Does computerized cognitive training improve diabetes self-management and cognition? A randomized control trial of middle-aged and older veterans with type 2 diabetes.

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 in the adaptive arm, with seven secondary outcomes. 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. 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. 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.

Anticholinergic Medication Burden-Associated Cognitive Impairment in Schizophrenia.

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.

Heritability of acoustic startle magnitude and latency from the consortium on the genetics of schizophrenia.

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.

The effects of age and sex on cognitive impairment in schizophrenia: Findings from the Consortium on the Genetics of Schizophrenia (COGS) study.

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.

Vitamin E Intake Is Associated with Lower Brain Volume in Haptoglobin 1-1 Elderly with Type 2 Diabetes.

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.

Short-term computerized cognitive training does not improve cognition compared to an active control in non-demented adults aged 80 years and above.

BACKGROUND: Older adults, especially those above age 80, are the fastest growing segment of the population in the United States and at risk for age-related cognitive decline and dementia. There is growing evidence that cognitive activity and training may allow adults to maintain or improve cognitive functioning, but little is known about the potential benefit in the oldest old. In this randomized trial, the effectiveness of a computerized cognitive training program (CCT program) was compared to an active control games program to improve cognition in cognitively normal individuals aged 80 and older. METHODS: Sixty-nine older adults were randomized to a 24-session CCT program (n = 39) or an active control program (n = 30). Participants completed a pre- and post- training neuropsychological assessment. The primary outcome measure was a global cognitive composite, and the secondary outcomes were the scores on specific cognitive domains (of memory, executive function/attention, and language). RESULTS: Using linear mixed models, there were no significant differences between the CCT and the active control program on the primary (p = 0.662) or any of the secondary outcomes (language functioning, p = .628; attention/executive functioning, p = .428; memory, p = .749). CONCLUSION: This study suggests that short-term CCT had no specific benefit for cognitive functioning in non-demented individuals aged 80 and older.

Genome-wide Association of Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia (COGS) Study.

Importance: The Consortium on the Genetics of Schizophrenia (COGS) uses quantitative neurophysiological and neurocognitive endophenotypes with demonstrated deficits in schizophrenia as a platform from which to explore the underlying neural circuitry and genetic architecture. Many of these endophenotypes are associated with poor functional outcome in schizophrenia. Some are also endorsed as potential treatment targets by the US Food and Drug Administration. Objective: To build on prior assessments of heritability, association, and linkage in the COGS phase 1 (COGS-1) families by reporting a genome-wide association study (GWAS) of 11 schizophrenia-related endophenotypes in the independent phase 2 (COGS-2) cohort of patients with schizophrenia and healthy comparison participants (HCPs). Design, Setting, and Participants: A total of 1789 patients with schizophrenia and HCPs of self-reported European or Latino ancestry were recruited through a collaborative effort across the COGS sites and genotyped using the PsychChip. Standard quality control filters were applied, and more than 6.2 million variants with a genotyping call rate of greater than 0.99 were available after imputation. Association was performed for data sets stratified by diagnosis and ancestry using linear regression and adjusting for age, sex, and 5 principal components, with results combined through weighted meta-analysis. Data for COGS-1 were collected from January 6, 2003, to August 6, 2008; data for COGS-2, from June 30, 2010, to February 14, 2014. Data were analyzed from October 28, 2016, to May 4, 2018. Main Outcomes and Measures: A genome-wide association study was performed to evaluate association for 11 neurophysiological and neurocognitive endophenotypes targeting key domains of schizophrenia related to inhibition, attention, vigilance, learning, working memory, executive function, episodic memory, and social cognition. Results: The final sample of 1533 participants included 861 male participants (56.2%), and the mean (SD) age was 41.8 (13.6) years. In total, 7 genome-wide significant regions (P < 5 × 10-8) and 2 nearly significant regions (P < 9 × 10-8) containing several genes of interest, including NRG3 and HCN1, were identified for 7 endophenotypes. For each of the 11 endophenotypes, enrichment analyses performed at the level of P < 10-4 compared favorably with previous association results in the COGS-1 families and showed extensive overlap with regions identified for schizophrenia diagnosis. Conclusions and Relevance: These analyses identified several genomic regions of interest that require further exploration and validation. These data seem to demonstrate the utility of endophenotypes for resolving the genetic architecture of schizophrenia and characterizing the underlying biological dysfunctions. Understanding the molecular basis of these endophenotypes may help to identify novel treatment targets and pave the way for precision-based medicine in schizophrenia and related psychotic disorders.

Recruitment of Older Veterans with Diabetes Risk for Alzheimer's Disease for a Randomized Clinical Trial of Computerized Cognitive Training.

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.

Distinct age-related associations for body mass index and cognition in cognitively healthy very old veterans.

ABSTRACTAssociations between high body mass index (BMI) and subsequent cognitive decline, reported in elderly averaging below age 75, become less consistent at older ages. We compared the associations of BMI with cognition in moderately old (ages 75-84, N = 154) and oldest-old (85+, N = 93) samples. BMI and cognition were assessed cross-sectionally in cognitively intact elderly (mean age = 84.5, SD = 4.4) male veterans. Regression analyses of three cognitive domains - executive functions/language, attention, and memory-compared relationship with BMI between the moderately old and oldest-old. Higher BMI was associated with relatively poorer executive functions/language performance in the moderately old, while the opposite relationship, higher BMI associated with relatively better performance, was found in the oldest-old. Associations for the other two cognitive domains did not differ significantly between age groups. The reversal of association direction for executive functions/language performance with higher BMI is consistent with the protected survivor model. This model posits a minority subpopulation with a protective factor-genetic or otherwise-against both mortality and cognitive decline associated with risk factor status. The very old who remain cognitively intact despite the presence of risk factors are more likely to possess protection.

The Association of Depressive Symptoms With Brain Volume Is Stronger Among Diabetic Elderly Carriers of the Haptoglobin 1-1 Genotype Compared to Non-carriers.

Aim: Depression is highly prevalent in type 2 diabetes and is associated with lower adherence to medical treatments, worse glycemic control, and increased risk for diabetes-related complications. The mechanisms underlying depression in type 2 diabetes are unclear. The haptoglobin (Hp) genotype is associated with type 2 diabetes related complications including increased risk for cerebrovascular pathology and worse cognitive performance. Its relationship with depression is unknown. We investigated the role of Hp genotype on the association of depression with brain and white matter hyperintensities (WMH) volumes. Methods: Depressive symptoms (measured with the 15-item Geriatric Depression Scale), brain MRI, and Hp genotypes, were examined in elderly subjects with type 2 diabetes [29 (13.8%) Hp 1-1 carriers and 181 (86.2%) non-carriers]. The interaction of Hp genotype with number of depressive symptoms on regional brain measures was assessed using regression analyses. Results: The significant interactions were such that in Hp 1-1 carriers but not in non-carriers, number of depressive symptoms was associated with overall frontal cortex (p = 0.01) and WMH (p = 0.04) volumes but not with middle temporal gyrus volume (p = 0.43). Conclusions: These results suggest that subjects with type 2 diabetes carrying the Hp 1-1 genotype may have higher susceptibility to depression in the context of white matter damage and frontal lobe atrophy. The mechanisms underlying depression in diabetes may differ by Hp genotype.

Age Modulates the Association of Caffeine Intake With Cognition and With Gray Matter in Elderly Diabetics.

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 (ß = .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.

Depression is more strongly associated with cognition in elderly women than men with type 2 diabetes.

Depression and cognitive impairment are highly prevalent in type 2 diabetes (T2D), yet little is known about how their relationship varies by sex. We examined this question in a large T2D sample (N = 897) of non-demented elderly (≥ 65) participating in the Israel Diabetes and Cognitive Decline (IDCD) Study. Cognition was evaluated by a comprehensive neuropsychological battery and depressive symptoms were assessed by the Geriatric Depression Scale (GDS). The results showed that in all but the executive function domain, the association of depressive symptoms with poorer cognitive function was stronger in women than men, with a significant interaction for language/semantic categorization and missed significance for episodic memory. When defining clinical depression as GDS of ≥6, women with depression had significantly poorer language/semantic categorization, episodic memory, and overall cognitive function. Inclusion of antidepressants in the model did not alter substantively the associations. Our results suggest that depressed T2D women may have poorer cognitive performance, highlighting the significance of sex-specific personalized management of depression in elderly diabetics.

Associations of hemoglobin A1c with cognition reduced for long diabetes duration.

INTRODUCTION: Associations of some risk factors with poor cognition, identified prior to age 75, are reduced or reversed in very old age. The Protected Survivor Model predicts this interaction due to enhanced survival of those with extended risk factor duration. In a younger sample, this study examines the association of cognition with the mean hemoglobin A1c risk factor over the time at risk, according to its duration. METHODS: The interaction of mean hemoglobin A1c (average = 9.8%), evaluated over duration (average = 116.8 months), was examined for overall cognition and three cognitive domains in a sample of 150 "young-old" veterans (mean age = 70) with type 2 diabetes. RESULTS: The predicted interactions were significant for overall cognition and attention, but not executive functions/language and memory. DISCUSSION: Findings extend the Protected Survivor Model to a "young-old" sample, from the very old. This model suggests focusing on individuals with good cognition despite prolonged high risk when seeking protective factors.

Depressive Symptoms Are Associated with Cognitive Function in the Elderly with Type 2 Diabetes.

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.

Outcome age-based prediction of successful cognitive aging by total cholesterol.

INTRODUCTION: Some associations of high total cholesterol with dementia risk diminish as the outcome age-age at cognitive assessment-increases. METHODS: The Framingham Heart Study provided 1897 participants with intact cognition at entry. Cox regression analysis for incident marked cognitive decline included "time-dependent" coefficients, with associations between total cholesterol and covariates changing by outcome age. Decline within age categories of 75-84 and 85-94 years was also examined. RESULTS: Significant associations of rising total cholesterol linear slope, low entry age, low education, and statin nonuse with risk diminished significantly by outcome age. At 85-94 years, falling linear slope was significant. DISCUSSION: The protected survival model posits a minority subpopulation with protection against mortality and cognitive decline associated with total cholesterol risk factors. It predicts the observed diminished or reversed cholesterol associations with increasing age. Protection is particularly likely for successful cognitive aging-intact cognition at very old age-despite increased risk from cholesterol.

The protected survivor model: Using resistant successful cognitive aging to identify protection in the very old.

For some cardiovascular risk factors, association with risk for cognitive impairment observed in early old age is reduced, or paradoxically even reversed, as age of outcome increases. Successful cognitive aging is intact cognition in the oldest-old; we define resistant successful cognitive aging as successful cognitive aging despite high risk. The protected survivor model posits that a minority of the general population has a protective factor that mitigates the negative effect of a risk factor on successful cognitive aging for the unprotected majority. As age increases, differential failure rates increase the proportion of survivors with protection. Among the unprotected, the proportion with low risk increases, but among those with protection, high risk and low risk do not differ. Due to differential mortality, half the survivors are eventually protected - a majority among those with high risk, and a minority among those with low risk. According to the protective survivor model, an example of Simpson's paradox, the association of the risk factor with survival does not change within an individual, but the association in the surviving population changes as its age increases. We created quantitative illustrations of a simplified protected survivor model applied to successful cognitive aging to explain how the usual association of a risk factor with cognitive decline is reversed in the very old. In the illustrations, probability of subsequent survival was higher for survivors with high risk (mostly protected) than low risk (mostly not protected), an example of Simpson's paradox. Resistance to disease despite the presence of risk factors is consistent with the presence of countervailing protection. Based on the protected survivor model, we hypothesize that studies seeking protective factors against cognitive decline will be more effective by limiting a successful cognitive aging sample to resistant successful cognitive aging - to contrast with a sample without successful cognitive aging.

Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension.

BACKGROUND: The Consortium on the Genetics of Schizophrenia (COGS) collected case-control endophenotype and genetic information from 2457 patients and healthy subjects (HS) across 5 test sites over 3.5 years. Analysis of the first "wave" (W1) of 1400 subjects identified prepulse inhibition (PPI) deficits in patients vs. HS. Data from the second COGS "wave" (W2), and the combined W(1+2), were used to assess: 1) the replicability of PPI deficits in this design; 2) the impact of response criteria on PPI deficits; and 3) PPI in a large cohort of antipsychotic-free patients. METHODS: PPI in W2 HS (n=315) and schizophrenia patients (n=326) was compared to findings from W1; planned analyses assessed the impact of diagnosis, "wave" (1 vs. 2), and startle magnitude criteria. Combining waves allowed us to assess PPI in 120 antipsychotic-free patients, including many in the early course of illness. RESULTS: ANOVA of all W(1+2) subjects revealed robust PPI deficits in patients across "waves" (p<0.0004). Strict response criteria excluded almost 39% of all subjects, disproportionately impacting specific subgroups; ANOVA in this smaller cohort confirmed no significant effect of "wave" or "wave x diagnosis" interaction, and a significant effect of diagnosis (p<0.002). Antipsychotic-free, early-illness patients had particularly robust PPI deficits. DISCUSSION: Schizophrenia-linked PPI deficits were replicable across two multi-site "waves" of subjects collected over 3.5years. Strict response criteria disproportionately excluded older, male, non-Caucasian patients with low-normal hearing acuity. These findings set the stage for genetic analyses of PPI using the combined COGS wave 1 and 2 cohorts.

Hemoglobin A1c Variability Predicts Symptoms of Depression in Elderly Individuals With Type 2 Diabetes.

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.

Modeling Deficits From Early Auditory Information Processing to Psychosocial Functioning in Schizophrenia.

IMPORTANCE: Neurophysiologic measures of early auditory information processing (EAP) are used as endophenotypes in genomic studies and biomarkers in clinical intervention studies. Research in schizophrenia has established correlations among measures of EAP, cognition, clinical symptoms, and functional outcome. Clarifying these associations by determining the pathways through which deficits in EAP affect functioning would suggest when and where to therapeutically intervene. OBJECTIVES: To characterize the pathways from EAP to outcome and to estimate the extent to which enhancement of basic information processing might improve cognition and psychosocial functioning in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional data were analyzed using structural equation modeling to examine the associations among EAP, cognition, negative symptoms, and functional outcome. Participants were recruited from the community at 5 geographically distributed laboratories as part of the Consortium on the Genetics of Schizophrenia 2 from July 1, 2010, through January 31, 2014. This well-characterized cohort of 1415 patients with schizophrenia underwent EAP, cognitive, and thorough clinical and functional assessment. MAIN OUTCOME AND MEASURES: Mismatch negativity, P3a, and reorienting negativity were used to measure EAP. Cognition was measured by the Letter Number Span test and scales from the California Verbal Learning Test-Second Edition, the Wechsler Memory Scale-Third Edition, and the Penn Computerized Neurocognitive Battery. Negative symptoms were measured by the Scale for the Assessment of Negative Symptoms. Functional outcome was measured by the Role Functioning Scale. RESULTS: Participants included 1415 unrelated outpatients diagnosed with schizophrenia or schizoaffective disorder (mean [SD] age, 46 [11] years; 979 males [69.2%] and 619 white [43.7%]). Early auditory information processing had a direct effect on cognition (ß = 0.37, P < .001), cognition had a direct effect on negative symptoms (ß = -0.16, P < .001), and both cognition (ß = 0.26, P < .001) and experiential negative symptoms (ß = -0.75, P < .001) had direct effects on functional outcome. The indirect effect of EAP on functional outcome was significant as well (ß = 0.14, P < .001). Overall, EAP had a fully mediated effect on functional outcome, engaging general rather than modality-specific cognition, with separate pathways that involved or bypassed negative symptoms. CONCLUSIONS AND RELEVANCE: The data support a model in which EAP deficits lead to poor functional outcome via impaired cognition and increased negative symptoms. Results can be used to help guide mechanistically informed, personalized treatments and support the strategy of using EAP measures as surrogate end points in early-stage procognitive intervention studies.