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1.Aims: This randomized control trial compared an adaptive computerized cognitive training intervention with a non-adaptive version. The primary hypothesis predicted better diabetes self-management in type 2 diabetes patients at 6 months post-intervention than baseline, with seven secondary outcomes. 2.Methods: Intent-to-treat analysis of veterans without dementia aged 55+ from the Bronx, NY and Ann Arbor, MI (N=90/per arm) used linear mixed model analyses. 3.Results: Contrary to the hypothesis, only memory showed more improvement in the adaptive arm (p<0.01). Post-hoc analyses combined the two arms; self-management improved at six-months post-intervention (p<0.001). Memory, executive functions/attention, prospective memory, diastolic blood pressure, and systolic blood pressure improved (p < 0.05); hemoglobin A1c and medication adherence did not improve significantly. 4.Conclusions: The adaptive computerized cognitive training was not substantially better than non-adaptive, but may improve memory. Post-hoc results for the combined arms suggest computer-related activities may improve diabetes self-management and other outcomes for middle-aged and older patients with type 2 diabetes. Practice effects or awareness of being studied cannot be ruled out. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article about the association of C-reactive protein, a systemic market of inflammation, and memory function to antagonistic pleiotropy in very old nondemented subjects.

Aims: To assess the relationships between early and late antemortem measures of dementia severity and Alzheimer disease (AD) neuropathology severity. Methods: 40 residents of a nursing home, average age at death 82.0, participated in this longitudinal cohort study with postmortem assessment. Severity of dementia was measured by Clinical Dementia Rating (CDR) at two time points, averaging 4.5 and 1.0 years before death. Densities of postmortem neuritic plaques (NPs) and neurofibrillary tangles (NFTs) were measured in the cerebral cortex, hippocampus, and entorhinal cortex. Results: For most brain areas, both early and late CDRs were significantly associated with NPs and NFTs. CDRs assessed proximal to death predicted NFTs beyond the contribution of early CDRs. NPs were predicted by both early and late CDRs. NPs were predictive of both early and late CDRs after controlling for NFTs. NFTs were only associated significantly with late CDR in the cerebral cortex after controlling for NPs. Conclusions: Even if assessed several years before death, dementia severity is associated with AD neuropathology. NPs are more strongly associated with dementia severity than NFTs. NFTs consistently associate better with late than early CDR, suggesting that these neuropathological changes may occur relatively later in the course of the disease. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background. In cross-sectional and longitudinal studies, type 2 diabetes has been positively associated with the risk of Alzheimer's disease (AD). The present descriptive study compared diabetic and nondiabetic subjects on the severity of neuritic plaques and neurofibrillary tangles (NFFs) in the cerebral cortex and in the hippocampus. Methods. The study included specimens from 385 consecutive autopsies of residents of a nursing home (15.8% diabetics). Mean age at death = 84 years [standard deviation (SD) = 10], 66% were female, Clinical Dementia Rating mean = 3.0 (SD = 1.6), and 32.5% had an APOE4 allele. Additional analyses limited the sample to 268 subjects (14.1% diabetics) without neuropathology other than AD. Results. Analyses of covariance controlling for age at death, dementia severity (Clinical Dementia Rating score), and APOE4 allele indicated that diabetics had significantly fewer neuritic plaques (p = .008) and NFTs (p = .047) in the cerebral cortex than did nondiabetics. In the hippocampus, diabetics had significantly lower plaque ratings than did nondiabetics (p = .019), but the lower ratings of NFFs did not achieve statistical significance (p = .082). In the entire sample, diabetics had significantly less AD-associated neuropathology in all four analyses. Conclusions. These results raise the possibility that the varied associations observed between diabetes and AD may be specific to as yet ill-defined subgroups of dementia and diabetic patients or may be more characteristic of younger patients than of those who survive to a mean age of 84 years. Future studies are encouraged to examine a variety of other characteristics such as age that may interact with diabetes affecting the incidence of AD. [ABSTRACT FROM AUTHOR]

Presents a study which examined the presence of autism-susceptibility gene on chromosome 2. Methods; Results; Discussion.

Studies of the familial aggregation of Alzheimer's disease have primarily used samples ascertained from tertiary care clinics which may not be representative of many AD patients, for example those residing at geriatric nursing homes. Survival analysis was used to investigate whether estimates of familial aggregation of AD based on a clinic-based AD proband (C-AD) sample (probands: N =544; first degree relatives; N =4267) differ from one ascertained at a nursing home (NH-AD; probands: N =225; first degree relatives; N =1772). The cumulative survival from AD was significantly worse in relatives of the C-AD probands and the overall relative risk (RR) of AD in this group was greater than twice that of relatives of the NH-AD probands. However, age at onset in C-AD probands was significantly earlier than in the NH-AD group and in both groups this factor was negatively associated with familial aggregation. When, for this reason, the proband samples were matched one-to-one by age at onset, dropping those probands with no match, the two curves were close to identical and the RR for the C-AD group of relatives was 1.0 The results suggest that estimates of familial risk of AD based on C-AD samples are not applicable and overestimate the extent of increased risk for relatives of more prevalent, later onset AD probands. However, the overestimate can be explained by the typically earlier age at onset in C-AD samples as opposed to a sampling bias related to the proband's family history status per se. The relationship between onset age and familial aggregation suggests that no single estimate of the age-dependent risk (survival curve) is uniformly appropriate for relatives of AD probands. Copyright © 2000 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Investigates the relationship between probands' age at onset of Alzheimer's disease with the risk of primary progressive dementia in the probands' first-degree relatives. Age at onset of Alzheimer's disease; Hazard rate of primary progressive dementia in relatives; Successive divisions of early-onset and late-onset Alzheimer's disease.

Investigates the familial propensity of schizophrenia-related and borderline personalities by using the family history method. Schizotypal personality; Morbid risk; Diagnostic and Statistical Manual, Third Edition (DSM-III); Case studies.

Background: Type 2 diabetes mellitus (T2DM) is prevalent in the general United States population, and in the veteran population. T2DM has consistently been linked to increased risk for cognitive impairment, dementia, and Alzheimer's disease. Computerized cognitive training (CCT) is practical and inexpensive cognitive interventions that is an alternative to medication.Objective: To report the recruitment methods and challenges to date in an ongoing two-site randomized controlled trial (RCT) of CCT on cognitive function and T2DM management in an older non-demented veteran population.Methods: Veterans are recruited primarily by targeted mailings or by direct contact at clinics and presentations.Results: From 1,459 original contacts, 437 expressed initial interest, 111 provided informed consent, and 97 completed baseline assessments. Participants from the two VA Medical Centers differed in demographics and baseline characteristics. Comparing recruitment methods, the proportion of individuals contacted who were ultimately consented was significantly less from mailings (5%) than other sources (20%), primarily face- to-face clinic visits (χ2 (1) = 38.331, p < 0.001).Conclusions: Mailings are cost-effective, but direct contact improved recruitment. Not using or lacking access to computers and ineligibility were major reasons for non-participation. Within-site comparisons of demographically diverse sites can address confounding of demographic and other site differences. [ABSTRACT FROM AUTHOR]

The article focuses on the sensitivity of schizophrenia endophenotype biomarkers to anticholinergic medication burden (ACMB). Topics include the impact of ACMB on cognitive performance in individuals with schizophrenia, the role of neurophysiological biomarkers (MMN and P3a) in early auditory information processing, and the association between ACMB and diminished MMN and P3a responses in schizophrenia patients.

Focuses on the identification of protective allele-bearing genes associated with late-onset Alzheimer disease (AD). Characterization of AD; Assessment of survival from AD in the relatives of nondemented probands groups; Examination of apolipoprotein E genotypes.

Objective: The aim of the study was to examine the association of religious education and observance with dementia among participants in the Israeli Ischemic Heart Disease study.Study Design and Setting: We assessed dementia in 1,890 participants among 2,604 survivors of 10,059 participants in the Israeli Ischemic Heart Disease study, a longitudinal investigation of the incidence and risk factors for cardiovascular disease among Jewish male civil servants in Israel. Face-to-face interviews were conducted with 651 subjects identified as possibly demented by the Modified Telephone Interview for Cognitive Status.Results: Of 1,628 subjects included in this analysis (mean age 82 at assessment), 308 (18.9%) had dementia. The prevalence rates of dementia (and odds ratios (ORs) relative to those with exclusively religious education, adjusted for age, area of birth, and socioeconomic status) were 27.1% for those with exclusively religious education, 12.6% (OR=0.49) for those with mixed education, and 16.1% (OR=0.76) for those with secular education. For religious self-definition and practice, the prevalence rates were 9.7%, 17.7%, 14.1%, 19.3%, and 28.8% for categories from least to most religious (ORs relative to the most religious: 0.43, 0.67, 0.48, 0.55).Conclusions: Examining lifestyles associated with religiosity might shed light onto environmental risks for dementia. Mechanisms underlying these associations remain elusive. [ABSTRACT FROM AUTHOR]

Objective: Many psychotropic medications used to treat schizophrenia have significant anticholinergic properties, which are linked to cognitive impairment and dementia risk in healthy subjects. Clarifying the impact of cognitive impairment attributable to anticholinergic medication burden may help optimize cognitive outcomes in schizophrenia. The aim of this study was to comprehensively characterize how this burden affects functioning across multiple cognitive domains in schizophrenia outpatients.Methods: Cross-sectional data were analyzed using inferential statistics and exploratory structural equation modeling to determine the relationship between anticholinergic medication burden and cognition. Patients with a diagnosis of schizophrenia or schizoaffective disorder (N=1,120) were recruited from the community at five U.S. universities as part of the Consortium on the Genetics of Schizophrenia-2. For each participant, prescribed medications were rated and summed according to a modified Anticholinergic Cognitive Burden (ACB) scale. Cognitive functioning was assessed by performance on domains of the Penn Computerized Neurocognitive Battery (PCNB).Results: ACB score was significantly associated with cognitive performance, with higher ACB groups scoring worse than lower ACB groups on all domains tested on the PCNB. Similar effects were seen on other cognitive tests. Effects remained significant after controlling for demographic characteristics and potential proxies of illness severity, including clinical symptoms and chlorpromazine-equivalent antipsychotic dosage.Conclusions: Anticholinergic medication burden in schizophrenia is substantial, common, conferred by multiple medication classes, and associated with cognitive impairments across all cognitive domains. Anticholinergic medication burden from all medication classes-including psychotropics used in usual care-should be considered in treatment decisions and accounted for in studies of cognitive functioning in schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response, and provides an index of neural processing speed. Schizophrenia subjects exhibit slowed latency compared to healthy controls. One prior publication reported significant heritability of latency. The current study was undertaken to replicate and extend this solitary finding in a larger cohort.Methods: Schizophrenia probands, their relatives, and control subjects from the Consortium on the Genetics of Schizophrenia (COGS-1) were tested in a paradigm to ascertain magnitude, latency, and prepulse inhibition of startle. Trial types in the paradigm were: pulse-alone, and trials with 30, 60, or 120 ms between the prepulse and pulse. Comparisons of subject groups were conducted with ANCOVAs to assess startle latency and magnitude. Heritability of startle magnitude and latency was analyzed with a variance component method implemented in SOLAR v.4.3.1.Results: 980 subjects had analyzable startle results: 199 schizophrenia probands, 456 of their relatives, and 325 controls. A mixed-design ANCOVA on startle latency in the four trial types was significant for subject group (F(2,973) = 4.45, p = 0.012) such that probands were slowest, relatives were intermediate and controls were fastest. Magnitude to pulse-alone trials differed significantly between groups by ANCOVA (F(2,974) = 3.92, p = 0.020) such that controls were lowest, probands highest, and relatives intermediate. Heritability was significant (p < 0.0001), with heritability of 34-41% for latency and 45-59% for magnitude.Conclusion: Both startle latency and magnitude are significantly heritable in the COGS-1 cohort. Startle latency is a strong candidate for being an endophenotype in schizophrenia. [ABSTRACT FROM AUTHOR]

Recently emerging evidence indicates accelerated age-related changes in the structure and function of the brain in schizophrenia, raising a question about its potential consequences on cognitive function. Using a large sample of schizophrenia patients and controls and a battery of tasks across multiple cognitive domains, we examined whether patients show accelerated age-related decline in cognition and whether an age-related effect differ between females and males. We utilized data of 1,415 schizophrenia patients and 1,062 healthy community collected by the second phase of the Consortium on the Genetics of Schizophrenia (COGS-2). A battery of cognitive tasks included the Letter-Number Span Task, two forms of the Continuous Performance Test, the California Verbal Learning Test, Second Edition, the Penn Emotion Identification Test and the Penn Facial Memory Test. The effect of age and gender on cognitive performance was examined with a general linear model. We observed age-related changes on most cognitive measures, which was similar between males and females. Compared to controls, patients showed greater deterioration in performance on attention/vigilance and greater slowness of processing social information with increasing age. However, controls showed greater age-related changes in working memory and verbal memory compared to patients. Age-related changes (η2p of 0.001 to.008) were much smaller than between-group differences (η2p of 0.005 to.037). This study found that patients showed continued decline of cognition on some domains but stable impairment or even less decline on other domains with increasing age. These findings indicate that age-related changes in cognition in schizophrenia are subtle and not uniform across multiple cognitive domains. [ABSTRACT FROM AUTHOR]

Backgrounds: The efficacy of vitamin E in prevention of diabetes-related complications differs by Haptoglobin (Hp) genotype.Objective: To examine the role of Hp genotype in the relationship of vitamin E intake with brain volume in cognitively normal elderly patients with type 2 diabetes.Methods: Brain volumes for the superior, middle, and inferior frontal gyri and for the middle temporal gyrus were generated from structural T1 MRI in 181 study participants (Hp 1-1: n = 24, Hp 2-1: n = 77, Hp 2-2: n = 80). Daily vitamin E intake was assessed using the Food Frequency Questionnaire. Analyses of covariance, controlling for demographic and cardiovascular variables was used to evaluate whether the association of daily vitamin E intake with brain volume was modified by Hp genotype.Results: Average age was 70.8 (SD = 4.2) with 40% females, and mean Mini-Mental State Examination score of 28.17 (SD = 1.90). A significant interaction was found between vitamin E intake and Hp genotype in inferior frontal gyrus' volume; p = 0.0108. For every 1 microgram increase in vitamin E intake, the volume of the inferior frontal gyrus decreased by 0.955% for Hp 1-1 (p = 0.0348), increased by 0.429% for Hp 2-1 (p = 0.0457), and by 0.077% for Hp 2-2 (p = 0.6318). There were no significant interactions between vitamin E intake and Hp genotype for the middle (p = 0.6011) and superior (p = 0.2025) frontal gyri or for the middle temporal gyrus (p = 0.503).Conclusions: The effect of dietary vitamin E on the brain may differ by Hp genotype. Studies examining the impact of vitamin E on brain-related outcomes should consider Hp genotype. [ABSTRACT FROM AUTHOR]

Background: The association between caffeine and cognitive performance has not been tested in older individuals with type 2 diabetes (T2D). Its association with brain volume in T2D has been tested only in animals.Methods: We examined the association of caffeine with cognitive function and brain volume in a sample of elderly diabetics participating in the Israel Diabetes and Cognitive Decline Study (n = 638) and the moderating effect of age on this association. In a subsample (n = 185) with magnetic resonance imaging, we also examined these associations with gray and white matter volumes (GM/WM).Results: Using linear regression adjusting for cognition-related covariates, we found that higher caffeine intake was associated with better function in overall cognition (p = .018), attention/working memory (p = .002), executive functioning (p = .047), and semantic categorization (p = .026). Interaction analyses of caffeine intake with age were significant for semantic categorization (p = .025), and approached significance for overall cognition (p = .066). This association was driven by the older group (above-median) for whom the association of caffeine intake with semantic categorization (p = .001), attention/working memory (p = .007), executive functioning (p = .005), and overall cognition (p = .002) were significant. In the magnetic resonance imaging subsample, there was an interaction (p = .034) of caffeine intake with age for GM volume; in the older group, higher caffeine intake was associated with greater GM volume (β = .198, p = .033).Conclusions: Caffeine intake may have a beneficial role in cognitive functioning of elderly adults with T2D, which may be moderated by age. Greater GM volume may be a mechanism underlying the association of higher caffeine intake with better cognitive function. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes (T2D) is a metabolic condition associated with poor clinical and cognitive outcomes including vascular disease, depressive symptoms, cognitive impairment, and dementia. In the general elderly population, depression has been consistently identified as a risk factor for cognitive impairment/decline. However, the association between depression and cognitive function in T2D has been understudied.Objective: We investigated the association between depression and cognitive function in a large sample of cognitively normal elderly with T2D.Methods: In this cross-sectional study, we examined 738 participants, aged 65-88 years old, enrolled in the Israel Diabetes and Cognitive Decline study. For each cognitive domain (Episodic Memory, Executive Function, Attention/Working Memory, Language/Semantic Categorization) and Overall Cognition, multiple linear regressions assessed its association with depression (score greater than 5 on the 15-item version of the Geriatric Depression Scale [GDS]), adjusting for age, sex, and education.Results: Depression (n = 66, 8.9%) was associated with worse performance on tasks of Executive Function (p = 0.004), Language/Semantic Categorization (p < 0.001), and Overall Cognition (p < 0.002), but not Episodic Memory (p = 0.643) or Attention/Working Memory (p = 0.488). Secondary analyses using GDS as a continuous variable did not substantially change the results. Adjusting also for a history of antidepressant medication use slightly weakened the findings.Conclusion: Significant associations of depression with several cognitive domains and Overall Cognition even in cognitively normal elderly with T2D, suggest that depression may have a role in impaired cognitive function in T2D, which may be attenuated by antidepressants. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to analyze the relationship of variability in hemoglobin A1c (HbA1c) over years with subsequent depressive symptoms.Research Design and Methods: Subjects (n = 837) were participants of the Israel Diabetes and Cognitive Decline (IDCD) study, which aimed to examine the relationship of characteristics of long-term type 2 diabetes with cognitive decline. All pertain to a diabetes registry established in 1998, which contains an average of 18 HbA1c measurements per subject. The results presented here are based on the IDCD baseline examination. Symptoms of depression were assessed using the 15-item version of the Geriatric Depression Scale (GDS). To quantify the association between variability in glycemic control (measured as the SD of HbA1c measurements [HbA1c-SD]) since 1998 with the number of depression symptoms at IDCD baseline, incidence rate ratios (IRRs) and corresponding 95% CIs were estimated via negative binomial regression modeling and used to account for the overdispersion in GDS scores.Results: Subjects' ages averaged 72.74 years (SD 4.63 years), and the mean number of years in the diabetes registry was 8.7 (SD 2.64 years). The mean GDS score was 2.16 (SD 2.26); 10% of subjects had a GDS score ≥6, the cutoff for clinically significant depression. Mean HbA1c significantly correlated with HbA1c-SD (r = 0.6625; P < 0.0001). The SD, but not the mean, of HbA1c measurements was significantly associated with the number of subsequent depressive symptoms. For each additional 1% increase in HbA1c-SD, the number of depressive symptoms increased by a factor of 1.31 (IRR = 1.31 [95% CI 1.03-1.67]; P = 0.03).Conclusions: Variability in glycemic control is associated with more depressive symptoms. [ABSTRACT FROM AUTHOR]

To find associations of age, sex, and education with neuropsychological test performance in cognitively normal Spanish-speaking Costa Rican nonagenarians with little education; to provide norms; and to compare their performance with similar Puerto Ricans. For 95 Costa Ricans (90-102 years old, 0-6 years of education), multiple regression assessed associations with demographics of performance on six neuropsychological tests. Analyses of covariance compared them with 23 Puerto Ricans (90-99 years old). Younger age and being female-but not education-were associated with better performance on some neuropsychological tests, in particular episodic memory. The Puerto Ricans performed better on learning and memory tasks. In cognitively intact Spanish-speaking nonagenarians with little or no education, education did not affect test performance. Additional studies of the effect of education on cognitive performance are warranted in other samples with extremely low education or old age. National differences in performance highlight the importance of group-specific norms. [ABSTRACT FROM AUTHOR]

Objective: The haptoglobin (Hp) genotype has been associated with cognitive function in type 2 diabetes. Because ethnicity/culture has been associated with both cognitive function and Hp genotype frequencies, we examined whether it modulates the association of Hp with cognitive function.Methods: This cross-sectional study evaluated 787 cognitively normal older individuals (>65 years of age) with type 2 diabetes participating in the Israel Diabetes and Cognitive Decline study. Interactions in two-way analyses of covariance compared Group (Non-Ashkenazi versus Ashkenazi Jews) on the associations of Hp phenotype (Hp 1-1 versus non- Hp 1-1) with five cognitive outcome measures. The primary control variables were age, gender, and education.Results: Compared with Ashkenazi Jews, non-Ashkenazi Jews with the Hp 1-1 phenotype had significantly poorer cognitive function than non-Hp 1-1 in the domains of Attention/Working Memory (p = 0.035) and Executive Function (p = 0.023), but not in Language/Semantic Categorization (p = 0.432), Episodic Memory (p = 0.268), or Overall Cognition (p = 0.082). After controlling for additional covariates (type 2 diabetes-related characteristics, cardiovascular risk factors, Mini-mental State Examination, and extent of depressive symptoms), Attention/Working Memory (p = 0.038) and Executive Function (p = 0.013) remained significant.Conclusions: Older individuals from specific ethnic/cultural backgrounds with the Hp 1-1 phenotype may benefit more from treatment targeted at decreasing or halting the detrimental effects of Hp 1-1 on the brain. Future studies should examine differential associations of Hp 1-1 and cognitive impairment, especially for groups with high prevalence of both, such as African-Americans and Hispanics. [ABSTRACT FROM AUTHOR]

In recent years, several promising susceptibility loci for late-onset Alzheimer׳s disease (AD) were discovered, by implementing genome-wide association studies (GWAS) approach. Recent GWAS meta-analysis has demonstrated the association of 19 loci (in addition to the APOE locus) with AD in the European ancestry population at genome-wide significance level. Since Type 2 Diabetes (T2D) is a substantial risk factor for cognitive decline and dementia, the 19 single nucleotide polymorphisms (SNPs) that represent the 19 AD loci were studied for association with performance in episodic memory, a primary cognitive domain affected by AD, in a sample of 848 cognitively normal elderly Israeli Jewish T2D patients. We found a suggestive association of SNP rs6733839, located near the bridging integrator 1 ( BIN1 ) gene, with this phenotype. Controlling for demographic (age, sex, education, disease duration and ancestry) covariates, carriers of two copies of the AD risk allele T (TT genotype) performed significantly worse ( p =0.00576; p= 0.00127 among Ashkenazi origin sub-sample) in episodic memory compared to carriers of the C allele (CT+CC genotypes). When including additional potential covariates (clinical and APOE genotype), results remained significant ( p =0.00769; p= 0.00148 among Ashkenazi). Interestingly, as validated in multiple large studies, BIN1 is one of the most established AD risk loci, with a high odds ratio. Although preliminary and require further replications, our findings support a contribution of BIN1 to individual differences in episodic memory performance among T2D patients. [ABSTRACT FROM AUTHOR]

Objective: The Consortium on the Genetics of Schizophrenia Family Study evaluated 12 primary and other supplementary neurocognitive and neurophysiological endophenotypes in schizophrenia probands and their families. Previous analyses of prepulse inhibition (PPI) and P50 gating measures in this sample revealed heritability estimates that were lower than expected based on earlier family studies. Here the authors investigated whether gating measures were more heritable in multiply affected families with a positive family history compared with families with only a single affected proband (singleton).Method: A total of 296 nuclear families consisting of a schizophrenia proband, at least one unaffected sibling, and both parents underwent a comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives. Among the families, 97 were multiply affected, and 96 were singletons.Results: Both PPI and P50 gating displayed substantially increased heritability in the 97 multiply affected families (47% and 36%, respectively) compared with estimates derived from the entire sample of 296 families (29% and 20%, respectively). However, no evidence for heritability was observed for either measure in the 96 singleton families. Schizophrenia probands derived from the multiply affected families also displayed a significantly increased severity of clinical symptoms compared with those from singleton families.Conclusions: PPI and P50 gating measures demonstrate substantially increased heritability in schizophrenia families with a higher genetic vulnerability for illness, providing further support for the commonality of genes underlying both schizophrenia and gating measures. [ABSTRACT FROM AUTHOR]

The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation. [ABSTRACT FROM AUTHOR]

Objective: Glycated hemoglobin (HbA1c) and C-reactive protein (CRP) have been associated with cognitive impairment independently. However, it is unclear if their combination exacerbates poor cognitive function. We assessed whether long-term glycemic level and glycemic variability modulate the association of systemic inflammation with cognitive function, in a sample of cognitively normal older people with type 2 diabetes.Methods: A retrospective cohort study of 777 randomly selected participants from ~11,000 patients in the Maccabi Healthcare Services Diabetes Registry, as part of the Israel Diabetes and Cognitive Decline study. Subjects averaged 18 (±9.4) HbA1c measures in the Maccabi Healthcare Services Registry, which were used to calculate long-term glycemic level (HbA1c-mean) and glycemic variability (HbA1c-standard deviation (SD)). Linear regression models assessed the interactions of CRP, a marker of systemic inflammation, with HbA1c-mean and HbA1c-SD on subjects' performance in tests of Memory, Executive Functions, Attention, and Semantic Categorization.Results: Quadratic interactions of CRP with HbA1c-SD approached significance for executive functions and overall cognition. However, after Bonferroni adjustment, none of the interactions of CRP with HbA1c were statistically significant. In partial correlations according to HbA1c-SD tertiles, CRP was weakly correlated in the middle tertile with decreased performance in the domains of semantic categorization (r = -0.166, p = 0.011), executive functions (r = -0.136, p = 0.038), and overall cognition (r = -0.157, p = 0.016).Conclusions: Glycated hemoglobin does not substantially modulate the association of CRP with cognition in a sample of cognitively normal, community dwelling older people with relatively well-managed type 2 diabetes. [ABSTRACT FROM AUTHOR]

We studied the relationship of adult body height with five cognitive outcomes (executive functioning, semantic categorization, attention/working memory, episodic memory, and an overall cognition measure) in 897 cognitively normal elderly with type 2 diabetes. Regression analyses controlling for sociodemographic, cardiovascular, and diabetes-related risk factors and depression demonstrated that in males, shorter stature was associated with poorer executive functioning (p = 0.001), attention/working memory (p = 0.007), and overall cognition (p = 0.016), but not with episodic memory (p = 0.715) or semantic categorization (p = 0.948). No relationship between height and cognition was found for females. In cognitively normal type 2 diabetes male subjects, shorter stature, a surrogate for early-life stress and poor nutrition, was associated with cognitive functions. [ABSTRACT FROM AUTHOR]

Attention/vigilance impairments are present in individuals with schizophrenia across psychotic and remitted states and in their first-degree relatives. An important question is whether deficits in attention/vigilance can be consistently and reliably measured across sites varying in many participant demographic, clinical, and functional characteristics, as needed for large-scale genetic studies of endophenotypes. We examined Continuous Performance Test (CPT) data from phase 2 of the Consortium on the Genetics of Schizophrenia (COGS-2), the largest-scale assessment of cognitive and psychophysiological endophenotypes relevant to schizophrenia. The CPT data from 2251 participants from five sites were examined. A perceptual-load vigilance task (the Degraded Stimulus CPT or DS-CPT) and a memory-load vigilance task (CPT-Identical Pairs or CPT-IP) were utilized. Schizophrenia patients performed more poorly than healthy comparison subjects (HCS) across sites, despite significant site differences in participant age, sex, education, and racial distribution. Patient–HCS differences in signal/noise discrimination (d′) in the DS-CPT varied significantly across sites, but averaged a medium effect size. CPT-IP performance showed large patient–HCS differences across sites. Poor CPT performance was independent of or weakly correlated with symptom severity, but was significantly associated with lower educational achievement and functional capacity. Current smoking was associated with poorer CPT-IP d′. Patients taking both atypical and typical antipsychotic medication performed more poorly than those on no or atypical antipsychotic medications, likely reflecting their greater severity of illness. We conclude that CPT deficits in schizophrenia can be reliably detected across sites, are relatively independent of current symptom severity, and are related to functional capacity. [ABSTRACT FROM AUTHOR]

Reduced auditory P300 amplitude is a robust schizophrenia deficit exhibiting the qualities of a viable genetic endophenotype. These include heritability, test–retest reliability, and trait-like stability. Recent evidence suggests that P300 may also serve as a predictive biomarker for transition to psychosis during the schizophrenia prodrome. Historically, the utility of the P300 has been limited by its clinical nonspecificity, cross-site measurement variability, and required EEG expertise. The Consortium on the Genetics of Schizophrenia (COGS-2) study provided an opportunity to examine the consistency of the measure across multiple sites with varying degrees of EEG experience, and to identify important modulating factors that contribute to measurement variability. Auditory P300 was acquired from 649 controls and 587 patients at 5 sites. An overall patient deficit was observed with effect size 0.62. Each site independently observed a significant patient deficit, but site differences also existed. In patients, site differences reflected clinical differences in positive symptomatology and functional capacity. In controls, site differences reflected differences in racial stratification, smoking and substance use history. These factors differentially suppressed the P300 response, but only in control subjects. This led to an attenuated patient-control difference among smokers and among African Americans with history of substance use. These findings indicate that the P300 can be adequately assessed quantitatively, across sites, without substantial EEG expertise. Measurements are suitable for both genetic endophenotype analyses and studies of psychosis risk and conversion. However, careful attention must be given to selection of appropriate comparison samples to avoid misleading false negative results. [ABSTRACT FROM AUTHOR]

The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) showed performance deficits in learning and memory on the California Verbal Learning Test, Second Edition (CVLT-II) in individuals with schizophrenia (SZ), compared to healthy comparison subjects (HCS). A question is whether the COGS-1 study, which used a family study design (i.e. studying relatively intact families), yielded “milder” SZ phenotypes than those acquired subsequently in the COGS-2 case–control design that did not recruit unaffected family members. CVLT-II performance was compared for the COGS-1 and COGS-2 samples. Analyses focused on learning, recall and recognition variables, with age, gender and education as covariates. Analyses of COGS-2 data explored effects of additional covariates and moderating factors in CVLT-II performance. 324 SZ subjects and 510 HCS had complete CVLT-II and covariate data in COGS-1, while 1356 SZ and 1036 HCS had complete data in COGS-2. Except for recognition memory, analysis of covariance showed significantly worse performance in COGS-2 on all CVLT-II variables for SZ and HCS, and remained significant in the presence of the covariates. Performance in each of the 5 learning trials differed significantly. However, effect sizes comparing cases and controls were comparable across the two studies. COGS-2 analyses confirmed SZ performance deficits despite effects of multiple significant covariates and moderating factors. CVLT-II performance was worse in COGS-2 than in COGS-1 for both the SZ and the HCS in this large cohort, likely due to cohort effects. Demographically corrected data yield a consistent pattern of performance across the two studies in SZ. [ABSTRACT FROM AUTHOR]

Background Although many endophenotypes for schizophrenia have been studied individually, few studies have examined the extent to which common neurocognitive and neurophysiological measures reflect shared versus unique endophenotypic factors. It may be possible to distill individual endophenotypes into composite measures that reflect dissociable, genetically informative elements. Methods The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) is a multisite family study that collected neurocognitive and neurophysiological data between 2003 and 2008. For these analyses, participants included schizophrenia probands ( n = 83), their nonpsychotic siblings ( n = 151), and community comparison subjects ( n = 209) with complete data on a battery of 12 neurocognitive tests (assessing domains of working memory, declarative memory, vigilance, spatial ability, abstract reasoning, facial emotion processing, and motor speed) and 3 neurophysiological tasks reflecting inhibitory processing (P50 gating, prepulse inhibition and antisaccade tasks). Factor analyses were conducted on the measures for each subject group and across the entire sample. Heritability analyses of factors were performed using SOLAR. Results Analyses yielded 5 distinct factors: 1) Episodic Memory, 2) Working Memory, 3) Perceptual Vigilance, 4) Visual Abstraction, and 5) Inhibitory Processing. Neurophysiological measures had low associations with these factors. The factor structure of endophenotypes was largely comparable across probands, siblings and controls. Significant heritability estimates for the factors ranged from 22% (Episodic Memory) to 39% (Visual Abstraction). Conclusions Neurocognitive measures reflect a meaningful amount of shared variance whereas the neurophysiological measures reflect largely unique contributions as endophenotypes for schizophrenia. Composite endophenotype measures may inform our neurobiological and genetic understanding of schizophrenia. [ABSTRACT FROM AUTHOR]

The impaired ability to make correct antisaccades (i.e., antisaccade performance) is well documented among schizophrenia subjects, and researchers have successfully demonstrated that antisaccade performance is a valid schizophrenia endophenotype that is useful for genetic studies. However, it is unclear how the ascertainment biases that unavoidably result from recruitment differences in schizophrenia subjects identified in family versus case–control studies may influence patient–control differences in antisaccade performance. To assess the impact of ascertainment bias, researchers from the Consortium on the Genetics of Schizophrenia (COGS) compared antisaccade performance and antisaccade metrics (latency and gain) in schizophrenia and control subjects from COGS-1, a family-based schizophrenia study, to schizophrenia and control subjects from COGS-2, a corresponding case–control study. COGS-2 schizophrenia subjects were substantially older; had lower education status, worse psychosocial function, and more severe symptoms; and were three times more likely to be a member of a multiplex family than COGS-1 schizophrenia subjects. Despite these variations, which were likely the result of ascertainment differences (as described in the introduction to this special issue), the effect sizes of the control–schizophrenia differences in antisaccade performance were similar in both studies (Cohen's d effect size of 1.06 and 1.01 in COGS-1 and COGS-2, respectively). This suggests that, in addition to the robust, state-independent schizophrenia-related deficits described in endophenotype studies, group differences in antisaccade performance do not vary based on subject ascertainment and recruitment factors. [ABSTRACT FROM AUTHOR]

Objectives Working memory impairment has been extensively studied in schizophrenia, but less is known about moderators of the impairment. Using the Consortium on the Genetics of Schizophrenia case-control study (COGS-2), we examined smoking status, types of antipsychotic medication, and history of substance as moderators for working memory impairment in schizophrenia. Methods From 5 sites, 1377 patients with schizophrenia or schizoaffective, depressed type and 1037 healthy controls completed the letter–number span (LNS) task. The LNS uses intermixed letter and digit stimuli that increase from 2 up to 8 stimuli. In the forward condition, participants repeated the letters and numbers in the order they were presented. In the reorder condition, participants repeated the digits in ascending order followed by letters in alphabetical order. Results Schizophrenia patients performed more poorly than controls, with a larger difference on reorder than forward conditions. Deficits were associated with symptoms, functional capacity, and functional outcome. Patients who smoked showed larger impairment than nonsmoking patients, primarily due to deficits on the reorder condition. The impairing association of smoking was more pronounced among patients taking first-generation than those taking second-generation antipsychotic medications. Correlations between working memory and community functioning were stronger for nonsmokers. History of substance use did not moderate working memory impairment. Conclusions Results confirm the working memory impairment in schizophrenia, and indicate smoking status as an important moderator for these deficits. The greater impairment in smokers may reflect added burden of smoking on general health or that patients with greater deficits are more likely to smoke. [ABSTRACT FROM AUTHOR]

Background Neurocognitive deficits in schizophrenia (SZ) are established and the Consortium on the Genetics of Schizophrenia (COGS) investigated such measures as endophenotypes in family-based (COGS-1) and case-control (COGS-2) studies. By requiring family participation, family-based sampling may result in samples that vary demographically and perform better on neurocognitive measures. Methods The Penn computerized neurocognitive battery (CNB) evaluates accuracy and speed of performance for several domains and was administered across sites in COGS-1 and COGS-2. Most tests were included in both studies. COGS-1 included 328 patients with SZ and 497 healthy comparison subjects (HCS) and COGS-2 included 1195 patients and 1009 HCS. Results Demographically, COGS-1 participants were younger, more educated, with more educated parents and higher estimated IQ compared to COGS-2 participants. After controlling for demographics, the two samples produced very similar performance profiles compared to their respective controls. As expected, performance was better and with smaller effect sizes compared to controls in COGS-1 relative to COGS-2. Better performance was most pronounced for spatial processing while emotion identification had large effect sizes for both accuracy and speed in both samples. Performance was positively correlated with functioning and negatively with negative and positive symptoms in both samples, but correlations were attenuated in COGS-2, especially with positive symptoms. Conclusions Patients ascertained through family-based design have more favorable demographics and better performance on some neurocognitive domains. Thus, studies that use case-control ascertainment may tap into populations with more severe forms of illness that are exposed to less favorable factors compared to those ascertained with family-based designs. [ABSTRACT FROM AUTHOR]

Mismatch negativity (MMN) and P3a are auditory event-related potential (ERP) components that show robust deficits in schizophrenia (SZ) patients and exhibit qualities of endophenotypes, including substantial heritability, test–retest reliability, and trait-like stability. These measures also fulfill criteria for use as cognition and function-linked biomarkers in outcome studies, but have not yet been validated for use in large-scale multi-site clinical studies. This study tested the feasibility of adding MMN and P3a to the ongoing Consortium on the Genetics of Schizophrenia (COGS) study. The extent to which demographic, clinical, cognitive, and functional characteristics contribute to variability in MMN and P3a amplitudes was also examined. Participants (HCS n = 824, SZ n = 966) underwent testing at 5 geographically distributed COGS laboratories. Valid ERP recordings were obtained from 91% of HCS and 91% of SZ patients. Highly significant MMN (d = 0.96) and P3a (d = 0.93) amplitude reductions were observed in SZ patients, comparable in magnitude to those observed in single-lab studies with no appreciable differences across laboratories. Demographic characteristics accounted for 26% and 18% of the variance in MMN and P3a amplitudes, respectively. Significant relationships were observed among demographically-adjusted MMN and P3a measures and medication status as well as several clinical, cognitive, and functional characteristics of the SZ patients. This study demonstrates that MMN and P3a ERP biomarkers can be feasibly used in multi-site clinical studies. As with many clinical tests of brain function, demographic factors contribute to MMN and P3a amplitudes and should be carefully considered in future biomarker-informed clinical studies. [ABSTRACT FROM AUTHOR]

Regression analyses compared 41 type 2 diabetes (T2D) and 131 non-T2D cognitively normal elderly males on the associations of arterial wall function measures [large artery elasticity index (LAEI), small artery elasticity index (SAEI), systemic vascular resistance (SVR), and total vascular impedance (TVI)] with cognitive performance (memory, language, and executive functions), controlling for socio-demographic and cardiovascular factors. Higher LAEI and lower TVI were significantly associated with better executive functions performance in T2D but not in non-T2D subjects. Lower TVI was more associated with better language performance in T2D. Results suggest that arterial wall function is associated with cognition in T2D. [ABSTRACT FROM AUTHOR]

Background DSM-5 places schizophrenia on a continuum from severe, chronic schizophrenia to the attenuated schizophrenia-like traits of schizotypal personality disorder (SPD), the prototypic schizophrenia-related personality disorder. SPD shares common genetic and neurobiological substrates with schizophrenia, including information processing abnormalities, although they are less marked. This is the first study to directly compare the P50 evoked electroencephalographic response—a measure of sensory gating and a neurophysiological endophenotype—between schizophrenia-spectrum groups. Two hypotheses were tested: (1) Compared with healthy controls (HCs), schizophrenia patients show reduced P50 suppression and SPD patients resemble schizophrenia but exhibit less marked deficits; and (2) Deficient P50 suppression in SPD is associated with greater clinical symptom severity. Methods P50 was assessed in 32 schizophrenia-spectrum disorder patients (12 SPD, 20 schizophrenia patients) and 25 demographically-matched HCs. The standard conditioning (C)-testing (T) paradigm was used and P50 suppression was quantified using the T–C difference and the T/C ratio. Results All P50 measures showed a linear, stepwise pattern with the SPD group intermediate between the HC and schizophrenia groups. Compared with HCs, both patient groups had lower conditioning and T–C difference values. Among the SPD group, greater clinical symptom severity was associated with greater conditioning-response amplitude deficits. Conclusion These findings: (1) are novel in showing that P50 deficits in SPD resemble those observed in schizophrenia, albeit less marked; (2) support the concept that the phenomenological link between SPD and schizophrenia lies in shared neurocognitive/neurophysiological pathologies; and (3) provide evidence that P50 is a neurophysiological endophenotype for schizophrenia-spectrum disorders. [ABSTRACT FROM AUTHOR]

We studied the relationship of adult body height with five cognitive outcomes (executive functioning, semantic categorization, attention/working memory, episodic memory, and an overall cognition measure) in 897 cognitively normal elderly with type 2 diabetes. Regression analyses controlling for sociodemographic, cardiovascular, and diabetes-related risk factors and depression demonstrated that in males, shorter stature was associated with poorer executive functioning (p = 0.001), attention/working memory (p = 0.007), and overall cognition (p = 0.016), but not with episodic memory (p = 0.715) or semantic categorization (p = 0.948). No relationship between height and cognition was found for females. In cognitively normal type 2 diabetes male subjects, shorter stature, a surrogate for early-life stress and poor nutrition, was associated with cognitive functions. [ABSTRACT FROM AUTHOR]

Regression analyses compared 41 type 2 diabetes (T2D) and 131 non-T2D cognitively normal elderly males on the associations of arterial wall function measures [large artery elasticity index (LAEI), small artery elasticity index (SAEI), systemic vascular resistance (SVR), and total vascular impedance (TVI)] with cognitive performance (memory, language, and executive functions), controlling for socio-demographic and cardiovascular factors. Higher LAEI and lower TVI were significantly associated with better executive functions performance in T2D but not in non-T2D subjects. Lower TVI was more associated with better language performance in T2D. Results suggest that arterial wall function is associated with cognition in T2D. [ABSTRACT FROM AUTHOR]

Self-injurious behavior in autism spectrum disorder (ASD) has been associated with lower whole blood serotonin levels and the role of serotonin transporter gene promoter region (5HTTLPR) polymorphisms is of interest because of their effects on transporter functioning. This study examined the association between self-injurious behavior in ASD and allelic frequencies of 5HTTLPR. Sixty-four children and adolescents with ASD who were not taking serotonergic medication at the time of the assessment were included in the analysis. Self-injury was assessed using the Autism Diagnostic Interview-Revised (ADI-R) and whole blood serotonin levels were measured using high-pressure liquid chromatography (HPLC) with fluorometic detection. DNA was extracted from saliva and PCR amplified with fluorescent primers. Self-injury significantly increased with the number of La alleles of the 5HTTLPR and decreased with the number of Lg alleles. Self-injury in ASD may be associated with a specific genotype of the serotonin transporter gene promoter region. Future studies should continue to explore subgroups to clarify the underlying clinical and genetic heterogeneity in ASD. [ABSTRACT FROM AUTHOR]

The variable length poly-T, rs10524523 ('523') located within the TOMM40 gene, was recently associated with several phenotypes of cognitive function. The short (S) allele is associated with later AD onset age and better cognitive performance, compared to the longer alleles (long and very-long (VL)). There is strong linkage disequilibrium between variants in the TOMM40 and APOE genes. In this study, we investigated the effect of '523' on cognitive performance in a sample of cognitively normal Jewish elderly with type 2 diabetes, a group at particularly high risk for cognitive impairment. Using a MANCOVA procedure, we compared homozygous carriers of the S/S allele (N=179) to carriers of the VL/VL allele (N=152), controlling for demographic and cardiovascular covariates. The S/S group performed better than the VL/VL group (p=0.048), specifically in the executive function (p=0.04) and episodic memory (p=0.050) domains. These results suggest that previous findings of an association of the TOMM40 short allele with better cognitive performance, independently from the APOE variant status, are pertinent to elderly with diabetes. [ABSTRACT FROM AUTHOR]

Aim To assess whether the APOE4 genotype affects the relationship of long-term glycemic control with cognitive function in elderly with type 2 diabetes (T2D). Methods Participants were cognitively normal and pertained to a Diabetes Registry which provided access to HbA1c levels and other T2D related factors since 1998. Glycemic control was defined as the mean of all HbA1c measurements available (averaging 18 measurements) per subject. Four cognitive domains (episodic memory, semantic categorization, attention/working memory and executive function), based on factor analysis and an overall cognitive score (the sum of the 4 cognitive domains) were the outcome measures. Results The analysis included 808 subjects; 107 (11.9%) subjects had ≥1ApoE4 allele. In ApoE4 carriers, higher mean HbA1c level was significantly associated with lower scores on all cognitive measures except attention/working memory ( p -values ranging from 0.047 to 0.003). In ApoE4 non-carriers, higher mean HbA1c level was significantly associated with lower scores on executive function, but not with other cognitive measures—despite the larger sample size. Compared to non-carriers, there were significantly stronger associations in ApoE4 carriers for overall cognition ( p =0.02), semantic categorization ( p =0.03) and episodic memory ( p =0.02), and the difference for executive function approached statistical significance ( p =0.06). Conclusion In this cross-sectional study of cognitively normal T2D subjects, higher mean HbA1c levels were generally associated with lower cognitive performance in ApoE4 carriers, but not in non-carriers, suggesting that ApoE4 affects the relationship between long-term glycemic control and cognition, so APOE4 carriers may be more vulnerable to the insults of poor glycemic control. [ABSTRACT FROM AUTHOR]

Objective: To study the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (T2D). Methods: Subjects (n = 835) pertain to a diabetes registry (DR) established in 1998 with an average of 18 HbA1c measurements per subject, permitting identification of distinctive trajectory groups of HbA1c and examining their association with cognitive function in five domains: episodic memory, semantic categorization, attention/working memory, executive function, and overall cognition. Analyses of covariance compared cognitive function among the trajectory groups adjusting for sociodemographic, cardiovascular, diabetes-related covariates and depression. Results: Subjects averaged 72.8 years of age. Six trajectories of HbA1c were identified, characterized by HbA1c level at entry into the DR (Higher/Lower), and trend over time (Stable/Decreasing/Increasing). Both groups with a trajectory of decreasing HbA1c levels had high HbA1c levels at entry into the DR (9.2%, 10.7%), and high, though decreasing, HbA1c levels over time. They had the worst cognitive performance, particularly in overall cognition (p<0.02) and semantic categorization (p<0.01), followed by that of subjects whose HbA1c at entry into the DR was relatively high (7.2%, 7.8%) and increased over time. Subjects with stable HbA1c over time had the lowest HbA1c levels at entry (6.0%, 6.8%) and performed best in cognitive tests. Conclusion: Glycemic control trajectories, which better reflect chronicity of T2D than a single HbA1c measurement, predict cognitive performance. A trajectory of stable HbA1c levels over time is associated with better cognitive function. [ABSTRACT FROM AUTHOR]

Objective To evaluate the relationships of age, education, and gender with performance on neuropsychological tests in a cognitively intact, older Israeli sample with type 2 diabetes (T2D). Methods We examined 862 participants, 65-84 years old, enrolled in the Israel Diabetes and Cognitive Decline study. Multiple regression assessed associations of performance on 17 neuropsychological tests, including the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery, with age, education, and gender. Results Higher education and younger age were consistently associated with better performance. Women outperformed men on all memory tasks; men outperformed women on two non-verbal measures. These patterns of demographic associations with cognitive performance were very similar to those of US cohorts. Conclusions In a cognitively intact, older Israeli sample with T2D, better test performance is associated primarily with higher education, followed by younger age and gender differences. Although T2D is associated with cognitive deficits, it recapitulates the patterns of relationships between cognitive performance and demographic characteristics seen in non-T2D diabetic samples. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Background: Startle inhibition by weak prepulses (PPI) is studied to understand the biology of information processing in schizophrenia patients and healthy comparison subjects (HCS). The Consortium on the Genetics of Schizophrenia (COGS) identified associations between PPI and single nucleotide polymorphisms in schizophrenia probands and unaffected relatives, and linkage analyses extended evidence for the genetics of PPI deficits in schizophrenia in the COGS-1 family study. These findings are being extended in a 5-site “COGS-2” study of 1800 patients and 1200 unrelated HCS to facilitate genetic analyses. We describe a planned interim analysis of COGS-2 PPI data. Methods: Eyeblink startle was measured in carefully screened HCS and schizophrenia patients (n=1402). Planned analyses of PPI (60ms intervals) assessed effects of diagnosis, sex and test site, PPI-modifying effects of medications and smoking, and relationships between PPI and neurocognitive measures. Results: 884 subjects met strict inclusion criteria. ANOVA of PPI revealed significant effects of diagnosis (p=0.0005) and sex (p<0.002), and a significant diagnosis×test site interaction. HCS>schizophrenia PPI differences were greatest among patients not taking 2nd generation antipsychotics, and were independent of smoking status. Modest but significant relationships were detected between PPI and performance in specific neurocognitive measures. Discussion: The COGS-2 multi-site study detects schizophrenia-related PPI deficits reported in single-site studies, including patterns related to diagnosis, prepulse interval, sex, medication and other neurocognitive measures. Site differences were detected and explored. The target COGS-2 schizophrenia “endophenotype” of reduced PPI should prove valuable for identifying and confirming schizophrenia risk genes in future analyses. [Copyright &y& Elsevier]

OBJECTIVE--Haptoglobin (Hp) genotype (Hp 1-1,1-2, or 2-2) is associated with risk for type 2 diabetes complications, but its relationship with cognitive compromise, a growing concern in type 2 diabetes, has rarely been studied. This study investigated whether Hp genotype is associated with cognitive function in cognitively normal elderly diabetic subjects. RESEARCH DESIGN AND METHODS--Relationships of Hp genotype with episodic memory, semantic categorization, attention/working memory and executive function, and an overall cognitive score were examined in subjects from the Israel Diabetes and Cognitive Decline (IDCD) study. RESULTS--In the present analysis, 812 subjects participated (84 with Hp 1-1, 335 with Hp 1-2, and 393 with Hp 2-2 genotypes). Average was 72.9 years of age (SD 4.7), and Mini-Mental State Exam (MMSE) was 28.0 (SD 1.8). Compared with subjects with Hp 1-2 genotype, Hp 1-1 subjects performed significantly worse in semantic categorization (F = 7.03; P = 0.008) and the overall cognitive score (F = 5.57; P = 0.02). A separate stepwise multiple regression analysis demonstrated that compared with subjects with Hp 2-2 genotype, Hp 1-1 subjects performed significantly worse in semantic categorization (F = 4.18; P = 0.04) and the overall cognitive score (F = 4.70; P = 0.03). The contribution of cardiovascular risk factors to cognition was significantly higher in subjects with Hp 1-1 genotype compared with Hp 2 carriers (Hp 1-2 and Hp 2-2) in the semantic categorization (P = 0.009) and attention/working memory (P = 0.002) cognitive domains. CONCLUSIONS--Compared with Hp 2 carriers, those with Hp 1-1 genotype present lower cognitive performance. Stronger relationships between cardiovascular risk factors and cognition in the latter group may suggest an underlying vascular mechanism. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the relationships of age, education, and gender with performance on neuropsychological tests in a cognitively intact, older Israeli sample with type 2 diabetes (T2D). Methods: We examined 862 participants, 65–84 years old, enrolled in the Israel Diabetes and Cognitive Decline study. Multiple regression assessed associations of performance on 17 neuropsychological tests, including the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery, with age, education, and gender. Results: Higher education and younger age were consistently associated with better performance. Women outperformed men on all memory tasks; men outperformed women on two non-verbal measures. These patterns of demographic associations with cognitive performance were very similar to those of US cohorts. Conclusions: In a cognitively intact, older Israeli sample with T2D, better test performance is associated primarily with higher education, followed by younger age and gender differences. Although T2D is associated with cognitive deficits, it recapitulates the patterns of relationships between cognitive performance and demographic characteristics seen in non-T2D diabetic samples. [ABSTRACT FROM AUTHOR]

Background: Numerous studies have documented that patients with schizophrenia show neurocognitive impairments, which are also heritable in schizophrenia families. In view of these findings, the current investigation tested the hypothesis that neurocognitive performance of schizophrenia probands can predict the neurocognitive performance of their unaffected family members. Methods: Participants (n=1967; schizophrenia=369; first-degree relatives=1072; community comparison subjects=526) in the Consortium on the Genetics of Schizophrenia were administered the Penn Computerized Neurocognitive Battery. Results: Consistent with prior work, probands showed significant neurocognitive impairment, and neurocognitive ability was significantly heritable across domains. On average, unaffected relatives did not differ from community comparison subjects in their neurocognitive performance. However, in six of seven domains, proband scores predicted the performance of their unaffected siblings. Male, but not female, proband performance was predictive of their unaffected relatives’ (siblings and mothers) performance, most consistently in face memory and spatial processing. Conclusions: Using a novel approach in which individual probands are paired with their respective unaffected relatives within each family, we found that male proband performance predicted both sister and brother performance, an effect that was most powerfully observed for face memory and spatial processing. Results suggest that the familial transmission of sexually dimorphic neurocognitive domains, in which a particular sex tends to show a performance advantage over the other, may not itself be sex specific in schizophrenia families. [Copyright &y& Elsevier]

Objective: The Consortium on the Genetics of Schizophrenia has undertaken a large multisite study to characterize 12 neurophysiological and neurocognitive endophenotypic measures as a step toward understanding the complex genetic basis of schizophrenia. The authors previously demonstrated the heritability of these endophenotypes; in the present study, genetic linkage was evaluated. Method: Each family consisted of a proband with schizophrenia, at least one unaffected sibling, and both parents. A total of 1,286 participants from 296 families were genotyped in two phases, and 1,004 individuals were also assessed for the endophenotypes. Linkage analyses of the 6,055 singlenucleotide polymorphisms that were successfully assayed, 5,760 of which were common to both phases, were conducted using both variance components and pedigreewide regression methods. Results: Linkage analyses of the 12 endophenotypes collectively identified one region meeting genome-wide significance criteria, with a LOD (log of odds) score of 4.0 on chromosome 3p14 for the antisaccade task, and another region on 1p36 nearly meeting genome-wide significance, with a LOD score of 3.5 for emotion recognition. Chromosomal regions meeting genome-wide suggestive criteria with LOD scores >2.2 were identified for spatial processing (2p25 and 16q23), sensorimotor dexterity (2q24 and 2q32), prepulse inhibition (5p15), the California Verbal Learning Test (8q24), the degradedstimulus Continuous Performance Test (10q26), face memory (10q26 and 12p12), and the Letter-Number Span (14q23). Conclusions: Twelve regions meeting genome-wide significant and suggestive criteria for previously identified heritable, schizophrenia-related endophenotypes were observed, and several genes of potential neurobiological interest were identified. Replication and further genomic studies are needed to assess the biological significance of these results. [ABSTRACT FROM AUTHOR]

Objective: Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia. Method: Based on the Lifetime Dimensions of Psychosis Scale ratings of 2,454 case subjects of European ancestry from the Molecular Genetics of Schizophrenia (MGS) sample, three symptom factors (positive, negative/disorganized, andmood) were identified with exploratory factor analysis. Quantitative scores for each factor from a confirmatory factor analysis were analyzed for association with 696,491 single-nucleotide polymorphisms (SNPs) using linear regression, with correction for age, sex, clinical site, and ancestry. Polygenic score analysis was carried out to determine whether case and comparison subjects in 16 Psychiatric GWAS Consortium (PGC) schizophrenia samples (excluding MGS samples) differed in scores computed by weighting their genotypes by MGS association test results for each symptom factor. Results: No genome-wide significant associations were observed between SNPs and factor scores. Most of the SNPs producing the strongest evidence for association were in or near genes involved in neurodevelopment, neuroprotection, or neurotransmission, including genes playing a role in Mendelian CNS diseases, but no statistically significant effect was observed for any defined gene pathway. Finally, polygenic scores based on MGS GWAS results for the negative/disorganized factor were significantly different between case and comparison subjects in the PGC data set; for MGS subjects, negative/ disorganized factor scores were correlated with polygenic scores generated using case-control GWAS results from the other PGC samples. Conclusions: The polygenic signal that has been observed in cross-sample analyses of schizophrenia GWAS data sets could be in part related to genetic effects on negative and disorganized symptoms (i.e., core features of chronic schizophrenia). [ABSTRACT FROM AUTHOR]