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1.  Association of Apolipoprotein E-e4 and Dementia Declines with Age 
Objective
To study the association of dementia with APOE-e4 and its interaction with age in a nonagenarian Costa Ricans (N-sample) and a general elderly contrast group (GE-sample).
Methods
In both case-control studies, participants were cognitively intact or demented. The N-sample (N=112) was at least age 90; the GE-sample (N=98) was at least age 65.
Results
Dementia and APOE-e4 were not significantly associated in the N-sample, but were in the GE-sample. There was a significant interaction of age with APOE-e4 in the N-sample, but not in the GE-sample. Descriptively dividing the N-sample at the median (age 93) showed a group interaction: APOE-e4 was more associated with dementia in the younger N-sample than in the older N-sample, where six of seven APOE-e4 carriers were cognitively intact.
Conclusions
The results support the reduction in association of APOE-e4 with dementia in extreme old age, consistent with a survivor effect model for successful cognitive aging.
doi:10.1016/j.jagp.2014.03.008
PMCID: PMC4163532  PMID: 24731780
Successful cognitive aging; oldest-old; dementia risk factors
2.  Paternal age of schizophrenia probands and endophenotypic differences from unaffected siblings 
Psychiatry research  2014;219(1):67-71.
Objective
To evaluate the discrepancy of endophenotypic performance between probands with schizophrenia and unaffected siblings by paternal age at proband birth, a possible marker for de novo mutations.
Methods
Pairs of schizophrenia probands and unaffected siblings (N=220 pairs) were evaluated on 11 neuropsychological or neurophysiological endophenotypes previously identified as heritable. For each endophenotype, the sibling-minus-proband differences were transformed to standardized scores. Then for each pair, the average discrepancy was calculated from its standardized scores. We tested the hypothesis that the discrepancy is associated with paternal age, controlling for the number of endophenotypes shared between proband and his or her sibling, and proband age, which were both associated with paternal age.
Results
The non-significant association between the discrepancy and paternal age was in the opposite direction from the hypothesis. Of the 11 endophenotypes only sensori-motor dexterity was significant, but in the opposite direction. Eight other endophenotypes were also in the opposite direction, but not significant.
Discussion
The results did not support the hypothesized association of increased differences between sibling/proband pairs with greater paternal age. A possible explanation is that the identification of heritable endophenotypes was based on samples for which schizophrenia was attributable to inherited rather than de novo/non-inherited causes.
doi:10.1016/j.psychres.2014.05.035
PMCID: PMC4110721  PMID: 24913833
de novo mutations; copy number variants; genetic risk; familial schizophrenia; sporadic schizophrenia
3.  The Apo E 4 genotype modifies the relationship of long-term glycemic control with cognitive functioning in elderly with type 2 diabetes 
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 noncarriers, 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.
doi:10.1016/j.euroneuro.2014.05.001
PMCID: PMC4132827  PMID: 24875283
ApoE; glycemic control; HbA1c; cognition; type 2 diabetes
4.  Verbal Working Memory in Schizophrenia from the Consortium on the Genetics of Schizophrenia (COGS) Study: The Moderating Role of Smoking Status and Antipsychotic Medications 
Schizophrenia research  2014;163(0):24-31.
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.
doi:10.1016/j.schres.2014.08.014
PMCID: PMC4368500  PMID: 25248939
schizophrenia; verbal working memory; letter-number span; moderators; smoking; antipsychotic medication
5.  The Utility of P300 as a Schizophrenia Endophenotype and Predictive Biomarker: Clinical and Socio-Demographic Modulators in COGS-2 
Schizophrenia research  2014;163(0):53-62.
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 control 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.
doi:10.1016/j.schres.2014.09.024
PMCID: PMC4382423  PMID: 25306203
P300; Schizophrenia; Endophenotype; Biomarker; Event-Related Potential
6.  Attention/Vigilance in Schizophrenia: Performance Results from a Large Multi-Site Study of the Consortium on the Genetics of Schizophrenia (COGS) 
Schizophrenia research  2015;163(0):38-46.
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. 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.
doi:10.1016/j.schres.2015.01.017
PMCID: PMC4382444  PMID: 25749017
schizophrenia; endophenotype; attention; Continuous Performance Test; cognition; functional capacity; genetics
7.  Validation of Mismatch Negativity and P3a for Use in Multi-Site Studies of Schizophrenia: Characterization of Demographic, Clinical, Cognitive, and Functional Correlates in COGS-2 
Schizophrenia research  2014;163(0):63-72.
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 data was 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.
doi:10.1016/j.schres.2014.09.042
PMCID: PMC4382452  PMID: 25449710
8.  Neurocognitive performance in family-based and case-control studies of schizophrenia 
Schizophrenia research  2015;163(0):17-23.
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.
doi:10.1016/j.schres.2014.10.049
PMCID: PMC4441547  PMID: 25432636
Neurocognition; schizophrenia; family-based; case-control; ascertainment
9.  Sensory Gating Disturbances in the Spectrum: Similarities and Differences in Schizotypal Personality Disorder and Schizophrenia 
Schizophrenia research  2014;161(0):283-290.
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.
doi:10.1016/j.schres.2014.11.020
PMCID: PMC4308515  PMID: 25482574
schizotypal personality disorder; schizophrenia; event-related potential; evoked potential; P50; psychophysiology; sensory gating
10.  Copy Number Variants in Schizophrenia: Confirmation of Five Previous Findings and New Evidence for 3q29 Microdeletions and VIPR2 Duplications 
The American journal of psychiatry  2011;168(3):302-316.
Objective
To evaluate previously reported associations of copy number variants (CNVs) with schizophrenia and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of Schizophrenia study (MGS) and additional available data.
Method
After quality control, MGS data for 3,945 subjects with schizophrenia or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and gene-wise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction.
Results
In analyses of MGS data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in NRXN1. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for vasoactive intestinal peptide receptor 2 (VIPR2), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (>100 kb and >1 Mb) but not duplications.
Conclusions
The data strongly confirm the association of schizophrenia with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic NRXN1 deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including VIPR2, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of schizophrenia.
doi:10.1176/appi.ajp.2010.10060876
PMCID: PMC4441324  PMID: 21285140
11.  Comparison of the Heritability of Schizophrenia and Endophenotypes in the COGS-1 Family Study 
Schizophrenia Bulletin  2014;40(6):1404-1411.
Background:
Twin and multiplex family studies have established significant heritability for schizophrenia (SZ), often summarized as 81%. The Consortium on the Genetics of Schizophrenia (COGS-1) family study was designed to deconstruct the genetic architecture of SZ using neurocognitive and neurophysiological endophenotypes, for which heritability estimates ranged from 18% to 50% (mean = 30%). This study assessed the heritability of SZ in these families to determine whether there is a “heritability gap” between the diagnosis and related endophenotypes.
Methods:
Nuclear families (N = 296) with a SZ proband, an unaffected sibling, and both parents (n = 1366 subjects; mean family size = 4.6) underwent 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 of interviewed subjects (N = 3304 subjects; mean family size = 11.2). Heritability estimates of psychotic disorders were computed for both nuclear and extended families.
Results:
The heritability of SZ was 31% and 44% for nuclear and extended families. The inclusion of bipolar disorder increased the heritability to 37% for the nuclear families. When major depression was added, heritability estimates dropped to 34% and 20% for nuclear and extended families, respectively.
Conclusions:
Endophenotypes and psychotic disorders exhibit comparable levels of heritability in the COGS-1 family sample. The ascertainment of families with discordant sibpairs to increase endophenotypic contrast may underestimate diagnostic heritability relative to other studies. However, population-based studies also report significantly lower heritability estimates for SZ. Collectively, these findings support the importance of endophenotype-based strategies and the dimensional view of psychosis.
doi:10.1093/schbul/sbu064
PMCID: PMC4193725  PMID: 24903414
schizophrenia; psychosis; endophenotypes; cognition; biomarkers; heritability
12.  The Israel Diabetes and Cognitive Decline (IDCD) study: Design and baseline characteristics 
Background
Type 2 diabetes (T2D) is associated with increased risk of dementia. The prospective longitudinal Israel Diabetes and Cognitive Decline study aims at identifying T2D-related characteristics associated with cognitive decline.
Methods
Subjects are population-based T2D 65+, initially cognitively intact. Medical conditions, blood examinations, and medication use data are since 1998; cognitive, functional, demographic, psychiatric, DNA, and inflammatory marker study assessments were conducted every 18 months. Because the duration of T2D reflects its chronicity and implications, we compared short (0–4.99 years), moderate (5–9.99), and long (10+) duration for the first 897 subjects.
Results
The long duration group used more T2D medications, had higher glucose, lower glomerular filtration rate, slower walking speed, and poorer cognitive functioning. Duration was not associated with most medical, blood, urine, and vital characteristics.
Conclusions
Tracking cognition, with face-to-face evaluations, exploiting 15 years of historical detailed computerized, easily accessible, and validated T2D-related characteristics may provide novel insights into T2D-related dementia.
doi:10.1016/j.jalz.2014.06.002
PMCID: PMC4330555  PMID: 25150735
Cognitive decline; Dementia; Type 2 diabetes; Elderly; Cognitively normal; Risk factors; Study design
13.  The Association of Duration of Type 2 Diabetes with Cognitive Performance is Modulated by Long-Term Glycemic Control 
Objectives
It is unclear why duration of type 2 diabetes (T2D) is associated with increased cognitive compromise. High hemoglobin A1c (HbA1c) has also been associated with dementia, and is the primary contributor to T2D complications. Here we investigated whether the association of duration of T2D with cognitive functioning is modulated by hemoglobin A1C levels.
Methods
This study examined non-demented community dwelling T2D elderly (n=897) participating in the Israel Diabetes and Cognitive Decline study, who were assessed with a broad neuropsychological battery. Subjects were all from the Maccabi Healthcare Services which has a Diabetes Registry with complete HbA1c measurements since 1998. Partial correlations were performed to examine the modulating effect of HbA1c on the relationship of duration of T2D with five cognitive measures, controlling for sociodemographic and cardiovascular risk factors.
Results
An interaction of duration of T2D with HbA1c was associated with executive functioning (p=.006), semantic categorization (p=.019), attention/working memory (p=.011), and overall cognition (p=.006), such that the associations between duration of T2D and cognitive impairment increased as HbA1c levels increased—but not for episodic memory (p=.984).
Conclusions
Since duration of T2D was associated with cognition in higher HbA1c levels and overall no associations were found in lower HbA1c levels, our results suggest that individuals with T2D may limit their risk of future cognitive decline by maintaining long-term good glycemic control.
doi:10.1016/j.jagp.2014.01.010
PMCID: PMC4108577  PMID: 24534521
cognitive performance; diabetes; hemoglobin A1c
14.  Correlation of arterial blood pressure and compliance with left ventricular structure and function in the very elderly 
There are very little data on the relationship between systolic blood pressure (SBP), diastolic blood pressure (DBP), arterial compliance and left ventricular structure and function, particularly left ventricular hypertrophy (LVH) in the very elderly (>75 years). SBP and arterial stiffness increase with age, and the question is: which of the two is the main stimulus to LV hypertrophy? This is a cross-sectional study to compare blood pressure and arterial stiffness measures with regard to their correlations with echocardiographic parameters of LV structure and function, controlling for age and cardiovascular risk factors, in a very elderly population. Arterial stiffness was determined by radial pulse waveform using pulse contour analysis. LV dimensions were measured by transthoracic M-mode echocardiography, and diastolic function by tissue Doppler measurements of diastolic mitral annular velocities. There were 179 subjects, all male, with a mean age of 81.8 years. Using age-adjusted partial correlations, SBP, DBP and mean arterial pressure (MAP) were correlated with parameters of LV structure and function. Correlation coefficients were: SBP v. left ventricular mass index (LVMI), r = 0.246; SBP v. early diastolic mitral annular velocity (MAV), r = -0.179; DBP v. LVMI, r = 0.199; DBP v. MAV, r = -0.199; MAP v. LVMI r = 0.276; and MAP v. MAV, r = -.206, all with p<0.05. However, neither capacitative nor reflective arterial compliance was significantly correlated with any parameter of LV structure and function. After controlling for age and ten cardiovascular and metabolic risk factors, the correlation between blood pressure and the measured LV parameters was substantially unchanged, as was the lack of correlation between indices of arterial compliance and the LV indices. Arterial blood pressure is correlated with LV structure and function in the very elderly, but arterial stiffness, as measured by diastolic pulse contour analysis, is not.
doi:10.1016/j.jash.2011.10.004
PMCID: PMC3259708  PMID: 22243840
Blood pressure; blood pressure; arterial stiffness; arterial compliance; myocardial remodeling; left ventricular hypertrophy; elderly
15.  Heritability of Cognitive Functions in Families of Successful Cognitive Aging Probands from the Central Valley of Costa Rica 
We sought to identify cognitive phenotypes for family/genetic studies of successful cognitive aging (SCA; maintaining intact cognitive functioning while living to late old age).We administered a battery of neuropsychological tests to nondemented nonagenarians (n = 65; mean age = 93.4±3.0) and their offspring (n = 188; mean age = 66.4±5.0) from the Central Valley of Costa Rica. After covarying for age, gender, and years of education, as necessary, heritability was calculated for cognitive functions at three pre-defined levels of complexity: specific neuropsychological functions (e.g., delayed recall, sequencing), three higher level cognitive domains (memory, executive functions, attention), and an overall neuropsychological summary. The highest heritability was for delayed recall (h2 = 0.74, se = 0.14, p < 0.0001) but significant heritabilities involving memory were also observed for immediate recall (h2 = 0.50), memory as a cognitive domain (h2 = 0.53), and the overall neuropsychological summary (h2 = 0.42). Heritabilities for sequencing (h2 = 0.42), fluency (h2 = 0.39), abstraction (h2 = 0.36), and the executive functions cognitive domain (h2 = 0.35) were also significant. In contrast, the attention domain and memory recognition were not significantly heritable in these families. Among the heritable specific cognitive functions, a strong pleiotropic effect (i.e., evidence that these may be influenced by the same gene or set of genes) for delayed and immediate recall was identified (bivariate statistic = 0.934, p < 0.0001) and more modest but significant effects were found for four additional bivariate relationships. The results support the heritability of good cognitive function in old age and the utilization of several levels of phenotypes, and they suggest that several measures involving memory may be especially useful for family/genetic studies of SCA.
doi:10.3233/JAD-2011-110782
PMCID: PMC3526368  PMID: 21908911
Family studies; hispanic population; neuropsychological phenotype; oldest-old; successful cognitive aging
17.  Increased Longevity in Offspring of Mothers With Alzheimer’s Disease 
Life expectancy is a familial trait. However, the effectiveness of using the age at death of a deceased parent to estimate life expectancy in their offspring can vary depending on whether death in the parent was due to extrinsic versus intrinsic causes, as well as demographic characteristics such as sex. While Alzheimer’s disease (AD) risk increases with increased age, mortality for individuals with AD is increased in contrast to comparably aged individuals without AD. Yet in most cases it is not the defining neuropathology of AD that directly terminates life but instead conditions and illnesses extrinsic to AD pathology that nevertheless have increased likelihood in its presence. For this reason, we hypothesized that offspring of AD mothers would have greater longevity than offspring of mothers without AD (insufficient numbers prevented a comparable analysis using fathers with AD). The longevity of 345 offspring of 100 deceased 60+ year old AD mothers was compared with 5,465 offspring in 1,312 deceased 60+ year old non-AD mothers. We used a proportional hazards model that accounted for clustered (nonindependent) observations due to the inclusion of several offspring from the same family. In both an unadjusted model and one that adjusted for the age at death in the mother, and the sex and birth year in the offspring we found evidence for increased longevity in the offspring of AD mothers. The results suggest that, in addition to genes that might directly affect pathways leading to AD, there may be familial/genetic factors not connected to specific pathophysiological processes in AD but instead associated with increased longevity that contribute to the familial aggregation observed in AD.
doi:10.1002/ajmg.b.30676
PMCID: PMC3085843  PMID: 18161858
Alzheimer’s disease; longevity; familiality; life expectancy; genetics
19.  Age, gender, and education are associated with cognitive performance in an Israeli elderly sample with type 2 diabetes 
Objectives
To evaluate the relationships of age, education, and gender with performance on neuropsychological tests in a cognitively intact, elderly Israeli sample with type 2 diabetes (T2D).
Methods
We examined 862 participants, 65-84 years old, enrolled in the Israel Diabetes and Cognitive Decline (IDCD) study. Multiple regression assessed associations of performance on 17 neuropsychological tests, including the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) 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 U.S. cohorts.
Conclusions
In a cognitively intact, elderly 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.
doi:10.1002/gps.4008
PMCID: PMC3918242  PMID: 23925856
neuropsychology; CERAD; cognitive functioning; diabetes; demographics; elderly
20.  Multi-site studies of acoustic startle and prepulse inhibition in humans: Initial experience and methodological considerations based on studies by the Consortium on the Genetics of Schizophrenia 
Schizophrenia research  2007;92(1-3):237-251.
Background:
Startle and its inhibition by weak lead stimuli (“prepulse inhibition”: PPI) are studied to understand the neurobiology of information processing in patients and community comparison subjects (CCS). PPI has a strong genetic basis in infrahumans, and there is evidence for its heritability, stability and reliability in humans. PPI has gained increasing use as an endophenotype to identify vulnerability genes for brain disorders, including schizophrenia. Genetic studies now often employ multiple, geographically dispersed test sites to accommodate the need for large and complex study samples. Here, we assessed the feasibility of using PPI in multi-site studies.
Methods:
Within a 7-site investigation with multiple measures, the Consortium on the Genetics of Schizophrenia conducted a methodological study of acoustic startle and PPI in CCS. Methods were manualized, videotaped and standardized across sites with intensive in-person training sessions. Equipment was acquired and programmed at the “PPI site” (UCSD), and stringent quality assurance (QA) procedures were used. Testing was completed on 196 CCS over 2.5 years, with 5 primary startle dependent measures: eyeblink startle magnitude, habituation, peak latency, latency facilitation and PPI.
Results:
Analyses identified significant variability across sites in some but not all primary measures, and determined factors both within the testing process and subject characteristics that influenced a number of test measures. QA procedures also identified non-standardized practices with respect to testing methods and procedural “drift”, which may be particularly relevant to multi-site studies using these measures.
Conclusion:
With thorough oversight and QA procedures, measures of acoustic startle PPI can be acquired reliably across multiple testing sites. Nonetheless, even among sites with substantial expertise in utilizing psychophysiological measures, multi-site studies using startle and PPI as dependent measures require careful attention to methodological procedures.
doi:10.1016/j.schres.2007.01.012
PMCID: PMC2039885  PMID: 17346930
endophenotype; prepulse inhibition; schizophrenia; sex differences; startle
21.  Biological Insights From 108 Schizophrenia-Associated Genetic Loci 
Ripke, Stephan | Neale, Benjamin M | Corvin, Aiden | Walters, James TR | Farh, Kai-How | Holmans, Peter A | Lee, Phil | Bulik-Sullivan, Brendan | Collier, David A | Huang, Hailiang | Pers, Tune H | Agartz, Ingrid | Agerbo, Esben | Albus, Margot | Alexander, Madeline | Amin, Farooq | Bacanu, Silviu A | Begemann, Martin | Belliveau, Richard A | Bene, Judit | Bergen, Sarah E | Bevilacqua, Elizabeth | Bigdeli, Tim B | Black, Donald W | Bruggeman, Richard | Buccola, Nancy G | Buckner, Randy L | Byerley, William | Cahn, Wiepke | Cai, Guiqing | Campion, Dominique | Cantor, Rita M | Carr, Vaughan J | Carrera, Noa | Catts, Stanley V | Chambert, Kimberley D | Chan, Raymond CK | Chan, Ronald YL | Chen, Eric YH | Cheng, Wei | Cheung, Eric FC | Chong, Siow Ann | Cloninger, C Robert | Cohen, David | Cohen, Nadine | Cormican, Paul | Craddock, Nick | Crowley, James J | Curtis, David | Davidson, Michael | Davis, Kenneth L | Degenhardt, Franziska | Del Favero, Jurgen | Demontis, Ditte | Dikeos, Dimitris | Dinan, Timothy | Djurovic, Srdjan | Donohoe, Gary | Drapeau, Elodie | Duan, Jubao | Dudbridge, Frank | Durmishi, Naser | Eichhammer, Peter | Eriksson, Johan | Escott-Price, Valentina | Essioux, Laurent | Fanous, Ayman H | Farrell, Martilias S | Frank, Josef | Franke, Lude | Freedman, Robert | Freimer, Nelson B | Friedl, Marion | Friedman, Joseph I | Fromer, Menachem | Genovese, Giulio | Georgieva, Lyudmila | Giegling, Ina | Giusti-Rodríguez, Paola | Godard, Stephanie | Goldstein, Jacqueline I | Golimbet, Vera | Gopal, Srihari | Gratten, Jacob | de Haan, Lieuwe | Hammer, Christian | Hamshere, Marian L | Hansen, Mark | Hansen, Thomas | Haroutunian, Vahram | Hartmann, Annette M | Henskens, Frans A | Herms, Stefan | Hirschhorn, Joel N | Hoffmann, Per | Hofman, Andrea | Hollegaard, Mads V | Hougaard, David M | Ikeda, Masashi | Joa, Inge | Julià, Antonio | Kahn, René S | Kalaydjieva, Luba | Karachanak-Yankova, Sena | Karjalainen, Juha | Kavanagh, David | Keller, Matthew C | Kennedy, James L | Khrunin, Andrey | Kim, Yunjung | Klovins, Janis | Knowles, James A | Konte, Bettina | Kucinskas, Vaidutis | Kucinskiene, Zita Ausrele | Kuzelova-Ptackova, Hana | Kähler, Anna K | Laurent, Claudine | Lee, Jimmy | Lee, S Hong | Legge, Sophie E | Lerer, Bernard | Li, Miaoxin | Li, Tao | Liang, Kung-Yee | Lieberman, Jeffrey | Limborska, Svetlana | Loughland, Carmel M | Lubinski, Jan | Lönnqvist, Jouko | Macek, Milan | Magnusson, Patrik KE | Maher, Brion S | Maier, Wolfgang | Mallet, Jacques | Marsal, Sara | Mattheisen, Manuel | Mattingsdal, Morten | McCarley, Robert W | McDonald, Colm | McIntosh, Andrew M | Meier, Sandra | Meijer, Carin J | Melegh, Bela | Melle, Ingrid | Mesholam-Gately, Raquelle I | Metspalu, Andres | Michie, Patricia T | Milani, Lili | Milanova, Vihra | Mokrab, Younes | Morris, Derek W | Mors, Ole | Murphy, Kieran C | Murray, Robin M | Myin-Germeys, Inez | Müller-Myhsok, Bertram | Nelis, Mari | Nenadic, Igor | Nertney, Deborah A | Nestadt, Gerald | Nicodemus, Kristin K | Nikitina-Zake, Liene | Nisenbaum, Laura | Nordin, Annelie | O’Callaghan, Eadbhard | O’Dushlaine, Colm | O’Neill, F Anthony | Oh, Sang-Yun | Olincy, Ann | Olsen, Line | Van Os, Jim | Pantelis, Christos | Papadimitriou, George N | Papiol, Sergi | Parkhomenko, Elena | Pato, Michele T | Paunio, Tiina | Pejovic-Milovancevic, Milica | Perkins, Diana O | Pietiläinen, Olli | Pimm, Jonathan | Pocklington, Andrew J | Powell, John | Price, Alkes | Pulver, Ann E | Purcell, Shaun M | Quested, Digby | Rasmussen, Henrik B | Reichenberg, Abraham | Reimers, Mark A | Richards, Alexander L | Roffman, Joshua L | Roussos, Panos | Ruderfer, Douglas M | Salomaa, Veikko | Sanders, Alan R | Schall, Ulrich | Schubert, Christian R | Schulze, Thomas G | Schwab, Sibylle G | Scolnick, Edward M | Scott, Rodney J | Seidman, Larry J | Shi, Jianxin | Sigurdsson, Engilbert | Silagadze, Teimuraz | Silverman, Jeremy M | Sim, Kang | Slominsky, Petr | Smoller, Jordan W | So, Hon-Cheong | Spencer, Chris C A | Stahl, Eli A | Stefansson, Hreinn | Steinberg, Stacy | Stogmann, Elisabeth | Straub, Richard E | Strengman, Eric | Strohmaier, Jana | Stroup, T Scott | Subramaniam, Mythily | Suvisaari, Jaana | Svrakic, Dragan M | Szatkiewicz, Jin P | Söderman, Erik | Thirumalai, Srinivas | Toncheva, Draga | Tosato, Sarah | Veijola, Juha | Waddington, John | Walsh, Dermot | Wang, Dai | Wang, Qiang | Webb, Bradley T | Weiser, Mark | Wildenauer, Dieter B | Williams, Nigel M | Williams, Stephanie | Witt, Stephanie H | Wolen, Aaron R | Wong, Emily HM | Wormley, Brandon K | Xi, Hualin Simon | Zai, Clement C | Zheng, Xuebin | Zimprich, Fritz | Wray, Naomi R | Stefansson, Kari | Visscher, Peter M | Adolfsson, Rolf | Andreassen, Ole A | Blackwood, Douglas HR | Bramon, Elvira | Buxbaum, Joseph D | Børglum, Anders D | Cichon, Sven | Darvasi, Ariel | Domenici, Enrico | Ehrenreich, Hannelore | Esko, Tõnu | Gejman, Pablo V | Gill, Michael | Gurling, Hugh | Hultman, Christina M | Iwata, Nakao | Jablensky, Assen V | Jönsson, Erik G | Kendler, Kenneth S | Kirov, George | Knight, Jo | Lencz, Todd | Levinson, Douglas F | Li, Qingqin S | Liu, Jianjun | Malhotra, Anil K | McCarroll, Steven A | McQuillin, Andrew | Moran, Jennifer L | Mortensen, Preben B | Mowry, Bryan J | Nöthen, Markus M | Ophoff, Roel A | Owen, Michael J | Palotie, Aarno | Pato, Carlos N | Petryshen, Tracey L | Posthuma, Danielle | Rietschel, Marcella | Riley, Brien P | Rujescu, Dan | Sham, Pak C | Sklar, Pamela | St Clair, David | Weinberger, Daniel R | Wendland, Jens R | Werge, Thomas | Daly, Mark J | Sullivan, Patrick F | O’Donovan, Michael C
Nature  2014;511(7510):421-427.
Summary
Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
doi:10.1038/nature13595
PMCID: PMC4112379  PMID: 25056061
22.  Haptoglobin 1-1 Genotype Is Associated With Poorer Cognitive Functioning in the Elderly With Type 2 Diabetes 
Diabetes Care  2013;36(10):3139-3145.
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.
doi:10.2337/dc12-2250
PMCID: PMC3781506  PMID: 23990521
23.  Antisaccade performance in schizophrenia patients, their first-degree biological relatives, and community comparison subjects: Data from the COGS study 
Psychophysiology  2010;47(5):846-856.
The antisaccade task is a widely used technique to measure failure of inhibition, an important cause of cognitive and clinical abnormalities found in schizophrenia. Although antisaccade performance, which reflects the ability to inhibit prepotent responses, is a putative schizophrenia endophenotype, researchers have not consistently reported the expected differences between first-degree relatives and comparison groups. Schizophrenia participants(n=219) from the large Consortium on the Genetics of Schizophrenia (COGS) sample (n=1078) demonstrated significant deficits on an overlap version of the antisaccade task compared to their first-degree relatives (n=443) and community comparison subjects (CCS; n=416). Although mean antisaccade performance of first-degree relatives was intermediate between schizophrenia participants and CCS, a linear mixed-effects model adjusting for group, site, age, and gender found no significant performance differences between the first-degree relatives and CCS. However, admixture analyses showed that two components best explained the distributions in all three groups, suggesting two distinct doses of an etiological factor. Given the significant heritability of antisaccade performance, the effects of a genetic polymorphism is one possible explanation of our results.
doi:10.1111/j.1469-8986.2010.01004.x
PMCID: PMC4176871  PMID: 20374545
Oculomotor; Endophenotype; Antisaccade; Schizophrenia; Family
24.  Trajectories in Glycemic Control over Time Are Associated with Cognitive Performance in Elderly Subjects with Type 2 Diabetes 
PLoS ONE  2014;9(6):e97384.
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.
doi:10.1371/journal.pone.0097384
PMCID: PMC4041655  PMID: 24887092
25.  Sex Differences in Familiality Effects on Neurocognitive Performance in Schizophrenia 
Biological psychiatry  2013;73(10):976-984.
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=1,967; schizophrenia=369; first-degree relatives=1,072; community comparison subjects=526) in the Consortium on the Genetics of Schizophrenia (COGS) were administered the Penn Computerized Neurocognitive Battery (CNB).
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 6 of 7 domains, probands’ score predicted the performance of their unaffected siblings. Male, but not female, probands’ 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 probands’ 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.
doi:10.1016/j.biopsych.2012.12.021
PMCID: PMC3954126  PMID: 23395246
Schizophrenia; neurocognition; endophenotype; heritability; genetics; sex differences

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