Adult Human Brain Tissue Cultures to Study NeuroHIV.

HIV-associated neurocognitive disorders (HAND) persist under antiretroviral therapy as a complex pathology that has been difficult to study in cellular and animal models. Therefore, we generated an ex vivo human brain slice model of HIV-1 infection from surgically resected adult brain tissue. Brain slice cultures processed for flow cytometry showed >90% viability of dissociated cells within the first three weeks in vitro, with parallel detection of astrocyte, myeloid, and neuronal populations. Neurons within brain slices showed stable dendritic spine density and mature spine morphologies in the first weeks in culture, and they generated detectable activity in multi-electrode arrays. We infected cultured brain slices using patient-matched CD4+ T-cells or monocyte-derived macrophages (MDMs) that were exposed to a GFP-expressing R5-tropic HIV-1 in vitro. Infected slice cultures expressed viral RNA and developed a spreading infection up to 9 days post-infection, which were significantly decreased by antiretrovirals. We also detected infected myeloid cells and astrocytes within slices and observed minimal effect on cellular viability over time. Overall, this human-centered model offers a promising resource to study the cellular mechanisms contributing to HAND (including antiretroviral toxicity, substance use, and aging), infection of resident brain cells, and new neuroprotective therapeutics.

High-frequency assessment of mood, personality, and cognition in healthy younger, healthy older and adults with cognitive impairment.

Increased variability in cognitive scores, mood or personality traits can be indicative of underlying neurological disorders. Whether variability in cognition is due to changes in mood or personality is unknown. A total of 66 younger adults, 51 healthy older adults and 38 participants with cognitive impairment completed 21 daily sessions of attention, working memory, mood, and personality assessment. Group differences in mean performance and variability were examined using Bayesian mixed effects location scale models. Variability in attention decreased from younger to older adults and then increased again in cognitive impairment. Younger adults were more variable in agreeableness, openness and conscientiousness compared to older adults. The clinically impaired group differed from the healthy older adults in terms of variability on attention, openness, and conscientiousness. Healthy aging results in greater stability in personality traits over short intervals yet this stability is not redundant with increased stability in cognitive scores.

Examining the Most Important Risk Factors Predicting Persistent and Distressing Psychotic-like Experiences in Youth.

BACKGROUND: Persistence and distress distinguish more clinically significant psychotic-like experiences (PLEs) from those that are less likely to be associated with impairment and/or need for care. Identifying risk factors that differentiate clinically relevant PLEs early in development is important for improving our understanding of the etiopathogenesis of these experiences. Machine learning analyses examined the most important baseline factors distinguishing persistent distressing PLEs. METHODS: Using Adolescent Brain Cognitive Development Study PLEs data over three time points (ages 9-13), individuals with persistent distressing PLEs (n=303), transient distressing PLEs (n=374), and demographically matched low-level PLEs groups were created. Random forest classification models were trained to distinguish among persistent distressing vs. low-level PLEs, transient distressing vs. low-level PLEs, and persistent distressing vs. transient distressing PLEs. Models were trained using identified baseline predictors as input features (i.e., cognitive, neural [cortical thickness, resting state functional connectivity (RSFC)], developmental milestone delays, internalizing symptoms, adverse childhood events). RESULTS: The model distinguishing persistent distressing vs. low-level PLEs showed the highest accuracy (test sample accuracy=69.33%; 95% CI:61.29%-76.59%). The most important predictors included internalizing symptoms, adverse childhood events, and cognitive functioning. Models distinguishing persistent vs. transient distressing PLEs generally performed poorly. CONCLUSIONS: Model performance metrics indicated that while most important factors overlapped across models (e.g., internalizing symptoms), adverse childhood events were especially important for predicting persistent distressing PLEs. Machine learning analyses proved useful for distinguishing the most clinically relevant group from the least clinically relevant group but showed limited ability to distinguish among clinically relevant groups that differed in PLE persistence.

Longitudinal within-person variability around personality trajectories.

Decades of research have identified average patterns of normative personality development across the lifespan. However, it is unclear how well these correspond to trajectories of individual development. Past work beyond general personality development might suggest these average patterns are oversimplifications, necessitating novel examinations of how personality develops and consideration of new individual difference metrics. This study uses five longitudinal data sets from Germany, Australia, the Netherlands, and the United States (N = 128,345; Mage = 45.42; 53% female) to examine personality development using mixed-effects location scale models. These models quantify individual differences in within-person residual variability, or sigma, around trajectories-thereby testing if models that assume sigma is homogeneous, unsystematic noise are appropriate. We investigate if there are individual differences in longitudinal within-person variability for Big Five trajectories, if there are variables associated with this heterogeneity, and if person-level sigma values can uniquely predict an outcome. Results indicated that, across all models, there was meaningful heterogeneity in sigma-the magnitude of which was comparable to and often even greater than that of intercepts and slopes. Individual differences in sigma were further associated with covariates central to personality development and had robust predictive utility for health status, an outcome with long-established personality associations. Collectively, these findings underscore the presence, degree, validity, and potential utility of heterogeneity in longitudinal within-person variability and indicate the typical linear model does not adequately depict individual development. We suggest it should become the default to consider this individual difference metric in personality development research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Replication and reliability of Parkinson's disease clinical subtypes.

BACKGROUND: We recently identified three distinct Parkinson's disease subtypes: "motor only" (predominant motor deficits with intact cognition and psychiatric function); "psychiatric & motor" (prominent psychiatric symptoms and moderate motor deficits); "cognitive & motor" (cognitive and motor deficits). OBJECTIVE: We used an independent cohort to replicate and assess reliability of these Parkinson's disease subtypes. METHODS: We tested our original subtype classification with an independent cohort (N = 100) of Parkinson's disease participants without dementia and the same comprehensive evaluations assessing motor, cognitive, and psychiatric function. Next, we combined the original (N = 162) and replication (N = 100) datasets to test the classification model with the full combined dataset (N = 262). We also generated 10 random split-half samples of the combined dataset to establish the reliability of the subtype classifications. Latent class analyses were applied to the replication, combined, and split-half samples to determine subtype classification. RESULTS: First, LCA supported the three-class solution - Motor Only, Psychiatric & Motor, and Cognitive & Motor- in the replication sample. Next, using the larger, combined sample, LCA again supported the three subtype groups, with the emergence of a potential fourth group defined by more severe motor deficits. Finally, split-half analyses showed that the three-class model also had the best fit in 13/20 (65%) split-half samples; two-class and four-class solutions provided the best model fit in five (25%) and two (10%) split-half replications, respectively. CONCLUSIONS: These results support the reproducibility and reliability of the Parkinson's disease behavioral subtypes of motor only, psychiatric & motor, and cognitive & motor groups.

Alcohol milestones and internalizing, externalizing, and executive function: longitudinal and polygenic score associations.

BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.

Effects of Antiretroviral Treatment on Central and Peripheral Immune Response in Mice with EcoHIV Infection.

HIV infection is an ongoing global health issue, despite increased access to antiretroviral therapy (ART). People living with HIV (PLWH) who are virally suppressed through ART still experience negative health outcomes, including neurocognitive impairment. It is increasingly evident that ART may act independently or in combination with HIV infection to alter the immune state, though this is difficult to disentangle in the clinical population. Thus, these experiments used multiplexed chemokine/cytokine arrays to assess peripheral (plasma) and brain (nucleus accumbens; NAc) expression of immune targets in the presence and absence of ART treatment in the EcoHIV mouse model. The findings identify the effects of EcoHIV infection and of treatment with bictegravir (B), emtricitabine (F), and tenofovir alafenamide (TAF) on the expression of numerous immune targets. In the NAc, this included EcoHIV-induced increases in IL-1α and IL-13 expression and B/F/TAF-induced reductions in KC/CXCL1. In the periphery, EcoHIV suppressed IL-6 and LIF expression, while B/F/TAF reduced IL-12p40 expression. In the absence of ART, IBA-1 expression was negatively correlated with CX3CL1 expression in the NAc of EcoHIV-infected mice. These findings identify distinct effects of ART and EcoHIV infection on peripheral and central immune factors and emphasize the need to consider ART effects on neural and immune outcomes.

Actin-nucleation promoting factor N-WASP influences alpha-synuclein condensates and pathology.

Abnormal intraneuronal accumulation of soluble and insoluble α-synuclein (α-Syn) is one of the main pathological hallmarks of synucleinopathies, such as Parkinson's disease (PD). It has been well documented that the reversible liquid-liquid phase separation of α-Syn can modulate synaptic vesicle condensates at the presynaptic terminals. However, α-Syn can also form liquid-like droplets that may convert into amyloid-enriched hydrogels or fibrillar polymorphs under stressful conditions. To advance our understanding on the mechanisms underlying α-Syn phase transition, we employed a series of unbiased proteomic analyses and found that actin and actin regulators are part of the α-Syn interactome. We focused on Neural Wiskott-Aldrich syndrome protein (N-WASP) because of its association with a rare early-onset familial form of PD. In cultured cells, we demonstrate that N-WASP undergoes phase separation and can be recruited to synapsin 1 liquid-like droplets, whereas it is excluded from α-Syn/synapsin 1 condensates. Consistently, we provide evidence that wsp-1/WASL loss of function alters the number and dynamics of α-Syn inclusions in the nematode Caenorhabditis elegans. Together, our findings indicate that N-WASP expression may create permissive conditions that promote α-Syn condensates and their potentially deleterious conversion into toxic species.

Effects of antiretroviral treatment on central and peripheral immune response in mice with EcoHIV infection.

HIV infection is an ongoing global health issue despite increased access to antiretroviral therapy (ART). People living with HIV (PLWH) who are virally suppressed through ART still experience negative health outcomes, including neurocognitive impairment. It is increasingly evident that ART may act independently or in combination with HIV infection to alter immune state, though this is difficult to disentangle in the clinical population. Thus, these experiments used multiplexed chemokine/cytokine arrays to assess peripheral (plasma) and brain (nucleus accumbens; NAc) expression of immune targets in the presence and absence of ART treatment in the EcoHIV mouse model. The findings identify effects of EcoHIV infection and of treatment with bictegravir (B), emtricitabine (F) and tenofovir alafenamide (TAF) on expression of numerous immune targets. In the NAc, this included EcoHIV-induced increases in IL-1α and IL-13 expression and B/F/TAF-induced reductions in KC/CXCL1. In the periphery, EcoHIV suppressed IL-6 and LIF expression, while B/F/TAF reduced IL-12p40 expression. In absence of ART, IBA-1 expression was negatively correlated with CX3CL1 expression in the NAc of EcoHIV-infected mice. These findings identify distinct effects of ART and EcoHIV infection on peripheral and central immune factors and emphasize the need to consider ART effects on neural and immune outcomes.

Worldwide divergence of values.

Social scientists have long debated the nature of cultural change in a modernizing and globalizing world. Some scholars predicted that national cultures would converge by adopting social values typical of Western democracies. Others predicted that cultural differences in values would persist or even increase over time. We test these competing predictions by analyzing survey data from 1981 to 2022 (n = 406,185) from 76 national cultures. We find evidence of global value divergence. Values emphasizing tolerance and self-expression have diverged most sharply, especially between high-income Western countries and the rest of the world. We also find that countries with similar per-capita GDP levels have held similar values over the last 40 years. Over time, however, geographic proximity has emerged as an increasingly strong correlate of value similarity, indicating that values have diverged globally but converged regionally.

EcoHIV Infection Modulates the Effects of Cocaine Exposure Pattern and Abstinence on Cocaine Seeking and Neuroimmune Protein Expression in Male Mice.

Cocaine use disorders (CUDs) and human immunodeficiency virus (HIV) remain persistent public health dilemmas throughout the world. One major hurdle for treating CUD is the increase in cocaine craving and seeking behavior that occurs over a protracted period of abstinence, an effect known as the incubation of craving. Little is known about how HIV may modulate this process. Thus, we sought to examine the impact of chronic HIV infection on the incubation of cocaine craving and associated changes in the central and peripheral immune systems. Here, mice were inoculated with EcoHIV, which is a chimeric HIV-1 construct that produces chronic HIV infection in mice. EcoHIV- and sham-infected mice were conditioned with cocaine daily or intermittently in a conditioned place preference (CPP) paradigm, followed by 1 or 21 days of forced abstinence prior to assessing preference for the cocaine-paired chamber. Under both conditioning regimens, sham mice exhibited incubation of cocaine CPP after 21 days of abstinence. EcoHIV-infected mice conditioned daily with cocaine showed enhanced cocaine seeking at both abstinence timepoints, whereas infected mice conditioned intermittently showed a reversal of the incubation effect, with higher cocaine seeking after 1 day of abstinence compared to 21 days. Analysis of corticolimbic CX3CL1-CX3CR1 and glutamate receptor expression revealed alterations in medial prefrontal cortex (mPFC) CX3CL1 and nucleus accumbens (NAc) GluN2A receptors that correlated with cocaine seeking following daily cocaine exposure. Moreover, examination of peripheral immune markers showed that the effect of abstinence and EcoHIV infection on these measures depended on the cocaine exposure regimen. Altogether, these results highlight the importance of cocaine abstinence and exposure pattern as critical variables that modulate HIV-associated neuroimmune outcomes and relapse vulnerability.

Augmented Reality-based Contextual Guidance through Surgical Tool Tracking in Neurosurgery.

External ventricular drain (EVD) is a common, yet challenging neurosurgical procedure of placing a catheter into the brain ventricular system that requires prolonged training for surgeons to improve the catheter placement accuracy. In this paper, we introduce NeuroLens, an Augmented Reality (AR) system that provides neurosurgeons with guidance that aides them in completing an EVD catheter placement. NeuroLens builds on prior work in AR-assisted EVD to present a registered hologram of a patient's ventricles to the surgeons, and uniquely incorporates guidance on the EVD catheter's trajectory, angle of insertion, and distance to the target. The guidance is enabled by tracking the EVD catheter. We evaluate NeuroLens via a study with 33 medical students and 9 neurosurgeons, in which we analyzed participants' EVD catheter insertion accuracy and completion time, eye gaze patterns, and qualitative responses. Our study, in which NeuroLens was used to aid students and surgeons in inserting an EVD catheter into a realistic phantom model of a human head, demonstrated the potential of NeuroLens as a tool that will aid and educate novice neurosurgeons. On average, the use of NeuroLens improved the EVD placement accuracy of the year 1 students by 39.4%, of the year 2 -4 students by 45.7%, and of the neurosurgeons by 16.7%. Furthermore, students who focused more on NeuroLens-provided contextual guidance achieved better results, and novice surgeons improved more than the expert surgeons with NeuroLens's assistance.

Beyond medical knowledge: a didactic curriculum focused on knowledge, wisdom, and application.

OBJECTIVE: The aim of this study was to determine whether a flipped classroom curriculum coupled with case-based learning would improve residents' perceptions of the learning environment, improve education outcomes, and increase faculty engagement. Research suggests that active learning yields better educational results compared with passive learning. However, faculty are more comfortable providing lectures that require only passive participation from learners. METHODS: A council was created to identify issues with the current format of the resident didactic curriculum and to redesign the neurosurgical curriculum and conference per Accreditation Council for Graduate Medical Education (ACGME) requirements. Trends from the authors' 2022 and 2023 ACGME Resident Surveys were tracked to assess changes in the organizational learning environment. Surveys of resident participants were conducted to assess learner satisfaction. RESULTS: Between July 2022 and June 2023, the authors gathered 127 survey responses from neurosurgical residents. The majority of respondents, comprising 50.4% (n = 64), were postgraduate year (PGY)-4 and PGY-5 residents. Sixty-six percent (n = 84) reported that the new format ranked within the top third of sessions they had experienced. On analysis of trends from these 2022 and 2023 ACGME Resident Surveys, the authors observed a positive trajectory in various key components. Notably, there was an upward trend in achieving an appropriate balance between service and education, in the availability of protected time for structured learning, faculty engagement and interest in education, and amount of clinical and didactic teaching. CONCLUSIONS: The results of this study suggest that this innovative educational model can have a positive impact on residents' perceptions of the learning environment, their educational outcomes, and faculty engagement. As residency education continues to evolve, the flipped classroom model offers an exciting avenue for enhancing the quality of residency education.

Assessment of the Surgical Oncology Case Volume Within the Public Sector in Tanzania.

PURPOSE: Surgery provides vital services to diagnose, treat, and palliate patients suffering from malignancies. However, despite its importance, there is little information on the delivery of surgical oncology services in Tanzania. METHODS: Operative logbooks were reviewed at all national referral hospitals that offer surgery, all zonal referral hospitals in Mainland Tanganyika and Zanzibar, and a convenience sampling of regional referral hospitals in 2022. Cancer cases were identified by postoperative diagnosis and deidentified data were abstracted for each cancer surgery. The proportion of the procedures conducted for patients with cancer and the total number of cancer surgeries done within the public sector were calculated and compared with a previously published estimate of the surgical oncology need for the country. RESULTS: In total, 69,195 operations were reviewed at 10 hospitals, including two national referral hospitals, five zonal referral hospitals, and three regional referral hospitals. Of the cases reviewed, 4,248 (6.1%) were for the treatment of cancer. We estimate that 4,938 cancer surgeries occurred in the public sector in Tanzania accounting for operations conducted at hospitals not included in our study. Prostate, breast, head and neck, esophageal, and bladder cancers were the five most common diagnoses. Although 387 (83%) of all breast cancer procedures were done with curative intent, 506 (87%) of patients with prostate and 273 (81%) of patients with esophageal cancer underwent palliative surgery. CONCLUSION: In this comprehensive assessment of surgical oncology service delivery in Tanzania, we identified 4,248 cancer surgeries and estimate that 4,938 likely occurred in 2022. This represents only 25% of the estimated 19,726 cancer surgeries that are annually needed in Tanzania. These results highlight the need to identify strategies for increasing surgical oncology capacity in the country.

Antecedents of mind wandering states in healthy aging and mild cognitive impairment.

OBJECTIVE: Mind wandering refers to periods of internally directed attention and comprises up to 30% or more of our waking thoughts. Frequent mind wandering can be detrimental to ongoing task performance. We aim to determine whether rates of mind wandering change in healthy aging and mild cognitive impairment and how differences in mind wandering contribute to differences in attention and working memory. METHOD: We administered a standard behavioral task, the Sustained Attention to Response Test, to measure mind wandering in healthy younger adults (N = 66), healthy older adults (N = 51), and adults with cognitive impairment (N = 38), that was completed daily for 3 weeks. The N-back test was also administered at a reduced frequency as a measure of working memory performance. RESULTS: Generally speaking, averaged across 3 weeks of testing, relative to healthy older adults, mind wandering was higher in younger adults and in cognitive impairment, although the specific patterns varied across mind wandering states. Multiple states of mind wandering also predicted working memory performance; however, reaction time variability tended to be the best predictor based on model comparisons. Each state was also modestly associated with different dispositional factors including mood and Agreeableness. CONCLUSIONS: Patterns of mind wandering change across healthy aging and cognitive impairment and are related to individual differences in multiple dispositional factors and also working memory performance. These results suggest that different states of mind wandering should be measured and accounted for when modeling cognitive change in healthy and pathological aging. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Automated segmentation of ablated lesions using deep convolutional neural networks: A basis for response assessment following laser interstitial thermal therapy.

BACKGROUND: Laser interstitial thermal therapy (LITT) of intracranial tumors or radiation necrosis enables tissue diagnosis, cytoreduction, and rapid return to systemic therapies. Ablated tissue remains in situ, resulting in characteristic post-LITT edema associated with transient clinical worsening and complicating post-LITT response assessment. METHODS: All patients receiving LITT at a single center for tumors or radiation necrosis from 2015 to 2023 with ≥9 months of MRI follow-up were included. An nnU-Net segmentation model was trained to automatically segment contrast-enhancing lesion volume (CeLV) of LITT-treated lesions on T1-weighted images. Response assessment was performed using volumetric measurements. RESULTS: Three hundred and eighty four unique MRI exams of 61 LITT-treated lesions and 6 control cases of medically managed radiation necrosis were analyzed. Automated segmentation was accurate in 367/384 (95.6%) images. CeLV increased to a median of 68.3% (IQR 35.1-109.2%) from baseline at 1-3 months from LITT (P = 0.0012) and returned to baseline thereafter. Overall survival (OS) for LITT-treated patients was 39.1 (9.2-93.4) months. Lesion expansion above 40% from volumetric nadir or baseline was considered volumetric progression. Twenty-one of 56 (37.5%) patients experienced progression for a volumetric progression-free survival of 21.4 (6.0-93.4) months. Patients with volumetric progression had worse OS (17.3 vs 62.1 months, P = 0.0015). CONCLUSIONS: Post-LITT CeLV expansion is quantifiable and resolves within 6 months of LITT. Development of response assessment criteria for LITT-treated lesions is feasible and should be considered for clinical trials. Automated lesion segmentation could speed the adoption of volumetric response criteria in clinical practice.

Accuracy of routine external ventricular drain placement following a mixed reality-guided twist-drill craniostomy.

OBJECTIVE: The traditional freehand placement of an external ventricular drain (EVD) relies on empirical craniometric landmarks to guide the craniostomy and subsequent passage of the EVD catheter. The diameter and trajectory of the craniostomy physically limit the possible trajectories that can be achieved during the passage of the catheter. In this study, the authors implemented a mixed reality-guided craniostomy procedure to evaluate the benefit of an optimally drilled craniostomy to the accurate placement of the catheter. METHODS: Optical marker-based tracking using an OptiTrack system was used to register the brain ventricular hologram and drilling guidance for craniostomy using a HoloLens 2 mixed reality headset. A patient-specific 3D-printed skull phantom embedded with intracranial camera sensors was developed to automatically calculate the EVD accuracy for evaluation. User trials consisted of one blind and one mixed reality-assisted craniostomy followed by a routine, unguided EVD catheter placement for each of two different drill bit sizes. RESULTS: A total of 49 participants were included in the study (mean age 23.4 years, 59.2% female). The mean distance from the catheter target improved from 18.6 ± 12.5 mm to 12.7 ± 11.3 mm (p = 0.0008) using mixed reality guidance for trials with a large drill bit and from 19.3 ± 12.7 mm to 10.1 ± 8.4 mm with a small drill bit (p < 0.0001). Accuracy using mixed reality was improved using a smaller diameter drill bit compared with a larger bit (p = 0.039). Overall, the majority of the participants were positive about the helpfulness of mixed reality guidance and the overall mixed reality experience. CONCLUSIONS: Appropriate indications and use cases for the application of mixed reality guidance to neurosurgical procedures remain an area of active inquiry. While prior studies have demonstrated the benefit of mixed reality-guided catheter placement using predrilled craniostomies, the authors demonstrate that real-time quantitative and visual feedback of a mixed reality-guided craniostomy procedure can independently improve procedural accuracy and represents an important tool for trainee education and eventual clinical implementation.

Relationships between hourly cognitive variability and risk of Alzheimer's disease revealed with mixed-effects location scale models.

OBJECTIVE: Observational studies on aging and Alzheimer's disease (AD) typically focus on mean-level changes in cognitive performance over relatively long periods of time (years or decades). Additionally, some studies have examined how trial-level fluctuations in speeded reaction time are related to both age and AD. The aim of the current project was to describe patterns of variability across repeated days of testing as a function of AD risk in cognitively normal older adults. METHOD: The current project examined the performance of the Ambulatory Research in Cognition (ARC) smartphone application, a high-frequency remote cognitive assessment paradigm, that administers brief tests of episodic memory, spatial working memory, and processing speed. Bayesian mixed-effects location scale models were used to explore differences in mean cognitive performance and intraindividual variability across 28 repeated sessions over a 1-week assessment interval as function of age and genetic risk of AD, specifically the presence of at least one apolipoprotein E (APOE) ε4 allele. RESULTS: Mean performance on processing speed and working memory was negatively related to age and APOE status. More importantly, e4 carriers exhibited increased session-level variability on a test of processing speed compared to noncarriers. Age and education did not consistently relate to cognitive variability, contrary to expectations. CONCLUSION: Preclinical AD risk, defined as possessing at least one APOE ε4 allele, is not only associated with mean-level performance differences, but also with increases in variability across repeated testing occasions particularly on a test of processing speed. Thus, cognitive variability may serve as an additional and important indicator of AD risk. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Integrated analysis of transcriptomic and proteomic alterations in mouse models of ALS/FTD identify early metabolic adaptions with similarities to mitochondrial dysfunction disorders.

OBJECTIVE: Sporadic and familial amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that results in loss of motor neurons and, in some patients, associates with frontotemporal dementia (FTD). Apart from the accumulation of proteinaceous deposits, emerging literature indicates that aberrant mitochondrial bioenergetics may contribute to the onset and progression of ALS/FTD. Here we sought to investigate the pathophysiological signatures of mitochondrial dysfunction associated with ALS/FTD. METHODS: By means of label-free mass spectrometry (MS) and mRNA sequencing (mRNA-seq), we report pre-symptomatic changes in the cortices of TDP-43 and FUS mutant mouse models. Using tissues from transgenic mouse models of mitochondrial diseases as a reference, we performed comparative analyses and extracted unique and common mitochondrial signatures that revealed neuroprotective compensatory mechanisms in response to early damage. RESULTS: In this regard, upregulation of both Acyl-CoA Synthetase Long-Chain Family Member 3 (ACSL3) and mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) were the most representative change in pre-symptomatic ALS/FTD tissues, suggesting that fatty acid beta-oxidation and mitochondrial protein translation are mechanisms of adaptation in response to ALS/FTD pathology. CONCLUSIONS: Together, our unbiased integrative analyses unveil novel molecular components that may influence mitochondrial homeostasis in the earliest phase of ALS.

Behavioral and psychiatric correlates of brain responses to social feedback.

Maladaptive responses to peer acceptance and rejection arise in numerous psychiatric disorders in adolescence; yet, homogeneity and heterogeneity across disorders suggest common and unique mechanisms of impaired social function. We tested the hypothesis that social feedback is processed similarly to other forms of feedback (e.g., monetary) by examining the correspondence between the brain's response to social acceptance and rejection and behavioral performance on a separate reward and loss task. We also examined the relationship between these brain responses and depression and social anxiety severity. The sample consisted of one hundred and thirteen 16-21-year olds who received virtual peer acceptance/rejection feedback in an event-related potential (ERP) task. We used temporospatial principal component analysis and identified a component consistent with the reward positivity (RewP) or feedback negativity (FN). RewP to social acceptance was not significantly related to reward bias or the FN to social rejection related to loss avoidance. The relationship between RewP and depression severity, while nonsignificant, was of a similar magnitude to prior studies. Exploratory analyses yielded a significant relationship between lower socioeconomic status (SES) and blunted RewP and between lower SES and heightened loss avoidance and blunted reward bias. These findings build on prior work to improve our understanding of the function of the brain's response to social feedback, while also suggesting a pathway for further study, whereby poverty leads to depression via social and reward learning mechanisms.