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Tanja Veselinović,1,2 Ingo Vernaleken,1,2 Paul Cumming,3,4 Uwe Henning,5 Lina Winkler,1,2 Peter Kaleta,1,2 Michael Paulzen,1,2 Christian Luckhaus,6 Gerhard Gründer1,2,7 1Department of Psychiatry, Psychotherapy, and Psychosomatics, Faculty of Medicine, RWTH Aachen University, Aachen, 2Translational Brain Medicine, Jülich Aachen Research Alliance (JARA), Jülich, Germany; 3IHBI, School of Psychology and Counselling, Queensland University of Technology, 4QIMR Berghofer Institute, Brisbane, Australia; 5Neurobiochemical Research Unit, Department of Psychiatry, Heinrich Heine University, Düsseldorf, 6LWL University Hospital Bochum, Department of Psychiatry, Division of Cognitive Neuropsychiatry and Psychiatric Preventive Medicine, Ruhr University Bochum, Bochum, 7Department of Molecular Neuroimaging, Central Institute of Mental Health, Mannheim, Germany Objectives: Off-label prescription of antipsychotics to patients without psychotic symptoms has become a routine matter for many psychiatrists and also some general practitioners. Nonetheless, little is known about the possibly detrimental effects of antidopaminergic medications on general psychopathology, subjective mental state, or a possible association with physiological parameters in nonpsychotic individuals.Methods: In this randomized, single-blinded study, groups of healthy volunteers (n=18) received low doses of reserpine, aripiprazole, haloperidol, or placebo on 7 successive days. Relevant physiological parameters (plasma prolactin, concentrations of catecholamine metabolites in plasma, and 24-hour urine) and each subject’s mental state (Positive and Negative Syndrome Scale, Hamilton Rating Scale for Depression, visual analogue scale, Beck Depression Inventory II) were assessed at the start and end of the trial.Results: Of the three active treatments, only reserpine caused a significant increase in some plasma- and urine-catecholamine metabolites, but all three medications evoked objective and subjective changes in general psychopathology scores, which correlated with individual increases in plasma homovanillic acid concentrations. Both objective and subjective impairments were significantly more pronounced in the subgroup with greatest increase of plasma prolactin. Subjects experiencing the most pronounced side effects under haloperidol, which compelled them to drop out, showed significantly higher prolactin concentration increases than those who tolerated haloperidol well.Conclusion: We found consistent associations between altered markers of dopamine transmission and several objective and subjective mental impairments in healthy volunteers after 1 week’s treatment with antidopaminergic medications. These findings should draw attention to a more intensive risk–benefit evaluation in cases of off-label prescription of antipsychotic medications. Keywords: catecholamine metabolites, HVA, prolactin, dopamine, reserpine, aripiprazole, haloperidol, off-label prescription

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BACKGROUND: The German Dementia Competence Network (DCN) has established procedures for standardized multicenter acquisition of clinical, biological and imaging data, for centralized data management, and for the evaluation of new treatments. METHODS: A longitudinal cohort study was set up for patients with mild cognitive impairment (MCI), patients with mild dementia and control subjects. The aims were to establish the diagnostic, differential diagnostic and prognostic power of a range of clinical, laboratory and imaging methods. Furthermore, 2 clinical trials were conducted with patients suffering from MCI and mild to moderate Alzheimer's Disease (AD). These trials aimed at evaluating the efficacy and safety of the combination of galantamine and memantine versus galantamine alone. RESULTS: Here, we report on the scope and projects of the DCN, the methods that were employed, the composition and flow within the diverse groups of patients and control persons and on the clinical and neuropsychological baseline characteristics of the group of 2,113 subjects who participated in the observational and clinical trials. CONCLUSION: These data have an impact on the procedures for the early and differential clinical diagnosis of dementias, the current standard treatment of AD as well as on future clinical trials in AD. [ABSTRACT FROM AUTHOR]

BACKGROUND AND AIMS: There is some disagreement between clinical and basic science as to the benefit of estrogen in preventing cognitive decline. For cardiovascular disease, estrogen effects have been shown to vary with estrogen receptor (ESR) genotype. The present study was conceived to review evidence of ESR association with Alzheimer's disease (AD) which could account for the variability observed in estrogen treatment outcome. METHODS: A metaanalysis was performed on data from 8288 cases and controls, controlling for ethnicity (Asian vs European). To explore the specificity of our findings further, a second meta-analysis of association studies was then appended, addressing non-AD forms of dementia or cognitive impairment (total n=11036). RESULTS: A significant overall association of AD with two neighboring ESR1 variants located in a transcription-enhancing region (p=0.015) was noted. The genotypic effect was driven by the minor alleles in Asian populations, and did not reach significance in European samples (OR=1.1, p>0.267). When the phenotype was extended to other forms of dementia or cognitive impairment, the association was no longer observed. CONCLUSIONS: ESR1 variability was confirmed to modulate susceptibility to AD in Asian individuals, but not in Europeans. More research is required to address possible clinical implications, e.g., for hormone replacement therapy in early stages of AD. [ABSTRACT FROM AUTHOR]

In recent years, an important role for the pathogenesis of Alzheimer''s disease (AD) has been ascribed to oxidative stress. Trans-4-hydroxy-2-nonenal, a product of lipid peroxidation, forms stable adducts with a variety of nucleophilic substituents such as thiols or amino moieties. Here, we report the quantification of 1,N2-propanodeoxyguanosine adducts of trans-4-hydroxy-2-nonenal (HNE-dGp) using the specific and very sensitive method of 32P-postlabeling of deoxyguanosine adducts derived from nuclear DNA in neuron rich areas of the hippocampus, the parietal cortex, and the cerebellum of postmortem brains from patients with AD and age matched controls. Adduct levels were highest in the hippocampus, followed by the cerebellum and parietal cortex irrespective of the disease. Neither age, postmortem delay time, gender, nor the extent of neurofibrillary deposits affected tissue adduct levels in the brain areas examined. Although distinctively present in the human brain, the level of HNE-dGp adducts appears not to be useful as a biomarker for AD. [Copyright &y& Elsevier]

Medical biobanking is concerned with establishing and maintaining large-scale repositories of biological specimens combined with comprehensive archives of clinical and biographical information on donors. This aims for controlled high and consistent quality of specimens for future biomedical research. One major objective is to assemble multiple blood components for various types of biochemical analysis and experimentation including different isolated cell types. With proper cryo-conservation, blood-derived cells can be conserved and revitalized after thawing and employed as in-vitro cell models carrying specific biological traits of donors. Optimizing pre-analytical methods can reduce pre-analytical variance thereby reducing imprecision of analytical data. This is particularly valuable for multivariate analyses of biological systems ("omics") and biomarker research. Introducing biobanking to psychiatry carries the challenge of making diagnostic allocation more compatible with biological entities than is achieved with current diagnostic categories of ICD-10 or DSM-V. Diagnostic or transdiagnostic subgroups can be stratified using biologically anchored clinical criteria. An important ethical issue of biobanking is the need for broad consent by the donors for specimen use in not yet defined future research projects. The organizational, logistic and financial costs of establishing and maintaining a biobank are considerable, but seem well warranted in view of the gainable advances in biomedical research quality, translations and clinical applications., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme. All rights reserved.)

Background: Over the past 15 years, comparative assessments of psychoactive substance harms to both users and others have been compiled by addiction experts. None of these rankings however have included synthetic cannabinoids or non-opioid prescription analgesics (NOAs, e.g., gabapentinoids) despite evidence of increasing recreational use. We present here an updated assessment by German addiction medicine experts, considering changing Western consumption trends-including those of NOAs. Methods: In an initial survey, 101 German addiction medicine physicians evaluated both physical and psychosocial harms (in 5 dimensions) of 33 psychoactive substances including opioids and NOAs, to both users and others. In a second survey, 36 addiction medicine physicians estimated the relative weight of each health and social harm dimension to determine the overall harm rank of an individual substance. We compared our ranking with the most recent European assessment from 2014. Results: Illicit drugs such as methamphetamine, heroin, cocaine and also alcohol were judged particularly harmful, and new psychoactive drugs (cathinones, synthetic cannabinoids) were ranked among the most harmful substances. Cannabis was ranked in the midrange, on par with benzodiazepines and ketamine-somewhat more favorable compared to the last European survey. Prescribed drugs including opioids (in contrast to the USA, Canada, and Australia) were judged less harmful. NOAs were at the bottom end of the ranking. Conclusion: In Germany, alcohol and illicit drugs (including new psychoactive substances) continue to rank among the most harmful addictive substances in contrast to prescribed agents including opioid analgesics and NOAs. Current laws are incongruent with these harm rankings. This study is the first of its kind to include comparative harm rankings of several novel abused substances, both licit/prescribed and illicit., (Copyright © 2020 Bonnet, Specka, Soyka, Alberti, Bender, Grigoleit, Hermle, Hilger, Hillemacher, Kuhlmann, Kuhn, Luckhaus, Lüdecke, Reimer, Schneider, Schroeder, Stuppe, Wiesbeck, Wodarz, McAnally and Scherbaum.)

The neuropeptide oxytocin (OT) is known to be an important modulator of social cognition. It has been shown that lower OT plasma concentrations are linked to impairments in social cognition. Studies have also shown that intranasal OT may enhance social-cognitive abilities in healthy subjects. We hypothesize that, besides baseline OT concentrations, the reactivity of the OT system may have an important role in social-cognitive functioning of individuals. In the present study, we explored if an emotional challenge paradigm is suitable to elicit OT release into plasma to make the reactivity of the OT system measurable. Therefore, 20 healthy male volunteers watched an emotional film clip, showing another person in pain during a severe dentist's treatment, while blood draws were conducted pre and post challenge. OT concentrations in plasma were measured by ELISA after solid phase extraction from plasma. OT plasma concentrations at baseline were significantly negatively correlated to an empathetic rating of our film clip and to measures of emotional empathy for positive and negative emotions, whereas the difference between post-challenge value and baseline was significantly positively correlated with the latter measures. Our data thus show that a short emotional video can be successfully employed as a challenge paradigm for eliciting an increase of peripheral OT in healthy male subjects. Calculating the relative OT change post- vs. pre-challenge may give a measure of OT reactivity. The combination of low peripheral OT at baseline with high OT reactivity may be a psychoendocrine trait that is linked to higher emotional functioning.

Background: The progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia can be predicted by cognitive, neuroimaging, and cerebrospinal fluid (CSF) markers. Since most biomarkers reveal complementary information, a combination of biomarkers may increase the predictive power. We investigated which combination of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR)-sum-of-boxes, the word list delayed free recall from the Consortium to Establish a Registry of Dementia (CERAD) test battery, hippocampal volume (HCV), amyloid-beta 1-42 (Aβ42), amyloid-beta 1-40 (Aβ40) levels, the ratio of Aβ42/Aβ40, phosphorylated tau, and total tau (t-Tau) levels in the CSF best predicted a short-term conversion from MCI to AD dementia., Methods: We used 115 complete datasets from MCI patients of the "Dementia Competence Network", a German multicenter cohort study with annual follow-up up to 3 years. MCI was broadly defined to include amnestic and nonamnestic syndromes. Variables known to predict progression in MCI patients were selected a priori. Nine individual predictors were compared by receiver operating characteristic (ROC) curve analysis. ROC curves of the five best two-, three-, and four-parameter combinations were analyzed for significant superiority by a bootstrapping wrapper around a support vector machine with linear kernel. The incremental value of combinations was tested for statistical significance by comparing the specificities of the different classifiers at a given sensitivity of 85%., Results: Out of 115 subjects, 28 (24.3%) with MCI progressed to AD dementia within a mean follow-up period of 25.5 months. At baseline, MCI-AD patients were no different from stable MCI in age and gender distribution, but had lower educational attainment. All single biomarkers were significantly different between the two groups at baseline. ROC curves of the individual predictors gave areas under the curve (AUC) between 0.66 and 0.77, and all single predictors were statistically superior to Aβ40. The AUC of the two-parameter combinations ranged from 0.77 to 0.81. The three-parameter combinations ranged from AUC 0.80-0.83, and the four-parameter combination from AUC 0.81-0.82. None of the predictor combinations was significantly superior to the two best single predictors (HCV and t-Tau). When maximizing the AUC differences by fixing sensitivity at 85%, the two- to four-parameter combinations were superior to HCV alone., Conclusion: A combination of two biomarkers of neurodegeneration (e.g., HCV and t-Tau) is not superior over the single parameters in identifying patients with MCI who are most likely to progress to AD dementia, although there is a gradual increase in the statistical measures across increasing biomarker combinations. This may have implications for clinical diagnosis and for selecting subjects for participation in clinical trials.

Background: Long-term air pollution exposure has been associated with chronic inflammation providing a link to the development of chronic health effects. Furthermore, there is evidence that pathways activated by endoplasmatic reticulum (ER) stress induce airway inflammation and thereby play an important role in the pathogenesis of inflammatory diseases., Objective: We investigated the role of genetic variation of the ER stress pathway on air pollution-induced inflammation., Methods: We used the follow-up examination of the German SALIA study (N=402, age 68-79 years). Biomarkers of inflammation were determined in induced sputum. We calculated biomarker-specific weighted genetic risk scores (GRS) out of eight ER stress related single nucleotide polymorphisms and tested their interaction with PM 2.5 , PM 2.5 absorbance, PM 10 and NO 2 exposure on inflammation by adjusted linear regression., Results: Genetic variation of the ER stress pathway was associated with higher concentration of inflammation-related biomarkers (levels of leukotriene (LT)B 4 , tumor necrosis factor-α (TNF-α), the total number of cells and nitric oxide (NO) derivatives). Furthermore, we observed a significant interaction between air pollution exposure and the ER stress risk score on the concentration of inflammation-related biomarkers. The strongest gene-environment interaction was found for LTB 4 (PM 2.5 : p-value=0.002, PM 2.5 absorbance: p-value=0.002, PM 10 : p-value=0.001 and NO 2 : p-value=0.004). Women with a high GRS had a 38% (95%-CI: 16-64%) higher LTB 4 level for an increase of 2.06μg/m³(IQR) in PM 2.5 (no associations in women with a low GRS)., Conclusion: These results indicate that genetic variation in the ER stress pathway might play a role in air pollution induced inflammation in the lung., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Genetic and environmental risk factors contribute to the pathogenesis of Alzheimer's dementia. Besides known genetic risk factors like the apolipoprotein (APO) Eε4 allele, single nuclear polymorphisms (SNPs) of the estrogen receptors (ESRs) are candidate genetic risk factors, while air pollution represents an environmental risk factor for dementia. Effects of these risk factors and their interaction were investigated in the SALIA cohort of 834 non-demented elderly women. Cognitive function was assessed by the CERAD-plus test battery. Air pollution was estimated by land use regression (LUR) models. Genotyping was carried out for nine ESR1 and ESR2 SNPs and two ApoE SNPs. Carriers of minor ESR2 alleles showed significantly reduced cognitive performance in the CERAD total score with most pronounced deficits in semantic memory (rs1256062, rs10144225, and rs2274705) and executive function (rs1256062). The minor allele effects of ESR2 were stronger in carriers of APOEε4 for the cognitive domain 'executive function' (p value of interaction 0.023 for rs1256062). The investigated ESR1 SNPs were not associated with cognition. Furthermore, we found a significant gene-environment interaction between the ESR2 SNP rs1256062 and air pollution on cognition. Carriers of two major alleles of rs1256062 were more susceptible for an air pollution-induced decrease in performance of 'figure copying' than carriers of minor alleles (p value of interaction, e.g., 0.031 for PM 2.5 ). In conclusion, ESR2 but not ESR1 minor alleles were associated with lower cognitive performance in elderly women with an indication of a gene-gene interaction with APOEε4. We also found indications for gene-environment interactions of ESR2 with traffic-related air pollution exposure on cognitive performance.

Background: The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials., Objective: To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI)., Methods: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences., Results: In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aβ42/tau ratio indicative of AD (n = 340, AUC = 0.78, p <  0.001), and predicted incident dementia within 1-3 years of follow-up (n = 525, AUC = 0.84, p <  0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects., Conclusion: These findings support the interpretation of δ as a construct capturing the disease-related "essence" of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research.

Introduction: Several studies have tested the N-methyl-D-aspartate-receptor antagonist memantine as an add-on to pre-existing treatment with acetylcholinesterase inhibitors. The objective of this study was to evaluate the efficacy and safety of a combined memantine and galantamine-CR de novo regimen compared with galantamine-CR only treatment in never treated patients with mild-to-moderate Alzheimer's disease (AD)., Methods: Antidementia drug-naïve participants (n = 232) with probable, mild-to-moderate AD, and mini-mental state examination scores between 15 and 26 (inclusive) were randomized to receive either 20 mg/day memantine plus 24 mg/day galantamine-CR or 24 mg/day galantamine-CR plus placebo in a 52-week, prospective, double-blind, controlled trial. The primary outcome measurement was the change on the Alzheimer's disease assessment scale-cognition score. Secondary measures comprised the Alzheimer's Disease Cooperative Study-activities of daily living inventory and the clinical dementia rating., Results: At the end of the trial, there were no statistically significant differences between the galantamine-CR/memantine combination and galantamine-CR only group in primary and secondary outcome measurements. The incidence and the severity of adverse events were similar between the groups., Discussion: In this trial, memantine in combination with galantamine-CR did not show an advantage with respect to cognition, function, and behavior in previously never treated patients with mild-to-moderate AD. There were no significant differences in tolerability and safety between the groups. Thus, a de novo combination treatment results in no significant improvement in disease progression (current controlled trials number: NCT01921972).

Background: Epidemiological studies have shown effects of long-term exposure to air pollution on cardiovascular and respiratory health. However, studies investigating the effects of air pollution on cognition and brain function are limited. We investigated if neurocognitive functions are associated with air pollution exposure and whether apolipoprotein E (ApoE) alleles modify the association of air pollution exposure with cognition., Methods: We investigated 789 women from the SALIA cohort during the 22-year follow-up examination (2008-2009). Exposure to particulate matter (PM) size fractions and nitrogen oxides (NOx) were assigned to home addresses. Traffic indicators were used to assess residential proximity to high traffic load. Level of cognitive performance was assessed using the CERAD-Plus test. Air pollution effects on cognitive functioning were estimated cross-sectionally using adjusted linear regression models., Results: Air pollution was negatively associated with cognitive function and cognitive performance in the subtests for semantic memory and visuo-construction. Significant associations could be observed for figure copying with an interquartile range increase of NO2 (β=-0.28 (95%CI:-0.44;-0.12)), NOx (β=-0.25 (95%CI:-0.40;-0.09)), PM10 (β=-0.14 (95%CI:-0.26;-0.02)) and PM2.5 (β=-0.19 (95%CI:-0.36;-0.02)). The association with traffic load was significant in carriers of one or two ApoE ɛ4 risk alleles., Conclusion: In this study of elderly women, markers of air pollution were associated with cognitive impairment in the visuospatial domain. The association of traffic exposure is significant in participants carrying the ApoE ε4 risk allele., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Advanced glycation end products (AGEs) may contribute to the development of type 2 diabetes and related complications, whereas their role in the early deterioration of glycaemia is unknown. While previous studies used antibody-based methods to quantify AGEs, data from tandem mass spectrometry coupled liquid chromatography (LC-MS/MS)-based measurements are limited to patients with known diabetes. Here, we used the LC-MS/MS method to test the hypothesis that plasma AGE levels are higher in individuals with impaired fasting glucose (IFG) than in those with normal fasting glucose (NFG). Secondary aims were to assess correlations of plasma AGEs with quantitative markers of glucose metabolism and biomarkers of subclinical inflammation. This study included on 60 women with NFG or IFG (n = 30 each, mean age 74 years) from the German SALIA cohort. Plasma levels of free metabolites (3-deoxyfructose, 3-deoxypentosone, 3-deoxypentulose), two hydroimidazolones, oxidised adducts (carboxymethyllysine, carboxyethyllysine, methionine sulfoxide) and Nε-fructosyllysine were measured using LC-MS/MS. Plasma concentrations of all tested AGEs did not differ between the NFG and IFG groups (all p>0.05). Associations between plasma levels of AGEs and fasting glucose, insulin and HOMA-IR as a measure of insulin resistance were weak (r between -0.2 and 0.2, all p>0.05). The association between 3-deoxyglucosone-derived hydroimidazolone with several proinflammatory biomarkers disappeared upon adjustment for multiple testing. In conclusion, plasma AGEs assessed by LC-MS/MS were neither increased in IFG nor associated with parameters of glucose metabolism and subclinical inflammation in our study. Thus, these data argue against strong effects of AGEs in the early stages of deterioration of glucose metabolism.

Introduction: White matter (WM) magnetic resonance imaging (MRI) hyperintensities are common in Alzheimer's disease (AD), but their pathophysiological relevance and relationship to genetic factors are unclear. In the present study, we investigated potential apolipoprotein E (APOE)-dependent effects on the extent and cognitive impact of WM hyperintensities in patients with AD., Methods: WM hyperintensity volume on fluid-attenuated inversion recovery images of 201 patients with AD (128 carriers and 73 non-carriers of the APOE ε4 risk allele) was determined globally as well as regionally with voxel-based lesion mapping. Clinical, neuropsychological and MRI data were collected from prospective multicenter trials conducted by the German Dementia Competence Network., Results: WM hyperintensity volume was significantly greater in non-carriers of the APOE ε4 allele. Lesion distribution was similar among ε4 carriers and non-carriers. Only ε4 non-carriers showed a correlation between lesion volume and cognitive performance., Conclusion: The current findings indicate an increased prevalence of WM hyperintensities in non-carriers compared with carriers of the APOE ε4 allele among patients with AD. This is consistent with a possibly more pronounced contribution of heterogeneous vascular risk factors to WM damage and cognitive impairment in patients with AD without APOE ε4-mediated risk.

Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI-O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1-42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The Disrupted-in-Schizophrenia 1 (DISC1) protein plays a key role in behavioral control and vulnerability for mental illnesses, including schizophrenia. In this study we asked whether peripheral DISC1 protein levels in lymphocytes of patients diagnosed with schizophrenia can serve as a trait marker for the disease. Since a prominent comorbidity of schizophrenia patients is nicotine abuse or addiction, we also examined modulation of lymphocyte DISC1 protein levels in smokers, as well as the relationship between nicotine and DISC1 solubility status. We show decreased DISC1 levels in patients diagnosed with schizophrenia independent of smoking, indicating its potential use as a trait marker of this disease. In addition, lymphocytic DISC1 protein levels were decreased in smoking, mentally healthy individuals but not to the degree of overriding the trait level. Since DISC1 protein has been reported to exist in different solubility states in the brain, we also investigated DISC1 protein solubility in brains of rats treated with nicotine. Sub-chronic treatment with progressively increasing doses of nicotine from 0.25mg/kg to 1mg/kg for 15 days led to a decrease of insoluble DISC1 in the medial prefrontal cortex. Our results demonstrate that DISC1 protein levels in human lymphocytes are correlated with the diagnosis of schizophrenia independent of smoking and thus present a potential biomarker. Reduced DISC1 protein levels in lymphocytes of healthy individuals exposed to nicotine suggest that peripheral DISC1 could have potential for monitoring the effects of psychoactive substances., (Copyright © 2014 Elsevier B.V. All rights reserved.)