Novel Schizophrenia Risk Gene TCF4 Influences Verbal Learning and Memory Functioning in Schizophrenia Patients

Background: Recently, a role of the transcription factor 4 (TCF4) gene in schizophrenia has been reported in a large genome-wide association study. It has been hypothesized that TCF4 affects normal brain development and TCF4 has been related to different forms of neurodevelopmental disorders. Schizophrenia patients exhibit strong impairments of verbal declarative memory (VDM) functions. Thus, we hypothesized that the disease-associated C allele of the rs9960767 polymorphism of the TCF4 gene led to impaired VDM functioning in schizophrenia patients. Method: The TCF4 variant was genotyped in 401 schizophrenia patients. VDM functioning was measured using the Rey Auditory Verbal Learning Test (RAVLT). Results: Carriers of the C allele were less impaired in recognition compared to those carrying the AA genotype (13.76 vs. 13.06; p = 0.049). Moreover, a trend toward higher scores in patients with the risk allele was found for delayed recall (10.24 vs. 9.41; p = 0.088). The TCF4 genotype did not influence intelligence or RAVLT immediate recall or total verbal learning. Conclusion: VDM function is influenced by the TCF4 gene in schizophrenia patients. However, the elevated risk for schizophrenia is not conferred by TCF4-mediated VDM impairment. Copyright (C) 2011 S. Karger AG, Base

Reduced P300 amplitude during retrieval on a spatial working memory task in a community sample of adolescents who report psychotic symptoms.

BACKGROUND: Deficits in working memory are widely reported in schizophrenia and are considered a trait marker for the disorder. Event-related potentials (ERPs) and imaging data suggest that these differences in working memory performance may be due to aberrant functioning in the prefrontal and parietal cortices. Research suggests that many of the same risk factors for schizophrenia are shared with individuals from the general population who report psychotic symptoms. METHODS: Forty-two participants (age range 11--13 years) were divided into those who reported psychotic symptoms (N = 17) and those who reported no psychotic symptoms, i.e. the control group (N = 25). Behavioural differences in accuracy and reaction time were explored between the groups as well as electrophysiological correlates of working memory using a Spatial Working Memory Task, which was a variant of the Sternberg paradigm. Specifically, differences in the P300 component were explored across load level (low load and high load), location (positive probe i.e. in the same location as shown in the study stimulus and negative probe i.e. in a different location to the study stimulus) and between groups for the overall P300 timeframe. The effect of load was also explored at early and late timeframes of the P300 component (250-430 ms and 430-750 ms respectively). RESULTS: No between-group differences in the behavioural data were observed. Reduced amplitude of the P300 component was observed in the psychotic symptoms group relative to the control group at posterior electrode sites. Amplitude of the P300 component was reduced at high load for the late P300 timeframe at electrode sites Pz and POz. CONCLUSIONS: These results identify neural correlates of neurocognitive dysfunction associated with population level psychotic symptoms and provide insights into ERP abnormalities associated with the extended psychosis phenotype

Social Cognition and Interaction Training (SCIT) versus Training in Affect Recognition (TAR) in patients with schizophrenia: A randomized controlled trial

INTRODUCTION: Training in Affect Recognition (TAR) is a "targeted" and computer-aided program that has been shown to effectively attenuate facial affect recognition deficits and improve social functioning in patients with schizophrenia. Social Cognition and Interaction Training (SCIT) is a group "broad-based" intervention, that has also been shown to improve emotion recognition, theory of mind (ToM), and social functioning. To date, no study has compared the efficacy of two different social cognitive interventions. OBJECTIVES: We aim to compare the efficacy of TAR and SCIT on schizophrenia patients' performance on facial affect recognition, theory of mind, attributional style and social functioning before, after treatment, and three months thereafter. METHODS: One hundred outpatients with a diagnosis of schizophrenia were randomly assigned to the TAR or SCIT condition and completed pre- (T0) and posttreatment (T1) assessments and a 3-month follow up (T2) of emotion recognition (ER-40), theory of mind (Hinting Task), attributional style (AIHQ) and social functioning (PSP). RESULTS: The entire sample, receiving TAR or SCIT, showed improvements in theory of mind, attributional style, clinical symptoms and social functioning. This effect was maintained at three-months. The TAR intervention was more efficacious than the SCIT program in improving the recognition of facial emotions (ER-40). The TAR intervention also demonstrated a lower drop-out rate than the SCIT intervention. CONCLUSIONS: There were improvements in social cognition, symptomatology and functioning of patients in the entire sample, receiving SCIT or TAR. Both TAR and SCIT appear as valuable treatments for people with schizophrenia and social cognitive deficits

Effects of abstinence on brain morphology in alcoholism: A MRI study

Chronic alcohol abuse leads to morphological changes of the brain. We investigated if these volumetric changes are reversible after a period of abstinence. For this reason 41 male and 15 female alcohol patients underwent MRI-scanning after in-patient detoxification (baseline) entering alcoholism treatment programs, and between 6 and 9 months later (follow-up), in a phase of convalescence. Additionally, 29 male and 16 female control subjects were examined. The MRI-scans were delineated and the resulting regions of interest, volumes of lateral ventricles and prefrontal lobes were expressed relatively to total brain volume. Compared to control subjects alcohol patients showed bilaterally decreased prefrontal lobes (11% reduction) and increased lateral ventricles (up to 42% enlargement). The extent of the ventricular increase was depending on patient’s additional psychiatric diagnosis, showing smaller lateral ventricles in patients with additional personality disorder. While at follow-up the size of prefrontal lobes remained unchanged, volumes of the lateral ventricles decreased (5–6% reduction) in alcohol patients with abstinence and improved drinking behavior, especially in patients that underwent only one detoxification. The extent of the ventricular enlargement correlated with the elevation of alcohol related laboratory measures (mean corpuscular volume, gamma-glutamyl transpeptidase). In conclusion this study confirms the hypothesis that alcoholism causes brain damages that are partially reversible. It should be analyzed in further studies with larger sample sizes, if complete brain regeneration is possible maintaining abstinence over a longer period

Mediterranean Diet, Alzheimer Disease Biomarkers, and Brain Atrophy in Old Age

Objective: To determine whether following a Mediterranean-like diet (MeDi) relates to cognitive functions and in vivo biomarkers for Alzheimer disease (AD), we analyzed cross-sectional data from the German DZNE-Longitudinal Cognitive Impairment and Dementia Study. Method: The sample (n = 512, mean age 69.5 ± 5.9 years) included 169 cognitively normal participants and individuals at higher AD risk (53 with relatives with AD, 209 with subjective cognitive decline, and 81 with mild cognitive impairment). We defined MeDi adherence according to the food frequency questionnaire. Brain volume outcomes were generated via voxel-based morphometry on T1-MRI, and cognitive performance was assessed with an extensive neuropsychological battery. AD-related biomarkers (β-amyloid42/40 [Aβ42/40] ratio, phosphorylated tau 181 [pTau181]) in CSF were assessed in n = 226 individuals. We analyzed the associations between MeDi and outcomes with linear regression models controlling for several covariates. In addition, we applied hypothesis-driven mediation and moderation analysis. Results: Higher MeDi adherence related to larger mediotemporal gray matter volume (p < 0.05 family-wise error corrected), better memory (β ± SE = 0.03 ± 0.02; p = 0.038), and less amyloid (Aβ42/40 ratio, β ± SE = 0.003 ± 0.001; p = 0.008) and pTau181 (β ± SE = −1.96 ± 0.68; p = 0.004) pathology. Mediotemporal volume mediated the association between MeDi and memory (40% indirect mediation). Finally, MeDi favorably moderated the associations among Aβ42/40 ratio, pTau181, and mediotemporal atrophy. Results were consistent correcting for APOE-ε4 status. Conclusion: Our findings corroborate the view of MeDi as a protective factor against memory decline and mediotemporal atrophy. They suggest that these associations might be explained by a decrease of amyloidosis and tau pathology. Longitudinal and dietary intervention studies should further examine this conjecture and its treatment implications

Blood glucose testing and primary prevention of diabetes mellitus type 2 - evaluation of the effect of evidence based patient information

<p>Abstract</p> <p>Background</p> <p>Evidence-based patient information (EBPI) has been recognised as important tool for informed choice in particular in the matter of preventive options. An objective, on the best scientific evidence-based consumer information about subthreshold elevated blood glucose levels (impaired fasting glucose and impaired glucose tolerance) and primary prevention of diabetes, is not available yet. Thus we developed a web-based EBPI and aim to evaluate its effects on informed decision making in people 50 years or older.</p> <p>Methods/Design</p> <p>We conduct a web-based randomised-controlled trial to evaluate the effect of information about elevated blood glucose levels and diabetes primary prevention on five specific outcomes: (i) knowledge of elevated blood glucose level-related issues (primary outcome); (ii) attitudes to a metabolic testing; (iii) intention to undergo a metabolic testing; (iv) decision conflict; (v) satisfaction with the information. The intervention group receives a specially developed EBPI about subthreshold elevated blood glucose levels and diabetes primary prevention, the control group information about this topic, available in the internet.</p> <p>The study population consists of people between 50 and 69 years of age without known diabetes. Participants will be recruited via the internet page of the cooperating health insurance company, Techniker Krankenkasse (TK), and the internet page of the German Diabetes Centre. Outcomes will be measured through online questionnaires. We expect better informed participants in the intervention group.</p> <p>Discussion</p> <p>The design of this study may be a prototype for other web-based prevention information and their evaluation.</p> <p>Trial registration</p> <p>Current Controlled Trial: ISRCTN22060616.</p

Different vulnerability indicators for psychosis and their neuropsychological characteristics in the Northern Finland 1986 Birth Cohor

This study is one of very few that has investigated the neuropsychological functioning of both familial and clinical high risk subjects for psychosis. Participants (N = 164) were members of the Northern Finland 1986 Birth Cohort in the following four groups: familial risk for psychosis (n = 62), clinical risk for psychosis (n = 20), psychosis (n = 13), and control subjects (n = 69). The neurocognitive performance of these groups was compared across 19 cognitive variables. The two risk groups did not differ significantly from controls, but differed from the psychosis group in fine motor function. Neuropsychological impairments were not evident in a non-help-seeking high-risk sample

Mini social cognition and emotional assessment: diagnostic performance and neural correlates in behavioural-variant frontotemporal dementia

We aimed at validating the Mini Social Cognition and Emotional Assessment (Mini-SEA) in a German cohort of mildly impaired behavioural-variant frontotemporal dementia (bvFTD) patients and healthy controls. The Mini-SEA comprises the Facial Emotion Recognition Test (FERT) and the Faux Pas Test (FPT) measuring Theory of Mind (ToM) abilities in social norm-related real-life stories. We examined the diagnostic performance of the Mini-SEA alongside other neuropsychological assessments and investigated its structural neural correlates. We included 32 bvFTD patients and 54 controls in logistic regression models with forward-stepwise selection containing demographics, standard neuropsychological battery (CERAD-NAB+) and the Mini-SEA scores to identify the most relevant variables. Demographic, neuropsychological and daily-life activity associations were explored. Voxel-based morphometry analysis was conducted in a subsample (14 bvFTD and 14 controls) on regions previously linked to emotion processing and ToM functions. The Mini-SEA yielded a very good performance, being in the best-fitting model with a high odds ratio alongside the executive-language and memory measures. Specifically, the FERT indicated the strongest effect in the group differentiation. Mini-SEA showed significant associations with executive-language tests and daily-life activities. In canonical emotion processing brain regions, we found associations of the Mini-SEA composite and the FERT with grey matter volumes in the left insula and lentiform nucleus of putamen. Within ToM regions, associations were found for the Mini-SEA composite and the FPT in cerebellar regions. The German Mini-SEA discriminates well between mildly impaired bvFTD patients and controls. We also demonstrated its significant value for neuropsychological assessment and neuro-behavioural associations in regions underlying emotion processing and ToM

The economic burden of subjective cognitive decline, mild cognitive impairment and Alzheimer's dementia: excess costs and associated clinical and risk factors

BACKGROUND: With the availability of first disease-modifying treatments, evidence on costs across the entire Alzheimer's Continuum, especially for early disease stages, becomes increasingly important to inform healthcare planning, resource allocation, and policy decisions. This study assessed costs and cost-associated factors in patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI) and Alzheimer's Disease (AD) dementia compared to healthy controls. METHODS: The German DELCODE cohort study assessed clinical data, healthcare resource use, and informal care provision. Costs were calculated from payer and societal perspectives using standardized unit costs, and multivariate regression analyses identified cost-associated factors. RESULTS: From a payer perspective, costs were elevated by 26% for SCD (adjusted mean 5,976€ [95%CI 4,598-7,355€]), 85% for MCI (8,795€ [6,200-11,391€]) and 36% for AD (6,454€ [2,796-10,111€]) compared to controls (4,754€ [3,586-5,922€]). Societal costs were elevated by 52% for SCD (adjusted mean 8,377€ [95%CI 6,009-10,746€]), 170% for MCI (14,886€ [9,524-20,248€]) and 307% for AD (22,481€ [9,994-34,969€]) compared to controls (5,522€ [3,814-7,230€]). APOE e4 negative patients showed higher costs compared to APOE e4 positive patients. Hypertension was associated with higher costs. CONCLUSIONS: Healthcare costs are already elevated in early subjective and objective cognitive impairment, driven by formal and informal care. The study emphasizes the importance of early interventions to reduce the economic burden and delay progression

Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS

Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values &gt;0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.</p