early AD pathology in SMI. The poorer memory performance at follow-up and the association of reduced longitudinal memory performance with hypometabolism in the precuneus at baseline support the concept of SMI as the earliest manifestation of AD.

Light exposure and cell viability in fluorescence microscopy.

Abstract: Test systems for measuring cell viability in optical microscopy (based on colony formation ability or lysosomal integrity) were established and applied to native cells as well as to cells incubated with fluorescence markers or transfected with genes encoding for fluorescent proteins. Human glioblastoma and Chinese hamster ovary cells were irradiated by various light doses, and maximum doses where at least 90% of the cells survived were determined. These tolerable light doses were in the range between 25 J cm⁻² and about 300 J cm⁻² for native cells (corresponding to about 250-3000 s of solar irradiance and depending on the wavelength as well as on the mode of illumination, e.g. epi- or total internal reflection illumination) and decreased to values between 50 J cm⁻² and less than 1 J cm⁻² upon application of fluorescent markers, fluorescent proteins or photosensitizers. In high-resolution wide field or laser scanning microscopy of single cells, typically 10-20 individual cell layers needed for reconstruction of a 3D image could be recorded with tolerable dose values. Tolerable light doses were also maintained in fluorescence microscopy of larger 3D samples, e.g. cell spheroids exposed to structured illumination, but may be exceeded in super-resolution microscopy based on single molecule detection.

An fMRI study on the acute effects of exercise on pain processing in trained athletes.

Abstract: Endurance exercise is known to promote sustained antinociceptive effects, and there is evidence that the reduction of pain perception mediated by exercise is driven by central opioidergic neurotransmission. To directly investigate the involved brain areas and the underlying neural mechanisms in humans, thermal heat-pain challenges were applied to 20 athletes during 4 separate functional magnetic resonance imaging (fMRI) scans, i.e., before and after 2 hours of running (exercise condition) and walking (control condition), respectively. Imaging revealed a reproducible pattern of distributed pain-related activation in all 4 conditions, including the mesial and lateral pain systems, and the periaqueductal gray (PAG) as a key region of the descending antinociceptive pathway. At the behavioral level, running as compared with walking decreased affective pain ratings. The influence of exercise on pain-related activation was reflected in a significant time × treatment interaction in the PAG, along with similar trends in the pregenual anterior cingulate cortex and the middle insular cortex, where pain-induced activation levels were elevated after walking, but decreased or unchanged after running. Our findings indicate that enhanced reactive recruitment of endogenous antinociceptive mechanisms after aversive repeated pain exposure is attenuated by exercise. The fact that running, but not walking, reproducibly elevated β-endorphin levels in plasma indicates involvement of the opioidergic system in exercise. This may argue for an elevated opioidergic tone in the brain of athletes, mediating antinociceptive mechanisms. Our findings provide the first evidence using functional imaging to support the role of endurance exercise in pain modulation.

Neurophysiological Correlates of Impaired Facial Affect Recognition in Individuals at Risk for Schizophrenia

Abstract: Background: Impairments in facial affect recognition are well documented in individuals suffering from schizophrenia. The aim of the present study was to characterize potential impairments in affect recognition and their electrophysiological correlates in at-risk individuals. Such characterization should add to the question whether the neural processes underlying facial affect recognition deficits might be part of a basic neural dysfunction reflecting a vulnerability factor of schizophrenia. Methods: To test facial affect recognition, a digitized series of pictures of facial affect, previously used in related studies, was presented to 37 at-risk individuals and 32 healthy controls. Simultaneously, event-related potentials (ERPs) were recorded to investigate electrophysiological activity during the task. Results: At-risk individuals showed significant impairments in facial affect recognition and reduced amplitudes in the ERP components P100, N170, and N250. Furthermore, prodromal signs in these individuals were associated with a poorer task performance and a diminished N250 amplitude. Conclusions: The findings suggest that impairments in facial affect recognition precede the onset of the initial psychotic episode. The impairments are associated with neurophysiological abnormalities similar to those observed in manifest schizophrenia and therefore may serve as indicators of vulnerability for developing schizophrenia.

Assessing cognitive changes in the elderly: Reliable Change Indices for the Mini‐Mental State Examination

Abstract: Stein J, Luppa M, Maier W, Wagner M, Wolfsgruber S, Scherer M, Kohler M, Eisele M, Weyerer S, Werle J, Bickel H, Mosch E, Wiese B, Prokein J, Pentzek M, Fuchs A, Leicht H, Konig H-H, Riedel-Heller SG for the AgeCoDe Study Group. Assessing cognitive changes in the elderly: Reliable Change Indices for the Mini-Mental State Examination. Objective: The diagnosis of dementia includes evidence of decline in cognitive functioning over time measured by objective cognitive tasks. Normative data for changes adjusted for the impact of socio-demographic factors on cognitive test performance are lacking to interpret changes in Mini-Mental State Examination (MMSE) test scores. Method: As part of the German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe Study), a sample of 1090 cognitively healthy individuals, aged 75 years and older, was assessed at 1.5-year intervals over a period of 4.5 years using the MMSE. Age- and education-specific Reliable Change Indices (RCIs) were computed. Results: Age and education were significantly associated with MMSE test performance, and gender indicated no impact. Across different age and education subgroups, changes from at least 2 up to 3 points indicated significant (i.e., reliable) changes in MMSE test scores at the 90% confidence level. Furthermore, the calculation of RCIs for individual patients is demonstrated. Conclusion: This study provides age- and education-specific MMSE norms based upon RCI methods to interpret cognitive changes in older age groups. The computation of RCI scores improves the interpretation of changes in MMSE test scores by controlling for measurement error, practice effects, or regression to the mean.

Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13.

Abstract: Objective In a genome-wide association study of Caucasian patients with juvenile idiopathic arthritis (JIA), we have previously described findings limited to autoimmunity loci shared by JIA and other diseases. The present study was undertaken to identify novel JIA-predisposing loci using genome-wide approaches. Methods The discovery cohort consisted of Caucasian JIA cases (n = 814) and local controls (n = 658) genotyped on the Affymetrix Genome-Wide SNP 6.0 Array, along with 2,400 out-of-study controls. In a replication study, we genotyped 10 single-nucleotide polymorphisms (SNPs) in 1,744 cases and 7,010 controls from the US and Europe. Results Analysis within the discovery cohort provided evidence of associations at 3q13 within C3orf1 and near CD80 (rs4688011) (odds ratio [OR] 1.37, P = 1.88 × 10−6) and at 10q21 near JMJD1C (rs647989 [OR 1.59, P = 6.1 × 10−8], rs12411988 [OR 1.57, P = 1.16 × 10−7], and rs10995450 [OR 1.31, P = 6.74 × 10−5]). Meta-analysis provided further evidence of association for these 4 SNPs (P = 3.6 × 10−7 for rs4688011, P = 4.33 × 10−5 for rs6479891, P = 2.71 × 10−5 for rs12411988, and P = 5.39 × 10−5 for rs10995450). Gene expression data on 68 JIA cases and 23 local controls showed cis expression quantitative trait locus associations for C3orf1 SNP rs4688011 (P = 0.024 or P = 0.034, depending on the probe set) and JMJD1C SNPs rs6479891 and rs12411988 (P = 0.01 or P = 0.04, depending on the probe set and P = 0.008, respectively). Using a variance component liability model, it was estimated that common SNP variation accounts for approximately one-third of JIA susceptibility. Conclusion Genetic association results and correlated gene expression findings provide evidence of JIA association at 3q13 and suggest novel genes as plausible candidates in disease pathology.

Schizophrenia risk polymorphisms in the TCF4 gene interact with smoking in the modulation of auditory sensory gating

Abstract: Several polymorphisms of the transcription factor 4 (TCF4) have been shown to increase the risk for schizophrenia, particularly TCF4 rs9960767. This polymorphism is associated with impaired sensorimotor gating measured by prepulse inhibition--an established endophenotype of schizophrenia. We therefore investigated whether TCF4 polymorphisms also affect another proposed endophenotype of schizophrenia, namely sensory gating assessed by P50 suppression of the auditory evoked potential. Although sensorimotor gating and sensory gating are not identical, recent data suggest that they share genetic fundamentals. In a multicenter study at six academic institutions throughout Germany, we applied an auditory P50 suppression paradigm to 1,821 subjects (1,023 never-smokers, 798 smokers) randomly selected from the general population. Samples were genotyped for 21 TCF4 polymorphisms. Given that smoking is highly prevalent in schizophrenia and affects sensory gating, we also assessed smoking behavior, cotinine plasma concentrations, exhaled carbon monoxide, and the Fagerstrom Test (FTND). P50 suppression was significantly decreased in carriers of schizophrenia risk alleles of the TCF4 polymorphisms rs9960767, rs10401120rs, rs17597926, and 17512836 (P < 0.0002-0.00005). These gene effects were modulated by smoking behavior as indicated by significant interactions of TCF4 genotype and smoking status; heavy smokers (FTND score ≥ 4) showed stronger gene effects on P50 suppression than light smokers and never-smokers. Our finding suggests that sensory gating is modulated by an interaction of TCF4 genotype with smoking, and both factors may play a role in early information processing deficits also in schizophrenia. Consequently, considering smoking behavior may facilitate the search for genetic risk factors for schizophrenia.

Moving after Separation: The Role of Location-specific Capital

Abstract: This paper addresses the role of location-specific capital—the ties that bind people to a place—in which ex-partners of two-sex couples move after separation or divorce. The study uses data from the first and second waves of the Netherlands Kinship Panel Study (N = 361) to test hypotheses on the impact of individual homeownership, prior residential history, and the nearby presence of parents on whether a separated person moves. Who owned the home and whether someone's ex-partner moved in upon partnership formation are of prime importance to whether a separated person moves. Furthermore, separated persons whose parents live nearby and those who have a long history of living in the same municipality have a smaller probability of moving than other separated persons.

Antisaccade performance in patients with obsessive–compulsive disorder and unaffected relatives: further evidence for impaired response inhibition as a candidate endophenotype

Abstract: Cognitive dysfunctions such as inhibitory deficits and visuospatial abnormalities are often found in patients with obsessive–compulsive disorder (OCD). Recent findings in unaffected relatives indicate that response inhibition and other neuropsychological functions may also constitute endophenotypes of OCD. In the present study, 30 OCD patients, 30 first-degree relatives, and 30 healthy control subjects were assessed using a comprehensive neuropsychological test battery. A subsample of 21 subjects of each group also performed an antisaccade task. The samples were matched according to age, gender, education, and verbal intelligence. The OCD patients and the unaffected OCD relatives showed increased antisaccade error rates compared with the healthy control group (p = 0.003, p = 0.028, respectively). Significantly prolonged antisaccade latencies as compared to prosaccade latencies were only found in the OCD patients compared with the healthy control group (p = 0.019). Only OCD patients but not the unaffected OCD relatives were impaired with regard to visuospatial functions, problem-solving, and processing speed. Antisaccade errors did not correlate with severity of OCD or depressive symptoms. This study confirms inhibitory deficits, as indicated by increased antisaccade error rates, as a candidate endophenotype of OCD. In agreement with previous findings from imaging studies, our data suggest that functional abnormalities in frontostriatal and parietal cortical regions form part of the vulnerability for OCD.

A promoter variant of SHANK1 affects auditory working memory in schizophrenia patients and in subjects clinically at risk for psychosis

Abstract: Mutations in postsynaptic scaffolding genes contribute to autism, thus suggesting a role in pathological processes in neurodevelopment. Recently, two de novo mutations in SHANK3 were described in schizophrenia patients. In most cases, abnormal SHANK3 genotype was also accompanied by cognitive disruptions. The present study queries whether common SHANK variants may also contribute to neuropsychological dysfunctions in schizophrenia. We genotyped five common coding or promoter variants located in SHANK1, SHANK2 and SHANK3. A comprehensive test battery was used to assess neuropsychological functions in 199 schizophrenia patients and 206 healthy control subjects. In addition, an independent sample of 77 subjects at risk for psychosis was analyzed for replication of significant findings. We found the T allele of the SHANK1 promoter variant rs3810280 to lead to significantly impaired auditory working memory as assessed with digit span (12.5 ± 3.6 vs. 14.8 ± 4.1, P < .001) in schizophrenia cases, applying strict Bonferroni correction for multiple testing. This finding was replicated for forward digit span in the at-risk sample (7.1 ± 2.0 vs. 8.3 ± 2.0, P = .044). Previously, altered memory functions and reduced dendritic spines and postsynaptic density of excitatory synapses were reported in SHANK1 knock-out mice. Moreover, the atypical neuroleptic clozapine was found to increase SHANK1 density in rats. Our findings suggest a role of SHANK1 in working memory deficits in schizophrenia, which may arise from neurodevelopmental changes to prefrontal cortical areas.

The schizophrenia risk gene ZNF804A influences the antipsychotic response of positive schizophrenia symptoms

Abstract: Genetic factors determining the response to antipsychotic treatment in schizophrenia are poorly understood. A new schizophrenia susceptibility gene, the zinc-finger gene ZNF804A, has recently been identified. To assess the pharmacogenetic importance of this gene, we treated 144 schizophrenia patients and assessed the response of positive and negative symptoms by PANSS. Patients homozygous for the ZNF804A risk allele for schizophrenia (rs1344706 AA) showed poorer improvement of positive symptoms (7.35 ± 0.46) compared to patients with a protective allele (9.41 ± 0.71, P = 0.022). This provides further evidence that ZNF804A is of functional relevance to schizophrenia and indicates that ZNF804A may be a novel target for pharmacological interventions.

Nicotine differentially modulates antisaccade performance in healthy male non-smoking volunteers stratified for low and high accuracy

Abstract: Nicotinergic agents are currently examined as possible pro-cognitive drugs for a variety of clinical conditions marked by cognitive deficits, such as attention deficit hyperactivity disorder (ADHD) or schizophrenia. The response to acute nicotine is heterogeneous across subjects and samples; however, only a few reliable predictors of response have been identified. We tested the hypothesis that baseline performance level in cognitive control may be a predictor of the cognitive effects of nicotine. We tested 28 healthy Caucasian, male, non-smoking volunteers with the antisaccade task, an oculomotor measure of cognitive control. Participants were given a 7-mg nicotine patch in a double-blind, placebo-controlled, counterbalanced, within-subjects design. Subjects were stratified into high and low performers based on their antisaccade error rate in the placebo condition (median split). Nicotine tended to reduce response time variability of prosaccade latency (p = 0.06). There was no main effect of nicotine on antisaccade error rate (p = 0.31). However, nicotine significantly reduced antisaccade error rate in the low-accuracy probands while leaving performance of the high-accuracy probands unaffected (interaction, p < 0.05). Furthermore, we found a nicotine-induced reduction of response time variability of antisaccade latency at one target location in the low-performing group (interaction, p < 0.05). The present results demonstrate the importance of baseline performance differences for the effectiveness of pharmacological enhancement of cognitive control. More generally, the results suggest that stimulation of the nicotinic acetylcholine receptor system might be an effective way of improving cognition in people with poor cognitive performance, such as patients with ADHD or schizophrenia.

The assessment of changes in cognitive functioning: age-, education-, and gender-specific reliable change indices for older adults tested on the CERAD-NP battery: results of the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe).

Abstract: Objectives The Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological (CERAD-NP) battery represents a commonly used neuropsychological instrument to measure cognitive functioning in the elderly. This study provides normative data for changes in cognitive function that normally occur in cognitively healthy individuals to interpret changes in CERAD-NP test scores over longer time periods. Design Longitudinal cohort study with three assessments at 1.5-year intervals over a period of 3 years. Setting Primary care medical record registry sample. Participants As part of the German Study on Ageing, Cognition, and Dementia in Primary Care Patients, a sample of 1,450 cognitively healthy general practitioner patients, age 75 years and older, was assessed. Measurements Age-, education-, and gender-specific Reliable Change Indices (RCIs) were computed for a 90% confidence interval for selected subtests of the CERAD-NP battery. Results Across different age, education, and gender subgroups, changes from at least six to nine points in Verbal Fluency, four to eight points in Word List Memory, two to four points in Word List Recall, and one to four points in Word List Recognition indicated significant (i.e. reliable) changes in CERAD-NP test scores at the 90% confidence level. Furthermore, the calculation of RCIs for individual patients is demonstrated. Conclusions Smaller changes in CERAD-NP test scores can be interpreted with only high uncertainty because of probable measurement error, practice effects, and normal age-related cognitive decline. This study, for the first time, provides age-, education-, and gender-specific CERAD-NP reference values on the basis of RCI methods for the interpretation of cognitive changes in older-age groups.

Motivational Reserve: Motivation-Related Occupational Abilities and Risk of Mild Cognitive Impairment and Alzheimer Disease

Abstract: Midlife motivational abilities, that is, skills to initiate and persevere in the implementation of goals, have been related to mental and physical health, but their association with risk of mild cognitive impairment (MCI) and Alzheimer's disease (AD) has not yet been directly investigated. This relation was examined with data from the German Study on Ageing, Cognition, and Dementia in Primary Care Patients (AgeCoDe). A total of 3,327 nondemented participants (50.3% of a randomly selected sample) aged 75-89 years were recruited in primary care and followed up twice (after 1.5 and 3 years). Motivation-related occupational abilities were estimated on the basis of the main occupation (assessed at follow-up II) using the Occupational Information Network (O* NET) database, which provides detailed information on worker characteristics and abilities. Cox proportional hazards models were used to evaluate the relative risk of developing MCI and AD in relation to motivation-related occupational abilities, adjusting for various covariates. Over the 3 years of follow-up, 15.2% participants developed MCI and 3.0% developed AD. In a fully adjusted model, motivation-related occupational abilities were found to be associated with a reduced risk of MCI (HR: 0.77; 95% CI: 0.64-0.92). Motivation-related occupational abilities were associated with reduced risk of AD in ApoE e4 carriers (HR: 0.48; CI: 0.25-0.91), but not in noncarriers (HR: 0.99; CI: 0.65-1.53). These results suggest that midlife motivational abilities are associated with reduced risk of MCI in general and with reduced risk of AD in ApoE e4 carriers. Revealing the mechanisms underlying this association may inform novel prevention strategies for decelerating cognitive decline in old age.

The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) is associated with schizophrenia and modulates verbal memory and the acoustic startle response.

Abstract: Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies. A potential psychopharmacological effect of NPS on schizophrenia psychopathology was demonstrated by showing that NPS can block NMDA antagonist-induced deficits in prepulse inhibition. We therefore explored a potential role of the NPSR1 Asn107Ile variation in schizophrenia. A case-control sample of 778 schizophrenia patients and 713 healthy control subjects was successfully genotyped for NPSR1 Asn107Ile. Verbal declarative memory and acoustic startle response were measured in subsamples of the schizophrenia patients. The case-control comparison revealed that the low-functioning NPSR1 Asn107 variant was significantly associated with schizophrenia (OR 1.19, p=0.017). Moreover, specifically decreased verbal memory consolidation was found in homozygous Asn107 carriers while memory acquisition was unaffected by NPSR1 genotype. The schizophrenia patients carrying the Ile107 variant demonstrated significantly reduced startle amplitudes but unaffected prepulse inhibition and habituation. The present study confirms findings from rodent models demonstrating an effect of NPS on memory consolidation and startle response in schizophrenia patients. Based on these findings, we consider NPS as a promising target for antipsychotic drug development.

Child neurology: paroxysmal stiffening, upward gaze, and hypotonia: hallmarks of sepiapterin reductase deficiency.

Abstract: Sepiapterin reductase deficiency (SRD) is a dopa-sensitive neurotransmitter disorder, caused by mutation of the SPR gene located on chromosome 2p14-p12.1 To date, 31 patients with 14 mutations have been diagnosed (BIODEF database, update November 2010, www.biopku.org). While classic tetrahydrobiopterin deficiencies present with hyperphenylalaninemia and deficiency of monoamine neurotransmitters, SRD is typically associated with normal phenylalanine levels in blood and pterins in urine2 and not detectable by neonatal screening for phenylketonuria. This implies how important it is to diagnose this condition clinically, in order to provide timely and proper treatment. A summary of the pathophysiology and biochemical pathway is provided by Bonafe et al.2 With the following case report and review of 21 published cases,2,–,10 we elucidate the clinical features of SRD as well as the diagnostic strategy and therapeutic approach. We present a 5-month-old girl, the first and only child born to consanguineous Turkish parents. The parents described the girl's abnormal movements at 3 months of age as sudden stiffening of the whole body, extension of the extremities, upward gaze, and chewing movements lasting for several minutes often after meals, which we also could observe during her hospital stay. Pregnancy and delivery were uneventful. Birthweight, length, and head circumference were within normal ranges. During EEG, a few episodes with chewing movements could be recorded, but no epileptic discharges were evident. The brain MRI was unremarkable. We suspected gastroesophageal reflux and started therapy with omeprazole. The parents reported that the episodes diminished. At 8 months of age, the patient was readmitted because the crises recurred with an increased frequency and duration of up to 25 minutes. During the episodes, the patient revealed circling movements of the hands and rhythmic tremor of the tongue in addition to the previously mentioned symptoms. Remarkably, the …

Association of amygdala volumes with cortisol secretion in unipolar depressed patients.

Abstract: Major depressive disorder (MDD) is accompanied by morphological changes of brain structures which are of great importance in the neural circuitry mediating depression like the hippocampus and the amygdala. Hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system resulting in enhanced glucocorticoid secretion can often be observed during depression and has been thought to play an important role in inducing these morphological changes. We used magnetic resonance imaging to investigate alterations of amygdala and hippocampal volumes in 86 in-patients with unipolar depression and 87 healthy controls, and we then correlated amygdala and hippocampal volumes of 76 in-patients with the area under the curve of cortisol secretion in the dexamethasone/corticotropin releasing hormone (Dex/CRH) test at baseline and during short-term antidepressant therapy. In line with recently published studies both left and right amygdala volumes of patients in a first depressive episode were smaller than those of healthy controls. Patients with recurrent depressive episodes showed a reduction of hippocampal volumes, while amygdala volumes were normal. Larger left and right amygdala volumes correlated with a more pronounced reduction of HPA activity, measured by the cortisol secretion in the combined DEX/CRH test, during antidepressant therapy in patients with recurrent depressive episodes.

Effect of Cardiovascular and Metabolic Disease on Cognitive Test Performance and Cognitive Change in Older Adults

Abstract: Objectives: To examine the effect of cardiovascular and metabolic diseases on initial cognitive test performance and rate of change in three cognitive measures. Design: Prospective cohort study. Setting: General practices in six towns throughout Germany. Participants: Three thousand three hundred twenty-seven participants aged 75 and older (average 79.7 ± 3.6). Measurements: Data were collected during home visits every 18 months and included sociodemographic variables, depression, disease status, drug intake, and cognition. Results: Although the presence of transient ischemic attack (TIA) or stroke and diabetes mellitus was related to poor initial cognitive test performance, the presence of those and other far-reaching chronic diseases or a higher disease burden were not related to the rate of change in cognition over time. Conclusion: Diabetes mellitus, stroke and TIA affect cognitive test performance beyond well-known sociodemographic variables and depressive symptoms, although none of these diseases contributed to cognitive decline over time. In practical terms, prevention and diagnosis of cardiovascular and metabolic diseases may be essential to cognitively healthy aging.

Genetic variation in the neuropeptide Y gene promoter is associated with increased risk of tobacco smoking.

Abstract: Background: Neuropeptide Y (NPY) is a strong candidate gene regarding the pathophysiology of tobacco dependence. It has been associated with various addictive and psychiatric disorders, and closely interacts with the brain reward system. The aim of the present study was to test for association between a functional genetic variant in the NP-Y promoter gene (SNP rs16147) and tobacco smoking. Methods: In a population-based case-control multicenter study designed for tobacco addiction research, a total of 550 Caucasian current smokers, and 544 never-smokers were genotyped for SNP rs16147 and behaviorally characterized with the State-Trait Anxiety Inventory (STAI). Results: Subjects with TT genotype of the SNP rs16147 were significantly more frequently smokers than never-smokers (p = 0.046). In addition, TT genotype exhibited increased state anxiety scores compared to carriers of the C allele (p = 0.037). Conclusions: Our results provide evidence for an involvement of the functionally relevant SNP rs16147 in the pathophysiology of tobacco dependence. Further studies are needed to confirm our findings.

Tumor cell differentiation by label-free fluorescence microscopy

Abstract: Autofluorescence spectra, images, and decay kinetics of U251-MG glioblastoma cells prior and subse- quent to activation of tumor suppressor genes are compared. While phase contrast images and fluorescence inten- sity patterns of tumor (control) cells and less malignant cells are similar, differences can be deduced from autofluorescence spectra and decay kinetics. In particular, upon near UV excitation, the fluorescence ratio of the free and protein-bound coenzyme nicotinamid adenine dinucleotide depends on the state of malignancy and reflects different cytoplasmic (including lysosomal) and mitochondrial contributions. While larger numbers of fluorescence spectra are evaluated by principal component analysis, a multivariate data analysis method, addi- tional information on cell metabolism is obtained from spectral imaging and fluorescence lifetime imaging micro-

Psychoedukation bei Personen mit erhöhtem Psychoserisiko

Abstract: Bisher liegen wenige Studien zur Wirksamkeit von Psychoedukation bei jungen Erwachsenen mit erhohtem Psychoserisiko vor, wahrend der Nutzen psychoedukativer Interventionen bei bereits manifestierten Psychosen mehrmals bestatigt wurde Ziel der vorgestellten Studie war es, die Effekte von Psychoedukation bei Personen mit erhohtem Psychoserisiko im psychosefernen Prodrom zu evaluieren Es wurde eine randomisierte, kontrollierte multizentrische Studie mit 128 hilfesuchenden Risikopatienten durchgefuhrt, die fur 12 Monate entweder eine Psychoedukation als Teil einer integrierten psychologischen Intervention (IPI) oder eine supportive Beratung (SB) erhielten Dabei wurden die Zeit bis zum Ubergang in eine Psychose zu den „Follow-up“-Erhebungen (12 und 24 Monate) sowie die soziale Anpassung anhand der Social Adjustment Scale-II (SAS-II) initial, zum Zeitpunkt des Ubergangs und nach Abschluss der Intervention erhoben Die spezifische Intervention war der SB sowohl in der 12-Monate- (3,2 vs 16,9%; p =0,008) als auch in der 24-Monate-Follow-up-Erhebung (6,3 vs 20,0% p =0,019) in der Pravention von Ubergangen signifikant uberlegen Dagegen zeigte sich keine Uberlegenheit in den SAS-II-Werten der Patienten Vielmehr konnten die Patienten beider Interventionen die soziale Anpassung im Pra-post-Vergleich signifikant verbessern Psychoedukation als Teil eines Gesamtbehandlungsprogramms scheint in der Pravention von Psychosen uber einen 24-Monate-Zeitraum effektiv zu sein Daruber hinaus profitieren Patienten sowohl von der die Psychoedukation umfassenden IPI als auch von der SB im Hinblick auf die soziale Anpassung

Transformation of Transverse Acoustic Velocity of the Burner Approach Flow Into Flame Dynamics

Abstract: Modern, large gas turbines for power generation have multiple burners, which are distributed around the circumference of the engine and which generate flames in combustors of either annular or can-annular geometry. In both cases considering only the axial modes has proven to be insufficient for the assessment of the thermoacoustic stability. An adequate analysis requires consideration of the circumferential acoustic coupling, generated by the acoustic field in the upstream and downstream annuli and the open passages between the cans, respectively. As in annular combustors the particularly critical eigenmodes with low frequencies are predominantly of circumferential nature, the stability of annular combustors is often governed by the onset of circumferential acoustic oscillations. In this study one single radial swirl burner is exposed to a transverse velocity fluctuation comparable to a circumferential oscillation in the plenum annulus. The transverse velocity fluctuation is transformed into a rotational flow oscillation through a convective process depending on excitation frequency and mass flow rate. The characteristics of this process are determined and the resulting dynamic flow structure in the burner nozzle is analyzed. Phase plots show that the rotational flow oscillation is transported into the flame causing a rotational flame pulsation. The influence of transverse velocity fluctuation on the global dynamic flame behavior is determined through FTF measurements. It is concluded from the increased FTF amplitude observed for transverse velocity excitation that the modification of the acoustic field at the burner exit due to circumferential acoustic modes has to be taken into account for a reliable prediction of the stability limits of annular gas turbines.Copyright © 2012 by ASME

Advances in Low Diffusion EUV Resists

Abstract: This paper reports on our development of low diffusion EUV resists based on polymer-bound PAG (PBP) technology. With our low diffusion resist, a wide process window for 30-nm hp of 280nm DOF over a 10% exposure range is achieved on the CNSE based Alpha Demo Tool (ADT) fullfield scanner. Line width roughness of 3.1nm is also achieved. Excellent resist profiles can be achieved on organic ULs or Si hardmask materials. This resist also shows only 1.1 nm carbon growth on witness plate mirrors for cleanables, and no reflectivity loss after mirror cleaning, making it a promising candidate for use on all NXE tools. We also have shown good pattern transfer for a Si HM stack using this resist. Finally, we report 17-nm hp resolution at a dose of 14.5mJ for a higher absorption resist.

Cholesterol-Dependent Energy Transfer between Fluorescent Proteins—Insights into Protein Proximity of APP and BACE1 in Different Membranes in Niemann-Pick Type C Disease Cells

Abstract: Forster resonance energy transfer (FRET) -based techniques have recently been applied to study the interactions between β-site APP-cleaving enzyme-GFP (BACE1-GFP) and amyloid precursor protein-mRFP (APP-mRFP) in U373 glioblastoma cells. In this context, the role of APP-BACE1 proximity in Alzheimer’s disease (AD) pathogenesis has been discussed. FRET was found to depend on intracellular cholesterol levels and associated alterations in membrane stiffness. Here, NPC1 null cells (CHO-NPC1−/−), exhibiting increased cholesterol levels and disturbed cholesterol transport similar to that observed in Niemann-Pick type C disease (NPC), were used to analyze the influence of altered cholesterol levels on APP-BACE1 proximity. Fluorescence lifetime measurements of whole CHO-wild type (WT) and CHO-NPC1−/− cells (EPI-illumination microscopy), as well as their plasma membranes (total internal reflection fluorescence microscopy, TIRFM), were performed. Additionally, generalized polarization (GP) measurements of CHO-WT and CHO-NPC1−/− cells incubated with the fluorescence marker laurdan were performed to determine membrane stiffness of plasma- and intracellular-membranes. CHO-NPC1−/− cells showed higher membrane stiffness at intracellular- but not plasma-membranes, equivalent to cholesterol accumulation in late endosomes/lysosomes. Along with higher membrane stiffness, the FRET efficiency between BACE1-GFP and APP-mRFP was reduced at intracellular membranes, but not within the plasma membrane of CHO-NPC1−/−. Our data show that FRET combined with TIRF is a powerful technique to determine protein proximity and membrane fluidity in cellular models of neurodegenerative diseases.

Gemeinschaftliche Wohnprojekte – Eine Wohnform für alle sozialen Lagen und Lebensalter?

Abstract: Gemeinschaftliche Wohnprojekte werden zunehmend attraktiver, besonders für ältere Menschen und junge Familien. Im Mittel leben 20 bis 30 Haushalte in einem Wohnprojekt. Basierend auf einer schriftlichen Befragung von über 200 Bewohnern solcher Wohnkonzepte in Nordrhein-Wesfalen werden Befunde zum Gemeinschaftsleben vorgestellt. Es zeigt sich, dass die Zufriedenheit mit dem gemeinschaftlichen Wohnen bei den Befragten insgesamt hoch ist. Befragte über 50 Jahre sind dabei zufriedener als jene unter 50 Jahre. Je nach sozialer Lage setzen die Befragten unterschiedliche Präferenzen, was ihnen beim gemeinschaftlichen Wohnen wichtig ist. Die gegenseitige Unterstützung besteht dabei vor allem in kleineren Gefälligkeiten. Es können aber auch enge und vertrauensvolle Bindungen aufgebaut werden.