Neuropsychological Test Performance Research Articles

Diffusion Tensor Imaging for Interpreting Fractional Anisotropy and Mean Diffusivity in Normal-appearing White Matter of Patients with HIV-associated Neurocognitive Disorders: A Case-control Study

Introduction: {Human Immunodeficiency Virus (HIV)-associated Neurocognitive Disorder (HAND)} affects the everyday functioning of patients. It is usually difficult to diagnose HAND in the outpatient setting as detailed neuropsychological performance testing, such as the International HIV Dementia Scale (IHDS), is required. Neuroimaging techniques hold great promise in the early diagnosis and management of HAND, but there is a paucity of studies on the evaluation of HAND using Diffusion Tensor Imaging (DTI) in the Indian population. Aim: To investigate DTI and interpret Fractional Anisotropy (FA) and Mean Diffusivity (MD) values in the White Matter (WM) of patients with HAND and compare them with age and sex- matched controls. Materials and Methods: A case-control study was conducted at the Department of Radiodiagnosis, ABVIMS and Dr. RML Hospital, New Delhi, India, from January 2021 to May 2022. Thirty subjects (15 cases and 15 controls) were included. HIV-positive patients underwent the IHDS to assess cognitive impairment. Magnetic Resonance Imaging (MRI) examination was performed at three tesla using conventional sequences, and DTI was applied. Maps of FA and MD values were generated. Mean FA and MD values of normal-appearing white matter tracts between cases and controls were compared using a t-test. Spearman's correlation test was applied to assess the correlation between IHDS scores and DTI parameters. Results: The majority of cases in the study were in the age group of 31-40 years, and the mean age of cases was 41.27±11.16 years. The present study revealed significantly lower FA values compared to controls in bilateral Frontal WM, Parieto-occipital WM, genu of the Corpus Callosum (CC), right hippocampal WM, and right corona radiata. The mean MD of bilateral Frontal WM, Parieto-occipital WM, corona radiata, and Hippocampal WM was significantly increased in cases compared to healthy controls. A significant association was found between the IHDS score and FA values of the genu of the CC (rho= 0.7), right corona radiata (rho= 0.7), right Hippocampal WM (rho= 0.9), and MD of the left Parieto-occipital WM (rho= -0.6), and left hippocampal WM (rho= -0.5). Conclusion: Diffusion tensor MR imaging can detect abnormalities that are missed by routine MR imaging. DTI provides a valuable marker to monitor HIV-associated Central Nervous System (CNS) injury, which can lead to neurocognitive impairment.

A comparison of cognitive performances based on differing rates of DNA methylation GrimAge acceleration among older men and women

Cognitive heterogeneity increases with age rendering sex differences difficult to identify. Given established sex differences in biological aging, we examined whether comparisons of men and women on neuropsychological test performances differed as a function of age rate. Data were obtained from 1921 adults enrolled in the 2016 wave of the Health and Retirement Study. The residual from regressing the DNA methylation GrimAge clock on chronological age was used as the measure of aging rate. Slow and fast age rates were predefined as 1 standard deviation below or above the sex-specific mean rates, respectively. ANCOVAs were used to test group differences in test performances. Pairwise comparisons revealed that slow aging men outperformed fast aging women (and vice versa) on measures of executive function/speed, visual memory and semantic fluency; however, when groups were matched by aging rates, no significant differences remained. In contrast, women, regardless of their aging rates, education or depressive symptoms maintained their advantage on verbal learning and memory. Implications for research on sex differences in cognitive aging are discussed.

Neuropsychological Assessment of Community-Dwelling Older Adults in Almaty, Kazakhstan.

Cognitive impairment in older adults is a major public concern for Kazakhstan's aging population. We aimed to (1) administer a neuropsychological test battery (NTB) in domains relevant to aging-associated cognitive impairment in a sample of adults aged 60+ without dementia in Almaty, Kazakhstan; (2) investigate the associations between demographic factors and test performance; and (3) provide information on the distribution of NTB scores as preliminary local normative data relevant for this population. A cross-sectional evaluation of 276 participants aged 60+ in Almaty, Kazakhstan, was conducted using cognitive instruments including tests of memory, attention, language, executive functions, visuospatial abilities, and processing speed. Multiple linear regression analyses were used to examine the association of demographic factors with neuropsychological test performance. The results from the regression analysis showed that those who are younger, have more years of education, are women, and are of Russian ethnicity had significantly better performance. The current study illustrated (1) the feasibility of administering the NTB to older adults in the general population in Kazakhstan; (2) the preliminary local normative neuropsychological measures; and (3) their independent associations with age, education, gender, and ethnicity. The findings are a platform for future research on dementia and cognitive impairment in older adults in Kazakhstan.

Meta‐analysis of age‐related cognitive decline reveals a novel locus for the attention domain and implicates a COVID‐19 related gene for global cognitive function

AbstractBackgroundCognition is a highly complex polygenic trait. A limited number of studies have explored the genetic basis of cognitive decline in aging populations using cognitive domain specific measures.MethodTo identify genetic markers for cognitive decline, we conducted a genome‐wide association meta‐analysis and gene‐based tests on five different cognitive domains (attention, language, executive function, visuospatial abilities, memory) and global cognition on 3,068 older individuals (≥65 years) of European ancestry derived from three prospective cohorts: Gingko Evaluation Memory Study (GEMS), Monongahela‐Youghiogheny Healthy Aging Team (MYHAT) and Monongahela Valley Independent Elders Survey (MoVIES). All subjects completed a comprehensive neuropsychological battery of tests covering the examined domains. A linear mixed effects model was used to estimate the longitudinal decline in cognitive scores after adjusting for sex, baseline age and education. Global cognitive decline was defined as a decline in average performance in neuropsychological tests across the five domains.ResultGenome‐wide significant association of APOE*4 was observed with decline in the memory domain (p= 8.93E‐09) and global cognitive function (p= 2.69E‐08).We identified a novel locus for decline in the attention domain on chromosome 9 in an intergenic region between RASEF/FRMD3 (p = 3.17E‐08). Gene‐based analysis identified TMPRSS11D as the top gene for decline in global cognition (Bonferroni corrected p= 2.48E‐06). TMPRSS11D plays a role in host‐defense system and recent studies have shown that it activates spike protein of SARS‐CoV‐2 and facilitates viral entry to cell (Viruses 2021;13:384; J Biol Chem 2021; 296:100135).ConclusionWe have identified a novel locus for longitudinal decline in the attention domain, replicated the association of APOE*4 with the global and memory domains, and potentially implicated the role of TMPRS11D in cognitive decline through gene‐based analysis. The association of TMPRSS11D with cognitive decline might help to explain cognitive impairment observed in some patients after COVID‐19 infection (Br J Anaesth 2021; 25:e54; JAMA Netw Open 2021; 4(10):e2130645 ). While functional studies might help to understand the underlying molecular mechanism of the associated loci, cognitive decline studies with larger samples are essential to establish these findings.

One-year predictions of delayed reward discounting in the adolescent brain cognitive development study.

Delayed reward discounting (DRD) refers to the extent to which an individual devalues a reward based on a temporal delay and is known to be elevated in individuals with substance use disorders and many mental illnesses. DRD has been linked previously with both features of brain structure and function, as well as various behavioral, psychological, and life-history factors. However, there has been little work on the neurobiological and behavioral antecedents of DRD in childhood. This is an important question, as understanding the antecedents of DRD can provide signs of mechanisms in the development of psychopathology. The present study used baseline data from the Adolescent Brain Cognitive Development Study (N = 4,042) to build machine learning models to predict DRD at the first follow-up visit, 1 year later. In separate machine learning models, we tested elastic net regression, random forest regression, light gradient boosting regression, and support vector regression. In five-fold cross-validation on the training set, models using an array of questionnaire/task variables were able to predict DRD, with these findings generalizing to a held-out (i.e., "lockbox") test set of 20% of the sample. Key predictive variables were neuropsychological test performance at baseline, socioeconomic status, screen media activity, psychopathology, parenting, and personality. However, models using magnetic resonance imaging (MRI)-derived brain variables did not reliably predict DRD in either the cross-validation or held-out test set. These results suggest a combination of questionnaire/task variables as antecedents of excessive DRD in late childhood, which may presage the development of problematic substance use in adolescence. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Preliminary results of computer‐based multimodal training in Alzheimer’s disease over six months – the multimodAAL study

AbstractBackgroundAlzheimer’s disease (AD) is associated with cognitive decline and limited therapeutic interventions to maintain cognitive function. The present study investigates the effectiveness of a computer‐based cognitive and physical training (CCPT) on a tablet device in patients with AD and aims to present preliminary results of the multimodAAL project (project number: FFG 875345).MethodTwenty‐three patients were randomly assigned to intervention and control group (randomized controlled trial). The intervention group received weekly multimodal CCPT with a trainer and were encouraged to train as often as possible alone or with a caregiver over six months. At the time of data analysis 14 subjects had a 6‐month follow‐up with comprehensive pre and post neuropsychological assessment including tests on global cognitive functions (Mini Mental Status Examination, MMSE), memory, working memory, executive function and verbal fluency. Repeated measures ANOVA comparing neuropsychological test performance over time was calculated to determine the between‐group difference. Analyses were corrected for disease duration. Paired t‐test was used for post‐test analyses.ResultIn this preliminary analysis six subjects from the intervention group (4 female, age: x̅ = 75.4, disease duration: x̅ = 30.3 months) and eight subjects from the control group (7 female, age: x̅ = 74.8, disease duration: x̅ = 30.75 months) were included. The results showed a significant interaction effect considering global cognition and group with a high effect size (MMSE: F(1,11) = 7.503, p = 0.019, ηp 2 = 0.405). Post‐tests revealed a maintenance of performance in the intervention group (+0.68 points in the MMSE over 6 months, t(5) = ‐1.2, p = 0.300) and a significant decrease in the performance of the control group (‐1.34 points in the MMSE over 6 months; t(7) = 2.5, p = 0.041). The other cognitive domains did not show significant results.ConclusionThese preliminary results indicate that CCPT over six months has the potential to maintain global cognitive functions in Alzheimer patients.

Feasibility and reliability of telephone‐based cognitive assessment in middle‐aged and older adults in the Wisconsin Alzheimer’s Disease Research Center

AbstractBackgroundUse of telephone‐based cognitive assessments became more widespread during the COVID‐19 pandemic. The National Alzheimer’s Coordinating Center (NACC) developed the telephone‐based cognitive battery (T‐Cog) to ensure continued data collection and participant retention. The objective of this study was to (1) assess the feasibility and reliability of T‐Cog data collected during the pandemic, (2) evaluate these data in the context of prior in‐person data and (3) inform future use of remote data collection.MethodThe Wisconsin ADRC Clinical Core staff administered T‐Cog batteries to participants with normal cognition, mild cognitive impairment (MCI), or dementia (n = 380, mean age = 68.7±8.9, 66.1% female, 78.4% white, mean education = 16.2±2.48) (Table 1). Examiners rated the validity of the testing session and noted reasons for an invalid session. Reliability was assessed by comparing individual neuropsychological test performances from the T‐Cog to the most recent in‐person evaluation using intraclass correlation coefficients (ICC). Chi‐square was used to test if research diagnoses (normal cognition, MCI, dementia) varied by modality (T‐Cog, in‐person).ResultsMost T‐Cog sessions were rated as valid by examiners (87.8%). The most common reasons for questionable or not valid session included hearing impairments, distractions, and interruptions (Figure 1). Measures of verbal fluency (Animal Naming (ICC = 0.69), F+L Fluency (ICC = 0.73)), list‐learning and memory (RAVLT Trials 1–5 (ICC = 0.75), RAVLT Long Delay Recall (ICC = 0.70), RAVLT Recognition (ICC = 0.71)), and story memory (Craft Story‐Immediate (ICC = 0.65), Craft Story‐Delayed (ICC = 0.73)) showed moderate to excellent reliability and were significant (p<0.01), suggesting good agreement between T‐Cog and in‐person assessments (Table 2). Measures of attention (Digit Span Forward (ICC = 0.66), Digit Span Backward (ICC = 0.15)) varied from moderately reliable to not reliable, respectively. Lastly, research diagnoses did not differ by testing modality.ConclusionThese results suggest T‐Cog assessments are feasible for participants who cannot complete in‐person visits, given adequate hearing and limited distractions and interruptions to ensure test validity. Preliminary comparisons of T‐Cog vs in‐person performances suggest good reliability for verbal fluency, story memory, and list‐learning measures. Although remote assessments can expand access and diversify the population involved in AD research, identifying assessments that are both feasible and reliable across varied administrations will be essential to track longitudinal change in cognitive status.

Cognitive functions and symptoms predicting later use of psychiatric services following mild traumatic brain injury in school-age

ABSTRACT Objective To investigate whether neuropsychological test performance or presence of some specific injury symptoms at 1–3 months following pediatric mild traumatic brain injury (mTBI) can help to identify the children at risk for developing post-traumatic psychiatric symptoms. Methods Data from 120 children and adolescents aged 7–15 years, treated at Turku University Hospital between 2010 and 2016 due to mTBI, and who had undergone neuropsychological evaluation at 1–3 months following injury, were enrolled from the hospital records. Neuropsychological test performancesand injury symptom reports were retrospectively retrieved from the patient files. Results Slow information processing speed (p = 0.044), emotion regulation deficit (p = 0.014), impulsivity (p = 0.013), verbal processing difficulties (p = 0.042) and headache (p = 0.026) were independent predictors for having later contact in psychiatric care. Conclusions Neuropsychological examination containing measure of information processing speed, injury symptom interview, and parental questionnaires on behavioural issues of the child at 1–3 months following mTBI seems to be useful in detecting children with risk for post traumatic psychiatric symptoms. Targeted support and guidance for this group of children and adolescents and their families are recommended to prevent the development of an unfavorable psychosocial outcome.

Abstract 14916: Computerized Working Memory Training for Hypertensive Individuals With Executive Function Impairment: A Randomized Clinical Trial

Introduction: Hypertension is a risk factor for working memory (WM) impairment, and the Cogmed training has been tested as a non-pharmacological alternative to WM rehabilitation. However, the benefits of Cogmed for the hypertensive population are unknown. Therefore, we aimed to evaluate Cogmed’s effects on WM performance of hypertensive individuals with executive function (EF) impairment. Methods: We included 40 hypertensive patients (aged 40 to 70 years, 68% female) with EF impairment. They were randomized in a 1:1 ratio to receive ten weeks of adaptive Cogmed training or a non-adaptive control training based on online games. The primary outcome was the WM performance. The secondary outcomes were the performance in other neuropsychological tests, as well as the indirect neuronal activity measured using functional magnetic resonance imaging (fMRI) under two WM task conditions: low (memorization of 4 spatial locations) and high (memorization of 6 spatial locations). An intention-to-treat (ITT) and per-protocol (PP) analysis were performed. The fMRI images were evaluated with the FSL tools. Cognitive outcomes were analyzed with a mixed model for repeated measures. Results: Compared to the control group, the Cogmed group did not show significant improvement in WM or any other cognitive outcome post-training (ITT and PP analysis). However, under the WM-low load and WM-high load conditions, respectively, the Cogmed group had an activation decrease in the right superior parietal lobe (ITT and PP analysis) and left inferior frontal lobe (PP analysis) in comparison to the control group (p<0.05). Conclusions: The Cogmed showed no effects on WM performance of hypertensive individuals with EF impairment. However, activation decreases were observed in frontoparietal areas related to the WM network, suggesting intervention-related increases in neural efficiency.

Comprehensive Analysis of MMPI-2-RF Symptom Validity Scales and Performance Validity Test Relationships in a Diverse Mixed Neuropsychiatric Setting.

The utility of symptom (SVT) and performance (PVT) validity tests has been independently established in neuropsychological evaluations, yet research on the relationship between these two types of validity indices is limited to circumscribed populations and measures. This study examined the relationship between SVTs on the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) and PVTs in a mixed neuropsychiatric setting. This cross-sectional study included data from 181 diagnostically and demographically diverse patients with neuropsychiatric conditions referred for outpatient clinical neuropsychological evaluation at an academic medical center. All patients were administered a uniform neuropsychological battery, including the MMPI-2-RF and five PVTs (i.e., Dot Counting Test; Medical Symptom Validity Test; Reliable Digit Span; Test of Memory Malingering-Trial 1; Word Choice Test). Nonsignificant associations emerged between SVT and PVT performance. Although the Response Bias Scale was most predictive of PVT performance, MMPI-2-RF SVTs generally had low classification accuracy for predicting PVT performance. Neuropsychological test performance was related to MMPI-2-RF SVT status only when overreporting elevations were at extreme scores. The current study further supports that SVTs and PVTs measure unique and dissociable constructs among diverse patients with neuropsychiatric conditions, consistent with literature from other clinical contexts. Therefore, objective evidence of symptom overreporting on MMPI-2-RF SVTs cannot be interpreted as definitively indicating invalid performance on tests of neurocognitive abilities. As such, clinicians should include both SVTs and PVTs as part of a comprehensive neuropsychological evaluation as they provide unique information regarding performance and symptom validity.

Plasma Phosphorylated Tau at Threonine 181 and Neuropsychiatric Symptoms in Preclinical and Prodromal Alzheimer Disease.

Plasma phosphorylated tau at threonine 181 (p-tau181), a well-validated marker of Alzheimer disease (AD) pathologic change, could be a more efficient way to diagnose AD than invasive or expensive biomarkers requiring CSF or PET. In some individuals, neuropsychiatric symptoms (NPS) are the earliest manifestation of AD, observed in advance of clear cognitive decline. However, the few studies assessing AD biomarkers in association with NPS have often had imprecision in capturing behavioral symptoms that represent sequelae of neurodegenerative disease. Thus, the mild behavioral impairment (MBI) construct was developed, framing NPS in a way to improve the precision of risk estimates for disease. MBI core criteria stipulate that NPS emerge de novo in later life and persist for at least 6 months. Here, cross-sectionally and longitudinally, we investigated associations of MBI with p-tau181, neuropsychological test performance, and incident AD. Cognitively unimpaired and mild cognitive impairment (MCI) Alzheimer's Disease Neuroimaging Initiative participants were selected. MBI status was derived from the Neuropsychiatric Inventory (NPI) using a published algorithm. NPI total scores at baseline and year 1 visits were used to operationalize MBI (score >0 at both visits), NPS not meeting the MBI criteria (NPS-not-MBI, score >0 at only 1 visit), and no NPS (score = 0 at both visits). Linear regressions were fitted for cross-sectional analyses; multilevel linear mixed-effects and Cox proportional hazards models were implemented to examine the longitudinal associations of MBI with changes in p-tau181 and cognition and incident dementia. The sample included 571 participants (age 72.2 years, 46.8% female, 64.8% MCI). Cross-sectionally (β = 8.1%, 95% CI 1.4%-15.2%, p = 0.02), MBI was associated with higher plasma p-tau181 levels compared with no NPS; NPS-not-MBI was not. Longitudinally, MBI was associated with higher p-tau181 (β = 0.014%, 95% CI 0.003-0.026, p = 0.02), in addition to a decline in memory and executive function. Survival analyses demonstrated a 3.92-fold greater dementia incidence in MBI, with no significant differences between NPS-not-MBI and no NPS. These findings extend the evidence base that MBI is associated with elevated risk of cognitive decline and dementia and a sequela of emerging Alzheimer-related proteinopathies. MBI offers a substantial improvement over current approaches that explore behavior as a proxy marker for Alzheimer-related proteinopathies, with both clinical and AD trial enrichment implications.

Prevalence of Alzheimer′s disease in rural and urban areas in Cuba and factors influencing on its occurrence: epidemiological cross-sectional protocol

IntroductionAccording to the World Alzheimer’s Report 2019, around 50 million people suffer from dementia, worldwide. Observational analysis revealed the existence of particular factors associated with the onset and progression of...

A Head-to-Head Comparison Between Plasma pTau181 and Tau PET Along the Alzheimer's Disease Continuum.

Both plasma tau phosphorylated at threonine-181 (pTau181) and tau PET show potential for detecting Alzheimer's disease (AD) pathology and predicting clinical progression. In this study, we performed a head-to-head comparison between plasma pTau181 and tau PET along the AD continuum. Methods: We included participants from the Amsterdam Dementia Cohort who underwent 18F-flortaucipir (tau) PET and had a plasma sample biobanked within 12 mo from tau PET. Fifty subjective cognitive decline (SCD) participants (31 Aβ-negative and 19 Aβ-positive) and 60 Aβ-positive participants with mild cognitive impairment (MCI) or dementia due to AD were included. A subset had 2-y longitudinal plasma pTau181 and tau PET available (n = 40). Longitudinal neuropsychological test data covering 3.2 ± 2.7 y from both before and after tau PET were available. Plasma pTau181 and tau PET were compared in their accuracies in discriminating between cognitive stage (MCI/AD vs. SCD) and preclinical Aβ status (SCD Aβ-positive vs. SCD Aβ-negative), their associations with cross-sectional and longitudinal neuropsychological test performance, and their longitudinal changes over time. Results: When discriminating between preclinical Aβ status, the area under the curve (AUC) for plasma pTau181 (0.83) and tau PET (entorhinal, 0.87; temporal, 0.85; neocortical, 0.67) were equally high (all DeLong P > 0.05), but tau PET outperformed plasma pTau181 in discriminating MCI/AD from SCD (AUC for plasma pTau181: 0.74; AUCs for tau PET: entorhinal, 0.89; temporal, 0.92; neocortical, 0.89) (all P < 0.01). Overall, tau PET showed stronger associations with cognitive decline and was associated with a wider variety of cognitive tests than plasma pTau181 (plasma pTau181, -0.02 > β < -0.12; tau PET, -0.01 > β < -0.22). Both plasma pTau181 and tau PET increased more steeply over time in MCI/AD than in SCD (P < 0.05), but only tau PET annual changes were associated with cognitive decline. Conclusion: Our results suggest that plasma pTau181 and tau PET perform equally well in identifying Aβ pathology but that tau PET better monitors disease stage and clinical progression.

Elevated C-Reactive Protein and Subsequent Patient-Reported Cognitive Problems in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study.

To examine longitudinal relationships between levels of C-reactive protein (CRP) and cognition in older breast cancer survivors and noncancer controls. English-speaking women age ≥ 60 years, newly diagnosed with primary breast cancer (stage 0-III), and frequency-matched controls were enrolled from September 2010 to March 2020; women with dementia, neurologic disorders, and other cancers were excluded. Assessments occurred presystemic therapy/enrollment and at annual visits up to 60 months. Cognition was measured using the Functional Assessment of Cancer Therapy-Cognitive Function and neuropsychological testing. Mixed linear effect models tested for survivor-control differences in natural log (ln)-transformed CRP at each visit. Random effect-lagged fluctuation models tested directional effects of ln-CRP on subsequent cognition. All models controlled for age, race, study site, cognitive reserve, obesity, and comorbidities; secondary analyses evaluated if depression or anxiety affected results. There were 400 survivors and 329 controls with CRP specimens and follow-up data (average age of 67.7 years; range, 60-90 years). The majority of survivors had stage I (60.9%), estrogen receptor-positive (87.6%) tumors. Survivors had significantly higher adjusted mean ln-CRP than controls at baseline and 12-, 24-, and 60-month visits (all P < .05). Higher adjusted ln-CRP predicted lower participant-reported cognition on subsequent visits among survivors, but not controls (P interaction = .008); effects were unchanged by depression or anxiety. Overall, survivors had adjusted Functional Assessment of Cancer Therapy-Cognitive Function scores that were 9.5 and 14.2 points lower than controls at CRP levels of 3.0 and 10.0 mg/L. Survivors had poorer neuropsychological test performance (v controls), with significant interactions with CRP only for the Trails B test. Longitudinal relationships between CRP and cognition in older breast cancer survivors suggest that chronic inflammation may play a role in development of cognitive problems. CRP testing could be clinically useful in survivorship care.

Correlation between CD4/CD8 ratio and neurocognitive performance during early HIV infection.

CD4/CD8 ratio is a marker of immune activation in HIV infection and has been associated with neurocognitive performance during chronic infection, but little is known about the early phases. The aim of this study was to examine the relationship between blood CD4/CD8 ratio and central nervous system endpoints in primary HIV infection (PHI) before and after antiretroviral treatment (ART). This was a retrospective analysis of the Primary Infection Stage CNS Events Study (PISCES) cohort. We longitudinally assessed blood and cerebrospinal fluid (CSF) markers of inflammation, immune activation and neuronal injury, and neuropsychological testing performance (NPZ4, an average of three motor and one processing speed tests, and a summarized total score, NPZ11, including also executive function, learning and memory) in ART-naïve participants enrolled during PHI. Spearman correlation and linear mixed models assessed the relationships between the trajectory of CD4/CD8 ratio over time and neurocognitive performance, blood and CSF markers of immune activation and neuronal injury. In all, 109 PHI participants were enrolled. The mean CD4/CD8 ratio decreased with longer time from infection to starting treatment (p < 0.001). Every unit increase in NPZ4 score was independently associated with a 0.15 increase in CD4/CD8 ratio (95% CI: 0.002-0.29; p=0.047), whereas no correlation was found between CD4/CD8 ratio and NPZ11. Among the cognitive domains, only a change in processing speed was correlated with CD4/CD8 ratio over time (p=0.03). The trajectory of the CD4/CD8 ratio was negatively correlated with change in CSF neurofilament light chain (p=0.04). The trajectory of CD4/CD8 ratio was independently associated with motor/psychomotor speed performance, suggesting that immune activation is involved in brain injury during the early stages of the infection.

Association between inflammatory biomarkers and cognitive aging.

Inflammatory cytokines and chemokines related to the innate and adaptive immune system have been linked to neuroinflammation in Alzheimer's Disease, dementia, and cognitive disorders. We examined the association of 11 plasma proteins (CD14, CD163, CD5L, CD56, CD40L, CXCL16, SDF1, DPP4, SGP130, sRAGE, and MPO) related to immune and inflammatory responses with measures of cognitive function, brain MRI and dementia risk. We identified Framingham Heart Study Offspring participants who underwent neuropsychological testing (n = 2358) or brain MRI (n = 2100) within five years of the seventh examination where a blood sample for quantifying the protein biomarkers was obtained; and who were followed for 10 years for incident all-cause dementia (n = 1616). We investigated the association of inflammatory biomarkers with neuropsychological test performance and brain MRI volumes using linear mixed effect models accounting for family relationships. We further used Cox proportional hazards models to examine the association with incident dementia. False discovery rate p-values were used to account for multiple testing. Participants included in the neuropsychological test and MRI samples were on average 61 years old and 54% female. Participants from the incident dementia sample (average 68 years old at baseline) included 124 participants with incident dementia. In addition to CD14, which has an established association, we found significant associations between higher levels of CD40L and myeloperoxidase (MPO) with executive dysfunction. Higher CD5L levels were significantly associated with smaller total brain volumes (TCBV), whereas higher levels of sRAGE were associated with larger TCBV. Associations persisted after adjustment for APOE ε4 carrier status and additional cardiovascular risk factors. None of the studied inflammatory biomarkers were significantly associated with risk of incident all-cause dementia. Higher circulating levels of soluble CD40L and MPO, markers of immune cell activation, were associated with poorer performance on neuropsychological tests, while higher CD5L, a key regulator of inflammation, was associated with smaller total brain volumes. Higher circulating soluble RAGE, a decoy receptor for the proinflammatory RAGE/AGE pathway, was associated with larger total brain volume. If confirmed in other studies, this data indicates the involvement of an activated immune system in abnormal brain aging.

Profile of Embedded Validity Indicators in Criminal Defendants with Verified Valid Neuropsychological Test Performance.

Few studies have examined the use of embedded validity indicators (EVIs) in criminal-forensic practice settings, where judgements regarding performance validity can carry severe consequences for the individual and society. This study sought to examine how various EVIs perform in criminal defendant populations, and determine relationships between EVI scores and intrapersonal variables thought to influence performance validity. Performance on 16 empirically established EVI cutoffs were examined in a sample of 164 criminal defendants with valid performance who were referred for forensic neuropsychological evaluation. Subsequent analyses examined the relationship between EVI scores and intrapersonal variables in 83 of these defendants. Half of the EVIs (within the Wechsler Adult Intelligence Scale Digit Span Total, Conners' Continuous Performance Test Commissions, Wechsler Memory Scale Logical Memory I and II, Controlled Oral Word Association Test, Trail Making Test Part B, and Stroop Word and Color) performed as intended in this sample. The EVIs that did not perform as intended were significantly influenced by relevant intrapersonal variables, including below-average intellectual functioning and history of moderate-severe traumatic brain injury and neurodevelopmental disorder. This study identifies multiple EVIs appropriate for use in criminal-forensic settings. However, based on these findings, practitioners may wish to be selective in choosing and interpreting EVIs for forensic evaluations of criminal court defendants.

Use of machine learning to identify functional connectivity changes in a clinical cohort of patients at risk for dementia.

ObjectiveProgressive conditions characterized by cognitive decline, including mild cognitive impairment (MCI) and subjective cognitive decline (SCD) are clinical conditions representing a major risk factor to develop dementia, however, the diagnosis of these pre-dementia conditions remains a challenge given the heterogeneity in clinical trajectories. Earlier diagnosis requires data-driven approaches for improved and targeted treatment modalities.MethodsNeuropsychological tests, baseline anatomical T1 magnetic resonance imaging (MRI), resting-state functional MRI (rsfMRI), and diffusion weighted scans were obtained from 35 patients with SCD, 19 with MCI, and 36 age-matched healthy controls (HC). A recently developed machine learning technique, Hollow Tree Super (HoTS) was utilized to classify subjects into diagnostic categories based on their FC, and derive network and parcel-based FC features contributing to each model. The same approach was used to identify features associated with performance in a range of neuropsychological tests. We concluded our analysis by looking at changes in PageRank centrality (a measure of node hubness) between the diagnostic groups.ResultsSubjects were classified into diagnostic categories with a high area under the receiver operating characteristic curve (AUC-ROC), ranging from 0.73 to 0.84. The language networks were most notably associated with classification. Several central networks and sensory brain regions were predictors of poor performance in neuropsychological tests, suggesting maladaptive compensation. PageRank analysis highlighted that basal and limbic deep brain region, along with the frontal operculum demonstrated a reduction in centrality in both SCD and MCI patients compared to controls.ConclusionOur methods highlight the potential to explore the underlying neural networks contributing to the cognitive changes and neuroplastic responses in prodromal dementia.

A Pilot randomized trial to examine effects of a hybrid closed-loop insulin delivery system on neurodevelopmental and cognitive outcomes in adolescents with type 1 diabetes

Type 1 diabetes (T1D) is associated with lower scores on tests of cognitive and neuropsychological function and alterations in brain structure and function in children. This proof-of-concept pilot study (ClinicalTrials.gov Identifier NCT03428932) examined whether MRI-derived indices of brain development and function and standardized IQ scores in adolescents with T1D could be improved with better diabetes control using a hybrid closed-loop insulin delivery system. Eligibility criteria for participation in the study included age between 14 and 17 years and a diagnosis of T1D before 8 years of age. Randomization to either a hybrid closed-loop or standard diabetes care group was performed after pre-qualification, consent, enrollment, and collection of medical background information. Of 46 participants assessed for eligibility, 44 met criteria and were randomized. Two randomized participants failed to complete baseline assessments and were excluded from final analyses. Participant data were collected across five academic medical centers in the United States. Research staff scoring the cognitive assessments as well as those processing imaging data were blinded to group status though participants and their families were not. Forty-two adolescents, 21 per group, underwent cognitive assessment and multi-modal brain imaging before and after the six month study duration. HbA1c and sensor glucose downloads were obtained quarterly. Primary outcomes included metrics of gray matter (total and regional volumes, cortical surface area and thickness), white matter volume, and fractional anisotropy. Estimated power to detect the predicted treatment effect was 0.83 with two-tailed, α = 0.05. Adolescents in the hybrid closed-loop group showed significantly greater improvement in several primary outcomes indicative of neurotypical development during adolescence compared to the standard care group including cortical surface area, regional gray volumes, and fractional anisotropy. The two groups were not significantly different on total gray and white matter volumes or cortical thickness. The hybrid closed loop group also showed higher Perceptual Reasoning Index IQ scores and functional brain activity more indicative of neurotypical development relative to the standard care group (both secondary outcomes). No adverse effects associated with study participation were observed. These results suggest that alterations to the developing brain in T1D might be preventable or reversible with rigorous glucose control. Long term research in this area is needed.

Addenbrooke's Cognitive Examination-Third Edition Predicts Neuropsychological Test Performance.

Effective screening tools can help providers with treatment decisions, including when to refer patients for neuropsychological evaluations, which are the gold standard for cognitive assessment of neurodegenerative disease. The authors examined whether performance on the Addenbrooke's Cognitive Examination-Third Edition (ACE-III), a readily available cognitive screening tool for older adults, predicted performance on subsequent neuropsychological evaluations. In total, 217 patients referred for neurocognitive concerns completed a neuropsychological evaluation, including the ACE-III. Patients were diagnosed as having normal cognition (NC, N=67), mild neurocognitive disorder (mild NCD, N=105), or major NCD (N=45). Regression analyses were used to determine whether ACE-III subscale scores predicted performance on neuropsychological measures assessing similar constructs. Logistic regression was used to assess whether ACE-III total score and overall neuropsychological test performance predicted diagnosis. Separate analyses compared those with higher and lower educational attainments. ACE-III subscales and total scores were compared by diagnostic group. Across all groups, ACE-III subscale scores predicted within-construct neuropsychological performances with moderate to strong effects (p<0.001) but were less predictive for those with lower educational attainment. ACE-III total score was less sensitive than overall neuropsychological test performance in predicting neurocognitive disorders. ACE-III subscale and total scores distinguished diagnostic groups (NC>mild NCD>major NCD, p<0.001). ACE-III subscale scores predicted performance on neuropsychological measures assessing similar constructs. However, overall performance on neuropsychological testing was more sensitive than ACE-III total score in predicting neurocognitive disorder diagnosis. Total ACE-III score differed by level of cognitive impairment. Comprehensive neuropsychological testing is recommended for patients who have lower educational status or complex symptom presentations or are younger.