APOE Genotype Disclosure Influences Decisions About Future Planning but not Adoption of Healthy Lifestyle Changes in Cognitively Unimpaired Individuals.

BACKGROUND: Studies have shown apolipoprotein E (APOE) genotype disclosure to be safe and well-tolerated in cognitively unimpaired (CU) older adults. This study aimed to examine the effect of the disclosure process on decisions about future directives and health behaviors in community-dwelling CU older adults from the Butler Alzheimer's Prevention Registry (BAPR). METHODS: CU APOE E4 non-carriers (n = 106) and carriers (n = 80) aged 58-78 completed in-person psychological readiness screening to undergo APOE disclosure. Follow-up assessments were completed online 3 days, 6 weeks, and 6 months post-disclosure. The primary outcomes were future directives, dietary habits, and physical activity scores. RESULTS: Disclosure was associated with decision making on future directives in E4 carriers (t = 3.59, P = .01) at 6 months compared to baseline, but not non-carriers. Family history of memory impairment, SCD endorsement, and education consistently predicted scores on future directives. A significant interaction between E4+ and SCD endorsement on future directive scores was noted (OR = 163.06, 9.5-2,799.8). E4 + carrier status was associated with physical activity (W = 60,148, P = .005) but not dietary habits scores. CONCLUSIONS: Our findings indicate that disclosure led to a change in future directives but not protective health behaviors, specifically in E4 carriers. Future work will explore whether pairing disclosure with education about the role of lifestyle factors in AD risk and providing guidelines on making risk-lowering lifestyle modifications as an intervention approach leads to positive change.

Remote and in-clinic digital cognitive screening tools outperform the MoCA to distinguish cerebral amyloid status among cognitively healthy older adults.

INTRODUCTION: We evaluated the accuracy of remote and in-person digital tests to distinguish between older adults with and without AD pathological change and used the Montreal Cognitive Assessment (MoCA) as a comparison test. METHODS: Participants were 69 cognitively normal older adults with known beta-amyloid (Aß) PET status. Participants completed smartphone-based assessments 3×/day for 8 days, followed by TabCAT tasks, DCTclock™, and MoCA at an in-person study visit. We calculated the area under the curve (AUC) to compare task accuracies to distinguish Aß status. RESULTS: Average performance on the episodic memory (Prices) smartphone task showed the highest accuracy (AUC = 0.77) to distinguish Aß status. On in-person measures, accuracy to distinguish Aß status was greatest for the TabCAT Favorites task (AUC = 0.76), relative to the DCTclockTM (AUC = 0.73) and MoCA (AUC = 0.74). DISCUSSION: Although further validation is needed, our results suggest that several digital assessments may be suitable for more widespread cognitive screening application.

Dissociating Statistically Determined Normal Cognitive Abilities and Mild Cognitive Impairment Subtypes with DCTclock.

OBJECTIVE: To determine whether the DCTclock can detect differences across groups of patients seen in the memory clinic for suspected dementia. METHOD: Patients (n = 123) were classified into the following groups: cognitively normal (CN), subtle cognitive impairment (SbCI), amnestic cognitive impairment (aMCI), and mixed/dysexecutive cognitive impairment (mx/dysMCI). Nine outcome variables included a combined command/copy total score and four command and four copy indices measuring drawing efficiency, simple/complex motor operations, information processing speed, and spatial reasoning. RESULTS: Total combined command/copy score distinguished between groups in all comparisons with medium to large effects. The mx/dysMCI group had the lowest total combined command/copy scores out of all groups. The mx/dysMCI group scored lower than the CN group on all command indices (p < .050, all analyses); and lower than the SbCI group on drawing efficiency (p = .011). The aMCI group scored lower than the CN group on spatial reasoning (p = .019). Smaller effect sizes were obtained for the four copy indices. CONCLUSIONS: These results suggest that DCTclock command/copy parameters can dissociate CN, SbCI, and MCI subtypes. The larger effect sizes for command clock indices suggest these metrics are sensitive in detecting early cognitive decline. Additional research with a larger sample is warranted.

A highly feasible, reliable, and fully remote protocol for mobile app-based cognitive assessment in cognitively healthy older adults.

Introduction: The early detection of cognitive impairment is one of the most important challenges in Alzheimer's disease (AD) research. The use of brief, short-term repeated test sessions via mobile app has demonstrated similar or better reliability and validity compared to standard in-clinic assessments in adult samples. The present study examined adherence, acceptability, and reliability for a remote, app-based cognitive screening protocol in healthy older adults. Methods: Cognitively unimpaired older adults (N = 52, ages 60-80) completed three brief cognitive testing sessions per day within morning, afternoon, and evening time windows, for 8 consecutive days using a mobile app-based cognitive testing platform. Cognitive tasks assessed visual working memory, processing speed, and episodic memory. Results: Participants completed an average of 93% (M = 22.3 sessions, standard deviation = 10.2) of the 24 assigned sessions within 8 to 9 days. Average daily adherence ranged from 95% of sessions completed on day 2 to 88% of sessions completed on day 8. There was a statistically significant effect of session time on adherence between the morning and afternoon sessions only F (1, 51) = 9.15, P  = .004, η p  2   = 0.152, with fewer afternoon sessions completed on average. The within-person reliabilities of average scores, aggregated across all 24 sessions, were exceptionally high, ranging from 0.89 to 0.97. Performance on the episodic memory task was positively and significantly associated with total score and word list recall score on the Telephone Interview for Cognitive Status. In an exit survey, 65% of participants reported that they "definitely" would complete the sessions again. Discussion: These findings suggests that remote, mobile app-based cognitive testing in short bursts is both highly feasible and reliable in a motivated sample of cognitively normal older adults. Limitations include the limited diversity and generalizability of the sample; this was a largely White, highly educated, and motivated sample self-selected for AD research.

Safety and Tolerability of APOE Genotyping and Disclosure in Cognitively Normal Volunteers From the Butler Alzheimer's Prevention Registry.

AIMS: Alzheimer's disease (AD) is a gradually progressive neurodegenerative disease that ultimately results in total loss of cognitive and functional independence in older adults. This study aimed to examine the safety and tolerability of APOE disclosure in community-dwelling, cognitively normal (CN) older adults from the Butler Alzheimer's Prevention Registry (BAPR), and to determine whether APOE disclosure impacted participant's decisions to participate in AD clinical research. METHODS: 186 (N = 106 ∊4 non-carriers, 80 ∊4 carriers) CN older adults aged 58-78 from the BAPR completed 2 visits: one for psychological readiness screening and genotyping and one for APOE disclosure. Online follow-ups were completed 3 days, 6 weeks, and 6 months post-disclosure. Primary outcomes were scores on self-report measures of depression, anxiety, impact of events, and perceived risk of AD, along with enrollment in AD clinical trials. RESULTS: ∊4 carriers and non-carriers did not differ significantly on measures of depression, anxiety, or suicidal ideation over the 6-month follow-up period. ∊4 carriers reported higher impact of disclosure than non-carriers immediately after disclosure, but both groups' scores on impact of events measures remained sub-clinical. ∊4 carriers and non-carriers were equally likely to participate in AD research after disclosure, with genotype-dependent differences in type of clinical trial enrollment. CONCLUSIONS: APOE genotyping and disclosure was safe and well tolerated in a group of CN, community-dwelling older adults, who were pre-screened after volunteering for AD research through BAPR. Implications for the inclusion of APOE genotyping and disclosure at AD clinical trial sites are discussed.

OCTA reveals remodeling of the peripheral capillary free zones in normal aging.

The retinal neurovascular unit consists of blood vessel endothelial cells, pericytes, neurons, astrocytes, and Müller cells that form the inner retinal blood barrier. A peripheral capillary free zone (pCFZ) represents the distance that oxygen and nutrients must diffuse to reach the neural retina, and serves as a metric of retinal tissue oxygenation. The pCFZs are formed based on oxygen saturation in the retinal arterioles and venules. Because retinal arterioles contain a larger concentration of oxygenated blood than venules, there is a reduced need for capillaries to exist closely to arterioles compared to venules. Therefore, in a healthy individual, larger periarteriole CFZs are expected compared to perivenule CFZs. With normal aging, there is atrophy of the inner retinal neurons, and consequently reduced extraction of oxygen and nutrients from the retinal vessels (i.e., increased oxygen saturation). Therefore, we hypothesized that the peripheral CFZ will remodel with normal aging. Using Optical Coherence Tomography Angiography, we showed that the pCFZs do remodel in normal aging with large (perivenule: η2p = 0.56) and moderate (periarteriole: η2p = 0.12) effect sizes, opening the possibility that such changes may be further increased by neurodegenerative diseases that adversely impact the health of the retinal neural cell layers.

Depression screening in cognitively normal older adults: Measurement bias according to subjective memory decline, brain amyloid burden, cognitive function, and sex.

INTRODUCTION: Understanding the associations among depression, subjective cognitive decline, and prodromal Alzheimer's disease (AD) has important implications for both depression and dementia screening in older adults. The Geriatric Depression Scale (GDS) is a depression screening tool for older adults that queries memory concerns. To determine whether depression symptoms on the GDS (15-item version), including self-reported memory problems, differ by levels of brain amyloid beta (Aß), a pathological hallmark of early stage AD, we investigated potential measurement bias with regard to Aß level. We also examined measurement bias attributable to level of cognitive functioning and sex as positive controls. METHODS: We examined 3961 cognitively normal older adults from the A4/LEARN Study. We used the MIMIC (multiple indicators, multiple causes) approach to detect measurement bias. RESULTS: We found measurement bias with small-to-moderate range effect sizes in several GDS-15 items with respect to Aß level, cognitive functioning, and sex. There was negligible impact of measurement bias attributable to Aß level on overall depressive symptom level. DISCUSSION: GDS-15 item responses are sensitive to Aß burden, cognitive functioning, and sex over and above what would be expected given the effect of those factors on depressive symptom severity overall. However, these direct effects for GDS item measurement bias are of small magnitude and do not appreciably impact the validity of inferences about depression based on the GDS-15.

Disruption of cholinergic neurotransmission, within a cognitive challenge paradigm, is indicative of Aß-related cognitive impairment in preclinical Alzheimer's disease after a 27-month delay interval.

BACKGROUND: Abnormal beta-amyloid (Aß) is associated with deleterious changes in central cholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist (J Prev Alzheimers Dis 1:1-4, 2017). Previously, we established the scopolamine challenge test (SCT) as a "cognitive stress test" screening measure to identify individuals at risk for AD (Alzheimer's & Dementia 10(2):262-7, 2014) (Neurobiol. Aging 36(10):2709-15, 2015). Here we aim to demonstrate the potential of the SCT as an indicator of cognitive change and neocortical amyloid aggregation after a 27-month follow-up interval. METHODS: Older adults (N = 63, aged 55-75 years) with self-reported memory difficulties and first-degree family history of AD completed the SCT and PET amyloid imaging at baseline and were then seen for cognitive testing at 9, 18, and 27 months post-baseline. Repeat PET amyloid imaging was completed at the time of the 27-month exam. RESULTS: Significant differences in both cognitive performance and in Aß neocortical burden were observed between participants who either failed vs. passed the SCT at baseline, after a 27-month follow-up period. CONCLUSIONS: Cognitive response to the SCT (Alzheimer's & Dementia 10(2):262-7, 2014) at baseline is related to cognitive change and PET amyloid imaging results, over the course of 27 months, in preclinical AD. The SCT may be a clinically useful screening tool to identify individuals who are more likely to both have positive evidence of amyloidosis on PET imaging and to show measurable cognitive decline over several years.

Developing retinal biomarkers for the earliest stages of Alzheimer's disease: What we know, what we don't, and how to move forward.

The last decade has seen a substantial increase in research focused on the identification, development, and validation of diagnostic and prognostic retinal biomarkers for Alzheimer's disease (AD). Sensitive retinal biomarkers may be advantageous because they are cost and time efficient, non-invasive, and present a minimal degree of patient risk and a high degree of accessibility. Much of the work in this area thus far has focused on distinguishing between symptomatic AD and/or mild cognitive impairment (MCI) and cognitively normal older adults. Minimal work has been done on the detection of preclinical AD, the earliest stage of AD pathogenesis characterized by the accumulation of cerebral amyloid absent clinical symptoms of MCI or dementia. The following review examines retinal structural changes, proteinopathies, and vascular alterations that have been proposed as potential AD biomarkers, with a focus on studies examining the earliest stages of disease pathogenesis. In addition, we present recommendations for future research to move beyond the discovery phase and toward validation of AD risk biomarkers that could potentially be used as a first step in a multistep screening process for AD risk detection.

Affective differences in Iowa Gambling Task performance associated with sexual risk taking and substance use among HIV-positive and HIV-negative men who have sex with men.

We investigated the relationship between emotional distress and decision making in sexual risk and substance use behavior among 174 (ages 25 to 50 years, 53% black) men who have sex with men (MSM), a population at increased risk for HIV. The sample was stratified by HIV status. Measures of affective decision making, depression, anxiety, sex acts, and substance use during the past 60 days were collected at our research center. Negative binomial regression models were used to examine the relationship between age, HIV status, anxiety, depression, and IGT performance in the prediction of number of risky sex acts and substance use days. Among those without anxiety or depression, both number of risky sex acts and drug use days decreased with better performance during risky trials (i.e., last two blocks) of the IGT. For those with higher rates of anxiety, but not depression, IGT risk trial performance and risky sex acts increased concomitantly. Anxiety also interacted with IGT performance across all trials to predict substance use, such that anxiety was associated with greater substance use among those with better IGT performance. The opposite was true for those with depression, but only during risk trials. HIV-positive participants reported fewer substance use days than HIV-negative participants, but there was no difference in association between behavior and IGT performance by HIV status. Our findings suggest that anxiety may exacerbate risk-taking behavior when affective decision-making ability is intact. The relationship between affective decision making and risk taking may be sensitive to different profiles of emotional distress, as well as behavioral context. Investigations of affective decision making in sexual risk taking and substance use should examine different distress profiles separately, with implications for HIV prevention efforts.

G-protein-coupled estrogen receptor 1 is anatomically positioned to modulate synaptic plasticity in the mouse hippocampus.

Both estrous cycle and sex affect the numbers and types of neuronal and glial profiles containing the classical estrogen receptors α and ß, and synaptic levels in the rodent dorsal hippocampus. Here, we examined whether the membrane estrogen receptor, G-protein-coupled estrogen receptor 1 (GPER1), is anatomically positioned in the dorsal hippocampus of mice to regulate synaptic plasticity. By light microscopy, GPER1-immunoreactivity (IR) was most noticeable in the pyramidal cell layer and interspersed interneurons, especially those in the hilus of the dentate gyrus. Diffuse GPER1-IR was found in all lamina but was most dense in stratum lucidum of CA3. Ultrastructural analysis revealed discrete extranuclear GPER1-IR affiliated with the plasma membrane and endoplasmic reticulum of neuronal perikarya and dendritic shafts, synaptic specializations in dendritic spines, and clusters of vesicles in axon terminals. Moreover, GPER1-IR was found in unmyelinated axons and glial profiles. Overall, the types and amounts of GPER1-labeled profiles were similar between males and females; however, in females elevated estrogen levels generally increased axonal labeling. Some estradiol-induced changes observed in previous studies were replicated by the GPER agonist G1: G1 increased PSD95-IR in strata oriens, lucidum, and radiatum of CA3 in ovariectomized mice 6 h after administration. In contrast, estradiol but not G1 increased Akt phosphorylation levels. Instead, GPER1 actions in the synapse may be due to interactions with synaptic scaffolding proteins, such as SAP97. These results suggest that although estrogen's actions via GPER1 may converge on the same synaptic elements, different pathways are used to achieve these actions.

Post-synaptic density-95 (PSD-95) binding capacity of G-protein-coupled receptor 30 (GPR30), an estrogen receptor that can be identified in hippocampal dendritic spines.

The estrogen 17ß-estradiol (E2) modulates dendritic spine plasticity in the cornu ammonis 1 (CA1) region of the hippocampus, and GPR30 (G-protein coupled estrogen receptor 1 (GPER1)) is an estrogen-sensitive G-protein-coupled receptor (GPCR) that is expressed in the mammalian brain and in specific subregions that are responsive to E2, including the hippocampus. The subcellular localization of hippocampal GPR30, however, remains unclear. Here, we demonstrate that GPR30 immunoreactivity is detected in dendritic spines of rat CA1 hippocampal neurons in vivo and that GPR30 protein can be found in rat brain synaptosomes. GPR30 immunoreactivity is identified at the post-synaptic density (PSD) and in the adjacent peri-synaptic zone, and GPR30 can associate with the spine scaffolding protein PSD-95 both in vitro and in vivo. This PSD-95 binding capacity of GPR30 is specific and determined by the receptor C-terminal tail that is both necessary and sufficient for PSD-95 interaction. The interaction with PSD-95 functions to increase GPR30 protein levels residing at the plasma membrane surface. GPR30 associates with the N-terminal tandem pair of PDZ domains in PSD-95, suggesting that PSD-95 may be involved in clustering GPR30 with other receptors in the hippocampus. We demonstrate that GPR30 has the potential to associate with additional post-synaptic GPCRs, including the membrane progestin receptor, the corticotropin releasing hormone receptor, and the 5HT1a serotonin receptor. These data demonstrate that GPR30 is well positioned in the dendritic spine compartment to integrate E2 sensitivity directly onto multiple inputs on synaptic activity and might begin to provide a molecular explanation as to how E2 modulates dendritic spine plasticity.

Profiles of executive functioning: associations with substance dependence and risky sexual behavior.

The present investigations applied a theoretical perspective regarding the impact of executive functioning (EF) on sexual risk among substance users, using a methodological approach designed to examine whether EF subtypes differentially predict behavior patterns. Participants included 104 substance-using HIV-negative gay and bisexual men. Participants completed 5 neuropsychological assessment tasks selected to tap discrete EF components, and these data were linked to data on substance dependence and behavioral reports of substance use and sexual risk in the past 30 days. Cluster analysis identified 3 EF subtypes: (a) high performing (good performance across all measures); (b) low performing (poor performance across all measures); and (c) poor IGT performance (impairment on the Iowa Gambling Task [IGT] and its variant, but good performance on all other tasks). The 3 subtypes did not differ in amount of substance use, but the low-performing subtype was associated with greater rates of substance dependence. The low-performing subtype reported the highest rates of sexual behavior and risk, while the poor-IGT-performance subtype reported the lowest rates of sexual risk taking. Global associations between substance use and sexual risk were strongest among the low-performing subtype, but event-level associations appeared strongest among individuals in the high-performing subtype. These data suggest complex associations between EF and sexual risk among substance users, and suggest that the relationship between substance use and sexual risk may vary by EF subtypes.

Age- and hormone-regulation of opioid peptides and synaptic proteins in the rat dorsal hippocampal formation.

Circulating estrogen levels and hippocampal-dependent cognitive functions decline with aging. Moreover, the responses of hippocampal synaptic structure to estrogens differ between aged and young rats. We recently reported that estrogens increase levels of post-synaptic proteins, including PSD-95, and opioid peptides leu-enkephalin and dynorphin in the hippocampus of young animals. However, the influence of ovarian hormones on synaptic protein and opioid peptide levels in the aging hippocampus is understudied. Here, young (3- to 5-month-old), middle-aged (9- to 12-month-old), and aged (about 22-month-old) female rats were ovariectomized and then, 4 weeks later, subcutaneously implanted with a silastic capsule containing vehicle or 17ß-estradiol. After 48 h, rats were subcutaneously injected with progesterone or vehicle and sacrificed 1 day later. Coronal sections through the dorsal hippocampus were processed for quantitative peroxidase immunohistochemistry of leu-enkephalin, dynorphin, synaptophysin, and PSD-95. With age, females showed opposing changes in leu-enkephalin and dynorphin levels in the mossy fiber pathway, particularly within the hilus, and regionally specific changes in synaptic protein levels. 17ß-estradiol, with or without progesterone, altered leu-enkephalin levels in the dentate gyrus and synaptophysin levels in the CA1 of young but not middle-aged or aged females. Additionally, 17ß-estradiol decreased synaptophysin levels in the CA3 of middle-aged females. Our results support and extend previous findings indicating 17ß-estradiol modulation of hippocampal opioid peptides and synaptic proteins while demonstrating regional and age-specific effects. Moreover, they lend credence to the "window of opportunity" hypothesis during which hormone replacement can modulate hippocampal structure and circuitry to improve cognitive outcomes.

Distribution of estrogen receptor ß containing cells in the brains of bacterial artificial chromosome transgenic mice.

In the brain, estrogen receptor beta (ERbeta) plays important roles in autonomic functions, stress reactivity and learning and memory processes. However, understanding the function of ERbeta has been restricted by the limited availability of specific antisera, by difficulties discriminating the discrete localization of ERbeta-immunoreactivity (ir) at the light microscopic level in many brain regions and the identification of ERbeta-containing neurons in neurophysiological and molecular studies. Here, we demonstrate that a Esr2 bacterial artificial chromosome (BAC) transgenic mouse line that expresses ERbeta identified by enhanced green fluorescent protein (EGFP) overcomes these shortcomings. Throughout the brain, ERbeta-EGFP was detected in the nuclei and cytoplasm of cells, the majority of which resembled neurons. EGFP often extended into dendritic processes and could be identified either natively or following intensification of EGFP using immunolabeling. The distribution of ERbeta-EGFP cells in brain closely corresponded to that reported for ERbeta protein and mRNA. In particular, ERbeta-EGFP cells were found in autonomic brain regions (i.e., hypothalamic paraventricular nucleus, rostral ventrolateral medulla and nucleus of the solitary tract), in regions associated with anxiety and stress behaviors (i.e., bed nucleus of the stria terminalis, amygdala, periaqueductal gray, raphe and parabrachial nuclei) and in regions involved in learning and memory processes (i.e., basal forebrain, cerebral cortex and hippocampus). Additionally, dual label light and electron microscopic studies in select brain areas demonstrate that cell containing ERbeta-EGFP colocalize with both nuclear and extranuclear ERbeta-immunoreactivity. These findings support the utility of Esr2 BAC transgenic reporter mice for future studies understanding the role of ERbeta in CNS function.