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Introduction: Research data show the impact of the endocannabinoid system on psychosis through its neurotransmission homeostatic functions. However, the effect of the endocannabinoid system genetic variability on the relationship between cannabis use and psychosis has been unexplored, even less in first-episode patients. Here, through a case-only design, we investigated the effect of cannabis use and the genetic variability of endocannabinoid receptors on clinical and cognitive outcomes in first-episode psychosis (FEP) patients. Methods: The sample comprised 50 FEP patients of European ancestry (mean age (sd) = 26.14 (6.55) years, 76% males), classified as cannabis users (58%) or cannabis non-users. Two Single Nucleotide Polymorphisms (SNP) were genotyped at the cannabinoid receptor type 1 gene (CNR1 rs1049353) and cannabinoid receptor type 2 gene (CNR2 rs2501431). Clinical (PANSS, GAF) and neuropsychological (WAIS, WMS, BADS) assessments were conducted. By means of linear regression models, we tested the main effect of cannabis use and its interaction with the polymorphic variants on the clinical and cognitive outcomes. Results: First, as regards cannabis effects, our data showed a trend towards more severe positive symptoms (PANSS, p = 0.05) and better performance in manipulative abilities (matrix test-WAIS, p = 0.041) among cannabis users compared to non-users. Second, concerning the genotypic effects, the T allele carriers of the CNR1 rs1049353 presented higher PANSS disorganization scores than CC homozygotes (p = 0.014). Third, we detected that the observed association between cannabis and manipulative abilities is modified by the CNR2 polymorphism (p = 0.022): cannabis users carrying the G allele displayed better manipulative abilities than AA genotype carriers, while the cannabis non-users presented the opposite genotype-performance pattern. Such gene–environment interaction significantly improved the overall fit of the cannabis-only model (Δ-R² = 8.4%, p = 0.019). Discussion: Despite the preliminary nature of the sample, our findings point towards the role of genetic variants at CNR1 and CNR2 genes in the severity of the disorganized symptoms of first-episode psychosis and modulating cognitive performance conditional to cannabis use. This highlights the need for further characterization of the combined role of endocannabinoid system genetic variability and cannabis use in the understanding of the pathophysiology of psychosis. [ABSTRACT FROM AUTHOR]

Objective: The authors sought to directly examine compromises in the semantic system in mild cognitive impairment and their possible relationship to everyday functional competencies. Method: Study participants were 25 patients who met criteria for amnestic mild cognitive impairment, 27 patients with mild or moderate Alzheimer's disease, and 70 healthy comparison subjects. The authors administered a novel semantic distance task in which participants make decisions about word or image stimuli that correspond to real-world entities that differ in physical size. The authors also administered a performance-based measure of everyday functional competence. Results: Participants in the mild cognitive impairment and Alzheimer's groups were consistently less accurate and slower than healthy comparison subjects in semantic decisions in which words were used as stimuli. When these participants had to make more fine-grained decisions about the semantic attribute of size, their performance in accuracy and reaction time disproportionately worsened relative to that of comparison subjects. In image-based conditions in which line drawings were used as stimuli, sensory-perceptual information (i.e., the size of the drawings themselves) had undue influence over semantic knowledge judgments in the mild cognitive impairment and Alzheimer's groups. Performance in the semantic distance task was a strong and significant predictor of everyday functional competence in the mild cognitive impairment and Alzheimer's groups. Conclusions: This study synthesized several distinct strands in the mild cognitive impairment literature by providing evidence for 1) compromises in the semantic system in mild cognitive impairment, not confounded by overt retrieval or refractory access; 2) intrusion of perceptual information on semantic processing; and 3) a robust relation between semantic corruption and difficulties in everyday functioning. [ABSTRACT FROM AUTHOR]

Importance: The emergence of psychotic symptoms in Alzheimer disease (AD) is associated with accelerated cognitive and functional decline that may be related to disease pathology., Objective: To investigate the longitudinal dynamics of plasma tau phosphorylated at threonine 181 (p-tau181) and neurofilament light chain protein (NfL) levels in association with the emergence of psychotic symptoms (delusions and hallucinations) in the context of AD., Design, Setting, and Participants: This cohort study used longitudinal data from the Alzheimer Disease Neuroimaging Initiative (ADNI). Baseline analyses compared patients with mild cognitive impairment (MCI) and AD (both with psychosis [AD+P] and without psychosis [AD-P]) and participants who were cognitively unimpaired (CU). For the longitudinal analysis, participants with MCI and AD were subdivided into patients with evidence of psychosis at baseline (AD+P baseline) and patients free of psychosis at baseline who showed incidence of psychosis over the course of the study (AD+P incident). Study data were analyzed between June and November 2023., Exposures: Plasma p-tau181 and NfL measures in individuals with MCI and AD, both with and without psychosis., Main Outcomes and Measures: Plasma p-tau181 and NfL quantifications up to 48 months and concurrent assessments of presence or absence of delusions and hallucinations via the Neuropsychiatric Inventory (NPI) questionnaire., Results: The cohort included 752 participants with AD (mean [SD] age, 74.2 [7.7] years; 434 male [57.7%]). A total of 424 CU participants had a mean (SD) age of 75.4 (6.6) years of whom 222 were female (52.4%). In the longitudinal analysis of p-tau181 trajectories of the AD+P group, the group of patients who showed incidence of psychosis over the course of follow-up (AD+P incident) demonstrated an associated increase in plasma p-tau181 levels compared with the group of patients who had psychosis at baseline (AD+P baseline) and showed an associated decrease in plasma p-tau181 levels (F4, 117 = 3.24; P = .01). The mean slope of p-tau181 change was significantly different in AD+P incident and AD+P baseline groups (F5,746 = 86.76, P < .0001) and when only individuals with amyloid-β positivity (Aβ+), which was determined using positron emission tomography, were compared (F5,455 = 84.60, P < .001). Patients who experienced psychosis at any time had increased levels of NfL relative to those who never experienced psychosis., Conclusions and Relevance: Results of this cohort study suggest that the emergence of psychosis in AD was associated with elevations in plasma levels of p-tau181, highlighting the potential utility of plasma p-tau181 as a biomarker of neuropsychiatric illness in AD, which could have implications for predictive and treatment response strategies.

We conducted a small, open-label, pilot study of daratumumab to explore target engagement, safety, and potential efficacy in patients with mild to moderate Alzheimer's disease. Daratumumab SC 1800 mg was given subcutaneously weekly for 8 weeks, then every 2 weeks for 16 weeks. Flow cytometry to measure the CD38+ proportion of CD8 + CD4- T cells and cognitive assessments were performed at baseline, day 176, and day 246. Daratumumab significantly reduced CD38 + CD8 + CD4- T cells after 24 weeks and this effect persisted 11 weeks thereafter. There was no hematological toxicity or unexpected adverse events. Responder analysis showed no improvement on cognitive outcome measures., Competing Interests: M.L. Gordon has received compensation for participating in Advisory Board meetings for Corium and Labcorp. He has been a clinical trial site Principal Investigator for AbbVie, Alector, Bristol Myers Squibb, Eisai, and Novo Nordisk (payments made to institution). J. Koppel has received grant support from NIA, NIMH, and Alzheimer’s Foundation of America, and has been a clinical trial site Principal Investigator for Karuna and Otsuka (payments made to institution). J. Gomar has received grant support from NIA and Alzheimer’s Association (payments made to institution). E. Christen, L. Keehlisen, M. Gong, F. Lam, and L. Giliberto have no disclosures., (© 2024 – The authors. Published by IOS Press.)

Psychosis in Alzheimer's disease (AD) represents a distinct disease subtype with a more rapid progression of illness evidenced by an increased velocity of cognitive decline and a hastened mortality. Previous biomarker and post-mortem studies have implicated tau neuropathology as a possible mediator of the accelerated decline in AD psychosis. Tau positron emission tomography (PET) neuroimaging provides the opportunity to evaluate tau pathology in-vivo, so that clinical symptomatology can be correlated with disease pathology. [ 18 F]-AV1451 (Flortaucipir) is a PET ligand with high affinity for insoluble paired-helical filaments (PHFs) of hyperphosphorylated tau. In order to determine whether the development of psychosis and worsened prognosis in AD is associated with an increased burden of tau pathology that can be identified with tau imaging, we identified subjects within the Alzheimer's disease neuroimaging initiative (ADNI) who had [ 18 F]-AV1451 imaging at baseline and became psychotic over the course of the study (N = 17) and matched them 1:3 for gender, age, and education to subjects who had [ 18 F]-AV1451 imaging at baseline and did not become psychotic (N = 50). We compared baseline [ 18 F]-AV1451 retention, in addition to cognitive and functional baseline and longitudinal change, in those who became psychotic over the course of participation in ADNI with those who did not. Results suggest that increases in tau pathology in frontal, medial temporal, and occipital cortices, visualized with [ 18 F]-AV1451 binding, are associated with psychosis and a more rapid cognitive and functional decline., (© 2022. The Author(s).)

Background: In individuals with only mild or very mild cognitive attenuations (i.e., so-called pre-clinical AD), performance-based measures of function may be superior to informant-based measures because of increased sensitivity, greater reliability, and fewer ceiling effects., Objective: We sought to determine if a performance-based measure of everyday function would demonstrate adequate psychometric properties and validity in the context of serial assessment over a one-year period in patients with Mild Cognitive Impairment (MCI) and early stage Alzheimer's disease (AD)., Design: Participants were assessed with the performance-based measure at baseline, six weeks, and one year., Setting: A specialized center for the assessment and treatment of AD., Participants: Three groups of subjects participated: a healthy subjects (HS) older cognitively intact group (N=43), an MCI group (N=20), and an AD group (N=26)., Measurements: A three subtest short form of the UCSD Performance-Based Skills Assessment (UPSA) (called the UPSA-3) was the measure of interest. It consisted of the Communication, Planning, and Finance subtests., Results: Mixed model repeated measures were used to assess performance over time. Large group effects were present (HS>MCI>AD). Additionally, the AD and MCI groups demonstrated declines over one year, while the HS group remained stable (group x time interaction p=.11). The MCI/AD group demonstrated adequate test-retest reliability and did not demonstrate ceiling or floor effects., Conclusion: Our data indicate that the UPSA-3 is suitable for clinical trials in that it has adequate ecological coverage and reasonable psychometric properties, and perhaps most importantly, demonstrates validity in serial assessments., Competing Interests: Dr. Goldberg has received funding from Neurocog Trials for consulting on functional competence measures for Alzheimer’s disease and royalties for the use of the Brief Assessment of Cognition in Schizophrenia (BACS) in clinical trials. Dr. Devanand is a consultant for Acadia, Eisai, Avanir, Genentech, Neuronix, and Grifols. He receives Research Support from National Institute of Aging. Dr. Harvey has received consulting fees or travel reimbursements from Alkermes, Boehringer Ingelheim, Intra-Cellular Therapies, Jazz Pharma, Minerva Pharma, Otsuka America, Sanofi Pharma, Sunovion Pharma, Takeda Pharma, and Teva during the past year. He receives royalties from the Brief Assessment of Cognition in Schizophrenia. He is chief scientific officer of i-Function, Inc. He has a research grant from Takeda and from the Stanley Medical Research Foundation. Dr. Richard Keefe currently or in the past 3+ years has received honoraria, served as a consultant, speaker, or advisory board member for Abbott Labs, Abbvie, Abide Therapeutics, Acadia, Aeglea Bio Therapeutics, Akebia, Akili Interactive Labs, Alkermes, Allergan, Amgen, Aptinyx, Armagen, Astellas, Asubio, Avanir, AviNeuro/ChemRar, Axovant Sciences, Biogen Idec, BiolineRx, Biomarin, Biomimetix, Boehringer-Ingelheim, Braincells, Bristol-Myers Squibb, Cerecor, CHDI, Composite Type, Critical Path Institute, Eli Lilly Laboratories, FORUM, Gammon, Howard and Zeszotarski, Global Medical Education, GW Pharmaceuticals, Helicon, Idorsia, Intra-Cellular Therapies, Janssen, JCR, Karuna, Kempharm (DCRI), LSK Global, Lundbeck, Lysogen, MedScape, Memory Pharmaceuticals, Mentis Cura, Merck, Merrakris Therapeutics, Minerva, Mitsubishi, Montana State University, Moscow Research Institute of Psychiatry, Neuralstem, Neuronix, NeuroSearch, New York State Office of Mental Health, Novartis, Orion, Orygen, Otsuka, Paradigm Testing, Parexel, Percept Solutions, Pfizer, Pharm-Olam, PsychoGenics, Regenxbio, Renuron, Reviva, Roche, Sangamo, Sanofi, Science 37, Shire, Six Degrees Medical, SOBI, Solvay, Sunovion, Takeda, Targacept, Teague, Rotenstreich, Stanaland, Fox and Holt, Thrombosis Research Institute, University of Moscow, University of Southern California, University of Texas Southwest Medical Center, WebMD, Wilson Therapeutics, and Wyeth. Dr. Keefe has currently or in the past 3+ years received research funding from Allon, Astra Zeneca, Boehringer-Ingelheim, Department of Veteran’s Affairs, Feinstein Institute for Medical Research, GlaxoSmithKline, National Institute of Mental Health, Novartis, Psychogenics, Research Foundation for Mental Hygiene, Inc., and Singapore Medical Research Council. Dr. Keefe receives royalties from versions of the BAC testing battery, the MATRICS Battery (BACS Symbol Coding), and the Virtual Reality Functional Capacity Assessment Tool (VRFCAT). Dr. Keefe is a shareholder in VeraSci and Sengenix

Introduction: The extent of working memory (WM) and executive function (EF) impairment in mild cognitive impairment (MCI) is not well-characterized., Methods: We compared 48 patients with MCI, 124 noncognitively impaired elderly healthy controls, and 57 patients with Alzheimer's disease (AD) on multiple WM/EF measures, frontal lobe integrity indexes, and functioning., Results: Patients with MCI demonstrated worse performance on nearly all WM/EF tests. This profile of impairment was refined in a factor analysis that identified three primary WM/EF constructs: WM storage; speed and controlled visual search; and manipulation of information and problem solving. EF impairments were associated with reductions in prefrontal cortical thickness. WM/EF accounted for over 50% of the variance in functional competence., Discussion: In MCI, WM/EF impairments are far from rare, based on specific compromises to frontal cortex circuitry, and are associated with loss of everyday functioning. WM/EF impairments, even at this potentially prodromal stage of AD, have clinically deleterious consequences.

Aim: To analyze age-related cerebral blood flow (CBF) using arterial spin labeling (ASL) MRI in healthy subjects with multivariate principal component analysis (PCA). Methods: 50 healthy subjects (mean age 45.8 ± 18.5 years, range 21-85) had 3D structural MRI and pseudo-continuous ASL MRI at resting state. The relationship between CBF and age was examined with voxel-based univariate analysis using multiple regression and two-sample t -test (median age 41.8 years as a cut-off). An age-related CBF pattern was identified using multivariate PCA. Results: Age correlated negatively with CBF especially anteriorly and in the cerebellum. After adjusting by global value, CBF was relatively decreased with aging in certain regions and relatively increased in others. The age-related CBF pattern showed relative reductions in frontal and parietal areas and cerebellum, and covarying increases in temporal and occipital areas. Subject scores of this pattern correlated negatively with age ( R 2 = 0.588; P < 0.001) and discriminated between the older and younger subgroups ( P < 0.001). Conclusion: A distinct age-related CBF pattern can be identified with multivariate PCA using ASL MRI.

Introduction: Episodic memory processes are supported by different subregions of the medial temporal lobe (MTL). In contrast to a unitary model of memory recognition supported solely by the hippocampus, a current model suggests that item encoding engages perirhinal cortex, whereas relational encoding engages parahippocampal cortex and the hippocampus. However, this model has not been examined in the context of aging, neurodegeneration, and MTL morphometrics., Methods: Forty-four healthy subjects (HSs) and 18 cognitively impaired subjects (nine mild cognitive impairment [MCI] and nine Alzheimer's disease [AD] patients) were assessed with the relational and item-specific encoding task (RISE) and underwent 3T magnetic resonance imaging. The RISE assessed the differential contribution of relational and item-specific memory. FreeSurfer was used to obtain measures of cortical thickness of MTL regions and hippocampus volume., Results: Memory accuracies for both item and relational memory were significantly better in the HS group than in the MCI/AD group. In MCI/AD group, relational memory was disproportionately impaired. In HSs, hierarchical regressions demonstrated that memory was predicted by perirhinal thickness after item encoding, and by hippocampus volume after relational encoding (both at trend level) and significantly by parahippocampal thickness at associative recognition. The same brain morphometry profiles predicted memory accuracy in MCI/AD, although more robustly perirhinal thickness for item encoding (R 2  = 0.31) and hippocampal volume and parahippocampal thickness for relational encoding (R 2  = 0.31)., Discussion: Our results supported a model of episodic memory in which item-specific encoding was associated with greater perirhinal cortical thickness, while relational encoding was associated with parahippocampal thickness and hippocampus volume. We identified these relationships not only in HSs but also in individuals with MCI and AD. In the subjects with cognitive impairment, reductions in hippocampal volume and impairments in relational memory were especially prominent.

Compromises in compensatory neurobiologic mechanisms due to aging and/or genetic factors (i.e., APOE gene) may influence brain-derived neurotrophic factor (BDNF) val66met polymorphism effects on temporal lobe morphometry and memory performance. We studied 2 cohorts from Alzheimer's Disease Neuroimaging Initiative: 175 healthy subjects and 222 with prodromal and established Alzheimer's disease. Yearly structural magnetic resonance imaging and cognitive performance assessments were carried out over 3 years of follow-up. Both cohorts had similar BDNF Val/Val and Met allele carriers' (including both Val/Met and Met/Met individuals) distribution. In healthy subjects, a significant trend for thinner posterior cingulate and precuneus cortices was detected in Met carriers compared to Val homozygotes in APOE E4 carriers, with large and medium effect sizes, respectively. The mild cognitive impairment/Alzheimer's disease cohort showed a longitudinal decline in entorhinal thickness in BDNF Met carriers compared to Val/Val in APOE E4 carriers, with effect sizes ranging from medium to large. In addition, an effect of BDNF genotype was found in APOE E4 carriers for episodic memory (logical memory and ADAS-Cog) and semantic fluency measures, with Met carriers performing worse in all cases. These findings suggest a lack of compensatory mechanisms in BDNF Met carriers and APOE E4 carriers in healthy and pathological aging., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Brain structural changes in schizoaffective disorder, and how far they resemble those seen in schizophrenia and bipolar disorder, have only been studied to a limited extent., Method: Forty-five patients meeting DSM-IV and RDC criteria for schizoaffective disorder, groups of patients with 45 matched schizophrenia and bipolar disorder, and 45 matched healthy controls were examined using voxel-based morphometry (VBM)., Results: Analyses comparing each patient group with the healthy control subjects found that the patients with schizoaffective disorder and the patients with schizophrenia showed widespread and overlapping areas of significant volume reduction, but the patients with bipolar disorder did not. A subsequent analysis compared the combined group of patients with the controls followed by extraction of clusters. In regions where the patients differed significantly from the controls, no significant differences in mean volume between patients with schizoaffective disorder and patients with schizophrenia in any of five regions of volume reduction were found, but mean volumes in the patients with bipolar disorder were significantly smaller in three of five., Conclusion: The findings provide evidence that, in terms of structural gray matter brain abnormality, schizoaffective disorder resembles schizophrenia more than bipolar disorder., (© 2015 The Authors. Acta Psychiatrica Scandinavica Published by John Wiley & Sons Ltd.)

Background: The Relational and Item-Specific Encoding task (RISE) measures episodic memory subcomponents, including item-specific and relational encoding of to-be-remembered stimuli. These memory components are neurobiologically relevant because they may engage distinct subregions of the medial temporal lobe, perirhinal and entorhinal cortices, parahippocampus, and hippocampus., Methods: A total of 125 participants, including 84 healthy controls (HC), 22 mild cognitive impairment-diagnosed and 19 Alzheimer disease (AD)-diagnosed participants, were administered the RISE and neuropsychological measures. Stepwise linear regressions assessed prediction of functional ability from RISE d' measures. ANOVAs and logistic regressions determined the ability of the RISE to discriminate between the diagnostic groups. In addition, the psychometric properties of the RISE were examined., Results: RISE measures predicted diagnosis with pseudo R2 values in the range of 0.25-0.30. Receiver operating characteristic curves demonstrated adequate sensitivity and specificity with areas under the curve in the range of 0.78-0.98. Memory following relational encoding was a significant predictor of everyday functional competence. The RISE had acceptable psychometric properties, with the exception of floor effects in the AD group., Conclusion: The RISE measures significantly predicted diagnosis and predicted everyday functional competence. The RISE offers unique advantages in the assessment of HC and individuals with preclinical AD., (© 2016 S. Karger AG, Basel.)

Background: The earliest stage of preclinical Alzheimer's disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood., Objective: To examine dynamic interrelationships between Aβ42 and tau in preclinical AD., Methods: We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n = 14); and 3) Aβ42 levels consistently abnormal (n = 18)., Results: In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = -0.60; p = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p <  0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p-tau., Conclusions: The evolution of Aβ42 and p-tau CSF biomarkers in CI subjects follows an anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.

The effectiveness of cognitive remediation therapy (CRT) for the neuropsychological deficits seen in schizophrenia is supported by meta-analysis. However, a recent methodologically rigorous trial had negative findings. In this study, 130 chronic schizophrenic patients were randomly assigned to computerized CRT, an active computerized control condition (CC) or treatment as usual (TAU). Primary outcome measures were 2 ecologically valid batteries of executive function and memory, rated under blind conditions; other executive and memory tests and a measure of overall cognitive function were also employed. Carer ratings of executive and memory failures in daily life were obtained before and after treatment. Computerized CRT was found to produce improvement on the training tasks, but this did not transfer to gains on the primary outcome measures and most other neuropsychological tests in comparison to either CC or TAU conditions. Nor did the intervention result in benefits on carer ratings of daily life cognitive failures. According to this study, computerized CRT is not effective in schizophrenia. The use of both active and passive CCs suggests that nature of the control group is not an important factor influencing results., (© The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: The neural and cognitive substrates of measures of orientation as used in clinical trials and examinations have not been comprehensively examined., Methods: We studied 473 subjects diagnosed with mild cognitive impairment (MCI) and Alzheimer's disease (AD) at baseline in Alzheimer's Disease Neuroimaging Initiative. Regression analyses at baseline were conducted to find significant predictors of orientation score among cognitive, brain morphometry, and glucose metabolism measures. Mixed model longitudinal analysis was performed to examine consequences of orientation on functional decline, and Cox hazard models examined the risk of conversion to AD in the MCI group., Results: In MCI and AD subjects, orientation was predicted by poorer neurocognitive performance on immediate and delayed episodic memory and attention and processing speed. Among magnetic resonance imaging measures, orientation was predicted by entorhinal cortex thickness, hippocampal volume, and inferior temporal cortex thickness. Glucose metabolism in both middle-inferior temporal cortex and hippocampus were also predictive of orientation score. Functioning was significantly lower in disoriented subjects after 4 years of follow-up, and MCI patients who also were disoriented showed a higher rate of conversion to AD with a hazard ratio of 1.5., Conclusions: Orientation is associated with medial temporal lobe structure, temporal lobe glucose metabolism, and episodic memory function. In MCI individuals orientation was a risk factor for progression to AD, also associated with rapid functional decline and worse prognosis. Thus, orientation may serve as a surrogate for episodic memory in clinical examination. These results have direct implications for the use of orientation in MCI and AD clinical trials including ceiling effects in healthy controls and issues of redundancy with measures of memory, when both are used in composite scores.

Background: This study examined the predictive value of different classes of markers in the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) over an extended 4-year follow-up in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database., Methods: MCI patients were assessed for clinical, cognitive, magnetic resonance imaging (MRI), positron emission tomography-fluorodeoxyglucose (PET-FDG), and cerebrospinal fluid (CSF) markers at baseline and were followed on a yearly basis for 4 years to ascertain progression to AD. Logistic regression models were fitted in clusters, including demographics, APOE genotype, cognitive markers, and biomarkers (morphometric, PET-FDG, CSF, amyloid-β, and tau)., Results: The predictive model at 4 years revealed that two cognitive measures, an episodic memory measure and a Clock Drawing screening test, were the best predictors of conversion (area under the curve = 0.78)., Conclusions: This model of prediction is consistent with the previous model at 2 years, thus highlighting the importance of cognitive measures in progression from MCI to AD. Cognitive markers were more robust predictors than biomarkers., (Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

The common APOE2 gene variant is neuroprotective against Alzheimer's disease (AD) and reduces risk by nearly 50%. However, the mechanisms by which APOE2 confers neuroprotection are largely unknown. Here we showed that ApoE protein abundance in human postmortem cortex follows an isoform-dependent pattern (E2>E3>E4). We also identified a unique downstream transcriptional profile determined by microarray and characterized by downregulation of long-term potentiation (LTP) related transcripts and upregulation of extracellular matrix (ECM)/integrin-related transcripts in E2 cases and corroborated this finding at the protein level by demonstrating increases in ECM collagens and laminins. In vivo studies of healthy older individuals demonstrated a unique and advantageous biomarker signature in E2 carriers. APOE2 also reduced the risk of mild cognitive impairment to AD conversion by half. Our findings suggest that ApoE2 protein abundance, coupled with its inability to bind to LDLRs, may act to increase amyloid-beta (Ab) clearance. In addition, increased ECM and reduced LTP-related expression results in diminished activity-dependent Ab secretion and/or excitotoxicity, and thus also promotes neuroprotection.

Background: Proton magnetic resonance spectroscopy ((1)H-MRS) studies on healthy aging have reported inconsistent findings and have not systematically taken into account the possible modulatory effect of APOE genotype. We aimed to quantify brain metabolite changes in healthy subjects in relation to age and the presence of the APOE E4 genetic risk factor for Alzheimer's disease. Additionally, we examined these measures in relation to cognition., Methods: We studied a cohort of 112 normal adults between 50 and 86 years old who were genotyped for APOE genetic polymorphism. Measurements of (1)H-MRS metabolites were obtained in the posterior cingulate and precuneus region. Measures of general cognitive functioning, memory, executive function, semantic fluency, and speed of processing were also obtained., Results: General linear model analysis demonstrated that older APOE E4 carriers had significantly higher choline/creatine and myo-inositol/creatine ratios than APOE E3 homozygotes. Structural equation modeling resulted in a model with an excellent goodness of fit and in which the APOE × age interaction and APOE status each had a significant effect on (1)H-MRS metabolites (choline/creatine and myo-inositol/creatine). Furthermore, the APOE × age variable modulation of cognition was mediated by (1)H-MRS metabolites., Conclusions: In a healthy aging normal population, choline/creatine and myo-inositol/creatine ratios were significantly increased in APOE E4 carriers, suggesting the presence of neuroinflammatory processes and greater membrane turnover in older carriers. Structural equation modeling analysis confirmed these possible neurodegenerative markers and also indicated the mediator role of these metabolites on cognitive performance among older APOE E4 carriers., (Copyright © 2014 Society of Biological Psychiatry. All rights reserved.)

Aims: To validate the Spanish version of the University of California Performance Skills Assessment (UPSA) in patients with severe mental disorders., Methods: Naturalistic, 6month follow-up, multicentre, validation study. 139 patients with schizophrenia, 57 bipolar patients and 31 controls were evaluated using the following scales: Spanish UPSA (Sp-UPSA), Clinical Global Impression, Severity (CGI-S), Global Assessment of Functioning (GAF), and Personal and Social Performance (PSP)., Results: Reliability: Internal consistency (Cronbach's alpha) was 0.81 in schizophrenia and 0.58 in bipolar patients. Test-retest was 0.74 and 0.65 (p<0.0001) respectively. Construct validity: Pearson correlation coefficients between Sp-UPSA and PSP total scores were 0.42 (p<0.0001) for schizophrenia and 0.44 (p=0.001) for bipolar patients. For Sp-UPSA and GAF scores correlation coefficients were 0.43 and 0.52 (p<0.0001) respectively. Discriminant validity: The Sp-UPSA discriminated between patients and controls. In schizophrenia patients it also discriminated among different levels of illness severity according to CGI-S scores. In control versus patients with schizophrenia contrasts, the area under the curve was 0.89 and a cut-off point of 85 provided a sensitivity of 82.7% and a specificity of 77.4%. In bipolar patients, the area under the curve was 0.85 and a cut-off point of 90 provided a sensitivity of 82.5% and a specificity of 64.5%., Conclusion: The Spanish UPSA is a reliable and valid instrument for assessing functional capacity in severe mentally ill patients. It seems to be appropriate for use in clinical trials and in everyday clinical practice as a means of monitoring functional outcomes., (© 2013.)

Background: The pathological basis of tardive dyskinesia is unknown. Although its clinical features implicate the basal ganglia, imaging studies have not found clear evidence that it is associated with volume changes in these or other brain structures., Aims: To determine, using voxel-based structural imaging, whether there are regions of grey matter volume change in people with schizophrenia who also have tardive dyskinesia compared with those without tardive dyskinesia., Method: A total of 81 people with chronic schizophrenia, 32 with tardive dyskinesia and 49 without, were examined using magnetic resonance imaging (MRI) and whole-brain, optimised voxel-based morphometry. A comparison group of 61 healthy controls was also examined., Results: Compared with those without tardive dyskinesia, patients with tardive dyskinesia showed a pattern of volume reductions in predominantly subcortical regions, including the basal ganglia and the thalamus. Within the basal ganglia, volume reductions were seen in the caudate nucleus, to a lesser extent in the putamen, and only marginally in the globus pallidus. The patients with tardive dyskinesia, but not those without, showed significant volume reductions in the basal ganglia compared with the healthy controls but both groups had smaller volumes than controls in other affected areas., Conclusions: The pathological process or processes that underlie the development of tardive dyskinesia are not just neurochemical in nature, but affect brain structure.

Background: Genetic studies have found that the interleukin-1β gene (IL1B, 2q13) influences the risk for schizophrenia, but the underlying biological mechanisms of the association are still unclear. Investigation of the effects of genetic variability in this gene on brain function could provide more information about its role in the disorder., Methods: The present study examined the effects of a functional polymorphism at IL1B gene promoter (-511C/T; rs16944) on brain correlates of working memory performance in schizophrenia. Forty-eight schizophrenia patients and 46 control subjects underwent functional magnetic resonance imaging while performing the n-back task., Results: In the pooled sample, genetic variability at this locus was associated with differential brain activation in a bilateral frontal region including the dorsolateral prefrontal cortex. There was also a significant diagnosis × genotype interaction effect in an overlapping frontal region: the IL1B polymorphism did not affect activation in the control subjects in this area, but the schizophrenia patients who were T carriers showed significantly higher activation than the CC homozygotes., Conclusions: The findings support a role for IL1B variability in the dorsolateral prefrontal cortex dysfunction classically associated with schizophrenia., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Deficits in memory and executive performance are well-established features of bipolar disorder and schizophrenia. By contrast, data on cognitive impairment in schizoaffective disorder are scarce and the findings are conflicting., Method: We used the Wechsler Memory Scale (WMS-III) and the Behavioural Assessment of the Dysexecutive Syndrome (BADS) to test memory and executive function in 45 schizophrenic patients, 26 schizomanic patients and 51 manic bipolar patients in comparison to 65 healthy controls. The patients were tested when acutely ill., Results: All three patient groups performed significantly more poorly than the controls on global measures of memory and executive functioning, but there were no differences among the patient groups. There were few differences in memory and executive function subtest scores within the patient groups. There were no differences in any test scores between manic patients with and without psychotic symptoms., Conclusions: Schizophrenic, schizomanic and manic patients show a broadly similar degree of executive and memory deficits in the acute phase of illness. Our results do not support a categorical differentiation across different psychotic categories with regard to neuropsychological deficits.

Background: It is not known whether first-episode psychosis is characterized by the same prefrontal cortex functional imaging abnormalities as chronic schizophrenia., Method: Thirty patients with a first episode of non-affective functional psychosis and 28 healthy controls underwent functional magnetic resonance imaging (fMRI) during performance of the n-back working memory task. Voxel-based analyses of brain activations and deactivations were carried out and compared between groups. The connectivity of regions of significant difference between the patients and controls was also examined., Results: The first-episode patients did not show significant prefrontal hypo- or hyperactivation compared to controls. However, they showed failure of deactivation in the medial frontal cortex. This area showed high levels of connectivity with the posterior cingulate gyrus/precuneus and parts of the parietal cortex bilaterally. Failure of deactivation was significantly greater in first-episode patients who had or went on to acquire a DSM-IV diagnosis of schizophrenia than in those who did not, and in those who met RDC criteria for schizophrenia compared to those who did not., Conclusions: First-episode psychosis is not characterized by hypo- or hyperfrontality but instead by a failure of deactivation in the medial frontal cortex. The location and connectivity of this area suggest that it is part of the default mode network. The failure of deactivation seems to be particularly marked in first-episode patients who have, or progress to, schizophrenia.

Background: Patients with schizophrenia have been found to show unawareness of cognitive impairment. However, its frequency and its relationship to lack of insight into illness are uncertain., Method: Forty-two patients with chronic schizophrenia were given tests of executive function and memory. Awareness of cognitive impairment was measured by means of discrepancy scores--differences between patient and psychologist ratings of memory and frontal/executive failures in daily life. Insight into illness was assessed using the Scale to Assess Unawareness of Mental Disorder (SUMD)., Results: A majority of the patients were found to underestimate their cognitive impairment; however, some overestimated it. Unawareness of cognitive impairment and lack of clinical insight loaded on different factors in a factor analysis, but these two factors were themselves correlated., Conclusions: The findings suggest that both unawareness and overestimation of cognitive impairment characterise patients with schizophrenia, although the former is more common. Awareness of cognitive impairment occurs independently of insight into illness at the clinical level, although the two phenomena may be linked at a deeper level., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Functional capacity includes basic and complex behaviors necessary to independently live in the community. It has been found that patients with cognitive impairment have daily living functional skills altered at very early stages of illness., Objectives: 1) To develop and validate a brief scale derived from the University of California, San Diego, performance-based skills assessment (UPSA); 2) to cross-validate this new UPSA short form with an independent healthy elderly sample., Method: Fifty-one healthy elderly subjects, 26 mild cognitive impairment (MCI) subjects defined per Petersen's criteria, and 22 probable Alzheimer Disease (AD) subjects according to National Institute of Neurological and Communicative Disorders and Stroke-AD and Related Disorders Association criteria were included. For cross-validation purpose, a comparison group of 108 older healthy subjects with Mini-Mental scores of 25 or greater was also recruited. A modified four-functional domain version of the UPSA was administered., Results: Communication and comprehension/planning domains accounted for almost 90% of the variance (R = 0.89) and in all models entered first and second, respectively. An UPSA short form using these two domains was significantly correlated with the full UPSA scale in all the groups examined: 0.86 for healthy controls; 0.87 for MCI; and 0.88 for AD. Acceptable sensitivity and specificity values for the UPSA short form were found in receiver operating characteristic (ROC) analysis. A correlation of 0.80 was found between the short and the full UPSA scales in the cross-validation sample., Conclusions: The UPSA short form is a rapid, reliable, and efficient measure of functional capacity that is able to detect performance impairment in an ecologically valid setting in much less time compared with the extended form of the scale. Furthermore, it demonstrated adequate discriminative properties among healthy subjects, MCI patients, and AD patients.

Background: Cognitive impairment is an established feature of schizophrenia. However, little is known about its relationship to the structural and functional brain abnormalities that characterise the disorder. Aims To identify structural and/or functional brain abnormalities associated with schizophrenic cognitive impairment., Method: We carried out structural magnetic resonance imaging (MRI) and voxel-based morphometry in 26 participants who were cognitively impaired and 23 who were cognitively preserved, all with schizophrenia, plus 39 matched controls. Nineteen of those who were cognitively impaired and 18 of those who were cognitively preserved plus 34 controls also underwent functional MRI during performance of a working memory task., Results: No differences were found between the participants who were cognitively intact and those who were cognitively impaired in lateral ventricular volume or whole brain volume. Voxel-based morphometry also failed to reveal clusters of significant difference in grey and white matter volume between these two groups. However, during performance of the n-back task, the participants who were cognitively impaired showed hypoactivation compared with those who were cognitively intact in the dorsolateral prefrontal cortex among other brain regions., Conclusions: Cognitive impairment in schizophrenia is not a function of the structural brain abnormality that accompanies the disorder but has correlates in altered brain function.

Context: Biomarkers have become increasingly important in understanding neurodegenerative processes associated with Alzheimer disease. Markers include regional brain volumes, cerebrospinal fluid measures of pathological Aβ1-42 and total tau, cognitive measures, and individual risk factors., Objective: To determine the discriminative utility of different classes of biomarkers and cognitive markers by examining their ability to predict a change in diagnostic status from mild cognitive impairment to Alzheimer disease., Design: Longitudinal study., Participants: We analyzed the Alzheimer's Disease Neuroimaging Initiative database to study patients with mild cognitive impairment who converted to Alzheimer disease (n = 116) and those who did not convert (n = 204) within a 2-year period. We determined the predictive utility of 25 variables from all classes of markers, biomarkers, and risk factors in a series of logistic regression models and effect size analyses., Setting: The Alzheimer's Disease Neuroimaging Initiative public database., Outcome Measures: Primary outcome measures were odds ratios, pseudo- R(2)s, and effect sizes., Results: In comprehensive stepwise logistic regression models that thus included variables from all classes of markers, the following baseline variables predicted conversion within a 2-year period: 2 measures of delayed verbal memory and middle temporal lobe cortical thickness. In an effect size analysis that examined rates of decline, change scores for biomarkers were modest for 2 years, but a change in an everyday functional activities measure (Functional Assessment Questionnaire) was considerably larger. Decline in scores on the Functional Assessment Questionnaire and Trail Making Test, part B, accounted for approximately 50% of the predictive variance in conversion from mild cognitive impairment to Alzheimer disease., Conclusions: Cognitive markers at baseline were more robust predictors of conversion than most biomarkers. Longitudinal analyses suggested that conversion appeared to be driven less by changes in the neurobiologic trajectory of the disease than by a sharp decline in functional ability and, to a lesser extent, by declines in executive function.

Background: Studies of procedural learning in schizophrenia have been inconsistent, sometimes finding it to be preserved and sometimes impaired. This study examined three factors that could account for the variability among findings: type of task, presence of general intellectual impairment, and the extrapyramidal side effects of neuroleptic treatment., Methods: Forty-three patients with schizophrenia and 22 normal control subjects were examined with three different paradigms: the pursuit rotor, mirror reading, and probabilistic learning ("weather prediction"). A subgroup of intellectually preserved patients was also examined. Patients with and without tardive dyskinesia and with and without Parkinsonism were also compared., Results: The schizophrenic patients showed learning comparable to the control subjects on the pursuit rotor and mirror reading but were impaired on the probabilistic learning task. However, this last difference disappeared when the subgroup of intellectually preserved patients was compared with a subgroup of matched control subjects. Patients with and without tardive dyskinesia or Parkinsonism showed similar learning on all three tasks, but patients with tardive dyskinesia showed poorer overall performance than those without., Conclusions: Procedural learning tends to be preserved in schizophrenia, and when impairment is found, differences in the overall level of intellectual function might be the determining factor., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Abnormal interactions between areas of the brain have been pointed as possible causes for schizophrenia. However, the nature of these disturbances and the anatomical location of the regions involved are still unclear. Here, we describe a method to estimate maps of net levels of connectivity in the resting brain, and we apply it to look for differential patterns of connectivity in schizophrenia. This method uses partial coherences as a basic measure of covariability, and it minimises the effect of major physiological noise. When overall (net) connectivity maps of a sample of 40 patients with schizophrenia were compared with the maps from a matched sample of 40 controls, a single area of abnormality was found. It is an area of patient hyper-connectivity and is located frontally, in medial and orbital structures, clearly overlapping the anterior node of the default mode network (DMN). When this area is used as a region of interest in a second-level analysis, it shows functional hyper-connections with several cortical and subcortical structures. Interestingly, the most significant abnormality is found with the caudate, which has a bilateral pattern of abnormality, pointing to a possible DMN-striatum deviant relation in schizophrenia. However, hyper-connectivity observed with other regions (right hippocampus and amygdala, and other cortical structures) suggests a more pervasive alteration of brain connectivity in this disease., (Copyright © 2010 Wiley-Liss, Inc.)

There is a growing interest in finding ways to summarize the local connectivity properties of the brain through single brain maps. Here we propose a method based on the conditional mutual information (CMI) in the frequency domain. CMI maps quantify the amount of non-redundant covariability between each site and all others in the rest of the brain, partialling out the joint variability due to gross physiological noise. Average maps from a sample of 45 healthy individuals scanned in the resting state show a clear and symmetric pattern of connectivity maxima in several regions of cortex, including prefrontal, orbitofrontal, lateral-parietal, and midline default mode network components; and in subcortical nuclei, including the amygdala, thalamus, and basal ganglia. Such cortical and subcortical hotspots of functional connectivity were more clearly evident at lower frequencies (0.02-0.1 Hz) than at higher frequencies (0.1-0.2 Hz) of endogenous oscillation. CMI mapping can also be easily applied to perform group analyses. This is exemplified by exploring effects of normal aging on CMI in a sample of healthy controls and by investigating correlations between CMI and positive psychotic symptom scores in a sample of 40 schizophrenic patients. Both the normative aging and schizophrenia studies reveal functional connectivity trends that converge with reported findings from other studies, thus giving further support to the validity of the proposed method.

The Val158Met polymorphism in the COMT gene has been found to be associated with differences in brain activation in both healthy subjects and patients with schizophrenia. The predominant finding has been increased prefrontal activation associated with the Val allele; however, genotype-related de-activations have not been studied. In this study 42 schizophrenia patients and 31 controls underwent fMRI while performing the n-back task. Brain differences related to presence/absence of disease and presence/absence of the Val/Val genotype were examined. Both disease and Val/Val genotype were associated with failure of de-activation in a cluster centred in the medial prefrontal cortex. There was no interaction between disease and genotype at this location, but clusters where there were significant interactions emerged in the right prefrontal cortex and left temporal/parietal cortex. These findings suggest that Val158Met polymorphism influences task-related de-activations in the default mode network in both healthy subjects and schizophrenia patients to an equivalent extent. However the Val158Met polymorphism also has disease-specific effects on DLPFC activation in schizophrenia., (Copyright © 2010. Published by Elsevier Inc.)

Neuroimaging studies have found evidence of altered brain structure and function in schizophrenia, but have had complex findings regarding the localization of abnormality. We applied multimodal imaging (voxel-based morphometry (VBM), functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) combined with tractography) to 32 chronic schizophrenic patients and matched healthy controls. At a conservative threshold of P=0.01 corrected, structural and functional imaging revealed overlapping regions of abnormality in the medial frontal cortex. DTI found that white matter abnormality predominated in the anterior corpus callosum, and analysis of the anatomical connectivity of representative seed regions again implicated fibres projecting to the medial frontal cortex. There was also evidence of convergent abnormality in the dorsolateral prefrontal cortex, although here the laterality was less consistent across techniques. The medial frontal region identified by these three imaging techniques corresponds to the anterior midline node of the default mode network, a brain system which is believed to support internally directed thought, a state of watchfulness, and/or the maintenance of one's sense of self, and which is of considerable current interest in neuropsychiatric disorders.