ApoE Alzheimer's Disease Aß-amyloid plaque morphology varies according to APOE isotype.

Background: The apolipoprotein E (APOE, gene; apoE, protein) ε4 allele is the most common identified genetic risk factor for typical late-onset sporadic Alzheimer's disease (AD). Each APOE ε4 allele roughly triples the relative risk for AD compared to that of the reference allele, APOE ε3. Methods: We have employed hyperspectral fluorescence imaging with an amyloidspecific, conformation-sensing probe, p-FTAA, to elucidate protein aggregate structure and morphology in fresh frozen prefrontal cortex samples from human postmortem AD brain tissue samples from patients homozygous for either APOE ε3 or APOE ε4. Results: As expected APOE ε4/ε4 tissues had significantly larger load of CAA than APOE ε3/ε3. APOE isoform-dependent morphological differences in amyloid plaques were also observed. Amyloid plaques in APOE ε3/ε3 tissue had small spherical cores and large corona while amyloid plaques in APOE ε4/ε4 tissues had large irregular and multilobulated plaques with relatively smaller corona. Despite the different morphologies of their cores, the p-FTAA stained APOE ε3/ε3 amyloid plaque cores had spectral properties identical to those of APOE ε4/ε4 plaque cores. Conclusions: These data support the hypothesis that one mechanism by which the APOE ε4 allele affects AD is by modulating the macrostructure of pathological protein deposits in brain. APOE ε4 is associated with a higher density of amyloid plaques (as compared to APOE ε3). We speculate that multilobulated APOE ε4-associated plaques arise from multiple initiation foci that coalesce as the plaques grow.

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.

Attention and Memory in Depersonalization-Spectrum Dissociative Disorders: Impact of Selective-Divided Attentional Condition, Stimulus Emotionality, and Stress.

We investigated cognition in depersonalization-spectrum dissociative disorders without comorbid posttraumatic stress disorder to explore evidence for emotionally avoidant information processing. Forty-eight participants with DSM-IV dissociative disorder (DD) (Depersonalization Disorder - 37, Dissociative Disorder NOS -11), 36 participants with Posttraumatic Stress Disorder (PTSD), and 56 healthy controls (HC) were administered the Weschler Adult Intelligence Scale-III (WAIS); the Weschler Memory Scale-III (WMS); and three Stroop tasks: the Standard Stroop, a selective-attention Emotional Stroop using neutral, dissociation, and trauma-related word categories, and a divided-attention Emotional Stroop using comparable words. Participants were also administered a paired-associates explicit and implicit memory test using emotionally neutral and negative words, before and after the Trier Social Stress Test. The DD and HC groups had comparable general intelligence and memory scores, though dissociation severity was inversely related to verbal comprehension and working memory. In the selective-attention condition, DD participants showed greater incidental recall across word categories with comparable interference. However in the divided-attention condition, DD participants significantly favored lesser attentional interference at the expense of remembering words. Across attentional conditions, DD participants had better recall for disorder-related than neutral words. Pre-stress, the DD group demonstrated better explicit memory for neutral versus negative words with reversal after stress, whereas the HC group demonstrated the opposite pattern; implicit memory did not differ. Cognition in the PTSD control group was generally dissimilar to the DD group. The findings in toto provide substantial evidence for emotionally avoidant information processing in DD, vulnerable to the impact of stress, at the level of both attention and memory.

Using structured implementation interventions to improve referral to substance use treatment among justice-involved youth: Findings from a multisite cluster randomized trial.

INTRODUCTION: Youth involved in the justice system have high rates of alcohol and other drug use, but limited treatment engagement. JJ-TRIALS tested implementation activities with community supervision (CS) and behavioral health (BH) agencies to improve screening, identification of substance use service need, referral, and treatment initiation and engagement, guided by the BH Services Cascade and EPIS frameworks. This paper summarizes intervention impacts on referrals to treatment among youth on CS. METHODS: This multisite cluster-randomized trial involved 18 matched pairs of sites in 36 counties in seven states randomly assigned to core or enhanced conditions after implementing the core intervention at all sites for six months. Enhanced sites received external facilitation for local change team activities to reduce unmet treatment needs; Core sites were encouraged to form interagency workgroups. The dependent variable was percentage referred to treatment among youth in need (N = 14,012). Two-level Bayesian regression assessed factors predicting referral across all sites and time periods. Generalized linear mixed models using logit transformation tested two hypotheses: (H1) referrals will increase from baseline to the experimental period, (H2) referral increases will be larger in enhanced sites than in core sites. RESULTS: Although the intervention significantly increased referral, condition did not significantly predict referral across all time periods. Youth who tested drug positive, had an alcohol/other drug-related or felony charge, were placed in secure detention or assigned more intensive supervision, or who were White were more likely to be referred. H1 (p < .05) and H2 (p < .0001) were both significant in the hypothesized direction. Interaction analyses comparing site pair differences showed that findings were not consistent across sites. CONCLUSIONS: The percentage of youth referred to treatment increased compared with baseline overall, and enhanced sites showed larger increases in referrals over time. However, variations in effects suggest that site-level differences were important. Researchers should carry out mixed methods studies to further understand reasons for the inconsistent findings within randomized site pairs, and how to further improve treatment referrals across CS and BH systems. Findings also highlight that even when CS agencies work collaboratively with BH providers to improve referrals, most justice-involved youth who need SU services are not referred.

Sexual Trauma Informed Understanding of Longitudinal Depression among Repeat Juvenile Offenders.

Childhood sexual assault (CSA) victimization and depression are global public health concerns that disproportionately affect youths involved in the juvenile justice system. Little research has examined the influence of CSA on the stability of depressive symptoms among repeat juvenile offenders. The present study tested a gendered model of the association between lifetime CSA victimization and depression for three time points: baseline juvenile assessment entry; second reentry; and third reentry. Further, covariate analyses were conducted to explore the impact of socio-demographics on CSA victimization and depression. Results indicate that CSA victimization was associated directly with baseline depression and indirectly with depression at second reentry for both male and female justice-involved youths. For white, male youth, there were significantly higher rates of depression over time, than other males. However, age, African American or Hispanic race/ethnicity, living situation, and urbanity were not significantly associated with CSA victimization at baseline or depression over time. These findings underscore the need for juvenile justice services that address exposure to childhood trauma and mental illness more effectively.

A Component or Multiple Components of Bleeding Gums May Ameliorate Both Glaucoma and Alzheimer's Disease.

BACKGROUND: Although clinical studies have shown an increased prevalence of primary open-angle glaucoma (POAG) in patients with Alzheimer's disease (AD), a population-based epidemiologic study from Denmark found no increased risk of Alzheimer's disease in patients with glaucoma, and other studies have failed to demonstrate a link. However, a possible relationship between POAG and AD might manifest in their association with oral pathology. Dental caries, periodontal disease, stomatitis, and the related inflammatory burden increase AD risk, while oral pathology and the oral microbiome correlate with POAG vulnerability. To further examine the relationship, we analyzed POAG, AD, and oral disease in the UK Biobank (UKBB) cohort. METHODS: Our analysis included all subjects with POAG and AD. POAG diagnosis was ascertained using the 10th Revision of the International Classification of Diseases (ICD-10), H40.11. AD diagnosis was ascertained using the 10th Revision of the International Classification of Diseases (ICD-10), G30. Oral cavity, ulceration, stomatitis, periodontitis, teeth, and dental problems were in UKBB data field 6149. RESULTS: A "yes" answer to a question about bleeding gums is associated with a greater proportional POAG reduction (24.2%) than a "yes" answer to having none of the six listed problems (6.3%). Similarly, bleeding gums were associated with a greater proportional AD reduction (46.2% versus 16.9%). Logistic regression controlling for age and sex showed that bleeding gums (no/yes) were negatively associated with AD (odds ratio (OR) = 0.713, 95% confidence interval (CI) = 0.521-0.976, p = 0.035). Age-weighted least-squares linear regression showed that the lower corneal-compensated intraocular pressure (IOP) in the left eye was associated with bleeding gums (unstandardized regression coefficient = -0.174, p < 0.001), controlling for type 2 diabetes and past smoking. CONCLUSION: It is difficult to predict what component or components of periodontal inflammation might be ameliorating POAG and AD. Prostaglandin is a possibility. Identification of the component or components could lead to new treatments for POAG and AD. Further studies are warranted.

Assessing the Validity of Self-Reports of Marijuana Use among Adolescents Entering the Juvenile Justice System: Gender Differences.

Objective: Scant research exists on the validity of self-reported marijuana use using biological assays among adolescents involved in the juvenile justice system. This exploratory study examined gender (sex) differences in underreporting of marijuana use and the impact of age, race/ethnicity, living situation, depression, family problems, sexual risk behaviors, previous drug treatment, and juvenile justice placement. Methods: Self-reports of past year marijuana use were validated with urinalysis, and those testing positive for marijuana use were selected for study. The sample was 256 females and 885 males, aged 12 to 18, entering an urban juvenile assessment center in a southeastern U.S. state between 2017 and 2019. Results: Results indicated significant differences in marijuana underreporting (tested positive but self-reported no use), with 37% of females and 55% of males underreporting use. For males, Hispanic ethnicity, African American race, sexually transmitted infection (STI), and secure detention placement increased the odds of underreporting, while having an incarcerate parent and previous drug treatment decreased the odds. For females, number of sexual partners decreased the odds of underreporting of marijuana use. Conclusion: These findings imply use of collateral information, such as urine tests, as a recommendation for juvenile justice intake to corroborate self-reports and guide risk assessment.

Individual- and Community-Level Factors in the STD Status of Justice-Involved Youth: Multi-Group, Exploratory Two-Level Analysis.

Justice-involved youth display higher prevalence rates of sexually transmitted diseases (STDs), in comparison with youth in the general population, highlighting a critical public health concern. Individual factors are important predictors of STDs, but only provide a partial understanding of this public health issue. Communities experiencing higher levels of disorder and lower levels of cohesion tend to have fewer institutional resources available, which may impact sexual risk behavior and STDs. However, few studies have examined the association between community characteristics and STD prevalence among adolescents. The current study examined community-level (n = 106) characteristics and individual-level attributes in explaining STDs among justice-involved youth (n = 1233: n = 515 female; n = 718 male). At the individual level, results showed older males and those with more drug-related problems were more likely to be STD positive, while females with more sexual partners and those with less drug-related problems were more likely to be STD positive. At the community level, females residing in areas with fewer educated residents were more likely to be STD positive. These gender differences were significant, suggesting a gendered perspective is important for understanding STD infection. The justice system represents a critical opportunity in the treatment and prevention of STDs for youth.

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.

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.

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.

A Multigroup, Longitudinal Study of Truant Youths, Marijuana Use, Depression, and STD-Associated Sexual Risk Behavior.

Truant youth are likely to engage in a number of problem behaviors, including sexual risky behaviors. Previous research involving non-truant youth has found sexual risk behaviors to be related to marijuana use and depression, with differential effects for male and female youth. Using data collected in a NIDA funded, prospective intervention project, results are reported of a male-female, multi-group, longitudinal analysis of the relationships among truant youth baseline sexual risk behavior, marijuana use, and depression, and their sexual risk behavior over four follow-up time points. Results indicated support for the longitudinal model, with female truants having higher depression scores, and showing stronger relationships between baseline depression and future engagement in sexual risk behavior, than male truants. Findings suggest that incorporating strategies to reduce depression and marijuana use may decrease youth sexual risk behavior.

Longitudinal Effects of a Second-Order Multi-Problem Factor of Sexual Risk, Marijuana Use, and Delinquency on Future Arrest Among Truant Youths.

Based on problem-behavior theory (Jessor & Jessor, 1977), a second-order problem behavior model of delinquency, marijuana use, and risky sexual behavior over five waves was estimated among truant adolescents. The study also investigated the influence of the problem factor on future arrest charges and the effect of socio-demographics on problem behavior and future crime. Results confirm the existence of a second-order latent factor of problem behaviors. Problem behaviors predicted more future arrest charges. Age was related to problem behaviors and future arrest charges, and family income was related to problem behavior. Implications for future research and practice are discussed.