NC Participants Research Articles

Early prediction of mastery of a computerized functional skills training program in participants with mild cognitive impairment.

Cognition in MCI has responded poorly to pharmacological interventions, leading to use of computerized training. Combining computerized cognitive training (CCT) and functional skills training software (FUNSAT) produced improvements in 6 functional skills in MCI, with effect sizes >0.75. However, 4% of HC and 35% of MCI participants failed to master all 6 tasks. We address early identification of characteristics that identify participants who do not graduate, to improve later interventions. NC participants (n = 72) received FUNSAT and MCI (n = 92) participants received FUNSAT alone or combined FUNSAT and CCT on a fully remote basis. Participants trained twice a week for up to 12 weeks. Participants "graduated" each task when they made one or fewer errors on all 3-6 subtasks per task. Tasks were no longer trained after graduation. Between-group comparisons of graduation status on baseline completion time and errors found that failure to graduate was associated with more baseline errors on all tasks but no longer completion times. A discriminant analysis found that errors on the first task (Ticket purchase) uniquely separated the groups, F = 41.40, p < .001, correctly classifying 94% of graduators. An ROC analysis found an AUC of .83. MOCA scores did not increase classification accuracy. More baseline errors, but not completion times, predicted failure to master all FUNSAT tasks. Accuracy of identification of eventual mastery was exceptional. Detection of risk to fail to master training tasks is possible in the first 15 minutes of the baseline assessment. This information can guide future enhancements of computerized training.

Comparison of 18F-FDG PET and arterial spin labeling MRI in evaluating Alzheimer’s disease and amnestic mild cognitive impairment using integrated PET/MR

BackgroundDeveloping biomarkers for early stage AD patients is crucial. Glucose metabolism measured by 18F-FDG PET is the most common biomarker for evaluating cellular energy metabolism to diagnose AD. Arterial spin labeling (ASL) MRI can potentially provide comparable diagnostic information to 18F-FDG PET in patients with neurodegenerative disorders. However, the conclusions about the diagnostic performance of AD are still controversial between 18F-FDG PET and ASL. This study aims to compare quantitative cerebral blood flow (CBF) and glucose metabolism measured by 18F-FDG PET diagnostic values in patients with Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) using integrated PET/MR.ResultsAnalyses revealed overlapping between decreased regional rCBF and 18F-FDG PET SUVR in patients with AD compared with NC participants in the bilateral parietotemporal regions, frontal cortex, and cingulate cortex. Compared with NC participants, patients with aMCI exclusively demonstrated lower 18F-FDG PET SUVR in the bilateral temporal cortex, insula cortex, and inferior frontal cortex. Comparison of the rCBF in patients with aMCI and NC participants revealed no significant difference (P > 0.05). The ROC analysis of rCBF in the meta-ROI could diagnose patients with AD (AUC, 0.87) but not aMCI (AUC, 0.61). The specificity of diagnosing aMCI has been improved to 75.56% when combining rCBF and 18F-FDG PET SUVR.ConclusionASL could detect similar aberrant patterns of abnormalities compared to 18F-FDG PET in patients with AD compared with NC participants but not in aMCI. The diagnostic efficiency of 18F-FDG-PET for AD and aMCI patients remained higher to ASL. Our findings support that applying 18F-FDG PET may be preferable for diagnosing AD and aMCI.

Evaluating cognitive phenotypes and associations with neuroimaging biomarkers of dementia in a sample of aging individuals using unsupervised machine learning

AbstractBackgroundOtherwise cognitively normal individuals can experience age‐related cognitive dysfunction and may present with heterogenous patterns of cognitive impairment. There is limited knowledge regarding the presence and stability of cognitive subtypes observed in individuals with mild cognitive impairment and dementia (e.g., dysexecutive, non‐amnestic). Further, the extent to which cognitive subtypes related to age‐ and dementia‐related neuroimaging biomarkers is uncertain.MethodThis study sought to evaluate the presence and composition of cognitive subtypes in a large diverse community sample of aging individuals without dementia (NC; Baseline N = 337; Table 1). Participants enrolled in the Wake Forest ADRC and completed an annual battery of cognitive assessments (Uniform Data Set; NACC), the Mini‐Mental State Exam (MMSE), and Clinical Diagnostic Rating Scale (CDR). Unsupervised machine learning (e.g., clustering: hierarchical, k‐means, and k‐medoids algorithms; 1000 bootstrap iterations; majority voting rule) was applied to the battery of cognitive assessments. Demographic characteristics and neuroimaging measures of amyloid deposition (global PiB PET SUVr; Aβ‐PET), total brain volume (BVOL), diffusion‐weighted fractional anisotropy (FA), and NODDI freewater (FW) were compared across prospective clusters using general linear models. Highly correlated cognitive metrics (r&gt;.85) were removed prior to analysis.ResultCluster analyses using baseline cognitive scores suggested NC participants could be partitioned into two to eight clusters; two primary clusters representing one large homogenous group of relatively unimpaired individuals and another heterogenous cluster composed of 4‐7 possible cognitive subgroups (Figure 1). The two‐cluster solution partitioned NC participants into higher and lower cognitive performers. Across cluster solutions, lower performing individuals were older, had higher Aβ‐PET, and lower total brain volume on average (p&lt;.05; Figure 2).ConclusionWe did not observe well‐defined clusters representing distinct cognitive subtypes reported in previous studies (e.g., dysexecutive, amnestic, visuospatial). However, a heterogenous subset of NC participants exhibited substantial variability across assessments. Three‐ and four‐cluster solutions identified individuals with greater impairment in executive functioning, and verbal learning and memory respectively. Findings highlight the need to model complex patterns of cognitive abilities in otherwise healthy older adults. Future longitudinal work will assess how health information and neuroimaging biomarkers of dementia contribute to the composition and stability of cognitively defined subgroups.

Later life Body composition and Alzheimer’s disease

AbstractBackgroundMid‐life obesity is linked with increased risk for late‐life dementia, however relationships between later‐life body composition and dementia are less clear.MethodUsing a combined cohort from two major observational studies (AIBL and ADNI) and categorising Body Mass Index (BMI) according to WHO criteria, we computed multivariable linear mixed‐effects models to determine association between BMI category and outcomes: brain beta‐amyloid PET quantification (centiloid); MRI (global, hippocampal and white matter hyperintensity volume); and cognition (PACC [preclinical Alzheimer cognitive composite], composite scores for attention, executive function and episodic memory). All models were adjusted by covariables age, gender, education, APOE ε4, and study (AIBL/ADNI).ResultsThe cohort included 4,668 observations from 2,828 individuals (49.4% male, mean age 73.8 years, 38.2% APOE ε4 carriage, 61.8% normal cognition [NC], 25.6% Mild Cognitive Impairment [MCI], 12.6% dementia due to Alzheimer’s disease). The average BMI was 26.8 kg/m2 (0.6% underweight, 37.7% normal‐range, 41.7% overweight, 20.0% obese [BMI &lt;18, 18‐25, 25‐30 and &gt;30 kg/m2, respectively]).Relative to normal‐range BMI, those with overweight‐or‐obese range BMI had a significant negative association with PET centiloid level, beta = ‐0.150 (0.037 se) and ‐0.309 (0.042), respectively (i.e. greater BMI had lower amyloid level). This remained significant for obese‐range BMI in fully‐adjusted models when restricted to only NC participants. Also, obesity was associated with greater hippocampal volume, beta = 0.192 (0.046), but this was not significant when restricted to NC only. Associations with total grey matter/cortical volume and white matter hyperintensities were not significant. Obese‐range BMI was associated with stronger performance on attention and episodic memory composites, but not for PACC and executive function. For NC‐only, there was only significant negative association between obesity and attention performance. In multivariate analyses, neither obesity category nor BMI were associated with longitudinal change in cognitive scores.ConclusionPresence of obesity in later life was associated with lower brain amyloid levels and less hippocampal atrophy in a mixed cohort including older adults with dementia, mild cognitive impairment and normal cognition. While mid‐life obesity is associated greater risk for AD, later life associations appear influenced by weight loss with emerging dementia.

Longitudinal retinal changes in mild cognitive impairment and Alzheimer’s Disease

AbstractBackgroundPrevious studies have shown retinal thickness and vascular alterations in Alzheimer’s disease (AD), even in patients with mild cognitive impairment (MCI), suggesting that retinal parameters are potential biomarkers for AD. However, the prospective observation of retinal markers is still insufficient. In this study, we aimed to observe longitudinal retinal thickness and vascular changes in patients with AD and MCI, and to identify critical retinal markers that significantly change over time.MethodPatients with AD (N = 22) and MCI (N = 21) were recruited from the Shanghai Memory Study. Age‐ and gender‐matched cognitively normal (NC) participants (N = 26) were included from the Shanghai Aging Study. Optical coherence tomography (OCT) and OCT angiography were performed in all participants at baseline and after an average 19.2 months follow‐up to assess changes in peripapillary retinal nerve fiber layer thickness (p‐RNFL), ganglion cell layer thickness (GCC), macular thickness and volume divided by the Early Treatment Diabetic Retinopathy Study grid, retinal vessel density, and fovea avascular zone (FAZ). Differences of monthly variation rate of retinal parameters between NC, MCI, and AD individuals were evaluated.ResultThe monthly variation rates among groups showed significant differences in thickness and volume of full temporal para‐fovea sector, inner temporal peri‐fovea sector, outer temporal para‐fovea sector, and thickness of outer superior hemisphere para‐fovea sector (all P&lt;0.05). There was no difference in the rate of change of p‐RNFL, GCC, retinal vessel density, and FAZ among all groups. Post hoc analysis revealed that the monthly change in thickness and volume of the full‐temporal and outer sectors were significantly faster in AD than in NC, whereas the inner‐temporal sectors changed faster in MCI than in NC groups (all P&lt;0.05). Furthermore, the monthly changes in inner temporal peri‐fovea thickness were faster in MCI than in NC and AD participants (all P&lt;0.05).ConclusionDuring follow‐up, retinal temporal thinning was faster in patients with AD, whilst inner retina‐temporal sector thinning was faster in participants with MCI. Accelerated thinning of temporal sectors of the retina, especially the inner‐temporal sector may be an early marker of AD disease progression.

Brief Test of Olfactory Dysfunction Based on Diagnostic Features of Specific Odors in Early-Stage Alzheimer Disease.

BACKGROUND Olfactory impairment is an early symptom of Alzheimer disease (AD). However, it is rarely assessed in clinical practice. This study aimed to assess the identification and discrimination of specific odors in patients with early-stage AD using the Sniffin' Sticks test and determine the items that would be most valuable in the diagnosis of early-stage AD in order to create a brief test of olfactory dysfunction. MATERIAL AND METHODS Three groups of participants were enrolled, including 30 patients with mild cognitive impairment due to AD (MCI-AD group), 30 with mild dementia due to AD (MD-AD group), and 30 older participants with normal cognition (NC group). All participants underwent cognitive (Clinical Dementia Rating, Mini-Mental State Examination, Alzheimer's Disease Assessment Scale-Cognitive Subscale, and verbal fluency tests) and olfactory (Burghart Sniffin' Sticks odor identification and odor discrimination tests) assessments. RESULTS The MD-AD group scored significantly lower than the MCI-AD group and the MCI-AD group scored significantly lower than the NC group in both the odor identification (P<0.001) and discrimination (P<0.05) tasks. The shortened versions of the odor identification and discrimination tasks showed good diagnostic properties in differentiating patients with AD from the NC participants (receiver operating characteristic [ROC] area under the curve [AUC]=0.912 and 0.954, respectively) and differentiating patients with MCI-AD from the NC participants (ROC AUC=0.871 and 0.959, respectively). CONCLUSIONS The brief versions of olfactory tests, containing selected items that were found to differ the most between cognitively normal participants and early-stage AD patients, have good diagnostic qualities and can aid clinicians in screening for early-stage AD.

Striatal dopamine synthesis and cognitive flexibility differ between hormonal contraceptive users and nonusers.

In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine (DA) neurotransmission. Yet less is known about hormonal regulation of the DA system in the human brain. Using positron emission tomography (PET), we address this gap by comparing hormonal contraceptive users and nonusers across multiple aspects of DA function: DA synthesis capacity via the PET radioligand 6-[18F]fluoro-m-tyrosine ([18F]FMT), baseline D2/3 receptor binding potential using [11C]raclopride, and DA release using methylphenidate-paired [11C]raclopride. Participants consisted of 36 healthy women (n = 15 hormonal contraceptive users; n = 21 naturally cycling/non users of hormonal contraception), and men (n = 20) as a comparison group. A behavioral index of cognitive flexibility was assessed prior to PET imaging. Hormonal contraceptive users exhibited greater DA synthesis capacity than NC participants, particularly in dorsal caudate, and greater cognitive flexibility. Furthermore, across individuals, the magnitude of striatal DA synthesis capacity was associated with cognitive flexibility. No group differences were observed in D2/3 receptor binding or DA release. Analyses by sex alone may obscure underlying differences in DA synthesis tied to women's hormone status. Hormonal contraception (in the form of pill, shot, implant, ring, or intrauterine device) is used by ~400 million women worldwide, yet few studies have examined whether chronic hormonal manipulations impact basic properties of the DA system. Findings from this study begin to address this critical gap in women's health.

Examining a Preclinical Alzheimer’s Cognitive Composite for Telehealth Administration, the tPACC, for Reliability between In-Person and Remote Cognitive Testing (P6-6.002)

<h3>Objective:</h3> To evaluate the concordance of tPACC scores from in-person and remote testing. <h3>Background:</h3> The clinical trial landscape in Alzheimer’s disease (AD) and related dementias is focused on targeting individuals in preclinical stages. The preclinical Alzheimer’s cognitive composite (PACC) was developed for in-person administration to capture subtle cognitive decline in amyloid positive individuals compared to amyloid negative. It is desirable to have a transportable, composite measurement sensitive to detecting cognitive changes across cognitively normal (NC) and impaired (MCI and dementia) participants. <h3>Design/Methods:</h3> We examined in-person cognitive data from 662 adults (70.2±8.1y) from the Wake Forest AD Research Center’s Clinical Core, who received clinical evaluation, cognitive testing, and adjudication. The PACC in-person only was calculated using RAVLT Delayed Recall, Digit Symbol Coding (DSC), semantic fluency, Craft Story Delayed Verbatim, and MMSE total scores using baseline NC participants as a reference. The tPACC used measurements that were available at both in-person and remote visits with modifications from the in-person PACC; Montreal Cognitive Assessment (MoCA) was used in place of MMSE, and DSC was not included. A subset analysis with PACC in-person and tPACC remote from a pilot study examined reliability between in-person and remote testing. We performed correlation analysis and generated Bland-Altman plots. <h3>Results:</h3> Of the 662 adults studied, 434 (66%) were female, 522 (79%) were White, 206 (34%) were <i>APOE</i>4 carriers, and mean education was 15.9±4.1 years. At baseline, there is a significant positive relationship between in-person tPACC and PACC (Overall group; r²=0.94, p=&lt;0.0001, n=640). Although there is a good agreement in both subgroups (Impaired: r²=0.86, p=&lt;0.0001, n=301 and NC: r²=0.90, p=&lt;0.0001, n=328), tPACC overestimates cognitive performance compared to PACC for those with lower scores. We also found good agreement between in-person PACC and remote tPACC (r²=0.83, p=&lt;0.0001, n=38). <h3>Conclusions:</h3> There is generally good agreement between tPACC and PACC for NC and impaired individuals. <b>Disclosure:</b> Miss Duran has nothing to disclose. The institution of Ms. Gaussoin has received research support from NIH. The institution of Dr. Lockhart has received research support from NIH. Dr. Rundle has nothing to disclose. The institution of Dr. Espeland has received research support from Alzheimer’s Association. The institution of Dr. Espeland has received research support from National Institutes of Health. Dr. Espeland has received personal compensation in the range of $500-$4,999 for serving as a Consultant with National Institutes of Health. Dr. Williams has nothing to disclose. Tim Hughes has nothing to disclose. Suzanne Craft has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cognito Therapeutics. Suzanne Craft has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for T3D Therapeutics. Suzanne Craft has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cyclerion Therapeutics. Suzanne Craft has received personal compensation in the range of $500-$4,999 for serving as a member, Board of Scientific Counselors with NIA. Bonnie Sachs has received research support from NIH. Bonnie Sachs has received research support from Alzheimer’s Association. The institution of Dr. Bateman has received research support from NIA.

Difficulties with positive emotion regulation in anorexia nervosa.

Individuals with anorexia nervosa (AN) have well-documented difficulties regulating negative emotions, but less is known about positive emotion regulation in this population. To address this gap, we compared responses on the Difficulties in Emotion Regulation Scale-Positive questionnaire and the traditional DERS questionnaire (measuring negative affect dysregulation) between females with AN (n=30) and demographically-matched controls without an eating disorder history (NC; n=30) and examined relations between positive emotion regulation and clinical symptoms. Results indicated that individuals with AN demonstrated greater difficulty regulating negative (p<0.001, d=2.75) and positive (p<0.001, d=1.08) emotions compared to NC participants. Specifically, the AN group reported heightened positive emotion nonacceptance (p=0.004, d=0.78) and impulsivity (p=0.003, d=0.81). Greater positive emotion nonacceptance was associated with higher anxiety (p=0.015) and depression (p=0.022) among individuals with AN. Unexpectedly, more positive emotion impulsivity was associated with less restrictive eating in AN (p<0.001). Findings were largely maintained even after controlling for negative emotion dysregulation and psychotropic medication use. The results suggest that reducing shame related to positive emotions could improve mood in AN; alternatively, relinquishing control when experiencing positive emotion could reduce restriction. More research is warranted on positive emotion regulation as a treatment target for AN.

Difference in allostatic interoceptive network connectivity by cognitive status

AbstractBackgroundThe allostatic interoceptive network (AIN) has been proposed as central to linking interoceptive processing and autonomic regulation and involved in emotional experience. Early pathologic changes in AD occur in hubs of the AIN, and changes in emotional reactivity have been identified at both the MCI and dementia stages of Alzheimer’s disease. Interoception has been proposed as a core feature in psychiatric disease, though relatively little attention has been paid to altered interoception in neuropsychiatric symptoms in dementia. We conducted a pilot analysis in cognitively normal (CN) participants and those with mild cognitive impairment (MCI) to identify alterations in functional connectivity of the AIN, default mode, and salience networks.MethodTwenty‐two participants from the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort including CN participants (n = 11, mean age = 67 ± 7) and MCI (n = 11, mean age = 72 ± 7) received 3T brain MRI using T1 for gray/white matter segmentation and BOLD for resting‐state functional connectivity. BOLD time series data were pre‐processed and de‐noised using standard techniques. Connectivity analyses were performed using the CONN functional connectivity toolbox. Briefly, we performed a comparison of within‐network connectivity of the allostasis and interoception system (comprised of the DMN, SN, and AIN seed regions) between MCI and NC participants while adjusting for age (p &lt; 0.05 uncorrected).Result Table lists the baseline demographic and clinical characteristics for CN and MCI groups. Participants with MCI had greater connectivity between limbic regions of the AIN and salience network compared with the CN group, and decreased connectivity between the left lateral parietal cortex and multiple hubs of the salience network. Within the AIN seed regions, the amygdala and dorsal posterior and mid insula had increased connectivity (Figure; p &lt; 0.05 uncorrected).ConclusionWe find differences in functional connectivity between CN adults and persons with MCI for three brain networks. Our analyses provide preliminary support that changes in an integrated allostasis and interoceptive system, integrating components of the DMN and SN, may have implications for emotional dysregulation in ADRD.

Hidden objective test

AbstractBackgroundAlzheimer’s disease patients frequently complaint that they lose things and be unable to find them again because of deficit in visuospatial memory. In this study we aimed to develop a novel visuospatial memory tests called the Hidden Objective Test (HOT) based on the ideas of patients’ complaint. Virtual reality (VR) is an optimal tool for developing this visuospatial memory tests in that real‐life settings implementation.MethodWe designed a pleasant and cozy living room. The photorealistic virtual environment interface with 360‐degree panoramas was rendered through HMD. The VR system enables the users to turn their head, to walk around, to open and close the furniture doors using controllers, and to track their movement in the VR living room. When the participant starts the test, the VR living room is shown and instructions for the prospective memory test are given. Nine items appeared on the white panel in order, and one by one, the item moved to the each furniture space and were hided. Memory test composed of 1) Item Free‐recall test, 2) Place Free‐recall test, 3) Item Recognition test, 4) Place‐item matching test, and 5) Prospective memory test.Participants were selected from those who visited the Memory Disorder Clinic at Samsung Medical Center in Seoul, Korea, between November 1st, 2019 and January 30th, 2020. This study group comprised 16 AD, 15 AMCI, and 15 NC participants.ResultThe performance of memory test was NC&gt;AMCI (p&lt;0.001), AMCI&gt;AD (p&lt;0.05), and NC &gt; AD (p&lt;0.001) in the Item Free‐recall test; NC&gt;AMCI (p&lt;0.01) and NC &gt; AD (p&lt;0.001) in the Place Free‐recall test; NC&gt;AMCI (p&lt;0.05), AMCI&gt;AD (p&lt;0.01), and NC &gt; AD (p&lt;0.001) in the Item Recognition test; NC&gt;AMCI (p&lt;0.001) and NC &gt; AD (p&lt;0.001) in the Place‐item matching test; NC &gt; AD (p&lt;0.05) in the Prospective memory test. Interestingly, the average movement path showed that NC participants went straight toward the target point whereas AD patients wandered to the target point when searching for hidden objects.ConclusionThe Hidden Objective Test (HOT) developed in this study, which incorporated virtual reality to experience real‐life events, showed potential to be used as a new memory screening test.

The contribution of sleep to anorexia nervosa severity.

Anorexia nervosa (AN) is associated with poor sleep and altered circadian rhythms. Evidence is unclear as to whether these features relate to ongoing psychiatric symptoms of AN, or are merely concomitant with low weight. In this study, we sought to evaluate subjective sleep quality and sleep-wake preferences in a sample of individuals with lifetime AN. Furthermore, we aimed to examine whether sleep quality would significantly predict AN symptom severity, after accounting for demographic features and negative emotions (depression, anxiety and stress). Adults with a lifetime diagnosis of AN (n = 96) or no lifetime psychiatric diagnoses (NC; n = 246) completed an online survey assessing demographics, sleep quality, circadian sleep-wake preferences, eating disorder symptoms, and negative emotions. AN participants reported significantly poorer sleep quality overall, including increased sleep disturbances, use of sleep medications, and daytime dysfunction, as compared to NC participants. Groups did not differ significantly in circadian sleep-wake preferences. Regression analysis showed that among AN participants, sleep quality and negative emotions significantly predicted AN symptom severity, while sex and body mass index (BMI) did not. The findings demonstrate that poor sleep quality was associated with more severe symptoms of AN, even when accounting for negative emotions and BMI. Future research should investigate causal interactions between sleep quality and AN symptom severity longitudinally and across different recovery stages. Level III-Cohort and case-control analytic studies.

Mediterranean and Western diet effects on Alzheimer's disease biomarkers, cerebral perfusion, and cognition in mid-life: A randomized trial.

IntroductionMid‐life dietary patterns are associated with Alzheimer's disease (AD) risk, although few controlled trials have been conducted.MethodsEighty‐seven participants (age range: 45 to 65) with normal cognition (NC, n = 56) or mild cognitive impairment (MCI, n = 31) received isocaloric diets high or low in saturated fat, glycemic index, and sodium (Western‐like/West‐diet vs. Mediterranean‐like/Med‐diet) for 4 weeks. Diet effects on cerebrospinal fluid (CSF) biomarkers, cognition, and cerebral perfusion were assessed to determine whether responses differed by cognitive status.ResultsCSF amyloid beta (Aβ)42/40 ratios increased following the Med‐diet, and decreased after West‐diet for NC adults, whereas the MCI group showed the reverse pattern. For the MCI group, the West‐diet reduced and the Med‐diet increased total tau (t‐tau), whereas CSF Aβ42/t‐tau ratios increased following the West‐diet and decreased following the Med‐diet. For NC participants, the Med‐diet increased and the West‐diet decreased cerebral perfusion.DiscussionDiet response during middle age may highlight early pathophysiological processes that increase AD risk.

A Novel Method for Assessing and Training Everyday Functional Skills

Older adults, especially those with cognitive impairments often experience difficulty performing everyday tasks such as medication management, which threatens independence. Thus, there is an interest in developing treatment approaches for those who are experiencing or at risk for cognitive problems. Cognitive remediation training (CRT) programs have shown to be effective in improving cognitive abilities, but there is limited evidence to suggest that CRT results in everyday task performance gains. This presentation will discuss findings from a trial evaluating an innovative computer -based functional skills assessment and skills training program (CFSAT), which includes ecologically valid simulations of everyday tasks (e.g., shopping, money and medication management). The sample includes non-cognitively impaired (NC) older adults (n=50) and those with mild cognitive impairment (MCI) (n = 40), ranging in age from 60 -86 years (M= 73.10; SD = 6.06), is primarily female (90%), and ethnically diverse (69% minority). Participants were randomized into the CFSAT condition or a CFSAT + CRT condition. Performance data includes real time measures of accuracy, response time and efficiency. The findings indicate that the assessment component of the CFSAT program differentiated between the NC and MCI groups at the baseline assessment. Both NC and MCI participants demonstrated improvements in performance following training across all tasks; though the MCI participants required more training. Participants who received CFSAT + CRT training demonstrated increased efficiency in skill acquisition. The results indicate that the CFSAT program is an efficacious tool for assessing and training functional performance in both non-cognitively and cognitively impaired older adults.

The effects of menstrual cycle stage and hormonal contraception on alcohol consumption and craving: A pilot investigation

Background and aimsAlthough alcohol research often comments on observed sex differences (i.e. patterns of consumption), there is a lack of investigation into the reasons for these differences. For females, the regular hormonal fluctuations across the menstrual cycle are a potential influencing factor for alcohol consumption. In this pilot we aimed to investigate the relationship between menstrual cycle phase (follicular-phase [FP] and luteal-phase [LP]) and status (naturally-cycling [NC] and hormonal-contraception [HC]) on alcohol consumption and craving of casual drinkers, and identify potential influencing factors in this relationship. MethodsStudy One: participants (n ​= ​28; 15 HC, 13 NC) were either NC or HC (between subject factor: hormonal status) and attended two lab-based sessions corresponding with their FP and LP (within factor: cycle phase [NC] or time [HC]). Participants completed a mock alcohol taste-test, in addition to pre- and post-consumption measures of craving, anxiety, stress, and mood. Study Two: participants (n ​= ​262; 144 HC, 118 NC) were either NC or HC (between subject factor) and completed an online study assessing menstrual cycle phase, alcohol use, craving, impulsivity, and stress. ResultsStudy One: A significant effect of cycle phase was found on alcohol craving (p ​= ​.019): craving was higher during the FP compared to the LP for NC participants, with HC participants showing no difference across sessions. There was no effect of phase or status on alcohol consumption, stress, or mood (ps ​> ​.05). Study Two: Regression analyses showed that age, craving, impulsivity and stress were significantly associated with alcohol consumption for NC participants (ps ​< ​.05), however only age and craving were associated with consumption for the HC participants (ps ​< ​.001). ConclusionsAlcohol craving was higher during the follicular, compared to the luteal, phase for the naturally cycling group, and different factors may be associated with drinking behaviour across women who are NC and those using HC. Future alcohol research should consider the menstrual cycle and contraceptive status for females.

Evaluation of a Novel Technology-Based Program Designed to Assess and Train Everyday Skills in Older Adults.

Background and ObjectivesPerformance of everyday activities is often challenging for older adults. We evaluated a novel computer-based functional skills assessment and training (CFSAT) program, which includes simulations of everyday tasks (e.g., money and medication management).Research Design and MethodsThe sample included noncognitively impaired (NC) older adults (n = 51) and cognitively impaired (CI) older adults (n = 43), who ranged in age from 60 to 86 years (M = 73.12; SD = 6.06), were primarily female (90%), and ethnically diverse (23% Hispanic, 51% African American). Participants (stratified by cognitive status) were randomized to 1 of the 2 conditions training alone (CFSAT) or CFSAT with computerized cognitive training and trained up to 24 training sessions. Task performance, using measures of completion time and efficiency (accuracy/completion time), was evaluated at baseline, the final training session, and immediately posttraining with an alternate form of the CFSAT assessment.ResultsBoth NC and CI participants demonstrated significant performance improvements across all tasks following training (all ps < .001). The CI participants demonstrated reduced training gains compared to the NC participants (all ps < .001). Training gains did not vary as a function of training conditions.Discussion and ImplicationsThe findings suggest that CFSAT is an efficacious program for assessing and training everyday task performance. CFSAT can ultimately be used as an intervention strategy to enhance functional independence for aging adults with and without cognitive impairments.

A Computerized Functional Skills Assessment and Training Program Targeting Technology Based Everyday Functional Skills.

Today, many functional skills are technology-based, so development of a technology-based training program has broad importance. Here we present a computerized functional skills training program that was paired in half of the participants with a commercially available cognitive training (CCT) program. Non-impaired older individuals (NC) aged 60+ (n=45) and similarly aged individuals with mild cognitive impairment (MCI; n=50) were randomized to receive 12 weeks of twice-weekly computerized functional skills training (CFST) or 12 weeks of twice-weekly sessions split between CCT and CFST. Skills trained were use of an ATM; internet banking; ticket kiosk; telephone and internet prescription refill; medication management; and internet shopping. As with previous functional capacity assessments, we focus on completion time for each simulation. 51 participants completed the training program, either by mastering all 6 tasks (34) or completing 12 weeks of training. 44 more participants completed 4 or more training sessions so they were also analyzed for improvement up to their last training session. Completion time for all 6 tests significantly improved from the baseline assessment to the final training session in both groups of participants (all p<0.001 with an average improvement in task completion time of 45%). Further, there was no differential improvement in MCI and NC in the 6 tests from baseline to end of training (all t<1.66, all p>0.12). Finally, combined CCT plus CFST did not differ from CSFT alone on any of the percent-change score measures (all t<1.64, all p>0.11). Both NC and MCI groups evidenced substantial improvements in performance. CCT supplementation led to similar functional gains with half as many training sessions. The NC participants proceeded through the training fairly rapidly even without CCT supplementation; MCI participants required more training but learned equivalently. These findings suggest that even in cases with memory impairments, functional skills can be efficiently learned with training.

Application of the NIA-AA Research Framework: Towards a Biological Definition of Alzheimer\u2019s Disease using Cerebrospinal Fluid Biomarkers in the AIBL Study

BackgroundThe National Institute on Aging and Alzheimer’s Association (NIA-AA) have proposed a new Research Framework: Towards a biological definition of Alzheimer’s disease, which uses a three-biomarker construct: Aß-amyloid, tau and neurodegeneration AT(N), to generate a biomarker based definition of Alzheimer’s disease.ObjectivesTo stratify AIBL participants using the new NIA-AA Research Framework using cerebrospinal fluid (CSF) biomarkers. To evaluate the clinical and cognitive profiles of the different groups resultant from the AT(N) stratification. To compare the findings to those that result from stratification using two-biomarker construct criteria (AT and/or A(N)).DesignIndividuals were classified as being positive or negative for each of the A, T, and (N) categories and then assigned to the appropriate AT(N) combinatorial group: A−T−(N)−; A+T-(N)−; A+T+(N)−; A+T−(N)+; A+T+(N)+; A−T+(N)−; A−T−(N)+; A−T+(N)+. In line with the NIA-AA research framework, these eight AT(N) groups were then collapsed into four main groups of interest (normal AD biomarkers, AD pathologic change, AD and non-AD pathologic change) and the respective clinical and cognitive trajectories over 4.5 years for each group were assessed. In two sensitivity analyses the methods were replicated after assigning individuals to four groups based on being positive or negative for AT biomarkers as well as A(N) biomarkers.SettingTwo study centers in Melbourne (Victoria) and Perth (Western Australia), Australia recruited MCI individuals and individuals with AD from primary care physicians or tertiary memory disorder clinics. Cognitively healthy, elderly NCs were recruited through advertisement or via spouses of participants in the study.ParticipantsOne-hundred and forty NC, 33 MCI participants, and 27 participants with AD from the AIBL study who had undergone CSF evaluation using Elecsys® assays.Intervention (if any)Not applicable.MeasurementsThree CSF biomarkers, namely amyloid β1–42, phosphorylated tau181, and total tau, were measured to provide the AT(N) classifications. Clinical and cognitive trajectories were evaluated using the AIBL Preclinical Alzheimer Cognitive Composite (AIBL-PACC), a verbal episodic memory composite, an executive function composite, California Verbal Learning Test–Second Edition; Long-Delay Free Recall, Mini-Mental State Examination, and Clinical Dementia Rating Sum of Boxes scores.ResultsThirty-eight percent of the elderly NCs had no evidence of abnormal AD biomarkers, whereas 33% had biomarker levels consistent with AD or AD pathologic change, and 29% had evidence of non-AD biomarker change. Among NC participants, those with biomarker evidence of AD pathology tended to perform worse on cognitive outcome assessments than other biomarker groups. Approximately three in four participants with MCI or AD had biomarker levels consistent with the research framework’s definition of AD or AD pathologic change. For MCI participants, a decrease in AIBL-PACC scores was observed with increasing abnormal biomarkers; and increased abnormal biomarkers were also associated with increased rates of decline across some cognitive measures.ConclusionsIncreasing biomarker abnormality appears to be associated with worse cognitive trajectories. The implementation of biomarker classifications could help better characterize prognosis in clinical practice and identify those at-risk individuals more likely to clinically progress, for their inclusion in future therapeutic trials.

Characterizing the landscape of peritoneal exosomal microRNAs in patients with ovarian cancer by high-throughput sequencing.

In the present study, differentially expressed microRNAs (miRNAs) in peritoneal exosomes that were isolated from 10 patients with epithelial ovarian cancer (EOC) with metastasis in the abdominal cavity and 10 participants without cancer (NC) were identified. These differentially expressed miRNAs that were revealed by next-generation sequencing were categorized by Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of their target genes. Notably, two miRNAs that were associated with EOC-miR-149-3p and miR-222-5p-were identified. There were significant differences in expression of miR-149-3p and miR-222-5p between EOC and NC samples, and the effect of the expression level of the two miRNAs on the patient survival was identified using publicly available data from The Cancer Genome Atlas. There is an association between these two miRNAs and EOC, that was further verified by reverse transcription-quantitative polymerase chain reaction in peritoneal exosomes from 10 patients with EOC and NC participants. These results indicated that miR-149-3p and miR-222-5p might be novel biomarkers for evaluating the prognosis of patients with EOC and that these two miRNAs might have potential therapeutic values.

Abstract LB-343: Development of plasma cell-free DNA (cfDNA) assays for early cancer detection: first insights from the Circulating Cell-Free Genome Atlas Study (CCGA)

Abstract CCGA [NCT02889978] is the largest study of cfDNA-based early cancer detection; the first CCGA learnings from multiple cfDNA assays are reported here. This prospective, multi-center, observational study has enrolled 10,012 of 15,000 demographically-balanced participants at 141 sites. Blood was collected from participants with newly diagnosed therapy-naive cancer (C, case) and participants without a diagnosis of cancer (noncancer [NC], control) as defined at enrollment. This preplanned substudy included 878 cases, 580 controls, and 169 assay controls (n=1627) across 20 tumor types and all clinical stages. All samples were analyzed by: 1) Paired cfDNA and white blood cell (WBC)-targeted sequencing (60,000X, 507 gene panel); a joint caller removed WBC-derived somatic variants and residual technical noise; 2) Paired cfDNA and WBC whole-genome sequencing (WGS; 35X); a novel machine learning algorithm generated cancer-related signal scores; joint analysis identified shared events; and 3) cfDNA whole-genome bisulfite sequencing (WGBS; 34X); normalized scores were generated using abnormally methylated fragments. In the targeted assay, non-tumor WBC-matched cfDNA somatic variants (SNVs/indels) accounted for 76% of all variants in NC and 65% in C. Consistent with somatic mosaicism (i.e., clonal hematopoiesis), WBC-matched variants increased with age; several were non-canonical loss-of-function mutations not previously reported. After WBC variant removal, canonical driver somatic variants were highly specific to C (e.g., in EGFR and PIK3CA, 0 NC had variants vs 11 and 30, respectively, of C). Similarly, of 8 NC with somatic copy number alterations (SCNAs) detected with WGS, 4 were derived from WBCs. WGBS data revealed informative hyper- and hypo-fragment level CpGs (1:2 ratio); a subset was used to calculate methylation scores. A consistent “cancer-like” signal was observed in &amp;lt;1% of NC participants across all assays (representing potential undiagnosed cancers). An increasing trend was observed in NC vs stages I-III vs stage IV (nonsyn. SNVs/indels per Mb [Mean±SD] NC: 1.01±0.86, stages I-III: 2.43±3.98; stage IV: 6.45±6.79; WGS score NC: 0.00±0.08, I-III: 0.27±0.98; IV: 1.95± 2.33; methylation score NC: 0±0.50; I-III: 1.02±1.77; IV: 3.94±1.70). These data demonstrate the feasibility of achieving &amp;gt;99% specificity for invasive cancer, and support the promise of cfDNA assay for early cancer detection. Additional data will be presented on detected plasma:tissue variant concordance and on multi-assay modeling. Citation Format: Alexander A. Aravanis, Geoffrey R. Oxnard, Tara Maddala, Earl Hubbell, Oliver Venn, Arash Jamshidi, Ling Shen, Hamed Amini, John A. Beausang, Craig Betts, Daniel Civello, Konstantin Davydov, Saniya Fazullina, Darya Filippova, Sante Gnerre, Samuel Gross, Chenlu Hou, Roger Jiang, Byoungsok Jung, Kathryn Kurtzman, Collin Melton, Shivani Nautiyal, Jonathan Newman, Joshua Newman, Cosmos Nicolaou, Richard Rava, Onur Sakarya, Ravi Vijaya Satya, Seyedmehdi Shojaee, Kristan Steffen, Anton Valouev, Hui Xu, Jeanne Yue, Nan Zhang, Jose Baselga, Rosanna Lapham, Daron G. Davis, David Smith, Donald Richards, Michael V. Seiden, Charles Swanton, Timothy J. Yeatman, Robert Tibshirani, Christina Curtis, Sylvia K. Plevritis, Richard Williams, Eric Klein, Anne-Renee Hartman, Minetta C. Liu. Development of plasma cell-free DNA (cfDNA) assays for early cancer detection: first insights from the Circulating Cell-Free Genome Atlas Study (CCGA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-343.