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The Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) manifests as impaired executive control, linguistic processing, visual spatial function, and affect regulation. The CCAS has been described in the spinocerebellar ataxias (SCAs), but its prevalence is unknown. We analyzed results of the CCAS/Schmahmann Scale (CCAS-S), developed to detect and quantify CCAS, in two natural history studies of 309 individuals Symptomatic for SCA1, SCA2, SCA3, SCA6, SCA7, or SCA8, 26 individuals Pre-symptomatic for SCA1 or SCA3, and 37 Controls. We compared total raw scores, domain scores, and total fail scores between Symptomatic, Pre-symptomatic, and Control cohorts, and between SCA types. We calculated scale sensitivity and selectivity based on CCAS category designation among Symptomatic individuals and Controls, and correlated CCAS-S performance against age and education, and in Symptomatic patients, against genetic repeat length, onset age, disease duration, motor ataxia, depression, and fatigue. Definite CCAS was identified in 46% of the Symptomatic group. False positive rate among Controls was 5.4%. Symptomatic individuals had poorer global CCAS-S performance than Controls, accounting for age and education. The domains of semantic fluency, phonemic fluency, and category switching that tap executive function and linguistic processing consistently separated Symptomatic individuals from Controls. CCAS-S scores correlated most closely with motor ataxia. Controls were similar to Pre-symptomatic individuals whose nearness to symptom onset was unknown. The use of the CCAS-S identifies a high CCAS prevalence in a large cohort of SCA patients, underscoring the utility of the scale and the notion that the CCAS is the third cornerstone of clinical ataxiology.

OBJECTIVE: Cognitive impairment is a common complaint in SLE, but approaches to measuring cognitive performance objectively vary. Leveraging data collected in a population-based cohort of individuals with validated SLE, we compared performance and potential impairment across multiple measures of cognition. METHODS: During a single study visit (October 2019-May 2022), times to complete the Trail Making Test B (TMTB; N=423) were recorded; potential impairment was defined as an age-corrected and education-corrected T-score 1.5 SD longer than the normative time). A clock drawing assessment (CLOX; N=435) with two parts (free clock draw (CLOX1) and copy (CLOX2)) was also performed (score range: 0-15; higher scores=better performance); potential impairment was defined as CLOX1 1.5 SD lower the normative score). RESULTS: Participants (mean age 46 years; 92% female; 82% black) had a median (IQR) TMTB time of 96 (76-130) s; median (IQR) CLOX1 and CLOX2 scores of 12 (10-13) and 14 (13-15); and a mean (SD) fluid cognition standard score of 87.2 (15.6). TMTB time and fluid cognition score (ρ=-0.53, p

Cognitive dysfunction and dementia are critical symptoms of Lewy Body dementias (LBD). Specifically, alpha-synuclein (αSyn) accumulation in the hippocampus leading to synaptic dysfunction is linked to cognitive deficits in LBD. Here, we investigated the pathological impact of αSyn on hippocampal neurons. We report that either αSyn overexpression or αSyn pre-formed fibrils (PFFs) treatment triggers the formation of cofilin-actin rods, synapse disruptors, in cultured hippocampal neurons and in the hippocampus of synucleinopathy mouse models and of LBD patients. In vivo, cofilin pathology is present concomitantly with synaptic impairment and cognitive dysfunction. Rods generation prompted by αSyn involves the co-action of the cellular prion protein (PrPC) and the chemokine receptor 5 (CCR5). Importantly, we show that CCR5 inhibition, with a clinically relevant peptide antagonist, reverts dendritic spine impairment promoted by αSyn. Collectively, we detail the cellular and molecular mechanism through which αSyn disrupts hippocampal synaptic structure and we identify CCR5 as a novel therapeutic target to prevent synaptic impairment and cognitive dysfunction in LBD.

BackgroundAlzheimer's disease (AD) is the most common form of dementia, progressively impairing cognitive abilities. While neuroimaging studies have revealed functional abnormalities in AD, how these relate to aberrant neuronal circuit mechanisms remains unclear. Using magnetoencephalography imaging we documented abnormal local neural synchrony patterns in patients with AD. To identify global abnormal biophysical mechanisms underlying the spatial and spectral electrophysiological patterns in AD, we estimated the parameters of a biophysical spectral graph model (SGM).MethodsSGM is an analytic neural mass model that describes how long-range fiber projections in the brain mediate the excitatory and inhibitory activity of local neuronal subpopulations. Unlike other coupled neuronal mass models, the SGM is linear, available in closed-form, and parameterized by a small set of biophysical interpretable global parameters. This facilitates their rapid and unambiguous inference which we performed here on a well-characterized clinical population of patients with AD (N = 88, age = 62.73 +/- 8.64 years) and a cohort of age-matched controls (N = 88, age = 65.07 +/- 9.92 years).ResultsPatients with AD showed significantly elevated long-range excitatory neuronal time scales, local excitatory neuronal time scales and local inhibitory neural synaptic strength. The long-range excitatory time scale had a larger effect size, compared to local excitatory time scale and inhibitory synaptic strength and contributed highest for the accurate classification of patients with AD from controls. Furthermore, increased long-range time scale was associated with greater deficits in global cognition.ConclusionsThese results demonstrate that long-range excitatory time scale of neuronal activity, despite being a global measure, is a key determinant in the local spectral signatures and cognition in the human brain, and how it might be a parsimonious factor underlying altered neuronal activity in AD. Our findings provide new insights into mechanistic links between abnormal local spectral signatures and global connectivity measures in AD.

ObjectiveMethamphetamine and cannabis are two widely used, and frequently co-used, substances with possibly opposing effects on the central nervous system. Evidence of neurocognitive deficits related to use is robust for methamphetamine and mixed for cannabis. Findings regarding their combined use are inconclusive. We aimed to compare neurocognitive performance in people with lifetime cannabis or methamphetamine use disorder diagnoses, or both, relative to people without substance use disorders.Method423 (71.9% male, aged 44.6 ± 14.2 years) participants, stratified by presence or absence of lifetime methamphetamine (M-/M+) and/or cannabis (C-/C+) DSM-IV abuse/dependence, completed a comprehensive neuropsychological, substance use, and psychiatric assessment. Neurocognitive domain T-scores and impairment rates were examined using multiple linear and binomial regression, respectively, controlling for covariates that may impact cognition.ResultsGlobally, M+C+ performed worse than M-C- but better than M+C-. M+C+ outperformed M+C- on measures of verbal fluency, information processing speed, learning, memory, and working memory. M-C+ did not display lower performance than M-C- globally or on any domain measures, and M-C+ even performed better than M-C- on measures of learning, memory, and working memory.ConclusionsOur findings are consistent with prior work showing that methamphetamine use confers risk for worse neurocognitive outcomes, and that cannabis use does not appear to exacerbate and may even reduce this risk. People with a history of cannabis use disorders performed similarly to our nonsubstance using comparison group and outperformed them in some domains. These findings warrant further investigation as to whether cannabis use may ameliorate methamphetamine neurotoxicity.

OBJECTIVES: Antipsychotics are widely used to treat first-episode psychosis but may have an anticholinergic burden, that is, a cumulative effect of medications that block the cholinergic system. Studies suggest that a high anticholinergic burden negatively affects memory in psychosis, where cognitive deficits, particularly those in verbal memory, are a core feature of the disease. The present study sought to replicate this in a large cohort of well-characterized first-episode psychosis patients. We expected that patients in the highest anticholinergic burden group would exhibit the poorest verbal memory compared to those with low anticholinergic burden and healthy controls at baseline (3 months following admission). We further hypothesized that over time, at month 12, patients verbal memory performance would improve but would remain inferior to controls. METHODS: Patients (n  =  311; low anticholinergic burden [n  =  241] and high anticholinergic burden [n  =  70], defined by a Drug Burden Index cut-off of 1) and healthy controls (n  =  128) completed a clinical and neurocognitive battery including parts of the Wechsler Memory Scale at months 3 and 12. RESULTS: Cross-sectionally, using an analysis of variance, patients in the highest anticholinergic burden group had the poorest performance in verbal memory when compared to the other groups at month 3, F(2,430)  =  52.33, P

The study of Alzheimers Disease (AD) has traditionally focused on neuropathological mechanisms that has guided therapies that attenuate neuropathological features. A new direction is emerging in AD research that focuses on the progressive loss of cognitive function due to disrupted neural circuit mechanisms. Evidence from humans and animal models of AD show that dysregulated circuits initiate a cascade of pathological events that culminate in functional loss of learning, memory, and other aspects of cognition. Recent progress in single-cell, spatial, and circuit omics informs this circuit-focused approach by determining the identities, locations, and circuitry of the specific cells affected by AD. Recently developed neuroscience tools allow for precise access to cell type-specific circuitry so that their functional roles in AD-related cognitive deficits and disease progression can be tested. An integrated systems-level understanding of AD-associated neural circuit mechanisms requires new multimodal and multi-scale interrogations that longitudinally measure and/or manipulate the ensemble properties of specific molecularly-defined neuron populations first susceptible to AD. These newly developed technological and conceptual advances present new opportunities for studying and treating circuits vulnerable in AD and represent the beginning of a new era for circuit-based AD research.

Deficits in social cognition are seen in both people living with HIV (PWH) and people with a history of methamphetamine (METH) dependence. Dually affected individuals may experience additive negative effects on social cognition due to these conditions. We evaluated social cognition in 4 diagnostic groups (HIV-/METH-, HIV-/METH+, HIV+/METH-, HIV+/METH+). First, we used traditional social-emotional functioning assessments, the Difficulties in Emotion Regulation Scale and the Faux Pas Task, to determine any significant effects of METH dependence and HIV on social cognition. Next, we quantified social cognition using the Human Behavioral Pattern Monitor by evaluating social behavior represented by interaction with novel objects. METH dependence significantly affected social-emotional functions and HIV significantly affected on object interactions, however no significant additive effects were observed using these methods. The nuanced relationship between HIV and METH dependence suggests that other factors (i.e., adaptive life skills) likely mediate social cognition-related behaviors.

BACKGROUND: Cognitive impairment is associated with increased mortality rates in late life, but it is unclear whether worse cognition predicts working-age mortality. METHODS: The data come from a U.S. national survey (N = 3 973 aged 32-84 at cognitive testing in 2004-06, mean age 56.6, 56.3% female; N = 3 055 retested in 2013-18 at ages 42-94, mean age 64.6, 56.6% female; mortality follow-up through 2019). We use Cox hazard models to investigate whether cognition is associated with mortality below age 65, how the magnitude of this risk compares with the risk in later life, and whether the association persists after adjusting for potential confounders. RESULTS: Worse cognition is associated with mortality, but the demographic-adjusted hazard ratio (HR) diminishes with age from 2.0 per standard deviation (SD; 95% confidence interval [CI], 1.7-2.4) at age 55-1.4 (95% CI, 1.3-1.6) at age 85. In the fully adjusted model, the corresponding HRs are 1.4 (95% CI, 1.2-1.7) and 1.3 (95% CI, 1.1-1.4), respectively. The absolute differences in mortality by level of cognition, however, are larger at older ages because mortality is rare at younger ages. The fully adjusted model implies a 2.7 percentage point differential in the estimated percentage dying between ages 55 and 65 for those with low cognition (1 SD below the overall mean, 5.7%) versus high cognition (1 SD above the mean, 3.0%). The corresponding differential between ages 75 and 85 is 8.4 percentage points (24.6% vs 16.2%, respectively). CONCLUSIONS: Cognitive function may be a valuable early warning sign of premature mortality, even at working ages, when dementia is rare.

OBJECTIVES: The relationship between optimism and cognitive functioning is not fully understood. We examined the association of optimism with risk of mild cognitive impairment (MCI) and dementia in the Womens Health Initiative Memory Study (WHIMS). METHODS: Optimism was measured by the Life Orientation Test-Revised (LOT-R) total score, and optimism and pessimism subscales. A panel of experts adjudicated cognitive endpoints based on annual cognitive assessments. We used cox proportional hazard regression models to examine the association of LOT-R total score and optimism and pessimism sub-scores with MCI/dementia. We also examined the relationship between vascular disease, LOT-R total score, optimism and pessimism, and cognition. RESULTS: Mean age was 70.5 (SD = 3.9) years. The sample (N = 7249) was 87% white, and 29.8% of participants had < 12 years of education. Total LOT-R score (HR = 0.96, 95% CI: 0.94, 0.98, p

BackgroundCancer patients and survivors often experience acute cognitive impairments; however, the long-term cognitive impact remains unclear particularly among Hispanics/Latinos. We examined the association between cancer history and neurocognitive test performance among middle-aged and older Hispanic/Latinos.MethodsParticipants included 9639 Hispanic/Latino adults from the community-based and prospective Hispanic Community Health Study/Study of Latinos. At baseline (2008-2011; V1), participants self-reported their cancer history. At V1 and again at a 7-year follow-up (2015-2018; V2), trained technicians administered neurocognitive tests including the Brief-Spanish English Verbal Learning Test (B-SEVLT), Word Fluency Test (WF), and Digit Symbol Substitution Test (DSS). We used survey linear regression to estimate the overall, sex-specific, and cancer site-specific [i.e., cervix, breast, uterus, and prostate] adjusted associations between cancer history and neurocognitive test performance at V1 and changes from V1 to V2.ResultsAt V1, a history of cancer (6.4%) versus no history of cancer (93.6%) was associated with higher WF scores (β = 0.14, SE = 0.06; p = 0.03) and global cognition (β = 0.09, SE = 0.04; p = 0.04). Among women, a history of cervical cancer predicted decreases in SEVLT-Recall scores (β = -0.31, SE = 0.13; p = 0.02) from V1 to V2, and among men, a history of prostate cancer was associated with higher V1 WF scores (β = 0.29, SE = 0.12; p = 0.02) and predicted increases in SEVLT-Sum (β = 0.46, SE = 0.22; p = 0.04) from V1 to V2.ConclusionAmong women, a history of cervical cancer was associated with 7-year memory decline, which may reflect the impacts of systemic cancer therapies. Among men, however, a history of prostate cancer was associated with improvements in cognitive performance, perhaps due in part to engaging in health promoting behaviors following cancer.

Cognitive control deficits are a hallmark of attention deficit hyperactivity disorder (ADHD) in children. Theoretical models posit that cognitive control involves reactive and proactive control processes but their distinct roles and inter-relations in ADHD are not known, and the contributions of proactive control remain vastly understudied. Here, we investigate the dynamic dual cognitive control mechanisms associated with both proactive and reactive control in 50 children with ADHD (16F/34M) and 30 typically developing (TD) children (14F/16M) aged 9-12 years across two different cognitive controls tasks using a within-subject design. We found that while TD children were capable of proactively adapting their response strategies, children with ADHD demonstrated significant deficits in implementing proactive control strategies associated with error monitoring and trial history. Children with ADHD also showed weaker reactive control than TD children, and this finding was replicated across tasks. Furthermore, while proactive and reactive control functions were correlated in TD children, such coordination between the cognitive control mechanisms was not present in children with ADHD. Finally, both reactive and proactive control functions were associated with behavioral problems in ADHD, and multi-dimensional features derived from the dynamic dual cognitive control framework predicted inattention and hyperactivity/impulsivity clinical symptoms. Our findings demonstrate that ADHD in children is characterized by deficits in both proactive and reactive control, and suggest that multi-componential cognitive control measures can serve as robust predictors of clinical symptoms.

BackgroundThough dementia rates vary by racial or ethnic groups, it is unknown if these disparities remain among those aged 90 or older.AimsTo test this hypothesis, we used baseline clinical evaluation of 541 ethnically and racially diverse individuals participating in the LifeAfter90 Study to assess how associations between core demographic characteristics and measures of physical and cognitive performance differ across the racial/ethnic groups.MethodsParticipants in this study were long-term non-demented members of Kaiser Permanente Northern California. They were clinically evaluated and diagnosed with normal or impaired cognition (mild cognitive impairment and dementia) through an in-person comprehensive clinical assessment consisting of a detailed medical history, physical and neurological examination, functional, and cognitive tests.ResultsThe average age at enrollment was 93.0 ± 2.6 years, 62.4% female and 34.2% non-Hispanic White. At initial evaluation 301 participants had normal cognition and 165 had mild cognitive impairment (MCI) and despite screening, 69 participants were determined to have dementia. Age, education, 3MS, FAQ and CDR scores were significantly associated with cognitive impairment (normal versus MCI and dementia), but not gender. There was a significant univariate association between race/ethnicity and cognitive impairment (p

Cognitive disorders are prevalent in people with HIV (PWH) despite antiretroviral therapy. Given the heterogeneity of cognitive disorders in PWH in the current era and evidence that these disorders have different etiologies and risk factors, scientific rationale is growing for using data-driven models to identify biologically defined subtypes (biotypes) of these disorders. Here, we discuss the state of science using machine learning to understand cognitive phenotypes in PWH and their associated comorbidities, biological mechanisms, and risk factors. We also discuss methods, example applications, challenges, and what will be required from the field to successfully incorporate machine learning in research on cognitive disorders in PWH. These topics were discussed at the National Institute of Mental Health meeting on "Biotypes of CNS Complications in People Living with HIV" held in October 2021. These ongoing research initiatives seek to explain the heterogeneity of cognitive phenotypes in PWH and their associated biological mechanisms to facilitate clinical management and tailored interventions.

OBJECTIVES: Telephone-administered cognitive assessments are a cost-effective and sometimes necessary alternative to face-to-face assessments. There is limited information in large studies concerning mode effects, or differences in cognition attributable to the assessment method, as a potential measurement threat. We evaluated mode effects on cognitive scores using a population-based sample of community-living older adults. METHODS: We used data from participants aged 65-79 in the 2014 Health and Retirement Study for whom the interview mode was randomized (n = 6,825). We assessed mode differences in test means, whether mode modifies associations of cognition with criterion variables, and formal measurement invariance testing. RESULTS: Relative to face-to-face assessment, telephone assessment was associated with higher scores for memory and calculation (0.06 to 0.013 standard deviations [SD]) and lower scores for nonmemory items (-0.09 to -0.01 SD). Cognition was significantly differentially related to instrumental activities of daily living difficulty depending on assessment mode. Measurement invariance testing identified evidence of mode differences in certain tests as a function of mode: adjusting for underlying cognition, the largest mode differences in memory and attention: immediate noun recall, delayed word recall, and serial-7s scores were higher given telephone administration. DISCUSSION: Differences by mode of administration are apparent in cognitive measurement in older adults, albeit to a small degree in our study, and most pronounced for tests of memory and attention. The importance of accounting for mode differences ultimately depends on ones research question and study sample: not all associations may be affected by mode differences, and such modification may only be apparent among those with lower cognitive functioning.

BackgroundMany studies have evaluated the stress-cognition association, but few have captured the cumulative nature of stress or distinguished the influences of stressors occurring in childhood versus adulthood. Using a lifecourse approach, we investigated whether cumulative stress exposures are associated with poorer cognitive function and faster cognitive decline.MethodsWe used data from the Midlife Development in the United States Study (N = 3,954, mean baseline age: 56 years). We fit marginal structural generalized estimating equations models to estimate the difference in baseline cognitive function per SD increment in the continuous stressor score, and, separately, between persons in each life course stressor profile and those who did not experience high stress in either childhood or adulthood. We also characterized differences in cognitive decline across levels of stress exposures.ResultsHigher cumulative stress exposure was associated with lower executive function (difference per SD in continuous stressor score = -0.12 SD units, 95% CI = -0.16, -0.08) and episodic memory (difference = -0.09 SD units, 95% CI = -0.13, -0.05). Baseline executive function and episodic memory were lower among those with high stress only in childhood, only in adulthood, and both, than among those without high stress in childhood or adulthood. There was little evidence that rate of change in executive function and episodic memory differed across levels of cumulative stress exposures.ConclusionsThese findings offer support to the hypothesis that stress exposures, accumulated over the life course, worsen cognitive performance, but limited support for the hypothesis that these exposures promote cognitive decline.

BACKGROUND AND HYPOTHESIS: Schizophrenia (SZ) and bipolar disorder (BD) share genetic risk factors, yet patients display differential levels of cognitive impairment. We hypothesized a genome-transcriptome-functional connectivity (frontoparietal)-cognition pathway linked to SZ-versus-BD differences, and conducted a multiscale study to delineate this pathway. STUDY DESIGNS: Large genome-wide studies provided single nucleotide polymorphisms (SNPs) conferring more risk for SZ than BD, and we identified their regulated genes, namely SZ-biased SNPs and genes. We then (a) computed the polygenic risk score for SZ (PRSSZ) of SZ-biased SNPs and examined its associations with imaging-based frontoparietal functional connectivity (FC) and cognitive performances; (b) examined the spatial correlation between ex vivo postmortem expressions of SZ-biased genes and in vivo, SZ-related FC disruptions across frontoparietal regions; (c) investigated SZ-versus-BD differences in frontoparietal FC; and (d) assessed the associations of frontoparietal FC with cognitive performances. STUDY RESULTS: PRSSZ of SZ-biased SNPs was significantly associated with frontoparietal FC and working memory test scores. SZ-biased genes expressions significantly correlated with SZ-versus-BD differences in FC across frontoparietal regions. SZ patients showed more reductions in frontoparietal FC than BD patients compared to controls. Frontoparietal FC was significantly associated with test scores of multiple cognitive domains including working memory, and with the composite scores of all cognitive domains. CONCLUSIONS: Collectively, these multiscale findings support the hypothesis that SZ-biased genetic risk, through transcriptome regulation, is linked to frontoparietal dysconnectivity, which in turn contributes to differential cognitive deficits in SZ-versus BD, suggesting that potential biomarkers for more precise patient stratification and treatment.

RATIONALE: Modafinil has been proposed as a potentially effective clinical treatment for neuropsychiatric disorders characterized by cognitive control deficits. However, the precise effects of modafinil, particularly on brain network functions, are not completely understood. OBJECTIVES: To address this gap, we examined the effects of modafinil on resting-state brain activity in 30 healthy adults using microstate analysis. Electroencephalographic (EEG) microstates are discrete voltage topographies generated from resting-state network activity. METHODS: Using a placebo-controlled, within-subjects design, we examined changes to microstate parameters following placebo (0 mg), low (100 mg), and high (200 mg) modafinil doses. We also examined the functional significance of these microstates via associations between microstate parameters and event-related potential indexes of conflict monitoring and automatic error processing (N2 and error-related negativity) and behavioral responses (accuracy and RT) from a subsequent flanker interference task. RESULTS: Five microstates emerged following each treatment condition, including four canonical microstates (A-D). Modafinil increased microstate C proportion and occurrence regardless of dose, relative to placebo. Modafinil also decreased microstate A proportion and microstate B proportion and occurrence relative to placebo. These modafinil-related changes in microstate parameters were not associated with similar changes in flanker ERPs or behavior. Finally, modafinil made transitions between microstates A and B less likely and transitions from A and B to C more likely. CONCLUSIONS: Previous fMRI work has correlated microstates A and B with auditory and visual networks and microstate C with a salience network. Thus, our results suggest modafinil may deactivate large-scale sensory networks in favor of a higher order functional network during resting-state in healthy adults.

Aim: Understanding and supporting quality of life (QoL) and daily functioning in glioma patients is a clinical imperative. In this study, we examined the relationship between cognition, psychological factors, measures of health-related QoL and functioning in glioma survivors. Materials & methods: We examined neuropsychological, self-reported cognition, mood and QoL correlates of work and non-work-related daily functioning in 23 glioma survivors, and carried out linear models of the best predictors. Results & conclusion: A total of 13/23 participants were working at the time of enrollment. The best model for worse work-related functioning (R2 = .83) included worse self-reported cognitive function, depression, loneliness and brain tumor symptoms. The best model for worse non-work-related functioning (R2 = .61) included worse self-reported cognitive functioning, anxiety, sleep disturbance and physical functioning. Neuropsychological variables were not among the most highly correlated with function. Worse cognitive, particularly self-reported and psychosocial outcomes may compromise optimal functioning in glioma survivors.

Benzodiazepine use is linked to neurocognitive impairment (NCI) in the general population and people with HIV (PWH); however, this relationship may depend on age-related factors such as medical comorbidities, which occur at an elevated rate and manifest earlier in PWH. We retrospectively examined whether chronological age or medical burden, a clinical marker for aging, moderated the relationship between benzodiazepine use and NCI in PWH. Participants were 435 PWH on antiretroviral therapy who underwent neurocognitive and medical evaluations, including self-reported current benzodiazepine use. A medical burden index score (proportion of accumulated multisystem deficits) was calculated from 28 medical deficits. Demographically corrected cognitive deficit scores from 15 neuropsychological tests were used to calculate global and domain-specific NCI based on established cut-offs. Logistic regressions separately modeled global and domain-specific NCI as a function of benzodiazepine x age and benzodiazepine x medical burden interactions, adjusting for current affective symptoms and HIV disease characteristics. A statistically significant benzodiazepine x medical burden interaction (p = .006) revealed that current benzodiazepine use increased odds of global NCI only among those who had a high medical burden (index score > 0.3 as indicated by the Johnson-Neyman analysis), which was driven by the domains of processing speed, motor, and verbal fluency. No age x benzodiazepine interactive effects on NCI were present. Findings suggest that the relationship between BZD use and NCI among PWH is specific to those with greater medical burden, which may be a greater risk factor for BZD-related NCI than chronological age.

This study evaluated stakeholders' perspectives regarding participation in two hypothetical neuromodulation trials focused on individuals with Alzheimer's disease and related disorders (ADRDs). Stakeholders (i.e., individuals at risk for ADRDs [n = 56], individuals with experience as a caregiver for someone with a cognitive disorder [n = 60], and comparison respondents [n = 124]) were recruited via MTurk. Primary outcomes were willingness to enroll (or enroll one's loved one), feeling lucky to have the opportunity to enroll, and feeling obligated to enroll in two protocols (transcranial magnetic stimulation, TMS; deep brain stimulation, DBS). Relative to the Comparison group, the At Risk group endorsed higher levels of "feeling lucky" regarding both research protocols, and higher willingness to participate in the TMS protocol. These findings provide tentative reassurance regarding the nature of decision making regarding neurotechnology-based research on ADRDs. Further work is needed to evaluate the full range of potential influences on research participation.

Traumatic brain injury (TBI) is one of the leading causes of long-term neurological disabilities in the world. TBI is a signature disease for soldiers and veterans, but also affects civilians, including adults and children. Following TBI, the brain resident and immune cells turn into a "reactive" state, characterized by the production of inflammatory mediators that contribute to the development of cognitive deficits. Other injuries to the brain, including radiation exposure, may trigger TBI-like pathology, characterized by inflammation. Currently there are no treatments to prevent or reverse the deleterious consequences of brain trauma. The recognition that TBI predisposes stem cell alterations suggests that stem cell-based therapies stand as a potential treatment for TBI. Here, we discuss the inflamed brain after TBI and radiation injury. We further review the status of stem cells in the inflamed brain and the applications of cell therapy in sequestering inflammation in TBI.

BackgroundNeurocognitive impairment remains prevalent in people with HIV (PWH) despite long term virological suppression by antiretroviral therapy (ART) regimens. Systemic and neuro-inflammatory processes are suggested to contribute to the complex pathology leading to cognitive impairment in this population, yet the underlying mechanisms remain unresolved. Extracellular vesicles (EVs) play a central role in intracellular communication and have emerged as key modulators of immunological and inflammatory responses. In this report, we examined the impact of EVs in PWH experiencing cognitive deficits to determine their relevance in HIV associated neuropathology.MethodsEV phenotypes were measured in plasma samples from 108 PWH with either cognitive impairment (CI, n=92) or normal cognition (NC, n=16) by flow cytometry. Matched cerebrospinal fluid (CSF)-derived EVs were similarly profiled from a subgroup of 84 individuals who underwent a lumbar puncture. Peripheral blood mononuclear cells were assayed by flow cytometry to measure monocyte frequencies in a subset of 32 individuals.ResultsPlasma-EVs expressing CD14, CD16, CD192, C195, and GFAP were significantly higher in HIV-infected individuals with cognitive impairment compared to individuals with normal cognition. Increased CSF-EVs expressing GFAP and CD200 were found in the cognitive impairment group compared to the normal cognition group. Frequencies of patrolling monocytes correlated with plasma-EVs expressing CD14, CD66b, MCSF, MAP2, and GFAP. Frequencies of CD195 expression on monocytes correlated positively with plasma-EVs expressing CD41a, CD62P, and CD63. Expression of CD163 on monocytes correlated positively with CSF-EVs expressing GFAP and CD200. Finally, the expression of CD192 on total monocytes correlated with CSF-EVs expressing CD200, CD62P, and CD63.ConclusionsEVs expressing monocyte activation and neuronal markers associated with HIV associated cognitive impairment, suggesting that distinct EV subsets may serve as novel biomarkers of neuronal injury in HIV infection. Further circulating platelet EV levels were linked to monocyte activation indicating a potential novel interaction in the pathogenesis of HIV-related cognitive impairment.

Cognitive Symptom Management and Rehabilitation Training (CogSMART) and Compensatory Cognitive Training (CCT) are evidence-based compensatory cognitive training interventions that improve cognition in persons with a history of traumatic brain injury or other neuropsychiatric disorders. Despite demonstrated efficacy, use and effectiveness of CogSMART/CCT in real-world settings is not known.We used a multi-method design to collect and analyze quantitative and qualitative survey data from several domains of the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to gather information about use of CogSMART/CCT in real-world settings from provider and patient perspectives. Surveys were sent to email addresses from persons who registered on the CogSMART website seeking access to training manuals and other resources. Descriptive statistics were generated, and we used Natural Language Processing methods to study the self-report free responses. Using n-gram analysis, we identified the most frequently reported responses.We found CogSMART/CCT was broadly used in real-world settings and delivered by a variety of providers for several patient groups with high attendance and overall high satisfaction. CogSMART/CCT seemed to be offered in VA- or university-related clinics more than in private practice or rehabilitation centers. The diversity of providers and variety of formats by which to deliver CogSMART/CCT (i.e., individual, group, telehealth) seemed to play a role in its widespread implementation, as did its adaptability. Most providers made adaptations to the intervention that reduced the length or number of sessions. These changes were most likely to be based on client characteristics. The low rates of formal training, however, may have contributed to lower levels of perceived helpfulness among patients.Reach and Adoption of a cognitive rehabilitation intervention improved by increasing access to the manuals. Attention to characteristics of dissemination and implementation in the design of an intervention may enhance its use in real-world settings. The relevant outcomes, easy access to training manuals, and adaptability of CogSMART/CCT seem to have been important factors in its use in a variety of settings and for several disorders with cognitive impairment. The adoption of CogSMART/CCT by a variety of providers other than neuropsychologists suggests its use may be broadened to other healthcare providers, if adequately trained, to increase access to an intervention with demonstrated efficacy for cognitive rehabilitation for several neuropsychiatric disorders.

BackgroundCognitive impairment, including dementia, is frequently under-detected in primary care. The Consortium for Detecting Cognitive Impairment, including Dementia (DetectCID) convenes three multidisciplinary teams that are testing novel paradigms to improve the frequency and quality of patient evaluations for detecting cognitive impairment in primary care and appropriate follow-up.ObjectiveOur objective was to characterize the three paradigms, including similarities and differences, and to identify common key lessons from implementation.MethodsA qualitative evaluation study with dementia specialists who were implementing the detection paradigms. Data was analyzed using content analysis.ResultsWe identified core components of each paradigm. Key lessons emphasized the importance of engaging primary care teams, enabling primary care providers to diagnose cognitive disorders and provide ongoing care support, integrating with the electronic health record, and ensuring that paradigms address the needs of diverse populations.ConclusionApproaches are needed that address the arc of care from identifying a concern to post-diagnostic management, are efficient and adaptable to primary care workflows, and address a diverse aging population. Our work highlights approaches to partnering with primary care that could be useful across specialties and paves the way for developing future paradigms that improve differential diagnosis of symptomatic cognitive impairment, identifying not only its presence but also its specific syndrome or etiology.

BackgroundCholinergic neurotransmitter system dysfunction contributes to cognitive impairment in Alzheimer's disease and other syndromes. However, the specific cholinergic mechanisms and brain structures involved, time course of alterations, and relationships with specific cognitive deficits are not well understood.MethodsThis study included 102 older adults: 42 cognitively unimpaired (CU), 28 with mild cognitive impairment (MCI), and 32 with Alzheimer's disease (AD) dementia. Each participant underwent a neuropsychological assessment. Regional brain α4β2 nicotinic cholinergic receptor binding (VT/fp) was measured using 2-[18F]fluoro-3-(2(S)azetidinylmethoxy)pyridine (2FA) and PET imaging. Voxel-wise analyses of group differences were performed. Relationships between receptor binding and cognition, age, and cholinesterase inhibitor medication use were assessed using binding values in six prespecified regions of interest.ResultsSPM analysis showed the group VT/fp binding differences in the bilateral entorhinal cortex, hippocampus, insula, anterior cingulate, thalamus, and basal ganglia (p

BACKGROUND: Sensory processing abnormalities are common in schizophrenia (SZ) and impact everyday functions, such as speech perception in noisy environments. Auditory-based targeted cognitive training (TCT) is a bottom up cognitive remediation intervention designed to enhance the speed and accuracy of low-level auditory information processing. However, the effects of TCT on behavioral measures of central auditory processing (CAP) and the role of CAP function on verbal learning outcomes in SZ are unknown. METHODS: SZ (n = 42) and healthy subjects (CTL; n = 18) underwent comprehensive clinical, neurocognitive, and auditory assessments, including tests of hearing sensitivity and speech recognition (Words-in-Noise (WIN), Quick Speech-in-Noise (SIN)). SZ patients were randomized to receive either treatment-as-usual (TAU); or 30-h of TCT + TAU using a stratified, parallel design. SZ patients repeated assessments ~10-12 weeks later. RESULTS: Patients exhibited deficits in both WIN (p

ObjectiveNeuropsychological impairments are observed in individuals with Bipolar Disorder (BD), yet knowledge of how cognitive deficits unfold in real-time remains limited. Given intraindividual variability in mood observed in people with BD, and the potential for mood and cognition to be mutually influential, we employed ambulatory assessment technologies to examine potential contemporaneous (same survey) and lagged (next survey) relationships of congition and mood.MethodsOutpatients with BD (n = 46) or no psychiatric disorders (heathy volunteers [HV]; n = 20) completed in-laboratory neurobehavioral assessments and 14 days of smartphone-administered mobile cognitive tests and ratings of affective variables. Linear mixed-effects models were used to analyze real-time relationships between mobile cognitive test performance and mood.ResultsOn in-laboratory tests, participants with BD showed worse cognitive performance than HVs as well as mild depression severity; mood and cognitive performance were unrelated. On mobile cognitive tests and surveys, participants with BD showed somewhat worse cognitive performance and ratings of lower energy and greater sadness relative to HV participants. Among those with BD, mania and sadness earlier in the day related to worse processing speed and better working memory performance, respectively, on the next survey. In contrast, same survey ratings of greater stress related to better working memory, and greater happiness related to better processing speed.ConclusionsReal-time assessments of mood and cognition provide incremental information beyond what can be gleaned from laboratory assessments. Understanding how these affect-related changes in processing speed emerge and play out in daily life may provide clinically useful information for treatment planning.

Alzheimer's disease (AD) is conceptualized as a synaptic failure disorder in which loss of glutamatergic synapses is a major driver of cognitive decline. Thus, novel therapeutic strategies aimed at regenerating synapses may represent a promising approach to mitigate cognitive deficits in AD patients. At present, no disease-modifying drugs exist for AD, and approved therapies are palliative at best, lacking in the ability to reverse the synaptic failure. Here, we tested the efficacy of a novel synaptogenic small molecule, SPG302 - a 3rd-generation benzothiazole derivative that increases the density of axospinous glutamatergic synapses - in 3xTg-AD mice. Daily dosing of 3xTg-AD mice with SPG302 at 3 and 30 mg/kg (i.p.) for 4 weeks restored hippocampal synaptic density and improved cognitive function in hippocampal-dependent tasks. Mushroom and stubby spine profiles were increased by SPG302, and associated with enhanced expression of key postsynaptic proteins - including postsynaptic density protein 95 (PSD95), drebrin, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) - and increased colocalization of PSD95 with synaptophysin. Notably, SPG302 proved efficacious in this model without modifying Aβ and tau pathology. Thus, our study provides preclinical support for the idea that compounds capable of restoring synaptic density offer a viable strategy to reverse cognitive decline in AD.

Schizophrenia is widely thought to involve elevated distractibility, which may reflect a general impairment in top-down inhibitory processes. Schizophrenia also appears to involve increased priming of previously performed actions. Here, we used a highly refined eye-tracking paradigm that makes it possible to concurrently assess distractibility, inhibition, and priming. In both healthy control subjects (HCS, N = 41) and people with schizophrenia (PSZ, N = 46), we found that initial saccades were actually less likely to be directed toward a salient "singleton" distractor than toward less salient distractors, reflecting top-down suppression of the singleton. Remarkably, this oculomotor suppression effect was as strong or stronger in PSZ than in HCS, indicating intact inhibitory control. In addition, saccades were frequently directed to the location of the previous-trial target in both groups, but this priming effect was much stronger in PSZ than in HCS. Indeed, PSZ directed gaze toward the location of the previous-trial target as often as they directed gaze to the location of the current-trial target. These results demonstrate that-at least in the context of visual search-PSZ are no more distractable than HCS and are fully capable of inhibiting salient-but-irrelevant stimuli. However, PSZ do exhibit exaggerated priming, focusing on recently attended locations even when this is not beneficial for goal attainment. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

BackgroundPeripheral levels of pro-inflammatory biomarkers have been shown to be altered in schizophrenia (SZ) and associated with cognitive impairments, but their relevance to specific cognitive domains remains unclear.MethodsPlasma levels of cytokines, chemokines, and vascular biomarkers were quantified and compared between SZ and healthy comparison (HC) groups. Cognition was assessed using the Delis-Kaplan Executive Function System Trail Making (TM) and Color Word Interference (CWI) tests. Linear regression analyses examined differential relationships of inflammatory biomarkers with executive function between groups.ResultsPlasma levels of TNFα, ICAM1, and MCP1 were higher in individuals with SZ compared to HCs. Higher level of MCP1 was associated with increased CWI Inhibition Switching Errors in SZ but not HCs.ConclusionLike other studies, we found evidence for increased peripheral inflammation in SZ. We also showed that SZ with particularly high MCP1 levels had poor cognitive flexibility. Interventions to reduce chemokine elevations might prove beneficial for cognitive performance.

Individuals with schizophrenia exhibit widespread cortical thinning associated with illness severity and deficits in cognition. However, intact cortical thickness (CTh) may serve as a protective factor. The current study sought to examine changes in CTh in response to auditory targeted cognitive training (TCT) in individuals with recent onset schizophrenia. Participants underwent MRI scanning and a cognitive assessment before and after being randomly assigned to 40 h of either TCT (N = 21) or a computer games control condition (CG; N = 22) over 16 weeks. Groups did not differ at baseline on demographic variables or measures of CTh. At the level of group averages, neither group showed significant pre-post changes in CTh in any brain region. However, changes in CTh related to individual differences in treatment outcome, as improved global cognition in the TCT group corresponded to reduced cortical thinning in frontal, temporal, parietal, and occipital lobes. These relationships were not observed in the CG group. The current findings suggest that TCT may be neuroprotective in early schizophrenia, such that individuals who improved in response to training also showed a reduction in cortical thinning that may be otherwise hastened due to age and illness.

Our objective was to examine the construct validity of the Brief Test of Adult Cognition by Telephone (BTACT) and its relationship to traumatic brain injury (TBI) of differing severities. Data were analyzed on 1422 patients with TBI and 170 orthopedic trauma controls (OTC) from the multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Participants were assessed at 6 months post-injury with the BTACT and an in-person neuropsychological battery. We examined the BTACT's factor structure, factorial group invariance, convergent and discriminant validity, and relationship to TBI and TBI severity. Confirmatory factor analysis supported both a 1-factor model and a 2-factor model comprising correlated Episodic Memory and Executive Function (EF) factors. Both models demonstrated strict invariance across TBI severity and OTC groups. Correlations between BTACT and criterion measures suggested that the BTACT memory indices predominantly reflect verbal episodic memory, whereas the BTACT EF factor correlated with a diverse range of cognitive tests. Although the EF factor and other BTACT indices showed significant relationships with TBI and TBI severity, some group effect sizes were larger for more comprehensive in-person cognitive tests than the BTACT. The BTACT is a promising, brief, phone-based cognitive screening tool for patients with TBI. Although the BTACT's memory items appear to index verbal Episodic Memory, items that purport to assess EFs may reflect a broader array of cognitive domains. The sensitivity of the BTACT to TBI severity is lower than domain-specific neuropsychological measures, suggesting it should not be used as a substitute for comprehensive, in-person cognitive testing at 6 months post-TBI.

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

OBJECTIVE: To determine whether and how cognitive assessment data should be included in a report for patients with SLE and their providers. METHODS: Leveraging experiences from prior studies, we created a cognitive report that included a hypothetical patients results on tests of multiple domains based on the NIH Toolbox Fluid Cognition Battery. In focus groups that comprised patients with SLE (two groups) and their providers (two groups), feedback was sought on the presentation of results as well as the potential value of the report in the clinical setting. RESULTS: Feedback regarding the presentation of the report was generally positive. Both patients with SLE and their providers liked its simple graphics and use of a colour-gradated scale to indicate performance. However, both groups stressed the importance of using non-stigmatising language in describing results. Several potential purposes of the report, including distinguishing cognitive versus other issues, explaining cognitive challenges, improving patient-provider interactions, guiding decision-making, improving functioning or preventing impairment and tracking cognitive function over time, were noted by the participants. Potential barriers, such as inadequate clinical staffing or time and lack of potential treatments for identified issues, were also discussed. CONCLUSION: In this exploratory study, we found that both patients with SLE and their providers were receptive to the idea of a patient-friendly report of cognitive test results. This study provides important information to guide future pragmatic research to optimise the delivery of cognitive information to patients with SLE.

BackgroundSeverity of negative symptoms has been associated with poor functioning, cognitive deficits, and defeatist beliefs in schizophrenia patients. However, one area that remains understudied is persistent negative symptoms (PNS). Negative symptoms, including PNS, have been observed in those at clinical high-risk (CHR) for psychosis. The aim of this study was to determine if PNS were associated with functioning, neurocognition, and defeatist beliefs in a CHR sample.MethodCHR participants (n = 764) were recruited for the North American Prodrome Longitudinal Study. Negative symptoms were rated on the Scale of Psychosis-risk Symptoms. Generalized linear mixed models for repeated measures were used to examine changes over time between and within groups (PNS vs non-PNS).ResultsThe PNS group (n = 67) had significant deficits in functioning at baseline, 6, 12, 18, and 24-months compared to the non-PNS group (n = 673). Functioning improved over time in the non-PNS group, while functioning in the PNS group remained relatively stable and poor over a two-year period. A consistent trend emerged demonstrating higher defeatist beliefs in the PNS group; however, this result was lost when controlling for persistent depressive symptoms. There were no significant differences between the groups on neurocognition, social cognition, and transition to psychosis.ConclusionsPNS exist in youth at CHR for psychosis, resulting in significant and persistent functional impairment, which remains when controlling for persistent depressive symptoms. PNS remain even in CHR youth who do not transition to psychosis. Thus, PNS may represent an unmet therapeutic need in CHR populations for which there are currently no effective treatments.

Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here, we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as Alzheimer's disease and limbic-predominant age-related TDP-43 encephalopathy (LATE). There may also be complex physiologic interactions between metabolic syndrome (e.g., hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that factored in comorbid diseases, B-ASC was independently associated with impairments of global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability.

Early diagnosis of cognitive disorders in older adults is a major healthcare priority with benefits to patients, families, and health systems. Rapid advances in digital technology offer potential for developing innovative diagnostic pathways to support early diagnosis. Brief self-administered computerized cognitive tools in particular hold promise for clinical implementation by minimizing demands on staff time. In this study, we conducted a systematic review of self-administered computerized cognitive assessment measures designed for the detection of cognitive impairment in older adults. Studies were identified via a systematic search of published peer-reviewed literature across major scientific databases. All studies reporting on psychometric validation of brief (≤30 minutes) self-administered computerized measures for detection of MCI and all-cause dementia in older adults were included. Seventeen studies reporting on 10 cognitive tools met inclusion criteria and were subjected to systematic review. There was substantial variability in characteristics of validation samples and reliability and validity estimates. Only 2 measures evaluated feasibility and usability in the intended clinical settings. Similar to past reviews, we found variability across measures with regard to psychometric rigor and potential for widescale applicability in clinical settings. Despite the promise that self-administered cognitive tests hold for clinical implementation, important gaps in scientific rigor in development, validation, and feasibility studies of these measures remain. Developments in technology and biomarker studies provide potential avenues for future directions on the use of digital technology in clinical care.

In perinatally HIV-infected (PHIV) children, neurodevelopment occurs in the presence of HIV-infection, and even with combination antiretroviral therapy (cART) the brain can be a reservoir for latent HIV. Consequently, patients often demonstrate long-term cognitive deficits and developmental delay, which may be reflected in altered functional brain activity. Our objective was to examine brain function in PHIV on cART by quantifying the amplitude of low frequency fluctuations (ALFF) and regional homogeneity (ReHo). Further, we studied ALFF and ReHo changes with neuropsychological performance and measures of immune health including CD4 count and viral loads in the HIV-infected youths. We found higher ALFF and ReHo in cerebral white matter in the medial orbital lobe for PHIV (N = 11, age mean ± sd = 22.5 ± 2.9 years) compared to controls (N = 16, age = 22.5 ± 3.0 years), with age and gender as co-variates. Bilateral cerebral white matter showed increased spontaneous regional activity in PHIV compared to healthy controls. No brain regions showed lower ALFF or ReHo in PHIV compared to controls. Higher log10 viral load was associated with higher ALFF and ReHo in PHIV in bilateral cerebral white matter and right cerebral white matter respectively after masking the outcomes intrinsic to the brain regions that showed significantly higher ALFF and ReHo in the PHIV compared to the control. Reductions in social cognition and abstract thinking in PHIV were correlated with higher ALFF at the left cerebral white matter in the left medial orbital gyrus and higher ReHo at the right cerebral white matter in the PHIV patients. Although neuroinflammation and associated neuro repair were not directly measured, the findings support their potential role in PHIV impacting neurodevelopment and cognition.

The goal of this study was to test for long-term benefits three years after the completion of a cognitive training intervention (Project: EVO™) in a subset of children with Sensory Processing Dysfunction (SPD). Our initial findings revealed that children with SPD who also met research criteria for Attention Deficit Hyperactivity Disorder (SPD+IA) showed a significant decrease in parent-observed inattentive behaviors, which remained stable in a nine-month follow-up assessment. Forty nine caregivers of participants who completed the Project: EVO™ training were contacted to be included in this follow up study. Each was emailed an invitation to complete the Vanderbilt ADHD Diagnostic Parent Rating Scale, which yielded a completion rate of 39/49 (80%). A Generalized Estimating Equations analysis was used to assess changes in symptoms over time, specifically to determine whether the initial improvements were retained. The SPD+IA cohort continued to show sustained benefits on their parent-reported scores of inattention, with 54% of SPD+IA individuals no longer meeting criteria for ADHD three years following intervention. These findings provide initial insights into the potential long-term benefits of a digital health intervention for children with attention-based issues.

BackgroundCopper (Cu) is an essential metal mediating a variety of vital biological reactions with its redox property. Its dyshomeostasis has been associated with accelerated cognitive decline and neurodegenerative disorders, such as Alzheimer's disease (AD). However, underlying neurotoxic mechanisms elicited by dysregulated Cu remain largely elusive. We and others previously demonstrated that exposure to Cu in drinking water significantly exacerbated pathological hallmarks of AD and pro-inflammatory activation of microglia, coupled with impaired phagocytic capacity, in mouse models of AD.MethodsIn the present study, we extended our investigation to evaluate whether chronic Cu exposure to wild-type (WT) and J20 mouse model of AD perturbs homeostatic dynamics of microglia and contributes to accelerated transformation of microglia towards degenerative phenotypes that are closely associated with neurodegeneration. We further looked for evidence of alterations in the microglial morphology and spatial memory of the Cu-exposed mice to assess the extent of the Cu toxicity.ResultsWe find that chronic Cu exposure to pre-pathological J20 mice upregulates the translation of degenerative genes and represses homeostatic genes within microglia even in the absence amyloid-beta plaques. We also observe similar expression signatures in Cu-exposed WT mice, suggesting that excess Cu exposure alone could lead to perturbed microglial homeostatic phenotypes and contribute to accelerated cognitive decline.ConclusionOur findings highlight the risk of chronic Cu exposure on cognitive decline and altered microglia activation towards degenerative phenotypes. These changes may represent one of the key mechanisms linking Cu exposure or its dyshomeostasis to an increased risk for AD.

Not surprisingly, our knowledge of the impact of radiation on the brain has evolved considerably. Decades of work have struggled with identifying the critical cellular targets in the brain, the latency of functional change and understanding how irradiation alters the balance between excitatory and inhibitory circuits. Radiation-induced cell kill following clinical fractionation paradigms pointed to both stromal and parenchymal targets but also defined an exquisite sensitivity of neurogenic populations of newly born cells in the brain. It became more and more apparent too, that acute (days) events transpiring after exposure were poorly prognostic of the late (months-years) waves of radiation injury believed to underlie neurocognitive deficits. Much of these gaps in knowledge persisted as NASA became interested in how exposure to much different radiation types, doses and dose rates that characterize the space radiation environment might impair central nervous system functionality, with possibly negative implications for deep space travel. Now emerging evidence from researchers engaged in clinical, translational and environmental radiation sciences have begun to fill these gaps and have uncovered some surprising similarities in the response of the brain to seemingly disparate exposure scenarios. This article highlights many of the commonalities between the vastly different irradiation paradigms that distinguish clinical treatments from occupational exposures in deep space.

Epidemiological studies have pointed at diabetes as a risk factor for Alzheimer's disease (AD) and this has been supported by several studies in animal models of both type 1 and type 2 diabetes. However, side-by-side comparison of the two types of diabetes is limited. We investigated the role of insulin deficiency and insulin resistance in the development of memory impairments and the effect of Exendin-4 (Ex4) treatment in a mouse model of AD. Three-4-month-old female wild type (WT) mice and mice overexpressing human tau and amyloid precursor protein (TAPP) were injected with streptozotocin (STZ) or fed a high-fat diet (HFD). A second study was performed in TAPP-STZ mice treated with Ex4, a long-lasting analog of GLP-1. Plasma and brain were collected at study termination for ELISA, Western blot, and immunohistochemistry analysis. Learning and memory deficits were impaired in TAPP transgenic mice compared with WT mice at the end of the study. Deficits were exaggerated by insulin deficiency in TAPP mice but 12 weeks of insulin resistance did not affect memory performances in either WT or TAPP mice. Levels of phosphorylated tau were increased in the brain of WT-STZ and TAPP-STZ mice but not in the brain of WT or TAPP mice on HFD. In the TAPP-STZ mice, treatment with Ex4 initiated after established cognitive deficits ameliorated learning, but not memory, impairments. This was accompanied by the reduction of amyloid β and phosphorylated tau expression. Theses studies support the role of Ex4 in AD, independently from its actions on diabetes.

Radiation-induced cognitive dysfunction (RICD) is a progressive and debilitating health issue facing patients following cranial radiotherapy to control central nervous system cancers. There has been some success treating RICD in rodents using human neural stem cell (hNSC) transplantation, but the procedure is invasive, requires immunosuppression, and could cause other complications such as teratoma formation. Extracellular vesicles (EV) are nanoscale membrane-bound structures that contain biological contents including mRNA, miRNA, proteins, and lipids that can be readily isolated from conditioned culture media. It has been previously shown that hNSC-derived EV resolves RICD following cranial irradiation using an immunocompromised rodent model. Here, we use immunocompetent wild-type mice to show that hNSC-derived EV treatment administered either intravenously via retro-orbital vein injection or via intracranial transplantation can ameliorate cognitive deficits following 9 Gy head-only irradiation. Cognitive function assessed on the novel place recognition, novel object recognition, and temporal order tasks was not only improved at early (5 weeks) but also at delayed (6 months) postirradiation times with just a single EV treatment. Improved behavioral outcomes were also associated with reduced neuroinflammation as measured by a reduction in activated microglia. To identify the mechanism of action, analysis of EV cargo implicated miRNA (miR-124) as a potential candidate in the mitigation of RICD. Furthermore, viral vector-mediated overexpression of miR-124 in the irradiated brain ameliorated RICD and reduced microglial activation. Our findings demonstrate for the first time that systemic administration of hNSC-derived EV abrogates RICD and neuroinflammation in cranially irradiated wild-type rodents through a mechanism involving miR-124. SIGNIFICANCE: Radiation-induced neurocognitive decrements in immunocompetent mice can be resolved by systemic delivery of hNSC-derived EVs involving a mechanism dependent on expression of miR-124.

ObjectiveDespite combined antiretroviral therapy, neuroinflammation may persist in persons living with HIV (PLWH) and contribute to cognitive impairment in this population. Positron emission tomography (PET) imaging targeting 18 kDa translocator protein (TSPO) has been used to localize neuroinflammation. We aimed to use TSPO-PET imaging to evaluate neuroinflammation in PLWH.DesignTwenty-four virologically suppressed PLWH on combined antiretroviral therapy and 13 HIV-negative (HIV-) controls completed TSPO-PET imaging using the radiotracer [C]PBR28. Because of tracer complexity and differing procedures used in previous studies, we employed an expansive methodological approach, using binding potential (BP) and standard uptake value ratio and multiple different reference regions to estimate [C]PBR28 binding.Methods[C]PBR28 binding was measured in 30 cortical and subcortical regions and compared between PLWH and HIV- controls. Pearson correlation evaluated the association between [C]PBR28 binding and cognition and clinical measures of HIV.ResultsAnalyses conducted using multiple reference regions and measures of tracer uptake revealed no significant differences between [C]PBR28 binding in PLWH compared with HIV- controls. In addition, [C]PBR28 binding in PLWH was not significantly associated with clinical measures of HIV or plasma biomarkers of inflammation. [C]PBR28 binding was not significantly elevated in cognitively impaired PLWH compared with unimpaired PLWH, but there were inverse relationships between cognitive performance (executive and global function) and [C]PBR28 binding in PLWH.ConclusionsOur results suggest that neuroinflammation may play a role in cognitive deficits, but overall neuroinflammatory levels as measured by TSPO-PET imaging in PLWH are not significantly different from those seen in HIV- controls.

Radiation-induced cognitive dysfunction (RICD) is a progressive and debilitating health issue facing patients following cranial radiotherapy to control central nervous system cancers. There has been some success treating RICD in rodents using human neural stem cell (hNSC) transplantation, but the procedure is invasive, requires immunosuppression, and could cause other complications such as teratoma formation. Extracellular vesicles (EV) are nanoscale membrane-bound structures that contain biological contents including mRNA, miRNA, proteins, and lipids that can be readily isolated from conditioned culture media. It has been previously shown that hNSC-derived EV resolves RICD following cranial irradiation using an immunocompromised rodent model. Here, we use immunocompetent wild-type mice to show that hNSC-derived EV treatment administered either intravenously via retro-orbital vein injection or via intracranial transplantation can ameliorate cognitive deficits following 9 Gy head-only irradiation. Cognitive function assessed on the novel place recognition, novel object recognition, and temporal order tasks was not only improved at early (5 weeks) but also at delayed (6 months) postirradiation times with just a single EV treatment. Improved behavioral outcomes were also associated with reduced neuroinflammation as measured by a reduction in activated microglia. To identify the mechanism of action, analysis of EV cargo implicated miRNA (miR-124) as a potential candidate in the mitigation of RICD. Furthermore, viral vector-mediated overexpression of miR-124 in the irradiated brain ameliorated RICD and reduced microglial activation. Our findings demonstrate for the first time that systemic administration of hNSC-derived EV abrogates RICD and neuroinflammation in cranially irradiated wild-type rodents through a mechanism involving miR-124. SIGNIFICANCE: Radiation-induced neurocognitive decrements in immunocompetent mice can be resolved by systemic delivery of hNSC-derived EVs involving a mechanism dependent on expression of miR-124.

ObjectiveTo describe clinical and pathologic characteristics of corticobasal degeneration (CBD) with cognitive predominant problems during the disease course.MethodsIn a series of autopsy-confirmed cases of CBD, we identified patients with cognitive rather than motor predominant features (CBD-Cog), including 5 patients thought to have Alzheimer disease (AD) and 10 patients thought to have behavioral variant frontotemporal dementia (FTD). We compared clinical and pathologic features of CBD-Cog with those from a series of 31 patients with corticobasal syndrome (CBD-CBS). For pathologic comparisons between CBD-Cog and CBD-CBS, we used semiquantitative scoring of neuronal and glial lesion types in multiple brain regions and quantitative assessments of tau burden from image analysis.ResultsFive of 15 patients with CBD-Cog never had significant motor problems during their disease course. The most common cognitive abnormalities in CBD-Cog were executive and visuospatial dysfunction. The frequency of language problems did not differ between CBD-Cog and CBD-CBS. Argyrophilic grain disease, which is a medial temporal tauopathy associated with mild cognitive impairment, was more frequent in CBD-Cog. Apathy was also more frequent in CBD-Cog. Tau pathology in CBD-Cog was greater in the temporal and less in perirolandic cortices than in CBD-CBS.ConclusionA subset of patients with CBD has a cognitive predominant syndrome than can be mistaken for AD or FTD. Our findings suggest that distribution of tau cortical pathology (greater in temporal and less in perirolandic cortices) may be the basis of this uncommon clinical variant of CBD.

OBJECTIVE: There is lack of Cameroonian adult neuropsychological (NP) norms, limited knowledge concerning HIV-associated neurocognitive disorders in Sub-Saharan Africa, and evidence of differential inflammation and disease progression based on viral subtypes. In this study, we developed demographically corrected norms and assessed HIV and viral genotypes effects on attention/working memory (WM), learning, and memory. METHOD: We administered two tests of attention/WM [Paced Auditory Serial Addition Test (PASAT)-50, Wechsler Memory Scale (WMS)-III Spatial Span] and two tests of learning and memory [Brief Visuospatial Memory Test-Revised (BVMT-R), Hopkins Verbal Learning Test-Revised (HVLT-R)] to 347 HIV+ and 395 seronegative adult Cameroonians. We assessed the effects of viral factors on neurocognitive performance. RESULTS: Compared to controls, people living with HIV (PLWH) had significantly lower T-scores on PASAT-50 and attention/WM summary scores, on HVLT-R total learning and learning summary scores, on HVLT-R delayed recall, BVMT-R delayed recall and memory summary scores. More PLWH had impairment in attention/WM, learning, and memory. Antiretroviral therapy (ART) and current immune status had no effect on T-scores. Compared to untreated cases with detectable viremia, untreated cases with undetectable viremia had significantly lower (worse) T-scores on BVMT-R total learning, BVMT-R delayed recall, and memory composite scores. Compared to PLWH infected with other subtypes (41.83%), those infected with HIV-1 CRF02_AG (58.17%) had higher (better) attention/WM T-scores. CONCLUSIONS: PLWH in Cameroon have impaired attention/WM, learning, and memory and those infected with CRF02_AG viruses showed reduced deficits in attention/WM. The first adult normative standards for assessing attention/WM, learning, and memory described, with equations for computing demographically adjusted T-scores, will facilitate future studies of diseases affecting cognitive function in Cameroonians.