Global Deficit Score Research Articles

Switching to Low Neurotoxic Antiretrovirals to Improve Neurocognition Among People Living With HIV-1-Associated Neurocognitive Disorder: The MARAND-X Randomized Clinical Trial

Background: The pathogenesis of HIV-associated neurocognitive (NC) impairment is multifactorial, and antiretroviral (ARV) neurotoxicity may contribute. However, interventional pharmacological studies are limited. Methods: Single-blind, randomized (1:1), controlled trial to assess the change of NC performance (Global Deficit Score, GDS, and domain scores) in PLWH with NC impairment randomized to continue their standard of care treatment or to switch to a less neurotoxic ARV regimen: darunavir/cobicistat, maraviroc, emtricitabine (MARAND-X). Participants had plasma and cerebrospinal fluid HIV RNA< 50 copies/mL, R5-tropic HIV, and were on ARV regimens that did not include efavirenz and darunavir. The change of resting-state electroencephalography was also evaluated. The outcomes were assessed at week 24 of the intervention through tests for longitudinal paired data and mixed-effect models. Results: Thirty-eight participants were enrolled and 28 completed the follow-up. Global Deficit Score improved over time but with no difference between arms in longitudinal adjusted models. Perceptual functions improved in the MARAND-X, while long-term memory improved only in participants within the MARAND-X for whom the central nervous system penetration-effectiveness (CNS penetration effectiveness) score increased by ≥3. No significant changes in resting-state electroencephalography were observed. Conclusions: In this small but well-controlled study, the use of less neurotoxic ARV showed no major beneficial effect over an unchanged regimen. The beneficial effects on the memory domain of increasing CNS penetration effectiveness score suggest that ARV neuropenetration may have a role in cognitive function.

B - 24 Assessing Cognitive Impairment within a High-Blast Risk Military Force

Abstract Objective Explosive Ordinance Disposal (EOD) is a military occupational specialty that is particularly high risk for blast exposures as well as psychologically traumatic combat experiences. We explore cognitive performance, symptom profiles, and blast exposure history of this group. Methods Participants were recruited from an active duty TBI rehabilitation center. Of 123 participants, 12 were EOD (Other N = 111). Learning and memory (HVLT-R), sustained attention (PASAT) and executive functioning (DKEFS) were assessed. A Global Deficit Score (GDS) was calculated to determine impairment. Neurobehavioral symptoms (NSI), PTSD and depressive symptoms (PCL-M and PHQ-8), combat (CES) and blast exposures (BETS) history were also assessed. Results When comparing EOD to Other, age, number of mTBIs, and blast exposures were comparable (p’s > 0.05). There was a trend for EOD to report fewer symptoms and more combat deployments. EOD reported greater exposure to combat (CES p = 0.004, d = 0.90) and performed stronger cognitively. HVLT-R-Total (EOD M = 48.50, SD = 9.46; Other M = 39.13, SD = 11.67; p = 0.008, d = 0.82), HVLT-R-Delayed (EOD M = 45.75, SD = 11.11, Other M = 38.61, SD = 13.76; p = 0.09, d = 0.53) and PASAT (EOD M = 54.10, SD = 7.37; Other M = 46.56, SD = 10.21; p = 0.014, d = 0.76). 50.4% of the overall sample and 16.7% of the EOD sample were determined to have cognitive impairment (GDS p = 0.015). Conclusions Results highlight the importance of baseline assessment for higher functioning specialized populations. EOD performed better than general forces on cognitive measures, including memory domains previously identified to be impacted by blast exposures. EOD presents with greater kinetic combat experiences that expose them to psychologically traumatic events despite reporting fewer symptoms. Most notable is the high rate of cognitive impairment in an active military force.

Childhood Neighborhood Disadvantage and Cognitive Function among Veterans Recovering from Mild Traumatic Brain Injury

Abstract Objective Identifying risk factors and interventions for chronic symptoms following mild traumatic brain injury (TBI) is an important area of research for Veterans. Growing up in a disadvantaged neighborhood is associated with poorer health outcomes. We examined the relationship between childhood neighborhood disadvantage and cognitive outcomes among symptomatic Veterans with history of mild TBI. Method 58 Participants completed neuropsychological tests (CVLT-3, TMT A&B, COWA, Category Test), NSI, and PCL-5. The Neighborhood Atlas was used to derive disadvantage scores using childhood addresses. Global deficit scores were calculated as described by Heaton (2004). Results Neighborhood disadvantage was significantly correlated with CVLT-3 Total Learning (r = −0.26, p = 0.046), but not the overall global deficit or deficit performance across CVLT-3 Delayed Recall, TMT-A, TMT-B, COWA, and Category Test. There was a significant difference in neighborhood disadvantage between participants scoring in the deficit and normal ranges on CVLT-3 Total Learning (p = 0.046). There were no other differences in neighborhood disadvantage across other neuropsychological tests. There was a significant difference in PTSD symptoms between participants scoring within the deficit and normal ranges on the COWA (p = 0.002). There were no other significant group differences in neuropsychiatric symptoms or PTSD symptom severity. Conclusions Among Veterans in this sample, neighborhood disadvantage was not associated with cognitive function or cognitive deficits. Although neighborhood disadvantage is an important psychosocial risk factor for poor outcomes in the civilian literature, these results suggest that it may not be an important contributing factor in recovery from mild TBI for military Veterans.

Neurocognitive Functioning is Impaired in Perinatally HIV-Infected Youth.

The present study examined neurocognitive differences between Perinatally HIV (PHIV)-infected-youth and age and gender matched healthy controls. Despite early, long-term anti-viral treatment (ART), significant neurocognitive deficiencies remain for PHIV-infected-youth reaching adulthood compared to controls. Participants were assessed with a comprehensive neuropsychological battery. An Overall Neurocognitive Composite Score and a Global Deficit Score (GDS) were created. Sleep, depression, and developmental level of intellectual functioning were also examined. PHIV-youth performed more poorly than controls in all neurocognitive domains. Very large effect sizes were observed for the Overall Neurocognitive Composite Score and GDS. PHIV-infected-youth appear to be significantly more depressed compared to controls, but there were no differences in amount or type of sleep observed. Despite early, long-term anti-viral treatment (ART), neurocognitive deficiencies remain for PHIV-infected-young-adults. The verbal learning domain was significantly impaired with implications for functioning. The PHIV-infected-youth were also depressed and not receiving treatment for depression.

Genetic Variations in EIF2AK3 are Associated with Neurocognitive Impairment in People Living with HIV

Based on emerging evidence on the role for specific single-nucleotide variants (SNVs) in EIF2AK3 encoding the integrated stress response kinase PERK, in neurodegeneration, we assessed the association of EIF2AK3 SNVs with neurocognitive performance in people with HIV (PWH) using a candidate gene approach. This retrospective study included the CHARTER cohort participants, excluding those with severe neuropsychiatric comorbidities. Genome-wide data previously obtained for 1047 participants and targeted sequencing of 992 participants with available genomic DNA were utilized to interrogate the association of three noncoding and three coding EIF2AK3 SNVs with the continuous global deficit score (GDS) and global neurocognitive impairment (NCI; GDS ≥ 0.5) using univariable and multivariable methods, with demographic, disease-associated, and treatment characteristics as covariates. The cohort characteristics were as follows: median age, 43.1 years; females, 22.8%; European ancestry, 41%; median CD4 + T cell counts, 175/µL (nadir) and 428/µL (current). At first assessment, 70.5% used ART and 68.3% of these had plasma HIV RNA levels ≤ 200 copies/mL. All three noncoding EIF2AK3 SNVs were associated with GDS and NCI (all p < 0.05). Additionally, 30.9%, 30.9%, and 41.2% of participants had at least one risk allele for the coding SNVs rs1805165 (G), rs867529 (G), and rs13045 (A), respectively. Homozygosity for all three coding SNVs was associated with significantly worse GDS (p < 0.001) and more NCI (p < 0.001). By multivariable analysis, the rs13045 A risk allele, current ART use, and Beck Depression Inventory-II value > 13 were independently associated with GDS and NCI (p < 0.001) whereas the other two coding SNVs did not significantly correlate with GDS or NCI after including rs13045 in the model. The coding EIF2AK3 SNVs were associated with worse performance in executive functioning, motor functioning, learning, and verbal fluency. Coding and non-coding SNVs of EIF2AK3 were associated with global NC and domain-specific performance. The effects were small-to-medium in size but present in multivariable analyses, raising the possibility of specific SNVs in EIF2AK3 as an important component of genetic vulnerability to neurocognitive complications in PWH.Graphical

Neuropsychological longitudinal study of patients with low-grade gliomas: Cognitive impairment

This study is part of a longitudinal research program, in which patients diagnosed with low-grade gliomas (LGG: n = 13), as well as healthy controls (n = 13), were consecutively recruited and neuropsychologically followed for 7 years. The patients are followed up regardless of variations in treatment. A composite score is used (Global Deficit Score: GDS) included cognitive measures where at least five patients had a negative change: information processing speed, speed of naming, construction ability, verbal fluency, non-verbal thinking, and immediate non-verbal memory. The most important finding in this 7-year follow-up study is that two-thirds of the patients developed cognitive impairment. The remaining third of the patients showed stability in their cognitive ability and were still alive 17 years after diagnosis. Younger patients with tumors in the right frontal or posterior regions showed a more favorable development. Patients with frontal tumors and a declined GDS show also significant changes in executive functions. Given the limited number, no firm conclusions can be drawn regarding the impact of tumor localization. The impact of LGG on cognition and the survival time after diagnosis varies considerably between patients. However, most of the patients (69%) showed cognitive impairment during the seven years we followed them.

COGNITIVE IMPAIRMENT, FRAILTY, AND GRIP FORCE GENERATION IN PEOPLE LIVING WITH HIV

Abstract People living with HIV (PLWH) face an earlier onset and higher rates of geriatric syndromes, including frailty and cognitive impairment. Grip force, an index of frailty, is sensitive to cognitive decline, central nervous system integrity, and may independently predict adverse health outcomes. The current study evaluates frailty, weakness, and cognitive impairment, as well as the neural correlates of grip force as they predict cognitive impairment. PLWH aged 55+ (N = 26; M = 61.9, SD = 4.7; 53.8% female; 76.9% Black) completed an fMRI task in which they were asked to generate 0%, 20%, 50%, and 80% of their maximum force, a neuropsychological battery, and a physical assessment. Cognitive impairment was indexed using the Global Deficit Score (GDS). Per Fried’s Frailty Phenotype, 3.8% of the sample was robust, 57.7% was pre-frail, and 38.5% was frail. Impairment in memory significantly predicted GDS, controlling for age (B = 0.3, t = 4.9, p &amp;lt; .001). Robust frailty status significantly predicted GDS, controlling for age (B = -1.1, t = -2.4, p &amp;lt; .05). Age was also a significant predictor of GDS, controlling for frailty status (B = -0.1, t = -2.7, p &amp;lt; .05). Weakness, as indexed by grip strength, predicted frailty (F = 4.5, p &amp;lt; .05). Additional analyses will be conducted to examine activation in brain regions germane to force generation during the fMRI task as a predictor of GDS. To our knowledge, this is the first study to examine neural correlates of grip force generation in PLWH.

Mild Traumatic Brain Injury in the Maturing Brain: An Investigation of Symptoms and Cognitive Performance in Soldiers Returning From Afghanistan and Iraq.

The majority of traumatic brain injuries (TBIs) are classified as mild and occur in young individuals. The course of recovery varies but can result in chronic or troubling outcomes. The impact of age on TBI outcomes in young adults before complete brain maturation is not well studied. In this study, we compared the effects of mild TBI on cognitive performance and self-reported TBI symptoms and posttraumatic stress disorder (PTSD) in 903 soldiers in 3 different age groups: 24 years or younger, 25 to 27 years, and 28 to 40 years. The soldiers had returned from war zones in Iraq and were screened for TBI within a few days of return. Cognitive performance was measured with the Automated Neuropsychological Assessment Metrics of Military TBI Version 4 (ANAM4). Symptoms associated with mild TBI were self-reported on the Neurobehavioral Symptom Inventory, and the PTSD Checklist-Civilian Version (PCL-C). Soldiers with TBI in every age group had significantly higher prevalence of most symptoms than those with no TBI. Soldiers with TBI also reported more chronic pain sites, regardless of age. Soldiers aged 28 to 40 years with TBI had the lowest cognitive performance scores (ANAM) across several subtests, both unadjusted and adjusted. The Global Deficit Score was significantly higher for soldiers aged 28 to 40 years and 25 to 27 years with TBI than for soldiers younger than 24 years with no TBI. After adjusting for PTSD symptoms, education, and number of lifetime TBIs, the overall test battery mean for soldiers aged 28 to 40 years with TBI was significantly lower than for soldiers younger than 24 years with no TBI. Soldiers with mild TBI in the younger age group show more symptoms associated to frontal lobe function while soldiers in the older group suffer more cognitive impairment. This may warrant further study as it may indicate a propensity to later cognitive decline among soldiers who were older at the time of injury.

Diagnostic utility of culture/language‐specific normative data on the Version 3 of the Uniform Data Set Neuropsychological Battery for differentiating stages of cognitive impairment among Latinos in the United States

AbstractBackgroundAccurate detection of neurocognitive disorders of aging among Latinos in the United States (U.S.) is an important step towards addressing disparities in Alzheimer’s disease and related dementias (ADRDs) and promoting health equity in this group. Federally‐funded Alzheimer’s Disease Research Centers (ADRCs) in the U.S. have utilized the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set Version 3 Neurobehavioral Battery (UDS3‐NB) since 2015. Normative data on this battery adjusted for age, education and sex were published for English‐speakers in 2018 (Weintraub et al., 2018) and expanded to consider differences among non‐Hispanics White and Black people in 2020 (Sachs et al., 2020). We aimed to determine whether the use of newly developed culture/language‐specific neuropsychological normative data for Spanish‐ and English‐speaking Latinos in the U.S. improved diagnostic accuracy of the UDS3‐NB in this group.MethodParticipants included 1,018 Latino adults age 50+ enrolled in ADRCs. Table 1 presents participant demographics by global Clinical Dementia Rating (CDR) score, as indicative of stage of neurocognitive impairment (0 = normal, 0.5 = questionable impairment, 1 = mild impairment, 2‐3 = moderate‐to‐severe impairment). Individual test raw scores were converted to demographically‐adjusted z scores utilizing normative data on the UDS3‐NB developed for Latinos and for other culture/language groups. Individual tests z scores were converted to deficit scores and averaged to compute global deficit scores and determine global neurocognitive impairment (NCI). Rates of NCI based on culture/language specific normative data were compared across the four CDR groups via Chi‐Square tests. Sensitivity and specificity were computed for differentiating participants with CDR = 0 (normal) and CDR = 1 (mild impairment) based on different sets of normative data.ResultsUtilizing culture/language‐specific normative data significantly differentiated CDR groups (p&lt;.001; Figure 1). These culture/language specific normative data performed better in differentiating between CDR = 0 and 1, than utilizing normative data developed for non‐Hispanic English speakers (Table 2).ConclusionCulture/language‐specific normative data improve diagnostic accuracy for neurocognitive impairment among Latinos in the U.S. relative to existing normative data developed for other groups. These culture/language‐specific norms can be used in research and clinical practice to enhance ADRD diagnosis among Latinos and represent an important step towards addressing ADRD disparities in this group.

An Automated Virtual Reality Program Accurately Diagnoses HIV-Associated Neurocognitive Disorders in Older People With HIV.

HIV-associated neurocognitive disorders (HANDs) remain prevalent despite antiretroviral therapy, particularly among older people with HIV (PWH). However, the diagnosis of HAND is labor intensive and requires expertise to administer neuropsychological tests. Our prior pilot work established the feasibility and accuracy of a computerized self-administered virtual reality program (DETECT; Display Enhanced Testing for Cognitive Impairment and Traumatic Brain Injury) to measure cognition in younger PWH. The present study expands this to a larger sample of older PWH. We enrolled PWH who were ≥60 years old, were undergoing antiretroviral therapy, had undetectable plasma viral loads, and were without significant neuropsychological confounds. HAND status was determined via Frascati criteria. Regression models that controlled for demographic differences (age, sex, education, race/ethnicity) examined the association between DETECT's cognition module and both HAND status and Global Deficit Score (GDS) derived via traditional neuropsychological tests. Seventy-nine PWH (mean age, 66 years; 28% women) completed a comprehensive neuropsychological battery and DETECT's cognition module. Twenty-five (32%) had HAND based on the comprehensive battery. A significant correlation was found between the DETECT cognition module and the neuropsychological battery (r = 0.45, P < .001). Furthermore, in two separate regression models, HAND status (b = -0.79, P < .001) and GDS impairment status (b = -0.83, P < .001) significantly predicted DETECT performance. Areas under the curve for DETECT were 0.78 for differentiating participants by HAND status (HAND vs no HAND) and 0.85 for detecting GDS impairment. The DETECT cognition module provides a novel means to identify cognitive impairment in older PWH. As DETECT is fully immersive and self-administered, this virtual reality tool holds promise as a scalable cognitive screening battery.

Mode of HIV exposure and excess burden of neurocognitive impairment in people living with HIV: a protocol for systematic review and meta-analysis of controlled studies

BackgroundChronic HIV infection significantly elevates the risk of brain pathology, precipitating neurocognitive impairment (NCI) among people living with HIV (PLWH). The diagnosis of NCI in PLWH hinges on evaluating deviations in neuropsychological test performance in comparison to HIV-seronegative normative controls. However, the adverse psychosocial conditions experienced by PLWH can also result in reduced test performance, potentially confounding the accurate NCI attribution to HIV infection. This planned systematic review aims to investigate potential disparities in the excess burden of NCI among PLWH in two groups of studies: (a) studies enrolling controls who shared a similar mode of HIV exposure (MoHE) with the PLWH participants (MoHE-adjusted) and (b) studies enrolling normative controls or controls without undefined MoHE (MoHE-naive).MethodsWe will systematically search five electronic databases (MEDLINE, Embase, PsycINFO, Web of Science, ProQuest) and registries (OpenGrey, ClinicalTrials.gov, ISRCTN registry). Studies reporting NCI in PLWH and HIV-seronegative controls with cross-sectional or baseline measurements, published from January 2007 to September 2023, will be included. To be classified as MoHE adjusted, a study must evidence ≥ 90% enrolment of both PLWH and their seronegative controls from the same MoHE group (e.g. men who have sex with men, people who use drugs or alcohol). Reports of test performance scores will be transformed into NCI proportions using simulated score distributions, applying a global deficit score cut-off ≥ 0.5 to estimate NCI cases.The Newcastle–Ottawa scale adapted to the purpose of the review will be used to appraise study quality. Random-effects meta-analysis will be used to pool the excess burden of NCI in prevalence ratios and test the difference between MoHE-adjusted and MoHE-naive studies. Furthermore, subgroup analyses and meta-regression will be undertaken across categorical study-level covariates (e.g. study locations, NCI diagnostic criteria) and continuous/ordinal covariates (nadir CD4, number of neurocognitive domains assessed), respectively.DiscussionThis systematic review will contribute towards a greater appreciation of the unique psychosocial conditions of PLWH that are missing from the current case definition of HIV-associated neurocognitive disorder. The findings will additionally highlight possible disparities in the distribution of the excess burden of NCI by MoHE groups, thereby guiding the prioritization of mitigation efforts.Systematic review registrationPROSPERO CRD42021271358

Intrathecal production of anti-Epstein-Barr virus viral capsid antigen IgG is associated with neurocognition and tau proteins in people with HIV.

HIV and Epstein-Barr virus (EBV) co-infection has been linked to increased immune activation and larger HIV reservoir. We assessed whether anti-EBV humoral responses are associated with increased cerebrospinal fluid (CSF) inflammation and with neurocognitive impairment (NCI) in people with HIV (PWH). Cross-sectional analysis in 123 EBV-seropositive PWH either on antiretroviral therapy ( n = 70) or not. Serum and CSF anti-EBV viral capsid antigen immunoglobulin G (anti-EVI) and CSF EBV DNA were measured by commercial immunoassay and RT-PCR. Seventy-eight participants without neurological confounding factors underwent neurocognitive assessment (Global Deficit Score, GDS). CSF total tau and 181-phosphorylated-tau (ptau) were measured by immunoassays together with biomarkers of blood-brain barrier (BBB) integrity, immune activation, astrocytosis, and intrathecal synthesis. Logistic and linear regressions and moderation analysis were used to investigate the relationships between CSF anti-EVI, GDS, and biomarkers. Twenty-one (17.1%) and 22 participants (17.9%) had detectable CSF anti-EVI (10.5-416.0 U/ml) and CSF EBV DNA (25-971 copies/ml). After adjusting for BBB integrity, age, and clinical factors, the presence of CSF anti-EVI was only associated with serum levels of anti-EVI, and not with CSF EBV DNA. CSF anti-EVI, tau and ptau showed reciprocal interactions affecting their associations with GDS. After adjusting for demographics and clinical parameters, higher CSF anti-EVI levels were associated with worse GDS (aβ 0.45, P < 0.001), and CSF levels of tau and ptau had a moderation effect on the strength of this association (models' P < 0.001). Humoral immune responses against EBV within the central nervous system may contribute to NCI in PWH through mechanisms that involve neuronal injury.

60 Differential Benefits of Internal Strengths and Socioemotional Support on Neurocognition and Daily Functioning Among People with HIV

Objective:Positive psychological attributes have been associated with better health outcomes and quality of life among people with HIV (PWH). Recently, we identified two latent factors (internal strengths, socioemotional support) among 7 positive psychological attributes through factor analysis (Ham et al., 2022). Depression was inversely associated with both factors. Our current aim was to investigate associations between these latent factors, neurocognition, and daily functioning among PWH.Participants and Methods:106 PWH and 90 HIV- participants were included in cross-sectional analyses (Mage = 51.3, 77% men, 60% White). Seven positive psychological questionnaires, a neuropsychological battery covering 7 domains, two daily functioning questionnaires (Patient’s Assessment of Own Functioning (PAOFI); Independent Activities of Daily Living (IADL)), and a depression symptom questionnaire (Center for Epidemiologic Studies Depression Scale) were administered. Internal strengths and socioemotional support composite z-scores were calculated using HIV- participants’ scores as reference. Outcomes included global and domain-specific neurocognitive T-scores (demographically-adjusted), global deficit score (GDS), number of functional impairments (PAOFI), and number of functional declines (IADL). Main effects of HIV status, latent factors, and their interaction were included in linear (neurocognition) and Poisson (daily functioning) regressions. Significant interactions were followed up by simple effects analyses and nonsignificant interactions were removed. Depressive symptoms and demographics associated with daily functioning were included as covariates.Results:PWH exhibited worse neurocognitive performance (global, executive functioning, processing speed, learning, recall, GDS) and reported greater functional difficulties and depressive symptoms compared to HIV-counterparts (ps &lt; 0.05). For neurocognition, there were socioemotional support x HIV status (B = 2.39, p = 0.04) and internal strengths x HIV status (B = 2.70, p &lt; 0.05) interactions on verbal fluency, accounting for depressive symptoms, such that only PWH had a positive association between socioemotional support and verbal fluency (B = 1.97, p = 0.01). Removing nonsignificant interactions, there was a main effect of socioemotional support on global cognition (B = 1.01, p = 0.04) and psychomotor speed (B = 1.83, p = 0.02), independent of HIV status and depressive symptoms. For daily functioning, there was a socioemotional support x HIV status interaction on IADL declines (B = 0.42, p = 0.02), accounting for depressive symptoms and education, such that only HIV- participants had an inverse relationship between socioemotional support and IADL declines (B = -0.64, p &lt; 0.001). Removing non-significant interactions, there were main effects of internal strengths on PAOFI impairments (B = -0.36, p &lt; 0.001) and IADL declines (B = -0.38, p &lt; 0.001), independent of HIV status and depressive symptoms.Conclusions:Among PWH, both positive psychological factors were associated with better neurocognition, even after adjusting for depressive symptomatology. Though internal strengths were associated with better daily functioning regardless of HIV status, socioemotional support was not related to daily functioning in PWH. While mechanisms underlying these associations cannot be established cross-sectionally, it is possible that among people with medical illnesses complicated by cognitive disturbance, positive psychological factors relate to improved health-related behaviors (e.g., better disease management). Additionally, better neurocognition, including cognitive reserve, may engender greater resilience and improved ability to marshal social support.

O011 Exploring Nocturnal Blood Pressure Surges Relationships with Brain Health and Cognitive Function.

Abstract Introduction Cerebral small vessel disease is a possible mechanism to explain the link between long-term incompletely treated obstructive sleep apnoea (OSA) and dementia. Recent evidence suggests nocturnal blood pressure (BP) surges triggered by OSA-related sympathetic hyperactivity could play a critical role. However, this remains to be determined as they often occur concurrently with desaturation events. Methods During an in-lab polysomnography study of 7 controls [AHI≤5] and 20 untreated OSA patients [AHI&amp;gt;5] aged 45-65 years the frequency of blood pressure surges (&amp;gt;10% systolic ↑BP) in the presence or not of desaturation events (↓SpO2&amp;gt;3%) were quantified with a SOMNOtouch™ NIBP device. Cerebral perfusion was assessed with pCASL MRI and brain lesions with anatomical MRI scans. The global deficit score was determined for cognitive function assessment. Inflammation was quantified with blood hs-CRP. Results After controlling for age, BMI, gender, blood glucose and cholesterol, higher AHI was associated with more frequent BP surges (r=0.52, P=0.03), BP surges occurring with desaturation events (r=0.87, P&amp;lt;0.001), but not with BP surges without oxygen desaturation (P = 0.11). Concurrent BP surges and oxygen desaturation was associated with increased hs-CRP (r=0.55, P=0.02). Frequency of BP surges was not related to cerebral perfusion, brain lesions or the global deficit score. Conclusions Recording nocturnal blood pressure surges during polysomnography may provide insight into the cardiovascular burden associated with OSA. Interestingly, an inflammatory response is associated with BP surges only during desaturations, i.e. during respiratory events. Further work is needed to assess the utility of BP surges in predicting longer-term cognitive deficits.

The kynurenine pathway relates to post-acute COVID-19 objective cognitive impairment and PASC.

To determine the prevalence and natural history of post-acute COVID-19 objective cognitive impairment and function, and their relationship to demographic, clinical factors, post-acute sequelae of COVID-19 (PASC), and biomarkers. A total of 128 post-acute COVID-19 patients (age = 46 ± 15; 42% women, acute disease severity: not hospitalized: 38.6% mild: 0-1 symptoms, 52% 2+ symptoms; 9.4% hospitalized) completed standard cognition, olfaction, and mental health examinations 2-, 4-, and 12-month post diagnosis. Over the same time frame, WHO-defined PASC was determined. Blood cytokines, peripheral neurobiomarkers, and kynurenine pathway (KP) metabolites were measured. Objective cognitive function was demographically/practice corrected, and impairment prevalence was determined using the evidence-based Global Deficit Score method to detect at least mild cognitive impairment (GDS > 0.5). Linear mixed effect regression models with time effect (month post diagnosis) evaluated the relationships to cognition. Across the 12-month study period, mild to moderate cognitive impairment ranged from 16% to 26%, and 46.5% were impaired at least once. Impairment associated with poorer work capacity (p < 0.05), and 2-month objectively tested anosmia (p < 0.05). PASC with (p = 0.01) and without disability (p < 0.03) associated with acute COVID-19 severity. KP measures showed prolonged activation (2 to 8 months) (p < 0.0001) linked to IFN-beta in those with PASC. Of the blood analytes, only the KP metabolites (elevated quinolinic acid, 3-hydroxyanthranilic acid, kynurenine, the kynurenine/tryptophan ratio) associated (p < 0.001) with poorer cognitive performance and greater likelihood of impairment. PASC, independent of disability associated with abnormal kynurenine/tryptophan (p < 0.03). The kynurenine pathway relates to post-acute COVID-19 objective cognitive impairment and PASC, thereby enabling biomarker and therapeutic possibilities.

Comparison of Resting State Functional Connectivity in Persons With and Without HIV: A Cross-sectional Study.

This study examined the effects of human immunodeficiency virus (HIV) on resting state functional connectivity (RSFC) in a large cohort of people with HIV (PWH) and healthy controls without HIV (PWoH). Within PWH analyses focused on the effects of viral suppression and cognitive impairment on RSFC. A total of 316 PWH on stable combination antiretroviral therapy and 209 demographically matched PWoH were scanned at a single institution. Effects of the virus were examined by grouping PWH by detectable (viral load > 20 copies/mL; VLD) and undetectable (VLU) viral loads and as being cognitively impaired (CI) (Global Deficit Score ≥ 0.5) or cognitively normal (CN). Regression analysis, object oriented data analysis, and spring embedded graph models were applied to RSFC measures from 298 established brain regions of interest comprising 13 brain networks to examine group differences. No significant RSFC differences were observed between PWH and PWoH. Within PWH, there were no significant differences in RSFC between VLD and VLU subgroups and CI and CN subgroups. There were no significant effects of HIV on RSFC in our relatively large cohort of PWH and PWoH. Future studies could increase the sample size and combine with other imaging modalities.

Social cognition and apathy between two cognitive subtypes of schizophrenia: Are there the same or different profiles?

ObjectiveCognitive impairment is an essential feature of schizophrenia, and it involves a broad array of nonsocial and social cognitive domains. This study aimed to examine whether there are the same or different social cognition profiles between two cognitive subtypes of schizophrenia. MethodThere were one hundred and two chronic and institutionalized patients with schizophrenia from two referral tracks. One group is “Cognitively Normal Range” (CNR) (N = 52), and another group is “Below Normal Range” (BNR) (N = 50). We assessed or collected their apathy, emotional perception judgment, facial expression judgment, and empathy by the Apathy Evaluation Scale, the International Affective Picture System, the Japanese and Caucasian Facial Expression of Emotion, and the Interpersonal Reactivity Index, respectively. ResultsWe found different impairment profiles depending on the cognitive subtypes of the patient with schizophrenia. Surprisingly, the CNR presented impairments in apathy, emotional perception judgment, facial expression judgment, and empathy and feature impairment in empathy and affective apathy. In contrast, even though the BNR had significant neurocognition impairments, they had almost intact empathy with significantly impaired cognitive apathy. Both groups' global deficit scores (GDSs) were comparable, and all reached at least a mild impairment level. ConclusionsThe CNR and the BNR had similar abilities in emotional perception judgment and facial emotion recognition. They also had differentiable deficits in apathy and empathy. Our findings provide important clinical implications for neuropsychological pathology and treatment in schizophrenia.

Subcortical Gray Matter Loss and Ventricular Enlargement Define Specific HIV Biotypes (S25.008)

<h3>Objective:</h3> To identify and characterize neurodegenerative biotypes in people with HIV (PWH). <h3>Background:</h3> PWH may develop brain atrophy and neurocognitive dysfunction despite suppressive antiretroviral therapy. Distinguishing biotypes within this population is critical since they may represent unique underlying pathophysiological mechanisms and require different therapeutic approaches. <h3>Design/Methods:</h3> Participants in a longitudinal natural history study of a large, well-characterized, diverse cohort of PWH and matched controls underwent deep phenotyping including MRI and neuropsychological testing. Subcortical gray matter (SGM) and ventricular volumetrics were derived from FreeSurfer, then transformed into percentiles adjusted for age, sex, skull size, and MRI scanner. Correlation coefficients between percentile and clinical variables were calculated. Logistic regression assessed effects of continuous clinical variables on binary percentiles. <h3>Results:</h3> Our cohort included 209 PWH (159 male, 50 female) and 64 controls (34 male, 30 female). Subsets with the worst 20^th percentile of SGM atrophy (n=51) or ventricular enlargement (n=77) were identified. In PWH with SGM atrophy (n=43), analyses controlled for age, sex, and IQ showed positive associations with overall T-score (r=0.41, p=0.008); executive (r=0.43, p=0.004), learning (r=0.37, p=0.015), memory (r=0.38, p=0.014), and motor (r=0.36, p=0.021) domains; and global deficit score (GDS) (r=−0.37, p=0.015). Interestingly, SGM percentile also negatively correlated with total cholesterol (r=−0.44, p=0.014). Ventricular enlargement was associated with lower overall T-score in both HIV+ males (OR=0.92, CI=0.87–0.98, p=0.011) and HIV+ females (OR=0.89, CI=0.80–0.98, p=0.032). In HIV+ males, ventricular enlargement was associated with reduced verbal (OR=0.94, CI=0.89–0.98, p=0.010), speed of information processing (OR=0.96, CI=0.91–1.00, p=0.037), and motor (OR=0.94, CI=0.89–0.98, p=0.004) performance. In HIV+ females, it was associated with increased GDS (OR=8.20, CI=1.43–81.56, p=0.042) and systolic blood pressure (OR=1.04, CI=1.00–1.09, p=0.038). <h3>Conclusions:</h3> PWH with neurodegeneration can be grouped into SGM atrophy or ventricular enlargement biotypes. These subsets associate with distinct neurocognitive deficits and clinical risk factors, suggesting disparate underlying pathophysiological mechanisms. <b>Disclosure:</b> Ms. Dietrich has nothing to disclose. Ms. McMahan has nothing to disclose. Tianxia Wu has nothing to disclose. Mr. Bhagavatheeshwaran has received research support from National Institutes of Health. Dr. Reich has received research support from NIH. The institution of Dr. Reich has received research support from Vertex Pharmaceuticals. The institution of Dr. Reich has received research support from Adelson Medical Research Foundation. The institution of Dr. Reich has received research support from Myelin Repair Foundation. The institution of Dr. Reich has received research support from Sanofi-Genzyme. The institution of Dr. Reich has received research support from Abata Therapeutics. The institution of Dr. Reich has received research support from National Multiple Sclerosis Society. Dr. Reich has received personal compensation in the range of $500-$4,999 for serving as a CME Faculty with PeerView. Dr. Reich has received personal compensation in the range of $500-$4,999 for serving as a CME Faculty with AcademicCME. Dr. Reich has a non-compensated relationship as a Advisor with Sanofi-Genzyme that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Board of Directors with ACTRIMS that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with Abata Therapeutics that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with Roche that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with American Brain Foundation that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with University of Basel RC2NB that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with Multiple Sclerosis Society of Canada that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with Tuscan Doctorate in Neuroscience that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Editorial Board with Multiple Sclerosis Journal that is relevant to AAN interests or activities. Dr. Reich has a non-compensated relationship as a Advisor with Glaxo-Smith-Kline that is relevant to AAN interests or activities. Dr. Snow has received research support from NIH/NIMH. The institution of Anuradha Ganesan has received research support from NIAID. Dr. Berjohn has received personal compensation in the range of $100,000-$499,999 for serving as a Active Duty Physician salary with US Navy. Brian K. Agan has received personal compensation for serving as an employee of Henry M. Jackson Foundation for the Advancement of Military Medicine. Dr. Nath has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Nath has received research support from National Institutes of Health. The institution of Dr. Nath has received research support from ALS Association. Dr. Smith has nothing to disclose.

Anemia and Erythrocyte Indices Are Associated With Neurocognitive Performance Across Multiple Ability Domains in Adults With HIV.

Anemia is linked to neurocognitive impairment (NCI) in people with HIV (PWH), but its impact within specific ability domains, and in diverse populations with HIV, is uncertain. Participants included 1339 PWH enrolled in observational HIV cohort studies with a mean of 3 comprehensive neurocognitive assessments over 30 months. Global and domain-specific neurocognitive function were assessed by the global deficit score and domain deficit score (GDS and DDS, respectively) or as GDS-defined or DDS-defined NCI (GDS ≥ 0.5, DDS > 0.5). Time-dependent associations of anemia or red-cell indices with neurocognitive function were evaluated by multivariable regression. The mean age at entry was 43.6 years (85% male, 23.9% Hispanic, 16.7% African ancestry by self-report, and 69.8% virally suppressed). Anemia occurred at entry in 297 (22.2%) and developed subsequently in another 129 (9.6%). Anemia (present in 26.8% of cognitively impaired PWH at entry) and lower hemoglobin were associated with higher (worse) GDS values; the association for anemia persisted after multivariable adjustment and in virally suppressed persons ( P < 0.0001). Anemia was also associated with reduced processing speed, motor function, learning, delayed recall, working memory (all P < 0.01), executive function ( P = 0.021), and verbal fluency ( P = 0.035), and these findings persisted in longitudinal analyses (adjusted P < 0.01 for all domains, except verbal fluency). Higher mean corpuscular volume and mean corpuscular hemoglobin were associated with less impairment in learning and recall (all P < 0.05). Anemia in diverse and virally suppressed PWH associates with reduced neurocognitive performance in multiple domains, cross-sectionally and over time. The impact of identifying and treating anemia to prevent or slow neurocognitive decline in PWH should be prospectively evaluated.

HIV-1 Subtype C Vpr Amino Acid Residue 45Y and Specific Conserved Fragments Are Associated with Neurocognitive Impairment and Markers of Viral Load.

There is increasing evidence that HIV-1 viral protein R (Vpr) plays an important role in the pathogenesis of cognitive impairment. We investigated the relationship between HIV-1 subtype C Vpr sequence variation and HIV-associated neurocognitive impairment as measured by global deficit score (GDS) in treatment-naive individuals. We used different bioinformatic tools and statistical models to correlate vpr variation and cognitive function. We identified a tyrosine at position 45 (45Y) as a signature for neurocognitive impairment and histidine (45H) as a signature in the non-impaired individuals. The presence of signature 45Y was associated by 3.66 times higher GDS, 525 times higher plasma viral load, 15.84 times higher proviral load, and 60% lower absolute CD4-T cell count compared with those without the signature. Additionally, we identified four conserved Vpr fragment sequences, PEDQGPQREPYNEWTLE (5-21), LGQYIY (42-47), TYGDTW (49-54), and PEDQGPQREPYNEW (5-18), that were associated with higher plasma viral load and proviral load. The implication of these findings is that variation of Vpr leads to neurocognitive impairment in HIV infection and worsens the progression of disease in general by promoting the production of provirus, promoting HIV replication and depletion of CD4+ T cells in the periphery.