Individual Differences in CD4/CD8 T-Cell Ratio Trajectories and Associated Risk Profiles Modeled From Acute HIV Infection.

OBJECTIVE: We examined individual differences in CD4/CD8 T-cell ratio trajectories and associated risk profiles from acute HIV infection (AHI) through 144 weeks of antiretroviral therapy (ART) using a data-driven approach. METHODS: A total of 483 AHI participants began ART during Fiebig I-V and completed follow-up evaluations for 144 weeks. CD4+, CD8+, and CD4/CD8 T-cell ratio trajectories were defined followed by analyses to identify associated risk variables. RESULTS: Participants had a median viral load (VL) of 5.88 copies/ml and CD4/CD8 T-cell ratio of 0.71 at enrollment. After 144 weeks of ART, the median CD4/CD8 T-cell ratio was 1.3. Longitudinal models revealed five CD4/CD8 T-cell ratio subgroups: group 1 (3%) exhibited a ratio >1.0 at all visits; groups 2 (18%) and 3 (29%) exhibited inversion at enrollment, with normalization 4 and 12 weeks after ART, respectively; and groups 4 (31%) and 5 (18%) experienced CD4/CD8 T-cell ratio inversion due to slow CD4+ T-cell recovery (group 4) or high CD8+ T-cell count (group 5). Persistent inversion corresponded to ART onset after Fiebig II, higher VL, soluble CD27 and TIM-3, and lower eosinophil count. Individuals with slow CD4+ T-cell recovery exhibited higher VL, lower white blood cell count, lower basophil percent, and treatment with standard ART, as well as worse mental health and cognition, compared with individuals with high CD8+ T-cell count. CONCLUSIONS: Early HIV disease dynamics predict unfavorable CD4/CD8 T-cell ratio outcomes after ART. CD4+ and CD8+ T-cell trajectories contribute to inversion risk and correspond to specific viral, immune, and psychological profiles during AHI. Adjunctive strategies to achieve immune normalization merit consideration.

Preoperative Cognitive Abnormality, Intraoperative Electroencephalogram Suppression, and Postoperative Delirium: A Mediation Analysis.

BACKGROUND: Postoperative delirium is a common complication that hinders recovery after surgery. Intraoperative electroencephalogram suppression has been linked to postoperative delirium, but it is unknown if this relationship is causal or if electroencephalogram suppression is merely a marker of underlying cognitive abnormalities. The hypothesis of this study was that intraoperative electroencephalogram suppression mediates a nonzero portion of the effect between preoperative abnormal cognition and postoperative delirium. METHODS: This is a prespecified secondary analysis of the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized trial, which enrolled patients age 60 yr or older undergoing surgery with general anesthesia at a single academic medical center between January 2015 and May 2018. Patients were randomized to electroencephalogram-guided anesthesia or usual care. Preoperative abnormal cognition was defined as a composite of previous delirium, Short Blessed Test cognitive score greater than 4 points, or Eight Item Interview to Differentiate Aging and Dementia score greater than 1 point. Duration of intraoperative electroencephalogram suppression was defined as number of minutes with suppression ratio greater than 1%. Postoperative delirium was detected via Confusion Assessment Method or chart review on postoperative days 1 to 5. RESULTS: Among 1,113 patients, 430 patients showed evidence of preoperative abnormal cognition. These patients had an increased incidence of postoperative delirium (151 of 430 [35%] vs.123 of 683 [18%], P < 0.001). Of this 17.2% total effect size (99.5% CI, 9.3 to 25.1%), an absolute 2.4% (99.5% CI, 0.6 to 4.8%) was an indirect effect mediated by electroencephalogram suppression, while an absolute 14.8% (99.5% CI, 7.2 to 22.5%) was a direct effect of preoperative abnormal cognition. Randomization to electroencephalogram-guided anesthesia did not change the mediated effect size (P = 0.078 for moderation). CONCLUSIONS: A small portion of the total effect of preoperative abnormal cognition on postoperative delirium was mediated by electroencephalogram suppression. Study precision was too low to determine if the intervention changed the mediated effect.

Diffusion Imaging Findings in US Service Members With Mild Traumatic Brain Injury and Posttraumatic Stress Disorder.

OBJECTIVE: Use diffusion tensor imaging to investigate white matter microstructure attributable to mild TBI (mTBI) and/or posttraumatic stress disorder (PTSD). PARTICIPANTS: Twenty-seven individuals with mTBI only, 16 with PTSD only, 42 with mTBI + PTSD, and 43 service members who sustained orthopedic injury. DESIGN: Descriptive cross-sectional study. MAIN MEASURES: Clinical diffusion tensor imaging sequence to assess fractional anisotropy, mean, axial, and radial diffusivity within selected regions of interest. RESULTS: Corrected analyses revealed a pattern of lower white matter integrity in the PTSD group for several scalar metrics. Regions affected included primarily right hemisphere areas of the internal capsule. These differences associated with the PTSD only cohort were observed in relation to all 3 comparison groups, while the mTBI + PTSD group did not exhibit any notable pattern of white matter abnormalities. CONCLUSION: Results suggest that lower resolution scan sequences are sensitive to post-acute abnormalities associated with PTSD, particularly in the right hemisphere. In addition, these findings suggest that ongoing PTSD symptoms are associated with differences in white matter diffusion that are more readily detected in a clinical scan sequence than mTBI abnormalities. Future studies are needed to prospectively assess service members prior to onset of injury to verify this pattern of results.

Relationships Between Subcortical Shape Measures and Subjective Symptom Reporting in US Service Members With Mild Traumatic Brain Injury.

OBJECTIVE: To assess interactions of subcortical structure with subjective symptom reporting associated with mild traumatic brain injury (mTBI), using advanced shape analysis derived from volumetric MRI. PARTICIPANTS: Seventy-six cognitively symptomatic individuals with mTBI and 59 service members sustaining only orthopedic injury. DESIGN: Descriptive cross-sectional study. MAIN MEASURES: Self-report symptom measures included the PTSD Checklist-Military, Neurobehavioral Symptom Inventory, and Symptom Checklist-90-Revised. High-dimensional measures of shape characteristics were generated from volumetric MRI for 7 subcortical structures in addition to standard volume measures. RESULTS: Several significant interactions between group status and symptom measures were observed across the various shape measures. These interactions were revealed in the right thalamus and globus pallidus for each of the shape measures, indicating differences in structure thickness and expansion/contraction for these regions. No relationships with volume were observed. CONCLUSION: Results provide evidence for the sensitivity of shape measures in differentiating symptomatic mTBI individuals from controls, while volumetric measures did not exhibit this same sensitivity. Disruptions to thalamic nuclei identified here highlight the role of the thalamus in the spectrum of symptoms associated with mTBI. Additional work is needed to prospectively, and longitudinally, assess these measures along with cognitive performance and advanced multimodal imaging methods to extend the utility of shape analysis in relation to functional outcomes in this population.

Genetic markers of cholesterol transport and gray matter diffusion: a preliminary study of the CETP I405V polymorphism.

Variations of the cholesteryl ester transfer protein polymorphism (CETP I405V/rs5882) have been associated with an increased risk for neurodegeneration, particularly when examined in conjunction with the epsilon 4 isoform of apolipoprotein E (ApoE4). Despite these identified relationships, the impact of I405V on gray matter microstructure remains unknown. The present study examined the impact of the CETP I405V polymorphism on gray matter integrity among 52 healthy adults between ages 51 and 85. Gray matter was measured bilaterally using diffusion tensor imaging (DTI) metrics of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Participants were grouped according to a dominant statistical model (II genotype vs. IV/VV genotypes) and secondary analyses were completed to examine the interactive effects of CETP and ApoE4 on DTI metrics. Compared to individuals with the IV/VV genotypes, II homozygotes demonstrated significantly higher MD in bilateral temporal, parietal, and occipital gray matter. Secondary analyses revealed higher FA and AD in the left temporal lobe of IV/VV genotypes with an ApoE4 allele. Our results provide preliminary evidence that CETP II homozygosity is a predisposing risk factor for gray matter abnormalities in posterior brain regions in healthy older adults, independent of an ApoE4 allele.

Triallelic relationships between the serotonin transporter polymorphism and cognition among healthy older adults.

The biallelic serotonin transporter polymorphism (5-hydroxytryptamine transporter linked polymorphic region (5-HTTLPR)) is a common genetic sequence associated with serotonin transporter (5-hydroxytryptamine transporter (5-HTT)) expression, which is further modulated by a triallelic single-nucleotide polymorphism (rs25531). Recent studies using the biallelic 5-HTTLPR have identified a beneficial role of low 5-HTT expression on cognitive performance, although no studies have examined the impact of the triallelic 5-HTTLPR/rs25531 marker on cognitive performance among healthy older adults. In the present study, we addressed this issue in 84 healthy older adults genotyped for biallelic and triallelic variants of 5-HTT. Groups were created based on low, medium and high levels of expression, as indicated by the triallelic marker. Results indicated that individuals with low 5-HTT expression performed significantly better on a test of memory compared with individuals with medium 5-HTT expression. This suggests that possession of low-expressing genetic variants of 5-HTT is modestly associated with enhanced cognitive performance among healthy older adults.

Plasma galectin-9 relates to cognitive performance and inflammation among adolescents with vertically acquired HIV.

OBJECTIVE: Adolescents with perinatally acquired HIV (AWH) are at an increased risk of poor cognitive development yet the underlying mechanisms remain unclear. Circulating galectin-9 (Gal-9) has been associated with increased inflammation and multimorbidity in adults with HIV despite antiretroviral therapy (ART); however, the relationship between Gal-9 in AWH and cognition remain unexplored. DESIGN: A cross-sectional study of two independent age-matched cohorts from India [AWH on ART ( n  = 15), ART-naive ( n  = 15), and adolescents without HIV (AWOH; n  = 10)] and Myanmar [AWH on ART ( n  = 54) and AWOH ( n  = 22)] were studied. Adolescents from Myanmar underwent standardized cognitive tests. METHODS: Plasma Gal-9 and soluble mediators were measured by immunoassays and cellular immune markers by flow cytometry. We used Mann-Whitney U tests to determine group-wise differences, Spearman's correlation for associations and machine learning to identify a classifier of cognitive status (impaired vs. unimpaired) built from clinical (age, sex, HIV status) and immunological markers. RESULTS: Gal-9 levels were elevated in ART-treated AWH compared with AWOH in both cohorts (all P  < 0.05). Higher Gal-9 in AWH correlated with increased levels of inflammatory mediators (sCD14, TNFα, MCP-1, IP-10, IL-10) and activated CD8 + T cells (all P  < 0.05). Irrespective of HIV status, higher Gal-9 levels correlated with lower cognitive test scores in multiple domains [verbal learning, visuospatial learning, memory, motor skills (all P  < 0.05)]. ML classification identified Gal-9, CTLA-4, HVEM, and TIM-3 as significant predictors of cognitive deficits in adolescents [mean area under the curve (AUC) = 0.837]. CONCLUSION: Our results highlight a potential role of Gal-9 as a biomarker of inflammation and cognitive health among adolescents with perinatally acquired HIV.

Impact of antiretroviral therapy intensification with C-C motif chemokine receptor 5 antagonist maraviroc on HIV-associated neurocognitive impairment.

OBJECTIVES: Chemokine receptor CCR5 is the principal co-receptor for entry of M-tropic HIV virus into immune cells. It is expressed in the central nervous system and may contribute to neuro-inflammation. The CCR5 antagonist maraviroc (MVC) has been suggested to improve HIV-associated neurocognitive impairment (NCI). DESIGN: A double-blind, placebo-controlled, 48-week, randomized study of MVC vs. placebo in people with HIV (PWH) on stable antiretroviral therapy (ART) for more than one year in Hawaii and Puerto Rico with plasma HIV RNA less than 50 copies/ml and at least mild NCI defined as an overall or domain-specific neuropsychological z (NPZ) score less than -0.5. METHODS: Study participants were randomized 2 : 1 to intensification of ART with MVC vs. placebo. The primary endpoint was change in global and domain-specific NPZ modeled from study entry to week 48. Covariate adjusted treatment comparisons of average changes in cognitive outcome were performed using winsorized NPZ data. Monocyte subset frequencies and chemokine expression as well as plasma biomarker levels were assessed. RESULTS: Forty-nine participants were enrolled with 32 individuals randomized to MVC intensification and 17 to placebo. At baseline, worse NPZ scores were seen in the MVC arm. Comparison of 48-week NPZ change by arm revealed no differences except for a modest improvement in the Learning and Memory domain in the MVC arm, which did not survive multiplicity correction. No significant changes between arms were seen in immunologic parameters. CONCLUSION: This randomized controlled study found no definitive evidence in favor of MVC intensification among PWH with mild cognitive difficulties.

Brain volumetrics differ by Fiebig stage in acute HIV infection.

OBJECTIVE: People with chronic HIV exhibit lower regional brain volumes compared to people without HIV (PWOH). Whether imaging alterations observed in chronic infection occur in acute HIV infection (AHI) remains unknown. DESIGN: Cross-sectional study of Thai participants with AHI. METHODS: One hundred and twelve Thai males with AHI (age 20-46) and 18 male Thai PWOH (age 18-40) were included. Individuals with AHI were stratified into early (Fiebig I-II; n  = 32) and late (Fiebig III-V; n  = 80) stages of acute infection using validated assays. T1-weighted scans were acquired using a 3 T MRI performed within five days of antiretroviral therapy (ART) initiation. Volumes for the amygdala, caudate nucleus, hippocampus, nucleus accumbens, pallidum, putamen, and thalamus were compared across groups. RESULTS: Participants in late Fiebig stages exhibited larger volumes in the nucleus accumbens (8% larger; P  = 0.049) and putamen (19%; P  < 0.001) when compared to participants in the early Fiebig. Compared to PWOH, participants in late Fiebig exhibited larger volumes of the amygdala (9% larger; P  = 0.002), caudate nucleus (11%; P  = 0.005), nucleus accumbens (15%; P  = 0.004), pallidum (19%; P  = 0.001), and putamen (31%; P  < 0.001). Brain volumes in the nucleus accumbens, pallidum, and putamen correlated modestly with stimulant use over the past four months among late Fiebig individuals ( P s < 0.05). CONCLUSIONS: Findings indicate that brain volume alterations occur in acute infection, with the most prominent differences evident in the later stages of AHI. Additional studies are needed to evaluate mechanisms for possible brain disruption following ART, including viral factors and markers of neuroinflammation.

Cognitive Phenotypes of HIV Defined Using a Novel Data-driven Approach.

The current study applied data-driven methods to identify and explain novel cognitive phenotypes of HIV. Methods: 388 people with HIV (PWH) with an average age of 46 (15.8) and median plasma CD4+ T-cell count of 555 copies/mL (79% virally suppressed) underwent cognitive testing and 3T neuroimaging. Demographics, HIV disease variables, and health comorbidities were recorded within three months of cognitive testing/neuroimaging. Hierarchical clustering was employed to identify cognitive phenotypes followed by ensemble machine learning to delineate the features that determined membership in the cognitive phenotypes. Hierarchical clustering identified five cognitive phenotypes. Cluster 1 (n=97) was comprised of individuals with normative performance on all cognitive tests. The remaining clusters were defined by impairment on action fluency (Cluster 2; n=46); verbal learning/memory (Cluster 3; n=73); action fluency and verbal learning/memory (Cluster 4; n=56); and action fluency, verbal learning/memory, and tests of executive function (Cluster 5; n=114). HIV detectability was most common in Cluster 5. Machine learning revealed that polysubstance use, race, educational attainment, and volumes of the precuneus, cingulate, nucleus accumbens, and thalamus differentiated membership in the normal vs. impaired clusters. The determinants of persistent cognitive impairment among PWH receiving suppressive treatment are multifactorial nature. Viral replication after ART plays a role in the causal pathway, but psychosocial factors (race inequities, substance use) merit increased attention as critical determinants of cognitive impairment in the context of ART. Results underscore the need for comprehensive person-centered interventions that go beyond adherence to patient care to achieve optimal cognitive health among PWH.

Deep Phenotyping of HIV Neurocognitive Complications Among Individuals Residing in High-Income Countries.

People living with HIV (PLWH) residing in high-income countries (HICs) are, in theory, well positioned to benefit from clinical care strategies that predict optimal neurocognitive and neuropsychiatric outcomes. However, there is substantial inter-individual variability in access to clinical care, prevalence of co-occurring risk factors, and comorbid health conditions that represent barriers to achieving the full potential of antiretroviral therapy (ART). Complex interactions between these variables translate into heterogeneity in HIV clinical phenotypes, including abnormalities in brain structure and function. The growing population of PLWH in HICs who are now reaching advanced age introduces additional causal pathways of neurocognitive variability among PLWH receiving ART. These patterns foreshadow trends expected to develop globally in response to increased access to ART. This chapter reviews the combination of highly dimensional risk factors for neurocognitive complications among PLWH residing in HICs. We begin with a brief description of the neuropathological, neuroimaging, and neurocognitive signatures of HIV, followed by a summary of controversies regarding the clinical presentation of HIV-associated neurocognitive disorders (HAND), including putative synergies between HIV disease dynamics and advanced age. Finally, we introduce innovative research strategies that have potential to advance the existing conceptual framework of HAND and, ideally, catalyze the development and of clinical interventions needed to achieve HIV treatment and eradication efforts.

Ensemble machine learning classification of daily living abilities among older people with HIV.

BACKGROUND: clinically relevant methods to identify individuals at risk for impaired daily living abilities secondary to neurocognitive impairment (ADLs) remain elusive. This is especially true for complex clinical conditions such as HIV-Associated Neurocognitive Disorders (HAND). The aim of this study was to identify novel and modifiable factors that have potential to improve diagnostic accuracy of ADL risk, with the long-term goal of guiding future interventions to minimize ADL disruption. METHODS: study participants included 79 people with HIV (PWH; mean age = 63; range = 55-80) enrolled in neuroHIV studies at University California San Francisco (UCSF) between 2016 and 2019. All participants were virally suppressed and exhibited objective evidence of neurocognitive impairment. ADL status was defined as either normative (n = 39) or at risk (n = 40) based on a task-based protocol. Gradient boosted multivariate regression (GBM) was employed to identify the combination of variables that differentiated ADL subgroup classification. Predictor variables included demographic factors, HIV disease severity indices, brain white matter integrity quantified using diffusion tensor imaging, cognitive test performance, and health co-morbidities. Model performance was examined using average Area Under the Curve (AUC) with repeated five-fold cross validation. FINDINGS: the univariate GBM yielded an average AUC of 83% using Wide Range Achievement test 4 (WRAT-4) reading score, self-reported thought confusion and difficulty reading, radial diffusivity (RD) in the left external capsule, fractional anisotropy (FA) in the left cingulate gyrus, and Stroop performance. The model allowing for two-way interactions modestly improved classification performance (AUC of 88%) and revealed synergies between race, reading ability, cognitive performance, and neuroimaging metrics in the genu and uncinate fasciculus. Conversion of Neuropsychological Assessment Battery Daily Living Module (NAB-DLM) performance from raw scores into T scores amplified differences between White and non-White study participants. INTERPRETATION: demographic and sociocultural factors are critical determinants of ADL risk status among older PWH who meet diagnostic criteria for neurocognitive impairment. Task-based ADL assessment that relies heavily on reading proficiency may artificially inflate the frequency/severity of ADL impairment among diverse clinical populations. Culturally relevant measures of ADL status are needed for individuals with acquired neurocognitive disorders, including HAND.

Neurocognitive Trajectories After 72 Weeks of First-Line Anti-retroviral Therapy in Vietnamese Adults With HIV-HCV Co-infection.

Background: Long-term neurocognitive outcomes following first-line suppressive anti-retroviral therapy (ART) remain uncertain for individuals with HIV and hepatitis C (HCV) co-infection. The study examined neurocognitive performance before and after 72 weeks of ART using repeated multivariate analyses and latent trajectory models. Methods: One hundred and sixty adults with chronic, untreated HIV infection (n = 80 with HCV co-infection and n = 80 HIV mono-infected) and 80 demographically similar healthy controls were recruited from the Hospital for Tropical Diseases in Ho Chi Minh City and the surrounding community, respectively. Neurocognitive measures (adapted for use in Vietnam) and liver enzyme tests were compared across groups at baseline. Repeated multivariate and group-based trajectory analyses (GBTA) examined neurocognitive subgroup profiles of the co-infected individuals after 72 weeks of de novo efavirenz- (n = 41) or raltegravir-based (n = 39) ART. Results: Baseline analyses revealed worse motor function in HIV-HCV co-infected individuals compared to both comparison groups. Longitudinal analyses revealed improved neurocognitive performance by week 48 for most participants regardless of treatment arm. GBTA identified a subgroup (35% of HIV-HCV sample) with persistent motor impairment despite otherwise successful ART. Higher HIV viral load and lower CD4+ T cell count at baseline predicted persistent motor dysfunction. Liver indices and ART regimen did not predict neurocognitive outcomes in HIV-HCV co-infected individuals. Conclusions: Most HIV-HCV co-infected individuals achieve normative neurocognitive performance after 48 weeks of de novo suppressive ART. However, individuals with more severe HIV disease prior to ART exhibited motor impairment at baseline and 72 weeks after otherwise successful treatment. Interventions aimed at improving motor symptoms at the time of HIV treatment onset may improve long-term clinical outcomes in HIV-HCV co-infected adults.

A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression.

Nitrous oxide at 50% inhaled concentration has been shown to improve depressive symptoms in patients with treatment-resistant major depression (TRMD). Whether a lower concentration of 25% nitrous oxide provides similar efficacy and persistence of antidepressant effects while reducing the risk of adverse side effects is unknown. In this phase 2 clinical trial (NCT03283670), 24 patients with severe TRMD were randomly assigned in a crossover fashion to three treatments consisting of a single 1-hour inhalation with (i) 50% nitrous oxide, (ii) 25% nitrous oxide, or (iii) placebo (air/oxygen). The primary outcome was the change on the Hamilton Depression Rating Scale (HDRS-21). Whereas nitrous oxide significantly improved depressive symptoms versus placebo (P = 0.01), there was no difference between 25 and 50% nitrous oxide (P = 0.58). The estimated differences between 25% and placebo were -0.75 points on the HDRS-21 at 2 hours (P = 0.73), -1.41 points at 24 hours (P = 0.52), -4.35 points at week 1 (P = 0.05), and -5.19 points at week 2 (P = 0.02), and the estimated differences between 50% and placebo were -0.87 points at 2 hours (P = 0.69), -1.93 points at 24 hours (P = 0.37), -2.44 points at week 1 (P = 0.25), and -7.00 points at week 2 (P = 0.001). Adverse events declined substantially with dose (P < 0.001). These results suggest that 25% nitrous oxide has comparable efficacy to 50% nitrous oxide in improving TRMD but with a markedly lower rate of adverse effects.

Machine Learning Analysis Reveals Novel Neuroimaging and Clinical Signatures of Frailty in HIV.

BACKGROUND: Frailty is an important clinical concern for the aging population of people living with HIV (PLWH). The objective of this study was to identify the combination of risk features that distinguish frail from nonfrail individuals. SETTING: Machine learning analysis of highly dimensional risk features was performed on a clinical cohort of PLWH. METHODS: Participants included 105 older (average age = 55.6) PLWH, with at least a 3-month history of combination antiretroviral therapy (median CD4 = 546). Predictors included demographics, HIV clinical markers, comorbid health conditions, cognition, and neuroimaging (ie, volumetrics, resting-state functional connectivity, and cerebral blood flow). Gradient-boosted multivariate regressions were implemented to establish linear and interactive classification models. Model performance was determined by sensitivity/specificity (F1 score) with 5-fold cross validation. RESULTS: The linear gradient-boosted multivariate regression classifier included lower current CD4 count, lower psychomotor performance, and multiple neuroimaging indices (volumes, network connectivity, and blood flow) in visual and motor brain systems (F1 score = 71%; precision = 84%; and sensitivity = 66%). The interactive model identified novel synergies between neuroimaging features, female sex, symptoms of depression, and current CD4 count. CONCLUSIONS: Data-driven algorithms built from highly dimensional clinical and brain imaging features implicate disruption to the visuomotor system in older PLWH designated as frail individuals. Interactions between lower CD4 count, female sex, depressive symptoms, and neuroimaging features suggest potentiation of risk mechanisms. Longitudinal data-driven studies are needed to guide clinical strategies capable of preventing the development of frailty as PLWH reach advanced age.

Subcortical shape and neuropsychological function among U.S. service members with mild traumatic brain injury.

In a recent manuscript, our group demonstrated shape differences in the thalamus, nucleus accumbens, and amygdala in a cohort of U.S. Service Members with mild traumatic brain injury (mTBI). Given the significant role these structures play in cognitive function, this study directly examined the relationship between shape metrics and neuropsychological performance. The imaging and neuropsychological data from 135 post-deployed United States Service Members from two groups (mTBI and orthopedic injured) were examined. Two shape features modeling local deformations in thickness (RD) and surface area (JD) were defined vertex-wise on parametric mesh-representations of 7 bilateral subcortical gray matter structures. Linear regression was used to model associations between subcortical morphometry and neuropsychological performance as a function of either TBI status or, among TBI patients, subjective reporting of initial concussion severity (CS). Results demonstrated several significant group-by-cognition relationships with shape metrics across multiple cognitive domains including processing speed, memory, and executive function. Higher processing speed was robustly associated with more dilation of caudate surface area among patients with mTBI who reported more than one CS variables (loss of consciousness (LOC), alteration of consciousness (AOC), and/or post-traumatic amnesia (PTA)). These significant patterns indicate the importance of subcortical structures in cognitive performance and support a growing functional neuroanatomical literature in TBI and other neurologic disorders. However, prospective research will be required before exact directional evolution and progression of shape can be understood and utilized in predicting or tracking cognitive outcomes in this patient population.

Comparing Two Processing Pipelines to Measure Subcortical and Cortical Volumes in Patients with and without Mild Traumatic Brain Injury.

PURPOSE: To compare volumetric results from NeuroQuant® and FreeSurfer in a service member setting. Since the advent of medical imaging, quantification of brain anatomy has been a major research and clinical effort. Rapid advancement of methods to automate quantification and to deploy this information into clinical practice has surfaced in recent years. NeuroQuant® is one such tool that has recently been used in clinical settings. Accurate volumetric data are useful in many clinical indications; therefore, it is important to assess the intermethod reliability and concurrent validity of similar volume quantifying tools. METHODS: Volumetric data from 148 U.S. service members across three different experimental groups participating in a study of mild traumatic brain injury (mTBI) were examined. Groups included mTBI (n = 71), posttraumatic stress disorder (n = 22), or a noncranial orthopedic injury (n = 55). Correlation coefficients and nonparametric group mean comparisons were used to assess reliability and concurrent validity, respectively. RESULTS: Comparison of these methods across our entire sample demonstrates generally fair to excellent reliability as evidenced by large intraclass correlation coefficients (ICC = .4 to .99), but little concurrent validity as evidenced by significantly different Mann-Whitney U comparisons for 26 of 30 brain structures measured. CONCLUSION: While reliability between the two segmenting tools is fair to excellent, volumetric outcomes are statistically different between the two methods. As suggested by both developers, structure segmentation should be visually verified prior to clinical use and rigor should be used when interpreting results generated by either method.

Vulnerability of white matter tracts and cognition to the SOD2 polymorphism: A preliminary study of antioxidant defense genes in brain aging.

Oxidative stress is a key mechanism of the aging process that can cause damage to brain white matter and cognitive functions. Polymorphisms in the superoxide dismutase 2 (SOD2) and catalase (CAT) genes have been associated with abnormalities in antioxidant enzyme activity in the aging brain, suggesting a risk for enhanced oxidative damage to white matter and cognition among older individuals with these genetic variants. The present study compared differences in white matter microstructure and cognition among 96 older adults with and without genetic risk factors of SOD2 (rs4880) and CAT (rs1001179). Results revealed higher radial diffusivity in the anterior thalamic radiation among SOD2 CC genotypes compared to CT/TT genotypes. Further, the CC genotype moderated the relationship between the hippocampal cingulum and processing speed, though this did not survive multiple test correction. The CAT polymorphism was not associated with brain outcomes in this cohort. These results suggest that the CC genotype of SOD2 is an important genetic marker of suboptimal brain aging in healthy individuals.

Cognitive reserve moderates the relationship between neuropsychological performance and white matter fiber bundle length in healthy older adults.

Recent work using novel neuroimaging methods has revealed shorter white matter fiber bundle length (FBL) in older compared to younger adults. Shorter FBL also corresponds to poorer performance on cognitive measures sensitive to advanced age. However, it is unclear if individual factors such as cognitive reserve (CR) effectively moderate the relationship between FBL and cognitive performance. This study examined CR as a potential moderator of cognitive performance and brain integrity as defined by FBL. Sixty-three healthy adults underwent neuropsychological evaluation and 3T brain magnetic resonance imaging. Cognitive performance was measured using the Repeatable Battery of Assessment of Neuropsychological Status (RBANS). FBL was quantified from tractography tracings of white matter fiber bundles, derived from the diffusion tensor imaging. CR was determined by estimated premorbid IQ. Analyses revealed that lower scores on the RBANS were associated with shorter whole brain FBL (p = 0.04) and lower CR (p = 0.01) CR moderated the relationship between whole brain FBL and RBANS score (p < 0.01). Tract-specific analyses revealed that CR also moderated the association between FBL in the hippocampal segment of the cingulum and RBANS performance (p = 0.03). These results demonstrate that lower cognitive performance on the RBANS is more common with low CR and short FBL. On the contrary, when individuals have high CR, the relationship between FBL and cognitive performance is attenuated. Overall, CR protects older adults against lower cognitive performance despite age-associated reductions in FBL.