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Prior research has revealed distinctive patterns of impaired language abilities across the three variants of Primary Progressive Aphasia (PPA): nonfluent/agrammatic (nfvPPA), logopenic (lvPPA) and semantic (svPPA). However, little is known about whether, and to what extent, non-verbal cognitive abilities, such as processing speed, are impacted in PPA patients. This is because neuropsychological tests typically contain linguistic stimuli and require spoken output, being therefore sensitive to verbal deficits in aphasic patients. The aim of this study is to investigate potential differences in processing speed between PPA patients and healthy controls, and among the three PPA variants, using a brief non-verbal tablet-based task (Match) modeled after the WAIS-III digit symbol coding test, and to determine its neural correlates. Here, we compared performance on the Match task between PPA patients (n = 61) and healthy controls (n = 59) and across the three PPA variants. We correlated performance on Match with voxelwise gray and white matter volumes. We found that lvPPA and nfvPPA patients performed significantly worse on Match than healthy controls and svPPA patients. Worse performance on Match across PPA patients was associated with reduced gray matter volume in specific parts of the left middle frontal gyrus, superior parietal lobule, and precuneus, and reduced white matter volume in the left parietal lobe. To conclude, our behavioral findings reveal that processing speed is differentially impacted across the three PPA variants and provide support for the potential clinical utility of a tabled-based task (Match) to assess non-verbal cognition. In addition, our neuroimaging findings confirm the importance of a set of fronto-parietal regions that previous research has associated with processing speed and executive control. Finally, our behavioral and neuroimaging findings combined indicate that differences in processing speed are largely explained by the unequal distribution of atrophy in these fronto-parietal regions across the three PPA variants.

BackgroundPlasma neurofilament light chain (NfL) is a promising biomarker of neurodegeneration with potential clinical utility in monitoring the progression of neurodegenerative diseases. However, the cross-sectional associations of plasma NfL with measures of cognition and brain have been inconsistent in community-dwelling populations.MethodsWe examined these associations in a large community-dwelling sample of early old age men (N = 969, mean age = 67.57 years, range = 61-73 years), who are either cognitively unimpaired (CU) or with mild cognitive impairment (MCI). Specifically, we investigated five cognitive domains (executive function, episodic memory, verbal fluency, processing speed, visual-spatial ability), as well as neuroimaging measures of gray and white matter.ResultsAfter adjusting for age, health status, and young adult general cognitive ability, plasma NfL level was only significantly associated with processing speed and white matter hyperintensity (WMH) volume, but not with other cognitive or neuroimaging measures. The association with processing speed was driven by individuals with MCI, as it was not detected in CU individuals.ConclusionsThese results suggest that in early old age men without dementia, plasma NfL does not appear to be sensitive to cross-sectional individual differences in most domains of cognition or neuroimaging measures of gray and white matter. The revealed plasma NfL associations were limited to WMH for all participants and processing speed only within the MCI cohort. Importantly, considering cognitive status in community-based samples will better inform the interpretation of the relationships of plasma NfL with cognition and brain and may help resolve mixed findings in the literature.

BACKGROUND: Between 29% and 67% of neuromyelitis optica spectrum disorder patients have cognitive alterations. OBJECTIVE: To assess the frequency of cognitive impairment in patients with neuromyelitis optica spectrum disorder in Mexico using the Brief International Cognitive Assessment for Multiple Sclerosis. METHODS: We evaluated 40 neuromyelitis optica spectrum disorder patients and 40 healthy controls from Mexico. RESULTS: 28 (70.0%) patients with neuromyelitis optica spectrum disorder had cognitive impairment in two or more cognitive domains. Student´s T test showed statistically poor performance by neuromyelitis optica spectrum disorder patients compared to healthy controls on all three neuropsychological test scores. This significant difference was observed on the Symbols Digit Modalities Test (t = 8.875; p ≤ 0.001); California Verbal Learning Test-II memory (t = 10.418; p ≤ 0.001); and Brief Visuospatial Memory Test Revised (t = 6.123; p ≤ 0.001). CONCLUSIONS: This study showed that 70% of neuromyelitis optica spectrum disorder patients exhibited cognitive impairment in two or more cognitive domains. Determining the frequency of cognitive impairment will guide the decision of Neuropsychologists in planning cognitive rehabilitation across various domains.

BACKGROUND: Cognitive development after schizophrenia onset can be shaped by interventions such as cognitive remediation, yet no study to date has investigated whether patterns of early behavioral development may predict later cognitive changes following intervention. We therefore investigated the extent to which premorbid adjustment trajectories predict cognitive remediation gains in schizophrenia. METHODS: In a total sample of 215 participants (170 first-episode schizophrenia participants and 45 controls), we classified premorbid functioning trajectories from childhood through late adolescence using the Cannon-Spoor Premorbid Adjustment Scale. For the 62 schizophrenia participants who underwent 6 months of computer-assisted, bottom-up cognitive remediation interventions, we identified MATRICS Consensus Cognitive Battery scores for which participants demonstrated mean changes after intervention, then evaluated whether developmental trajectories predicted these changes. RESULTS: Growth mixture models supported three premorbid functioning trajectories: stable-good, deteriorating, and stable-poor adjustment. Schizophrenia participants demonstrated significant cognitive remediation gains in processing speed, verbal learning, and overall cognition. Notably, participants with stable-poor trajectories demonstrated significantly greater improvements in processing speed compared to participants with deteriorating trajectories. CONCLUSIONS: This is the first study to our knowledge to characterize the associations between premorbid functioning trajectories and cognitive remediation gains after schizophrenia onset, indicating that 6 months of bottom-up cognitive remediation appears to be sufficient to yield a full standard deviation gain in processing speed for individuals with early, enduring functioning difficulties. Our findings highlight the connection between trajectories of premorbid and postmorbid functioning in schizophrenia and emphasize the utility of considering the lifespan developmental course in personalizing therapeutic interventions.

IntroductionCardiovascular fat is a novel risk factor that may link to dementia. Fat volume and radiodensity are measurements of fat quantity and quality, respectively. Importantly, high fat radiodensity could indicate healthy or adverse metabolic processes.MethodsThe associations of cardiovascular fat (including epicardial, paracardial, and thoracic perivascular adipose tissue [PVAT]) quantity and quality assessed at mean age of 51 with subsequent cognitive performance measured repeatedly over 16 years of follow-up were examined using mixed models among 531 women.ResultsHigher thoracic PVAT volume was associated with a higher future episodic memory (β[standard error (SE)] = 0.08 [0.04], P = 0.033), while higher thoracic PVAT radiodensity with lower future episodic (β[SE] = -0.06 [0.03], P = 0.045) and working (β[SE] = -0.24 [0.08], P = 0.003) memories. The latter association is prominent at higher volume of thoracic PVAT.DiscussionMid-life thoracic PVAT may have a distinct contribution to future cognition possibly due to its distinct adipose tissue type (brown fat) and anatomical proximity to the brain circulation.HighlightsHigher mid-life thoracic perivascular adipose tissue (thoracic PVAT) volume is related to a better future episodic memory in women. Higher mid-life thoracic PVAT radiodensity is related to worse future working and episodic memories. Negative association of high thoracic PVAT radiodensity with working memory is prominent at higher thoracic PVAT volume. Mid-life thoracic PVAT is linked to future memory loss, an early sign of Alzheimer's disease. Mid-life women's epicardial and paracardial fat are not related to future cognition.

IntroductionWe investigated associations between neighborhood racial/ethnic segregation and cognitive change.MethodsWe used data (n = 1712) from the Multi-Ethnic Study of Atherosclerosis. Racial/ethnic segregation was assessed using Getis-Ord (Gi*) z-scores based on American Community Survey Census tract data (higher Gi* = greater spatial clustering of participant's race/ethnicity). Global cognition and processing speed were assessed twice, 6 years apart. Adjusted multilevel linear regression tested associations between Gi* z-scores and cognition. Effect modification by race/ethnicity, income, education, neighborhood socioeconomic status, and neighborhood social support was tested.ResultsParticipants were on average 67 years old; 43% were White, 11% Chinese, 29% African American/Black, 17% Hispanic; 40% had high neighborhood segregation (Gi* > 1.96). African American/Black participants with greater neighborhood segregation had greater processing speed decline in stratified analyses, but no interactions were significant.DiscussionSegregation was associated with greater processing speed declines among African American/Black participants. Additional follow-ups and comprehensive cognitive batteries may further elucidate these findings.HighlightsA study of neighborhood racial/ethnic segregation and change in cognition. Study was based on a racially and geographically diverse, population-based cohort of older adults. Racial/ethnic segregation (clustering) was measured by the Getis-ord (Gi*) statistic. We saw faster processing speed decline among Black individuals in segregated neighborhoods.

INTRODUCTION: We are developing the California Cognitive Assessment Battery (CCAB) to provide neuropsychological assessments to patients who lack test access due to cost, capacity, mobility, and transportation barriers. METHODS: The CCAB consists of 15 non-verbal and 17 verbal subtests normed for telemedical assessment. The CCAB runs on calibrated tablet computers over cellular or Wi-Fi connections either in a laboratory or in participants homes. Spoken instructions and verbal stimuli are delivered through headphones using naturalistic text-to-speech voices. Verbal responses are scored in real time and recorded and transcribed offline using consensus automatic speech recognition which combines the transcripts from seven commercial ASR engines to produce timestamped transcripts more accurate than those of any single ASR engine. The CCAB is designed for supervised self-administration using a web-browser application, the Examiner. The Examiner permits examiners to record observations, view subtest performance in real time, initiate video chats, and correct potential error conditions (e.g., training and performance failures, etc.,) for multiple participants concurrently. RESULTS: Here we describe (1) CCAB usability with older (ages 50 to 89) participants; (2) CCAB psychometric properties based on normative data from 415 older participants; (3) Comparisons of the results of at-home vs. in-lab CCAB testing; (4) We also present preliminary analyses of the effects of COVID-19 infection on performance. Mean z-scores averaged over CCAB subtests showed impaired performance of COVID+ compared to COVID- participants after factoring out the contributions of Age, Education, and Gender (AEG). However, inter-cohort differences were no longer significant when performance was analyzed with a comprehensive model that factored out the influences of additional pre-existing demographic factors that distinguished COVID+ and COVID- cohorts (e.g., vocabulary, depression, race, etc.,). In contrast, unlike AEG scores, comprehensive scores correlated significantly with the severity of COVID infection. (5) Finally, we found that scoring models influenced the classification of individual participants with Mild Cognitive Impairment (MCI, z-scores < -1.50) where the comprehensive model accounted for more than twice as much variance as the AEG model and reduced racial bias in MCI classification. DISCUSSION: The CCAB holds the promise of providing scalable laboratory-quality neurodiagnostic assessments to underserved urban, exurban, and rural populations.

BackgroundBrain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an important role in regulating synaptic activity and plasticity.ObjectiveGiven that type-2 diabetes (T2DM) increases the risk of cognitive decline, and studies have suggested lower BDNF levels may be a risk factor of diabetic neurovascular complications, we sought to investigate total white matter hyperintensities (WMH) as a moderator of the effect of BDNF on hippocampal volume and cognition.MethodsOlder adults without dementia from the Alzheimer's Disease Neuroimaging Initiative (N = 454 including 49 with T2DM and 405 without diabetes) underwent neuropsychological evaluation, magnetic resonance imaging to quantify hippocampal and WMH volumes, and blood draw to assess BDNF.ResultsAdjusting for age, sex, and APOE ɛ4 carrier status, there was a significant interaction between total WMH and BDNF on bilateral hippocampal volume in the non-T2DM group (t = 2.63, p = 0.009). Examination of main effect models with a dichotomous high/low BNDF group revealed a significant main effect for low BDNF (t = -4.98, p

ObjectiveChronic inflammation and vascular dysfunction (e.g., chronic endothelial activation) are related yet dissociable mechanisms of HIV-associated neurocognitive impairment (NCI), even among those on antiretroviral therapy (ART). However, how these mechanisms differentially contribute to domain-specific deficits in people with and without HIV (PWH, PWoH) is unclear. We empirically-derived profiles of NCI and examined relationships with peripheral inflammatory and vascular biomarkers.MethodsParticipants were 84 virally-suppressed PWH and 126 PWoH who underwent neuropsychological testing and blood draw. Cluster analysis identified subgroups based on domain deficit scores. ANOVAs examined HIV serostatus and cluster group differences in composite plasma biomarker z-scores of inflammation (IL-6, CXCL10/IP-10, CCL2/MCP-1) and vascular injury (VCAM-1, ICAM-1, uPAR). Confirmatory regressions examined the interaction of HIV and biomarker z-scores on domain-specific T-scores, controlling for cardiovascular disease (CVD) risk and psychosocial factors.ResultsCluster analysis identified three groups: Unimpaired (n = 129), Learning/Recall (n = 52, isolated learning/recall deficits), Dysexecutive/Slow (n = 29, executive function, working memory, processing speed, and motor deficits). PWH had higher odds of Dysexecutive/Slow membership, which related to CVD risk and higher vascular dysfunction, but not inflammation, in PWH. Vascular biomarkers moderated adverse HIV effects on executive function, processing speed, and working memory such that PWH had lower T-scores only when vascular dysfunction was high.ConclusionsIn PWH with controlled disease, peripheral markers of endothelial dysfunction and vascular permeability are selectively associated with an empirically-derived subgroup that exhibits domain deficits commonly impacted by cerebrovascular disease. Findings support the presence of a vascular NCI subgroup of PWH who may benefit from interventions that directly target the neurovascular unit.

OBJECTIVES: Late Life Depression (LLD) is associated with persistent cognitive dysfunction even after depression symptoms improve. The present study was designed to examine cognitive outcomes associated with the pattern of depression severity change during psychotherapy intervention for LLD. METHODS: 96 community-dwelling adults ages 65-91 with major depressive disorder completed 12 sessions of Problem-Solving Therapy at the University of California, San Francisco. Nonlinear trajectories of depression severity ratings using the Hamilton Depression Rating Scale were computed from multiple time points collected throughout the weekly psychotherapy intervention. Performance on measures of cognition (information processing speed, executive functioning, verbal learning, memory) was assessed at baseline and post-treatment. Linear mixed-effects models examined associations between nonlinear depression severity trajectories and post-treatment change in cognitive performance. RESULTS: Broadly, different patterns of depression change during treatment were associated with improved cognition post-treatment. Greater and more consistent interval improvements in depression ratings were differentially associated with improvements in aspects of verbal learning, memory, and executive function post-treatment, while no associations were found with information processing speed. CONCLUSIONS: The heterogeneity of depression trajectories associated with improved cognitive outcomes suggests that the temporal pattern of depression response may impact specific cognitive processes distinctly. Results suggest that use of nonlinear depression severity trajectories may help to elucidate complex associations between the time course of depression response and cognitive outcomes of psychotherapy in LLD. These findings have important implications for identifying treatment targets to enhance clinical and cognitive outcomes of psychotherapy in LLD.

ObjectivesThe relationship between wisdom and fluid intelligence (Gf) is poorly understood, particularly in older adults. We empirically tested the magnitude of the correlation between wisdom and Gf to help determine the extent of overlap between these two constructs.DesignCross-sectional study with preregistered hypotheses and well-powered analytic plan (https://osf.io/h3pjx).SettingMemory and Aging Center at the University of California San Francisco, located in the USA.Participants141 healthy older adults (mean age = 76 years; 56% female).MeasurementsWisdom was quantified using a well-validated self-report-based scale (San Diego Wisdom Scale or SD-WISE). Gf was assessed via composite measures of processing speed (Gf-PS) and executive functioning (Gf-EF). The relationships of SD-WISE scores to Gf-PS and Gf-EF were tested in bivariate correlational analyses and multiple regression models adjusted for demographics (age, sex, and education). Exploratory analyses evaluated the relationships between SD-WISE and age, episodic memory performance, and dorsolateral and ventromedial prefrontal cortical volumes on magnetic resonance imaging.ResultsWisdom showed a small, positive association with Gf-EF (r = 0.181 [95% CI 0.016, 0.336], p = .031), which was reduced to nonsignificance upon controlling for demographics, and no association with Gf-PS (r = 0.019 [95% CI -0.179, 0.216], p = .854). Wisdom demonstrated a small, negative correlation with age (r = -0.197 [95% CI -0.351, -0.033], p = .019), but was not significantly related to episodic memory or prefrontal volumes.ConclusionsOur findings indicate that most of the variance in wisdom (>95%) is unaccounted for by Gf. The independence of wisdom from cognitive functions that reliably show age-associated declines suggests that it may hold unique potential to bolster decision-making, interpersonal functioning, and other everyday activities in older adults.

Speeded Matching (SpM) is a new processing speed match-to-sample test within the NIH Toolbox Cognitive Battery. It was designed to developmentally extend feasibility to younger children or individuals with intellectual or developmental disabilities (IDD). SpM reduces cognitive demands to tapping an identical match as opposed to judging and indicating whether two stimuli are identical. In this study, we piloted SpM among 148 participants with fragile X syndrome, Down syndrome, or other intellectual disabilities (chronological age mean = 17.8 years, sd = 5.4; nonverbal mental age mean = 65 months, sd = 19.4). SpM had a high feasibility (96%) and internal consistency (rxx = 0.98). It converged well with other measures of processing speed, fluid cognition, and nonverbal mental age and diverged appropriately from crystallized cognitive skills. The correlation between nonverbal mental age and SpM in the IDD sample was not significantly different than the correlation between chronological age and SpM in a separate sample of 118 neurotypical children (age mean = 3.9 years sd = 0.8). This study provides initial evidence for the reliability and validity of the new SpM task, which may be appropriate as an outcome measure of processing speed for future clinical trials. It is more feasible than tasks designed for adults; it is brief, easy to administer, and engaging for young children and older individuals with lower mental ages associated with IDD.

ObjectivesThe relationship between wisdom and fluid intelligence (Gf) is poorly understood, particularly in older adults. We empirically tested the magnitude of the correlation between wisdom and Gf to help determine the extent of overlap between these two constructs.DesignCross-sectional study with preregistered hypotheses and well-powered analytic plan (https://osf.io/h3pjx).SettingMemory and Aging Center at the University of California San Francisco, located in the USA.Participants141 healthy older adults (mean age = 76 years; 56% female).MeasurementsWisdom was quantified using a well-validated self-report-based scale (San Diego Wisdom Scale or SD-WISE). Gf was assessed via composite measures of processing speed (Gf-PS) and executive functioning (Gf-EF). The relationships of SD-WISE scores to Gf-PS and Gf-EF were tested in bivariate correlational analyses and multiple regression models adjusted for demographics (age, sex, and education). Exploratory analyses evaluated the relationships between SD-WISE and age, episodic memory performance, and dorsolateral and ventromedial prefrontal cortical volumes on magnetic resonance imaging.ResultsWisdom showed a small, positive association with Gf-EF (r = 0.181 [95% CI 0.016, 0.336], p = .031), which was reduced to nonsignificance upon controlling for demographics, and no association with Gf-PS (r = 0.019 [95% CI -0.179, 0.216], p = .854). Wisdom demonstrated a small, negative correlation with age (r = -0.197 [95% CI -0.351, -0.033], p = .019), but was not significantly related to episodic memory or prefrontal volumes.ConclusionsOur findings indicate that most of the variance in wisdom (>95%) is unaccounted for by Gf. The independence of wisdom from cognitive functions that reliably show age-associated declines suggests that it may hold unique potential to bolster decision-making, interpersonal functioning, and other everyday activities in older adults.

ObjectiveThis study examined rates of objective cognitive and functional impairments and associations between cognitive performance and performance-based functional capacity in a well-characterized sample of adults experiencing homelessness.MethodsOne hundred participants completed a brief neuropsychological and functional capacity assessment and self-report questionnaires. Cognitive impairment rates were determined by comparing mean scores with published normative data, as well as by examining frequency of scores >1 SD below the mean. Pearson correlations were used to examine associations between cognitive and functional capacities.ResultsOverall, 65% of the study participants had scores in the cognitively impaired range on a brief cognitive screening test, 30% had impaired processing speed, and 11% met cognitive criteria for intellectual disability. Furthermore, 48% of the sample met functional impairment criteria, and poorer cognitive performance was strongly associated with poorer performance-based functional capacity (p

We examined the joint effects of depressive symptoms (Beck Depression Inventory-II (BDI-II)) and systemic inflammation (plasma C-reactive protein (CRP)) on longitudinal profiles of neurocognition in a cohort of 143 people with HIV (PWH) on antiretroviral therapy. Global neurocognition, processing speed, motor skills, and attention/working memory all worsened as CRP increased but only among PWH who, on average, exhibited moderate to severe depressive symptoms (BDI-II > 22). Findings suggest that some PWH with chronically elevated depressive symptoms may have an inflammatory subtype of depression and a particular vulnerability to neurocognitive changes that may respond to drugs targeting inflammation or its neural sequelae.

ObjectiveDespite potential for dependence and adverse neurological effects, long-term benzodiazepine (BZD) use is common among people living with HIV (PLWH). As PLWH are at risk for central nervous system dysfunction, we retrospectively examined the association between BZD use and HIV-associated neurocognitive impairment (NCI).MethodsThree hundred six PLWH underwent comprehensive neurobehavioral evaluations. Current BZD use (BZD+) was determined through self-report. Using propensity scores, 153 BZD- individuals were matched to 153 BZD+ participants on demographics and medical comorbidities. Multiple regression models examined NCI and demographically adjusted neurocognitive T-scores as a function of BZD status, adjusting for estimated premorbid ability, current affective symptoms, and nadir CD4 count. Secondary analyses explored neurocognitive correlates of positive BZD urine toxicology screens (TOX+) and specific BZD agents.ResultsMedian duration of BZD use was 24 months. Current BZD use related to higher likelihood of NCI (odds ratio = 2.13, P = 0.003) and poorer global (d = -0.28, P = 0.020), processing speed (d = -0.23, P = 0.047), and motor T-scores (d = -0.32, P = 0.008). Compared with BZD-/TOX-, BZD+/TOX+ exhibited additional decrements in executive function (d = -0.48, P = 0.013), working memory (d = -0.49, P = 0.011), and delayed recall (d = -0.41, P = 0.032). For individual agents, diazepam, lorazepam, and alprazolam were most strongly associated with NCI (odds ratios >2.31).DiscussionBZD use may elevate risk for NCI in PLWH, potentially through diffuse neurocognitive slowing and acute compromise of recall and higher-order capacities. These effects are robust to psychosocial and HIV-specific factors and occur in comparison with a tightly matched BZD- group. Prospective and interventional studies should evaluate causal associations between NCI and BZD use and explore treatment alternatives to BZDs in PLWH.

A growing literature associates the neuropeptides oxytocin (OT) and arginine vasopressin (AVP) with affiliative and cognitive outcomes. The majority of this work in humans, however, considers these neuropeptides separately. Also, despite evidence that OT and AVP interact with gonadal hormones, still warranted is an examination of sex and age variations in endogenous neuropeptide levels, their interrelations, and their functional relationships with attachment and cognition in humans. This study measured endogenous plasma OT and AVP levels in generally healthy young (18-31 years) and older (63-81 years) men and women to (i) determine levels of and interrelations between OT and AVP; (ii) explore functional relationships with self-reported attachment (attachment anxiety and avoidance) and performance-based cognition (processing speed, verbal memory); and (iii) identify variations in these effects by sex and age. We observed sex- and age-differential patterns of results: Women had higher plasma OT levels than men and older adults had higher plasma AVP levels than young adults. The two neuropeptides were highly negatively intercorrelated across all groups. Functionally, higher AVP levels were associated with greater attachment anxiety and higher OT and lower AVP levels were associated with faster sensorimotor processing speed, with sex and age moderating these effects. This integrated approach identifies variations in endogenous peripheral neuropeptide levels in humans, supporting their sex- and age-specific role as "difference makers" in attachment and cognition.

ObjectiveProcessing Speed (PS) is an important domain in cognitive aging that is characterized by multiple related but nonidentical abilities. Few studies have directly investigated the relationships among PS measures, and none have used genetically informed methods. In this study, we examined the relationship between measures of PS at up to two time points during middle age.MethodWe examined data from 1,262 middle-aged men when the sample was at a mean age of 56 and a mean age 62 years. Participants completed 6 measures of PS from three different cognitive tests. We used a genetically informative, confirmatory factor analytic approach to evaluate the phenotypic and genetic relationships cross-sectionally at both single time points and across time.ResultsA higher-order common PS factor accounted for the covariance among three test-specific factors, and each test-specific factor accounted for the covariance between two observed measures. The general PS factor was explained primarily by genetic influences at both time points (a²age56 = .75, a²age62 = .64), and all test-specific factors were heritable (a² range: .45 to .65). Factor loadings from the test-specific factors to the general PS factor varied from λ = .46 to .82. The model was stable over time, although there were differing rates of phenotypic change among latent factors (.20 SD to .44 SD). Cross-time genetic correlations were near unity for all latent factors.ConclusionThese results suggest that PS is highly heritable when considered at a latent variable level, and that there are different rates of change in tests of PS within this sample. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Cerebral perfusion declines across the lifespan and is altered in the early stages of several age-related neuropathologies. Little is known, however, about the longitudinal evolution of perfusion in healthy older adults, particularly when perfusion is quantified using magnetic resonance imaging with arterial spin labeling (ASL). The objective was to characterize longitudinal perfusion in typically aging adults and elucidate associations with cognition and brain structure. Adults who were functionally intact at baseline (n = 161, ages 47-89) underwent ASL imaging to quantify whole-brain gray matter perfusion; a subset (n = 136) had repeated imaging (average follow-up: 2.3 years). Neuropsychological testing at each visit was summarized into executive function, memory, and processing speed composites. Global gray matter volume, white matter microstructure (mean diffusivity), and white matter hyperintensities were also quantified. We assessed baseline associations among perfusion, cognition, and brain structure using linear regression, and longitudinal relationships using linear mixed effects models. Greater baseline perfusion, particularly in the left dorsolateral prefrontal cortex and right thalamus, was associated with better executive functions. Greater whole-brain perfusion loss was associated with worsening brain structure and declining processing speed. This study helps validate noninvasive MRI-based perfusion imaging and underscores the importance of cerebral blood flow in cognitive aging.

IntroductionSelf-administered in-home digital therapeutics could expand access to cognitive rehabilitation for individuals with multiple sclerosis (MS), over half of whom experience cognitive impairment (CI). However, feasibility in an MS population must be clarified. This study was conducted to assess the feasibility of deploying a videogame-like digital treatment for CI in MS, including initial efficacy and barriers to adherence.MethodsIn this pilot study, 21 participants with MS completed an in-clinic baseline neurological evaluation. Cognitive tests included paper-and-pencil Brief International Cognitive Assessment for Multiple Sclerosis [BICAMS-which included the Symbol Digit Modalities Test (SDMT)] and other unsupervised tablet-based tests (including Match: an unsupervised test of executive functions and processing speed, developed at UCSF; and the Cogstate MS Battery). Participants then completed an in-home, tablet-based, videogame-like investigational digital treatment (Project: EVO™) for 25 min daily, 5 days weekly, for 4 weeks. This was followed by a repeat in-clinic evaluation.ResultsOf the 21 participants (mean [standard deviation, SD] age 53.8 [11.6] years, median Expanded Disability Status Scale (EDSS) 2.5 [SD 2.0, IQR [2-3.5]]) enrolled to use the digital therapeutic at home (mean [SD] SDMT z score: - 0.21 [1.16]), 18 completed the study, during which they completed an average of 19.7 days (median [SD]: 20.5 [8.4]). Overall, 78% of these 18 participants completed 75% of prescribed days (i.e., at least 15), and 50% completed all 20 days or more. Over the 4-week period, scores of processing speed improved significantly (based on one-sided t test), including SDMT (p = 0.003) and Match (p = 0.006). The Cogstate DET test (psychomotor function) also increased (p = 0.006). Mean increase in SDMT was 3.6 points. Male sex, not being employed, and higher baseline anxiety all were significantly associated with greater improvement in SDMT over the 4-week period. Interestingly, lower baseline cognitive scores were associated with greater number of sessions completed (e.g., SDMT: p = 0.003, R2 = 0.44). Adjusting for employment, a proxy for time available, did not significantly improve the model fit.DiscussionDeploying an in-home digital tool to improve processing speed in MS is feasible, and shows preliminary efficacy. A larger, randomized controlled clinical trial is ongoing.

Age-related cognitive decline is a public health problem but highly diverse and difficult to predict. We captured nonoverlapping cognitive phenotypes in high-functioning adults and identified baseline factors differentiating trajectories. Three hundred fourteen functionally normal adults (M = 69 y) completed 2+ visits. Participants with sample-based longitudinal slopes in memory or processing speed less than -1 SD were classified as "declining" on that measure; 29 and 50 individuals had slopes less than -1 SD on processing speed or memory, respectively; 2.5% met criteria for both, who were excluded. At baseline, speed decliners demonstrated greater age, inflammation, and cognitive complaints compared with speed-stable adults; memory decliners were more likely to be male and had lower depressive symptoms, gray matter volumes, and white matter hyperintensities compared with memory-stable adults. Baseline speed, TNFα, and cognitive complaints accurately classified 96.3% of future speed decliners; baseline memory, sex, precuneal volume, and white matter hyperintensities accurately classified 88.5% of future memory decliners. There are discrete cognitive aging phenotypes reflecting nonoverlapping vulnerabilities in high-functioning adults. Early markers can predict cognition even within the "normal" spectrum and underscore therapeutic targets.

Executive function (EF) supports goal-directed behavior and includes key aspects such as working memory, inhibitory control, cognitive flexibility, attention, processing speed, and planning. Fragile X syndrome (FXS) is the leading inherited monogenic cause of intellectual disability and is phenotypically characterized by EF deficits beyond what is expected given general cognitive impairments. Yet, a systematic review of behavioral studies using performance-based measures is needed to provide a summary of EF deficits across domains in males and females with FXS, discuss clinical and biological correlates of these EF deficits, identify critical limitations in available research, and offer suggestions for future studies in this area. Ultimately, this review aims to advance our understanding of the underlying pathophysiological mechanisms contributing to EF in FXS and to inform the development of outcome measures of EF and identification of new treatment targets in FXS.

While previous models of economic decision-making offer de-scriptive accounts of behavior, they often overlook the com-putational complexity of estimating expected utility. Here,we seek to understand how both environmental and individualconstraints on cognition shape our daily decision. Informedby the predictions of a recently-proposed resource-rationalprocess model of risky choice, sample-based expected utility(SbEU; Nobandegani, da Silva Castanheira, Otto, & Shultz,2018), we reveal that both time pressure and individual dif-ferences in processing speed have a convergent effect on riskpreferences during a risky decision-making task. Under severetime constraints, participants’ risk preferences manifested astrong framing effect compared to little time pressure in whichchoice adhered to the classic fourfold pattern of risk prefer-ences. Similarly, individual differences in processing speed,measured using an established task, predicted similar effectsupon risk attitudes as extrinsic time pressure. These findingsreveal a converging contribution of environmental and individ-ual limitations on risky choice, and provide empirical supportfor SbEU as a resource-rational process model of risky deci-sion making. Notably, SbEU serves as a single-process modelof two well-established biases, and the transition between thetwo, in risky choice.

OBJECTIVE: The purpose of this trial was to study the effects of chronic resveratrol use on cognitive function in humans. DESIGN: The authors conducted a double-blind, Phase IIa randomized, placebo-controlled trial to obtain preliminary estimates of the effects of resveratrol supplementation on cognitive function over a 90-day period in older adults. LOCATION: University of Florida in Gainesville, FL. SUBJECTS: Sedentary, overweight older adults (N = 32; age range: 65-93 years, M age = 73.34 years, SD age = 7.02 years). INTERVENTION: Participants were randomized to one of three treatment groups (placebo, 300 mg/day resveratrol, 1000 mg/day resveratrol) for 90 days. OUTCOME MEASURES: Cognitive function was assessed before and after treatment using a well-characterized test battery: Trail Making, Digits Forward and Backward, Erikson-Flanker, Controlled Oral Word Association, Hopkins Verbal Learning Test-Revised, and Task Switching. RESULTS: Psychomotor speed improved on the Trail Making Test part A in participants taking 1000 mg/day of resveratrol compared with participants in both the 300 mg/day condition and the placebo condition (p = 0.02). CONCLUSION: This pilot study suggests that 90 days of resveratrol supplementation at a dose of 1000/mg per day selectively improves psychomotor speed but does not significantly affect other domains of cognitive function in older adults. These findings provide modest support to further study the effects of resveratrol on cognitive function in older adults.

Neuropsychological functioning underlies behavioral symptoms of attention-deficit/hyperactivity disorder (ADHD). Children with all forms of ADHD are vulnerable to working memory deficits and children presenting with the inattentive form of ADHD (ADHD-I) appear particularly vulnerable to processing speed deficits. As ADHD-I is the most common form of ADHD presented by children in community settings, it is important to consider how treatment interventions for children with ADHD-I may be affected by deficits in processing speed and working memory. We utilize data collected from 199 children with ADHD-I, aged 7 to 11 years, who participated in a randomized clinical trial of a psychosocial-behavioral intervention. Our aims are first to determine whether processing speed or working memory predict treatment outcomes in ADHD-I symptom severity, and second whether they moderate treatment effects on ADHD-I symptom severity. Results of linear regression analyses reveal that baseline processing speed significantly predicts posttreatment ADHD-I symptom severity when controlling for baseline ADHD-I symptom severity, such that better processing speed is associated with greater symptom improvement. However, predictive effects of working memory and moderation effects of both working memory and processing speed are not supported in the present study. We discuss study limitations and implications of the relation between processing speed and treatment benefits from psychosocial treatments for children with ADHD-I.

Books designed for beginning readers typically intermix textwith illustrations in close proximity. Prior research suggeststhis standard layout may reduce literacy skills due toincreased attentional competition between text andillustrations. The current study extends this work byexamining whether manipulations to the book layout canenhance reading performance and explores whether individualdifferences in executive function and processing speed arerelated to children’s decoding and reading comprehensionwhen reading books which utilize the standard layout.Separating text and illustrations improved readingcomprehension. Preliminary results also suggest workingmemory, inhibitory control, and processing speed are relatedto reading performance.

We investigated the relation between dimensional aspects of inattention and hyperactivity-impulsivity in childhood and peer problems 4 years later, as well as the potential mediating effects of intellectual function. The sample included 127 children (32 with attention-deficit/hyperactivity disorder). Symptoms of inattention and hyperactivity-impulsivity were assessed via parent and teacher reports on Swanson Nolan and Pelham-IV questionnaire. Peer problems were assessed by parent reports on the Strengths and Difficulties Questionnaire, and children's intellectual functioning by the third edition of the Wechsler Intelligence Scale for Children. Linear regressions showed a significant effect of inattention on future peer problems, partially mediated by slow processing speed. These effects remained significant when ADHD status was covaried. Findings highlight the importance of processing speed in explaining the predictive relation between childhood inattention and later peer problems. Inattention and processing speed in early childhood are potentially malleable factors influencing adolescent social functioning.

ObjectivesBipolar disorder (BD) is associated with compromised white matter (WM) integrity and deficits in processing speed (PS). Few studies, however, have investigated age relationships with WM structure and cognition to understand possible changes in brain health over the lifespan. This investigation explored whether BD and healthy counterpart (HC) participants exhibited differential age-related associations with WM and cognition, which may be suggestive of accelerated brain and cognitive aging.DesignCross-sectional study.SettingUniversity of California San Diego and the Veterans Administration San Diego Healthcare System.Participants33 euthymic BD and 38 HC participants.MeasurementsDiffusion tensor imaging was acquired as a measure of WM integrity, and tract-specific fractional anisotropy (FA) was extracted utilizing the Johns Hopkins University probability atlas. PS was assessed with the Number and Letter Sequencing conditions of the Delis-Kaplan Executive Function System Trail Making Test.ResultsBD participants demonstrated slower PS compared with the HC group, but no group differences were found in FA across tracts. Multiple linear regressions revealed a significant group-by-age interaction for the right uncinate fasciculus, the left hippocampal portion of the cingulum, and for PS, such that older age was associated with lower FA values and slower PS in the BD group only. The relationship between age and PS did not significantly change after accounting for uncinate FA, suggesting that the observed age associations occur independently.ConclusionsResults provide support for future study of the accelerated aging hypothesis by identifying markers of brain health that demonstrate a differential age association in BD.

This study compared magnetoencephalographic (MEG) imaging-derived indices of auditory and somatosensory cortical processing in children aged 8-12 years with autism spectrum disorder (ASD; N = 18), those with sensory processing dysfunction (SPD; N = 13) who do not meet ASD criteria, and typically developing control (TDC; N = 19) participants. The magnitude of responses to both auditory and tactile stimulation was comparable across all three groups; however, the M200 latency response from the left auditory cortex was significantly delayed in the ASD group relative to both the TDC and SPD groups, whereas the somatosensory response of the ASD group was only delayed relative to TDC participants. The SPD group did not significantly differ from either group in terms of somatosensory latency, suggesting that participants with SPD may have an intermediate phenotype between ASD and TDC with regard to somatosensory processing. For the ASD group, correlation analyses indicated that the left M200 latency delay was significantly associated with performance on the WISC-IV Verbal Comprehension Index as well as the DSTP Acoustic-Linguistic index. Further, these cortical auditory response delays were not associated with somatosensory cortical response delays or cognitive processing speed in the ASD group, suggesting that auditory delays in ASD are domain specific rather than associated with generalized processing delays. The specificity of these auditory delays to the ASD group, in addition to their correlation with verbal abilities, suggests that auditory sensory dysfunction may be implicated in communication symptoms in ASD, motivating further research aimed at understanding the impact of sensory dysfunction on the developing brain.

We investigated the relation between dimensional aspects of inattention and hyperactivity-impulsivity in childhood and peer problems 4 years later, as well as the potential mediating effects of intellectual function. The sample included 127 children (32 with attention-deficit/hyperactivity disorder). Symptoms of inattention and hyperactivity-impulsivity were assessed via parent and teacher reports on Swanson Nolan and Pelham-IV questionnaire. Peer problems were assessed by parent reports on the Strengths and Difficulties Questionnaire, and children's intellectual functioning by the third edition of the Wechsler Intelligence Scale for Children. Linear regressions showed a significant effect of inattention on future peer problems, partially mediated by slow processing speed. These effects remained significant when ADHD status was covaried. Findings highlight the importance of processing speed in explaining the predictive relation between childhood inattention and later peer problems. Inattention and processing speed in early childhood are potentially malleable factors influencing adolescent social functioning.

Objective: To examine the impact of genetic, inflammatory, cardiovascular, lifestyle, and neuroanatomical factors on cognitive processing speed (CPS) change over time in functionally intact older adults. Methods: This observational study conducted over two time points, included 120 community dwelling cognitively normal older adults between the ages of 60 and 80 from the University of California San Francisco Memory and Aging Center. Participants were followed with composite measures of CPS, calculated based on norms for 20-30 year-olds. Variables of interest were AD risk genes (APOE, CR1), markers of inflammation (interleukin 6) and cardiovascular health (BMI, LDL, HDL, mean arterial pressure, fasting insulin), self-reported physical activity, and corpus callosum (CC) volumes. The sample was divided into three groups: 17 "resilient-agers" with fast and stable processing speed; 56 "average-agers" with average and stable processing speed; and 47 "sub-agers" with average baseline speed who were slower at follow-up. Results: Resilient-agers had larger baseline CC volumes than sub-agers (p < 0.05). Resilient-agers displayed lower levels of interleukin-6 (IL-6) and insulin (ps < 0.05) than sub-agers, and reported more physical activity than both average- and sub-agers (ps < 0.01). In a multinomial logistic regression, physical activity and IL-6 predicted average- and sub-ager groups. Resilient-agers displayed a higher frequency of APOE e4 and CR1 AA/AG alleles. Conclusion: Robust and stable CPS is associated with larger baseline CC volumes, lower levels of inflammation and insulin, and greater self-reported physical activity. These findings highlight the relevance of neuroanatomical, biological, and lifestyle factors in the identification and prediction of heterogeneous cognitive aging change over time.

The goal of this fMRI study was to examine how well developmental improvements in reasoning ability can be explained by changes in functional connectivity between specific nodes in prefrontal and parietal cortices. To this end, we examined connectivity within the lateral fronto-parietal network (LFPN) and its relation to reasoning ability in 132 children and adolescents aged 6-18 years, 56 of whom were scanned twice over the course of 1.5 years. Developmental changes in strength of connections within the LFPN were most prominent in late childhood and early adolescence. Reasoning ability was related to functional connectivity between left rostrolateral prefrontal cortex (RLPFC) and inferior parietal lobule (IPL), but only among 12-18-year olds. For 9-11-year olds, reasoning ability was most strongly related to connectivity between left and right RLPFC; this relationship was mediated by working memory. For 6-8-year olds, significant relationships between connectivity and performance were not observed; in this group, processing speed was the primary mediator of improvement in reasoning ability. We conclude that different connections best support reasoning at different points in development and that RLPFC-IPL connectivity becomes an important predictor of reasoning during adolescence.

Huntington disease (HD) is a neurodegenerative condition with prominent motor (including oculomotor), cognitive, and psychiatric effects. While neuropsychological deficits are present in HD, motor impairments may impact performance on neuropsychological measures, especially those requiring a speeded response, as has been demonstrated in multiple sclerosis and schizophrenia. The current study is the first to explore associations between oculomotor functions and neuropsychological performance in HD. Participants with impaired oculomotor functioning performed worse than those with normal oculomotor functioning on cognitive tasks requiring oculomotor involvement, particularly on psychomotor speed tasks, controlling for covariates. Consideration of oculomotor dysfunction on neuropsychological performance is critical, particularly for populations with motor deficits.

Cognitive slowing is a prevalent symptom observed in Gulf War Illness (GWI). The present study assessed the extent to which functional connectivity between dorsolateral prefrontal cortex (DLPFC) and other task-relevant brain regions was predictive of GWI-related cognitive slowing. GWI patients (n = 54) and healthy veteran controls (n = 29) were assessed on performance of a processing speed task (the Digit Symbol Substitution Task; DSST) while undergoing functional magnetic resonance imaging (fMRI). GWI patients were slower on the DSST relative to controls. Bilateral DLPFC connectivity with task-relevant nodes was altered in GWI patients compared to healthy controls during DSST performance. Moreover, hyperconnectivity in these networks predicted GWI-related increases in reaction time on the DSST, whereas hypoconnectivity did not. These results suggest that GWI-related cognitive slowing reflects reduced efficiency in cortical networks.

Cognitive slowing is a prevalent symptom observed in Gulf War Illness (GWI). The present study assessed the extent to which functional connectivity between dorsolateral prefrontal cortex (DLPFC) and other task-relevant brain regions was predictive of GWI-related cognitive slowing. GWI patients (n = 54) and healthy veteran controls (n = 29) were assessed on performance of a processing speed task (the Digit Symbol Substitution Task; DSST) while undergoing functional magnetic resonance imaging (fMRI). GWI patients were slower on the DSST relative to controls. Bilateral DLPFC connectivity with task-relevant nodes was altered in GWI patients compared to healthy controls during DSST performance. Moreover, hyperconnectivity in these networks predicted GWI-related increases in reaction time on the DSST, whereas hypoconnectivity did not. These results suggest that GWI-related cognitive slowing reflects reduced efficiency in cortical networks.

Cognitive development is influenced by maturational changes in processing speed, a construct reflecting the rapidity of executing cognitive operations. Although cognitive ability and processing speed are linked to spindles and sigma power in the sleep electroencephalogram (EEG), little is known about such associations in early childhood, a time of major neuronal refinement. We calculated EEG power for slow (10-13 Hz) and fast (13.25-17 Hz) sigma power from all-night high-density electroencephalography (EEG) in a cross-sectional sample of healthy preschool children (n = 10, 4.3 ± 1.0 years). Processing speed was assessed as simple reaction time. On average, reaction time was 1409 ± 251 ms; slow sigma power was 4.0 ± 1.5 μV²; and fast sigma power was 0.9 ± 0.2 μV². Both slow and fast sigma power predominated over central areas. Only slow sigma power was correlated with processing speed in a large parietal electrode cluster (p < 0.05, r ranging from -0.6 to -0.8), such that greater power predicted faster reaction time. Our findings indicate regional correlates between sigma power and processing speed that are specific to early childhood and provide novel insights into the neurobiological features of the EEG that may underlie developing cognitive abilities.

Reduced speed of cerebral information processing is a cognitive deficit associated with schizophrenia. Normal information processing speed (PS) requires intact white matter (WM) physiology to support information transfer. In a cohort of 107 subjects (47/60 patients/controls), we demonstrate that PS deficits in schizophrenia patients are explained by reduced WM integrity, which is measured using diffusion tensor imaging, mediated by the mismatch in WM/gray matter blood perfusion, and measured using arterial spin labeling. Our findings are specific to PS, and testing this hypothesis for patient-control differences in working memory produces no explanation. We demonstrate that PS deficits in schizophrenia can be explained by neurophysiological alterations in cerebral WM. Whether the disproportionately low WM integrity in schizophrenia is due to illness or secondary due to this disorder deserves further examination.

This study investigated the relationship between insulin-resistance and constituent components of executive function in a sample of neurologically intact older adult subjects using the homeostasis model assessment (HOMA-IR) and latent factors of working memory, cognitive control and processing speed derived from confirmatory factor analysis. Low-density lipoprotein (LDL), mean arterial pressure (MAP), along with body mass index (BMI) and white matter hypointensity (WMH) were used to control for vascular risk factors, adiposity and cerebrovascular injury. The study included 119 elderly subjects recruited from the University of California, San Francisco Memory and Aging Center. Subjects underwent neuropsychological assessment, fasting blood draw and brain magnetic resonance imaging (MRI). Partial correlations and linear regression models were used to examine the HOMA-IR-executive function relationship. Pearson correlation adjusting for age showed a significant relationship between HOMA-IR and working memory (rp = -.18; p = .047), a trend with cognitive control (rp = -.17; p = .068), and no relationship with processing speed (rp = .013; p = .892). Linear regression models adjusting for demographic factors (age, education, and gender), LDL, MAP, BMI, and WMH indicated that HOMA-IR was negatively associated with cognitive control (r = -.256; p = .026) and working memory (r = -.234; p = .054). These results suggest a greater level of peripheral insulin-resistance is associated with decreased cognitive control and working memory. After controlling for demographic factors, vascular risk, adiposity and cerebrovascular injury, HOMA-IR remained significantly associated with cognitive control, with working memory showing a trend. These findings substantiate the insulin-resistance-executive function hypothesis and suggest a complex interaction, demonstrated by the differential impact of insulin-resistance on processing speed and specific aspects of executive function.

A major goal of animal research is to identify interventions that can promote successful aging and delay or reverse age-related cognitive decline in humans. Recent advances in standardizing cognitive assessment tools for humans have the potential to bring preclinical work closer to human research in aging and Alzheimer’s disease. The National Institute of Health (NIH) has led an initiative to develop a comprehensive Toolbox for Neurologic Behavioral Function (NIH Toolbox) to evaluate cognitive, motor, sensory and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age. This paper aims to analyze the strengths and limitations of animal behavioral tests that can be used to parallel those in the NIH Toolbox. We conclude that there are several paradigms available to define a preclinical battery that parallels the NIH Toolbox. We also suggest areas in which new tests may benefit the development of a comprehensive preclinical test battery for assessment of cognitive function in animal models of aging and Alzheimer’s disease.