Unveiling the proteome-wide autoreactome enables enhanced evaluation of emerging CAR-T therapies in autoimmunity.

Given the global surge in autoimmune diseases, it is critical to evaluate emerging therapeutic interventions. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leveraged advances in programmable-phage immunoprecipitation (PhIP-Seq) methodology to explore the modulation, or lack thereof, of autoantibody profiles, proteome-wide, in both health and disease. Using a custom set of over 730,000 human derived peptides, we demonstrated that each individual, regardless of disease state, possesses a distinct and complex constellation of autoreactive antibodies. For each individual, the set of resulting autoreactivites constituted a unique immunological fingerprint, or "autoreactome," that was remarkably stable over years. Using the autoreactome as a primary output, we evaluated the relative effectiveness of various immunomodulatory therapies in altering autoantibody repertoires. We found that therapies targeting B-Cell Maturation Antigen (BCMA) profoundly altered an individual's autoreactome, while anti-CD19 and CD20 therapies had minimal effects. These data both confirm that the autoreactome is comprised of autoantibodies secreted by plasma cells, and strongly suggest that BCMA or other plasma cell targeting therapies may be highly effective in treating currently refractory autoantibody mediated diseases.

Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations (C9orf72, GRN, MAPT) compared to 39 noncarrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of 1) sporadic progressive supranuclear palsy-Richardson syndrome and 2) frontotemporal dementia spectrum syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. 'Hub' proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.

Neuropsychiatric profiles and cerebral amyloid burden in adults without dementia.

INTRODUCTION: We comprehensively evaluated how self- and informant-reported neuropsychiatric symptoms (NPS) differentially associated with cerebral amyloid-beta (Aß) PET levels in older adults without dementia. METHODS: 221 participants (48% female, age=73.4y±8.4, CDR=0 [n=184] or 0.5 [n=37]) underwent an Aß-PET scan (Florbetapir or PIB), comprehensive neuropsychological testing, and self-reported (Geriatric Depression Scale- 30 item), and informant-reported interview (Neuropsychiatric Inventory Questionnaire) of NPS. Cerebral Aß burden was quantified using Centiloids (CL). NPI-Q and GDS-30 queried presence of NPS within 4 subdomains and 6 subscales, respectively. Regression models examined the relationship between NPS and Aß-PET CL. RESULTS: Both higher self- and informant-reported NPS were associated with higher Aß burden. Among specific NPI-Q subdomains, informant-reported changes in depression, anxiety, and irritability were all associated with higher Aß-PET. Similarly, self-reported (GDS-30) subscales of depression, apathy, anxiety, and cognitive concern associated with higher Aß-PET. When simultaneously entered, only self-reported cognitive concern associated with Aß-PET in the GDS-30 model, while both informant-reported anxiety and depression associated with Aß-PET in the NPI-Q model. Clinical status moderated the association between self-reported NPS and Aß-PET, such that the positive relationship between self-perceived NPS and Aß burden strengthened with increasing functional difficulties. CONCLUSIONS: In a cohort of older adults without dementia, both self- and informant-reported measures of global NPS, particularly patient-reported cognitive concerns and informant-reported anxiety and depression, corresponded with cerebral Aß burden. NPS may appear early in the prodromal disease state and relate to initial AD proteinopathy burden, a relationship further exaggerated in those with greater clinical severity.

Latent Profile Analysis of Cognitive Performance and Depressive Symptoms Among People with HIV.

Depression and cognitive impairment are prevalent conditions among people with HIV (PWH), likely attributable to shared causes and common risk factors. Identifying subtypes of PWH with similar patterns of neurocognitive impairment (NCI) and depressive symptoms may inform development of patient-centered interventions that target-specific profiles. This study aimed to (1) classify PWH based on patterns of domain-specific NCI and depression; and (2) determine the relationship between latent class membership and pertinent clinical characteristics. PWH (N = 580, 86.2% male, 57.1% non-Hispanic White, 69.2% unemployed) completed a comprehensive neuropsychological test battery assessing global and domain-specific cognition. Domain-specific NCI was classified as deficit score >0.5. Participants completed the Beck Depression Inventory-II (BDI-II), and domain-specific BDI-II scores reflecting cognitive, affective, and somatic symptoms were computed. Latent profile analysis (LPA) was used to determine latent subgroups of NCI and depression. The optimal LPA solution consisted of five classes: minimal NCI and minimal depression (Class 1), amnestic and minimal depression (Class 2), severe multi-domain NCI and moderate depression (somatic and affective; Class 3), mild NCI and mild depression (Class 4), and moderate multi-domain NCI and severe depression (Class 5). Despite similar levels of functional impairment, Class 5 had a significant psychiatric profile, whereas Class 3 had a complex medical profile (i.e., higher frailty index, higher medications, greater proportion of AIDS diagnosis). In contrast, Class 1 had the lowest medication use and frailty index, with similar HIV disease characteristics to Classes 3 and 5. Our results suggest there are multiple pathways to cognitive and functional impairment among PWH with co-occurring depression and cognitive impairment, and these groups may respond differently to interventions. Of note, our sample was majority non-Hispanic White and male, which is nonrepresentative of the US population of PWH. Future interventions should consider a more integrated, person-centered approach that addresses cognitive and emotional health to optimize health outcomes in PWH.

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss.

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we found that CT-KIBRA stabilized the protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. Thus, our results distinguished KIBRA both as a biomarker of synapse dysfunction and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

Plasma phosphorylated tau-217 exhibits sex-specific prognostication of cognitive decline and brain atrophy in cognitively unimpaired adults.

INTRODUCTION: Accumulating evidence indicates disproportionate tau burden and tau-related clinical progression in females. However, sex differences in plasma phosphorylated tau (p-tau)217 prediction of subclinical cognitive and brain changes are unknown. METHODS: We measured baseline plasma p-tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in 163 participants (85 cognitively unimpaired [CU], 78 mild cognitive impairment [MCI]). In CU, linear mixed effects models examined sex differences in plasma biomarker prediction of longitudinal domain-specific cognitive decline and brain atrophy. Cognitive models were repeated in MCI. RESULTS: In CU females, baseline plasma p-tau217 predicted verbal memory and medial temporal lobe trajectories such that trajectories significantly declined once p-tau217 concentrations surpassed 0.053 pg/ml, a threshold that corresponded to early levels of cortical amyloid aggregation in secondary amyloid positron emission tomography analyses. CU males exhibited similar rates of cognitive decline and brain atrophy, but these trajectories were not dependent on plasma p-tau217. Plasma GFAP and NfL exhibited similar female-specific prediction of medial temporal lobe atrophy in CU. Plasma p-tau217 exhibited comparable prediction of cognitive decline across sex in MCI. DISCUSSION: Plasma p-tau217 may capture earlier Alzheimer's disease (AD)-related cognitive and brain atrophy hallmarks in females compared to males, possibly reflective of increased susceptibility to AD pathophysiology.

The clinical utility of three frailty measures in identifying HIV-associated neurocognitive disorders.

OBJECTIVE: Frailty measures vary widely and the optimal measure for predicting HIV-associated neurocognitive disorders (HAND) is unclear. DESIGN: A study was conducted to examine the clinical utility of three widely used frailty measures in identifying HIV-associated neurocognitive disorders. METHODS: The study involved 284 people with HIV (PWH) at least 50 years enrolled at UC San Diego's HIV Neurobehavioral Research Program. Frailty measurements included the Fried Phenotype, the Rockwood Frailty Index, and the Veterans Aging Cohort Study (VACS) Index. HAND was diagnosed according to Frascati criteria. ANOVAs examined differences in frailty severity across HAND conditions. ROC analyses evaluated sensitivity and specificity of each measure to detect symptomatic HAND [mild neurocognitive disorder (MND) and HIV-associated dementia (HAD)] from no HAND. RESULTS: Across all frailty measures, frailty was found to be higher in HAD compared with no HAND. For Fried and Rockwood (not VACS), frailty was significantly more severe in MND vs. no HAND and in HAD vs. ANI (asymptomatic neurocognitive impairment). For discriminating symptomatic HAND from no HAND, Fried was 37% sensitive and 92% specific, Rockwood was 85% sensitive and 43% specific, and VACS was 58% sensitive and 65% specific. CONCLUSION: These findings demonstrate that Fried and Rockwood outperform VACS in predicting HAND. However, ROC analyses suggest none of the indices had adequate predictive validity in detecting HAND. The results indicate that the combined use of the Rockwood and Fried indices may be an appropriate alternative.

Multimodal lifestyle engagement patterns support cognitive stability beyond neuropathological burden.

BACKGROUND: Modifiable lifestyle behaviors account for a large proportion of dementia risk. However, the combined contributions of multidomain lifestyle patterns to cognitive aging are poorly understood, as most studies have examined individual lifestyle behaviors in isolation and without neuropathological characterization. This study examined data-driven patterns of lifestyle behaviors across multiple domains among older adults and tested their associations with disease-specific neuropathological burden and cognitive decline. METHODS: Participants included 2059 older adults enrolled in the longitudinal Memory and Aging Project (MAP) at the Rush Alzheimer's Disease Center; none of whom had dementia at baseline (73% no cognitive impairment (NCI), 27% mild cognitive impairment [MCI]). All participants completed cognitive testing annually. Lifestyle factors were measured during at least one visit and included (1) actigraphy-measured physical activity, as well as self-reported (2) sleep quality, (3) life space, (4) cognitive activities, (5) social activities, and (6) social network. A subset of participants (n = 791) had autopsy data for which burden of Alzheimer's disease (AD), cerebrovascular disease (CVD), Lewy body disease, and hippocampal sclerosis/TDP-43 was measured. Latent profile analysis across all 2059 participants identified distinct subgroups (i.e., classes) of lifestyle patterns. Linear mixed-effects models examined relationships between lifestyle classes and global cognitive trajectories, with and without covarying for all neuropathologies. Classes were also compared on rates of incident MCI/dementia. RESULTS: Five classes were identified: Class 1Low Life Space (lowest lifestyle engagement), Class 2PA (high physical activity), Class 3Low Avg (low to average lifestyle engagement), Class 4Balanced (high average lifestyle engagement), and Class 5Social (large social network). Classes 4Balanced and 5Social had the lowest AD burden, and Class 2PA had the lowest CVD burden. Classes 2-5 had significantly less steep global cognitive decline compared to Class 1Low Life Space, with comparable effect sizes before and after covarying for neuropathological burden. Classes 4Balanced and 5Social exhibited the lowest rates of incident MCI/dementia. CONCLUSIONS: Lifestyle behavior patterns among older adults account for differential rates of cognitive decline and clinical progression. Those with at least average engagement across all lifestyle domains exhibit greater cognitive stability after adjustment for neuropathology, highlighting the importance of engagement in multiple healthy lifestyle behaviors for later life cognitive health.

Moderating role of physical activity on hippocampal iron deposition and memory outcomes in typically aging older adults.

Physical activity (PA) is linked to better cognitive and brain health, though its mechanisms are unknown. While brain iron is essential for normal function, levels increase with age and, when excessive, can cause detrimental neural effects. We examined how objectively measured PA relates to cerebral iron deposition and memory functioning in normal older adults. Sixty-eight cognitively unimpaired older adults from the UCSF Memory and Aging Center completed neuropsychological testing and brain magnetic resonance imaging, followed by 30-day Fitbit monitoring. Magnetic resonance imaging quantitative susceptibility mapping (QSM) quantified iron deposition. PA was operationalized as average daily steps. Linear regression models examined memory as a function of hippocampal QSM, PA, and their interaction. Higher bilateral hippocampal iron deposition correlated with worse memory but was not strongly related to PA. Covarying for demographics, PA moderated the relationship between bilateral hippocampal iron deposition and memory such that the negative effect of hippocampal QSM on memory performances was no longer significant above 9120 daily steps. PA may mitigate adverse iron-related pathways for memory health.

KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss.

Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we define a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIdney/BRAin (KIBRA) protein (CT-KIBRA). We show that CT-KIBRA restores plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we find that CT-KIBRA binds to and stabilizes protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. In humans we find that reduced KIBRA in brain and increased KIBRA in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. Thus, our results distinguish KIBRA both as a novel biomarker of synapse dysfunction in AD and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.

Data-driven physical actigraphy patterns relate to cognitive and vascular health in older adults.

Health benefits of physical activity (PA) are well known; however, specific PA patterns that relate most strongly to cognitive aging outcomes are poorly understood. We characterized latent profiles of PA among older adults and examined associations with cognition and vascular burden. 124 functionally normal older adults wore a Fitbit™ for 30 days. Daily average step count, sedentary time (0 steps/min), and high-intensity time (≥120 steps/min) were calculated. Participants completed neurocognitive testing assessing cognitive domains of executive functioning and memory; medical history, from which vascular burden (i.e., a count of cardiovascular conditions) was calculated; and brain MRI (n = 44). Subgroups with similar PA patterns were identified via latent profile analysis. Three latent PA classes emerged: Class 1Low PA (n = 49), Class 2Average PA (n = 59), and Class 3High-intensity PA (n = 16). PA class related to executive functioning and vascular burden, driven by better outcomes in Class 3 than Class 1. Sex-stratified analyses revealed these associations were strongest in males. Post hoc analyses showed a positive association between high-intensity PA and white matter integrity among males. High-intensity PA related to better cognitive and vascular health, particularly among males. Findings inform physical activity-specific and person-specific recommendations for optimal cognitive aging.

Sex-specific effects of SNAP-25 genotype on verbal memory and Alzheimer's disease biomarkers in clinically normal older adults.

INTRODUCTION: We tested sex-dependent associations of variation in the SNAP-25 gene, which encodes a presynaptic protein involved in hippocampal plasticity and memory, on cognitive and Alzheimer's disease (AD) neuroimaging outcomes in clinically normal adults. METHODS: Participants were genotyped for SNAP-25 rs1051312 (T > C; SNAP-25 expression: C-allele > T/T). In a discovery cohort (N = 311), we tested the sex by SNAP-25 variant interaction on cognition, Aß-PET positivity, and temporal lobe volumes. Cognitive models were replicated in an independent cohort (N = 82). RESULTS: In the discovery cohort, C-allele carriers exhibited better verbal memory and language, lower Aß-PET positivity rates, and larger temporal volumes than T/T homozygotes among females, but not males. Larger temporal volumes related to better verbal memory only in C-carrier females. The female-specific C-allele verbal memory advantage was evidenced in the replication cohort. CONCLUSIONS: In females, genetic variation in SNAP-25 is associated with resistance to amyloid plaque formation and may support verbal memory through fortification of temporal lobe architecture. HIGHLIGHTS: The SNAP-25 rs1051312 (T > C) C-allele results in higher basal SNAP-25 expression. C-allele carriers had better verbal memory in clinically normal women, but not men. Female C-carriers had higher temporal lobe volumes, which predicted verbal memory. Female C-carriers also exhibited the lowest rates of amyloid-beta PET positivity. The SNAP-25 gene may influence female-specific resistance to Alzheimer's disease (AD).

Sex Differences in the Relationship between Perceived Stress and Cognitive Trajectories.

OBJECTIVE: Chronic stress adversely affects cognition, in part due to stress-induced inflammation. Rodent models suggest females are more resilient against stress-related cognitive dysfunction than males; however, few studies have examined this in humans. We examined sex differences in the relationship between perceived stress, cognitive functioning, and peripheral inflammation over time among cognitively normal older adults. DESIGN: Longitudinal observational study. SETTING: University research center. PARTICIPANTS: 274 community-dwelling older adults (baseline age: M=70.7, SD=7.2; 58% women; Clinical Dementia Rating=0) who completed at least two study visits. MEASUREMENTS: Neurocognitive functioning and perceived stress (Perceived Stress Scale [PSS]) were assessed at each visit. Plasma was analyzed for interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in a subset of 147 participants. Linear mixed effects models examined the interaction between average PSS (i.e., averaged within persons across visits), sex, and time on cognitive domains and on inflammatory markers. RESULTS: The interaction between stress, sex, and time predicted executive functioning (ß = 0.26, SE = 0.10, p = 0.01) such that higher average PSS related to steeper declines in men, but not in women. Among the 147 participants with inflammatory data, higher average PSS was associated with steeper increases in IL-6 over time in men, but not in women. CONCLUSION: Consistent with animal models, results showed older men were more vulnerable to negative effects of stress on cognitive aging, with domain-specific declines in executive function. Findings also suggest systemic immunological mechanisms may underlie increased risk for cognitive decline in men with higher levels of stress. Future work is needed to examine the potential efficacy of person-specific stress interventions.

Plasma biomarkers of vascular dysfunction uniquely relate to a vascular-risk profile of neurocognitive deficits in virally-suppressed adults with HIV.

Objective: Chronic inflammation and vascular dysfunction (e.g., chronic endothelial activation) are related yet dissociable mechanisms of HIV-associated neurocognitive impairment (NCI), even among those on antiretroviral therapy (ART). However, how these mechanisms differentially contribute to domain-specific deficits in people with and without HIV (PWH, PWoH) is unclear. We empirically-derived profiles of NCI and examined relationships with peripheral inflammatory and vascular biomarkers. Methods: Participants were 84 virally-suppressed PWH and 126 PWoH who underwent neuropsychological testing and blood draw. Cluster analysis identified subgroups based on domain deficit scores. ANOVAs examined HIV serostatus and cluster group differences in composite plasma biomarker z-scores of inflammation (IL-6, CXCL10/IP-10, CCL2/MCP-1) and vascular injury (VCAM-1, ICAM-1, uPAR). Confirmatory regressions examined the interaction of HIV and biomarker z-scores on domain-specific T-scores, controlling for cardiovascular disease (CVD) risk and psychosocial factors. Results: Cluster analysis identified three groups: Unimpaired (n = 129), Learning/Recall (n = 52, isolated learning/recall deficits), Dysexecutive/Slow (n = 29, executive function, working memory, processing speed, and motor deficits). PWH had higher odds of Dysexecutive/Slow membership, which related to CVD risk and higher vascular dysfunction, but not inflammation, in PWH. Vascular biomarkers moderated adverse HIV effects on executive function, processing speed, and working memory such that PWH had lower T-scores only when vascular dysfunction was high. Conclusions: In PWH with controlled disease, peripheral markers of endothelial dysfunction and vascular permeability are selectively associated with an empirically-derived subgroup that exhibits domain deficits commonly impacted by cerebrovascular disease. Findings support the presence of a vascular NCI subgroup of PWH who may benefit from interventions that directly target the neurovascular unit.

Combined Effects of Synaptic and Axonal Integrity on Longitudinal Gray Matter Atrophy in Cognitively Unimpaired Adults.

BACKGROUND AND OBJECTIVES: Synaptic dysfunction and degeneration is a predominant feature of brain aging and synaptic preservation buffers against Alzheimer's disease (AD) protein-related brain atrophy. We tested whether cerebrospinal fluid (CSF) synaptic protein concentrations similarly moderate the effects of axonal injury, indexed via CSF neurofilament light [NfL], on brain atrophy in clinically normal adults. METHODS: Clinically normal older adults enrolled in the observational Hillblom Aging Network study at the UCSF Memory and Aging Center completed baseline lumbar puncture and longitudinal brain MRI (Mean scan [follow-up]=2.6 [3.7 years]). CSF was assayed for synaptic proteins (synaptotagmin-1, synaptosomal-associated protein 2 [SNAP-25], neurogranin, growth associated protein 43 [GAP-43]), axonal injury (NfL), and core AD biomarkers (ptau181/Aß42 ratio; reflecting AD proteinopathy). Ten bilateral temporo-parietal gray matter ROIs shown to be sensitive to clinical AD were summed to generate a composite temporo-parietal ROI. Linear mixed-effects models tested statistical moderation of baseline synaptic proteins on baseline NfL-related temporo-parietal trajectories, controlling for ptau181/Aß42 ratios. RESULTS: Forty-six clinically normal older adults (Mean age=70; 43% female) were included. Synaptic proteins exhibited small to medium correlations with NfL (r range: .10 to .36). Higher baseline NfL, but not ptau181/Aß42 ratios, predicted steeper temporo-parietal atrophy (NfL x time: ß=-0.08, p<.001; ptau181/Aß42 x time: ß=-0.02, p=.31). SNAP-25, neurogranin, and GAP-43 significantly moderated NfL-related atrophy trajectories (-0.07≤ßs≥-0.06, ps<.05) such that NfL was associated with temporo-parietal atrophy at high (more abnormal) but not low (more normal) synaptic protein concentrations. At high NfL concentrations, atrophy trajectories were 1.5 to 4.5 times weaker when synaptic protein concentrations were low (ß range: -0.21 to -0.07) than high (ß range: -0.33 to -0.30). CONCLUSIONS: The association between baseline CSF NfL and longitudinal temporo-parietal atrophy is accelerated by synaptic dysfunction and buffered by synaptic integrity. Beyond AD proteins, concurrent examination of in vivo axonal and synaptic biomarkers may improve detection of neural alterations that precede overt structural changes in AD-sensitive brain regions.

Cognitive and Physiologic Reserve Independently Relate to Superior Neurocognitive Abilities in Adults Aging With HIV.

BACKGROUND: To investigate joint contributions of cognitive and physiologic reserve to neurocognitive SuperAging in older persons with HIV (PWH). METHODS: Participants included 396 older PWH (age range: 50-69 years) who completed cross-sectional neuropsychological and neuromedical evaluations. Using published criteria, participants exhibiting global neurocognition within normative expectations of healthy 25-year-olds were classified as SuperAgers (SA; n = 57). Cognitively normal (CN; n = 172) and impaired (n = 167) participants were classified with chronological age-based norms. Cognitive reserve was operationalized with an estimate of premorbid verbal intelligence, and physiologic reserve was operationalized with a cumulative index of 39 general and HIV-specific health variables. Analysis of variance with confirmatory multinomial logistic regression examined linear and quadratic effects of cognitive and physiologic reserve on SA status, adjusting for chronological age, depression, and race/ethnicity. RESULTS: Univariably, SA exhibited significantly higher cognitive and physiologic reserve compared with CN and cognitively impaired ( d s ≥ 0.38, p s < 0.05). Both reserve factors independently predicted SA status in multinomial logistic regression; higher physiologic reserve predicted linear increases in odds of SA, and higher cognitive reserve predicted a quadratic "J-shaped" change in odds of SA compared with CN (ie, odds of SA > CN only above 35th percentile of cognitive reserve). CONCLUSIONS: Each reserve factor uniquely related to SA status, which supports the construct validity of our SA criteria and suggests cognitive and physiologic reserve reflect nonoverlapping pathways of neuroprotection in HIV. Incorporation of proxy markers of reserve in clinical practice may improve characterization of age-related cognitive risk and resilience among older PWH, even among PWH without overt neurocognitive impairment.

The association between benzodiazepine use and greater risk of neurocognitive impairment is moderated by medical burden in people with HIV.

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

Neopterin Relates to Lifetime Depression in Older Adults With HIV on Suppressive Antiretroviral Therapy.

BACKGROUND: Chronic inflammation contributes to the pathogenesis of depression in persons with HIV (PWH). Neopterin, a biomarker of HIV-related immune activation that partially normalizes with antiretroviral therapy (ART), correlates with major depressive disorder (MDD) and subclinical depressive symptoms in persons without HIV and acutely infected, young PWH. The sensitivity of neopterin, however, to both lifetime and current depression is poorly understood in older PWH on suppressive ART. METHODS: Participants were 70 PWH and 35 persons without HIV (HIV-) who were at least 50 years old and completed standardized neurobehavioral and neuromedical assessments. Depressive symptoms in the past 2 weeks, measured with the Beck Depression Inventory-II (BDI-II), and lifetime MDD diagnoses, defined as meeting Diagnostic and Statistical Manual of Mental Disorders-IV criteria for a depressive episode at any point in one's lifetime, were separately modeled as a function of plasma neopterin levels in the full sample and by HIV serostatus. RESULTS: Compared with HIV- adults, PWH had higher neopterin levels (P < 0.001) and BDI-II scores (P < 0.01) and were more likely to have lifetime MDD (P < 0.01). Higher neopterin related to lifetime MDD, but only in PWH, even after controlling for clinically relevant comorbidities and treatment factors in logistic regression (odds ratio = 3.11, P = 0.002). Higher neopterin correlated with higher BDI-II scores in the full sample (rs = 0.25; P = 0.010), but not within either group (PWH: rs = 0.03, P = 0.819; HIV-: rs = 0.09, P = 0.588). CONCLUSION: Neopterin was associated with lifetime MDD, but not current depressive symptoms in older PWH on suppressive ART. This may reflect a legacy of inflammation-related disruptions to amino acid metabolism and neurotransmitter synthesis, similar to prior observations. Identification of biopsychosocial and resilience factors underlying the null association between neopterin and current depression in older PWH is warranted.

Relationship of the balloon analog risk task to neurocognitive impairment differs by HIV serostatus and history of major depressive disorder.

HIV and major depressive disorder (MDD) commonly co-occur and are both linked to greater risk-taking behavior, possibly due to neurocognitive impairment (NCI). The present study examined the concordance of the Balloon Analog Risk Task (BART), a gold standard measure of risk-taking propensity, with NCI and real-world sexual risk behaviors in PWH with comorbid MDD. Participants included 259 adults, stratified by HIV serostatus (HIV + /HIV -) and lifetime MDD (MDD + /MDD -), who completed neuropsychological testing, the BART, and sexual risk behavior questionnaires. Logistic regression, stratified by HIV serostatus, examined joint effects of MDD and BART (linear and quadratic) on NCI. Follow-up linear regressions examined sexual risk behavior and neurocognitive domain T-scores as correlates of the BART. NCI prevalence was lowest in HIV - /MDD - , but BART scores did not differ by HIV/MDD status. In the HIV + group, BART performance predicted NCI such that high and low BART scores related to greater odds of NCI, but only in dual-risk HIV + /MDD + individuals. HIV + /MDD + individuals with both low and high BART scores exhibited poorer learning and recall, whereas processing speed and executive function were only poor in low BART risk-taking HIV + /MDD + . Higher BART scores linearly related to higher sexual risk behaviors only in MDD + individuals, independent of HIV serostatus. Low and high risk-taking on the BART may reflect discrete neurocognitive profiles in HIV + /MDD + individuals, with differential implications for real-world sexual risk behavior. HIV and comorbid MDD may disturb corticostriatal circuits responsible for integrating affective and neurocognitive components of decision-making, thereby contributing to risk-averse and risk-taking phenotypes.