Neuropsychiatric Profiles and Cerebral Amyloid Burden in Adults without Dementia.

INTRODUCTION: We comprehensively evaluated how self- and informant-reported neuropsychiatric symptoms (NPS) were differentially associated with cerebral amyloid-beta (Aß) PET levels in older adults without dementia. METHODS: Two hundred and twenty-one participants (48% female, age = 73.4 years ± 8.4, Clinical Dementia Rating = 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 [GDS-30]) and informant-reported interview (Neuropsychiatric Inventory Questionnaire [NPI-Q]) of NPS. Cerebral Aß burden was quantified using centiloids (CL). NPI-Q and GDS-30 queried the 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 were associated with higher Aß-PET. When simultaneously entered, only self-reported cognitive concern was associated with Aß-PET in the GDS-30 model, while both informant-reported anxiety and depression were 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.

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.

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.

A longitudinal study of cannabis use and risk for cognitive and functional decline among older adults with HIV.

Cannabis use is rapidly increasing among older adults in the United States, in part to treat symptoms of common health conditions (e.g., chronic pain, sleep problems). Longitudinal studies of cannabis use and cognitive decline in aging populations living with chronic disease are lacking. We examined different levels of cannabis use and cognitive and everyday function over time among 297 older adults with HIV (ages 50-84 at baseline). Participants were classified based on average cannabis use: frequent (> weekly) (n = 23), occasional (≤ weekly) (n = 83), and non-cannabis users (n=191) and were followed longitudinally for up to 10 years (average years of follow-up = 3.9). Multi-level models examined the effects of average and recent cannabis use on global cognition, global cognitive decline, and functional independence. Occasional cannabis users showed better global cognitive performance overall compared to non-cannabis users. Rates of cognitive decline and functional problems did not vary by average cannabis use. Recent cannabis use was linked to worse cognition at study visits when participants had THC+ urine toxicology-this short-term decrement in cognition was driven by worse memory and did not extend to reports of functional declines. Occasional (≤ weekly) cannabis use was associated with better global cognition over time in older adults with HIV, a group vulnerable to chronic inflammation and cognitive impairment. Recent THC exposure may have a temporary adverse impact on memory. To inform safe and efficacious medical cannabis use, the effects of specific cannabinoid doses on cognition and biological mechanisms must be investigated in older adults.

RESUMEN: El consumo de cannabis está aumentando rápidamente entre los adultos mayores en los Estados Unidos, en parte para tratar síntomas de afecciones de salud comunes (p. ej. dolor crónico, problemas de dormir). Actualmente, hay pocos estudios longitudinales sobre el consumo de cannabis y el deterioro cognitivo en poblaciones que envejecen y viven con enfermedades crónicas. Examinamos diferentes niveles del consumo de cannabis y funciones cognitivas a lo largo del tiempo entre 297 adultos mayores con VIH (de 50 a 84 años al principio de la investigación). Los participantes se clasificaron según el consumo promedio de cannabis: consumidores de cannabis frecuentes (> semanal) (n = 23) ocasionales (≤ semanal) (n = 83), y no consumidores de cannabis (n=191) fueron seguidos longitudinalmente hasta por 10 años (promedio = 3,9 años). Los modelos multinivel investigaron los efectos del consumo promedio y reciente de cannabis en la cognición global, el deterioro cognitivo global, y la independencia funcional. Los consumidores ocasionales de cannabis mostraron un mejor rendimiento cognitivo global en comparación con los no consumidores. El nivel de deterioro cognitivo y problemas funcionales no estuvieron asociado con el uso de cannabis. El consumo reciente de cannabis se vinculó con una peor cognición en las visitas del estudio cuando los participantes tenían toxicología de orina de THC positivo­esta disminución a corto plazo de la cognición se debió a una peor memoria, pero no se extendió a los informes de deterioros funcionales. El consumo ocasional (≤ semanal) de cannabis se asoció con una mejor cognición global a lo largo del tiempo en adultos mayores con VIH, un grupo susceptible a la inflamación crónica y la disfunción cognitiva. La exposición reciente al THC puede tener un impacto negativo temporal en la memoria. Los efectos de dosis específicas de cannabinoides en la cognición y sus mecanismos de acción biológicos deben ser investigados en personas mayores con el fin de informar el uso seguro y eficaz del cannabis medicinal.

Impact of PTSD and Obstructive Sleep Apnea on Cognition in Older Adult Veterans.

Background: Posttraumatic stress disorder (PTSD) and obstructive sleep apnea (OSA) are highly prevalent and comorbid among older adult male veterans. Both PTSD and OSA are independently associated with cognitive deficits in older adults, but little research regarding the impact of comorbid PTSD and OSA among older adults exists. Purpose: The current study aimed to examine the independent and interactive effects of PTSD and OSA on cognitive functioning in older adult veterans. Study Sample: Older adult male veterans with (n = 106) and without PTSD (n = 69), ranging in age from 55 to 89 (M = 63.35). Data Collection: Participants underwent polysomnography evaluation to assess severity of OSA symptoms and comprehensive neuropsychological evaluation to assess cognitive functioning in 3 domains: attention and processing speed, learning and memory, and executive functioning. Results: Multiple regression analyses showed that the interaction between PTSD and OSA did not predict cognitive performance. However, PTSD significantly predicted poorer attention and processing speed, and increased OSA severity predicted poorer learning and memory. Conclusions: While PTSD and OSA did not have a synergistic detrimental impact on cognition, each independently predicted poorer cognitive functioning within certain domains, suggesting that older adults with these comorbid conditions may experience a wider array of cognitive difficulties.

Regional Vulnerability of the Corpus Callosum in the Context of Cardiovascular Risk.

Many factors outside of cardiovascular health can impact the structure of white matter. Identification of reliable and clinically meaningful biomarkers of the neural effects of systemic and cardiovascular health are needed to refine etiologic predictions. We examined whether the corpus callosum demonstrates regional vulnerability to systemic cardiovascular risk factors. Three hundred and ninety-four older adults without dementia completed brain MRI, neurobehavioral evaluations, and blood draws. A subset (n = 126, n = 128) of individuals had blood plasma analyzed for inflammatory markers of interest (IL-6 and TNF-alpha). Considering diffusion tensor imaging (DTI) is a particularly reliable measure of white matter integrity, we utilized DTI to examine fractional anisotropy (FA) of anterior and posterior regions of the corpus callosum. Using multiple linear regression models, we simultaneously examined FA of the genu and the splenium to compare their associations with systemic and cardiovascular risk factors. Lower FA of the genu but not splenium was associated with greater systemic and cardiovascular risk, including higher systolic blood pressure (ß = -0.17, p = .020), hemoglobin A1C (ß = -0.21, p = .016) and IL-6 (ß = -0.34, p = .005). FA of the genu was uniquely associated with cognitive processing speed (ß = 0.20, p = .0015) and executive functioning (ß = 0.15, p = .012), but not memory performances (ß = 0.05, p = .357). Our results demonstrated differential vulnerability of the corpus callosum, such that frontal regions showed stronger, independent associations with biomarkers of systemic and cardiovascular health in comparison to posterior regions. Posterior white matter integrity may not reflect cardiovascular health. Clinically, these findings support the utility of examining the anterior corpus callosum as an indicator of cerebrovascular health.

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).

Social Contact Frequency and Pain among Older Adults with HIV: An Ecological Momentary Assessment Study.

BACKGROUND: Social relationships are important for pain management among individuals with HIV, but the impact of daily social contact on pain responses in real-time, real-world settings has never been specifically examined. PURPOSE: The purpose of the present study was to examine the relationship between social contact frequency and pain, and the role of negative and positive affect in this relationship among older adults with HIV using ecological momentary assessment (EMA). METHODS: A total of 66 (Mage = 59.3, SD = 6.3, range: 50-74) older adults with HIV completed EMA surveys that included social contact frequency, pain level, and negative and positive affect four times per day for 2 weeks. Mixed-effects regression models were used to examine concurrent and lagged associations between social contact frequency, pain, and negative and positive affect. RESULTS: Greater recent social contact frequency was associated with less severe current pain (unstandardized B = -0.04, 95% CI: -0.08, -0.01, p = .014), while greater current pain was associated with lower subsequent social contact frequency (unstandardized B = -0.07, 95% CI: -0.11, -0.03, p < .001). Further, higher current negative affect was related to greater current pain, and this relationship was dampened by increased recent social contact frequency (unstandardized B = -0.17, 95% CI: -0.26, -0.08, p < .001). Neither negative nor positive affect was significantly associated with the relationship between current pain and subsequent social contact frequency. CONCLUSIONS: Social contact frequency and pain are bidirectionally and inversely associated among older adults with HIV. Further, recent social contact influences current pain by attenuating negative affect. Together, these results highlight the need to address social engagement in interventions for pain among older adults with HIV.

Binge Drinking Relates to Worse Neurocognitive Functioning Among Adults Aging with HIV.

OBJECTIVE: Given the aging population of people with HIV (PWH), along with increasing rates of binge drinking among both PWH and the general older adult population, this study examined the independent and interactive effects of HIV, binge drinking, and age on neurocognition. METHOD: Participants were 146 drinkers stratified by HIV and binge drinking status (i.e., ≥4 drinks for women and ≥5 drinks for men within approximately 2 h): HIV+/Binge+ (n = 30), HIV-/Binge+ (n = 23), HIV+/Binge- (n = 55), HIV-/Binge- (n = 38). All participants completed a comprehensive neuropsychological battery measuring demographically-corrected global and domain-specific neurocognitive T scores. ANCOVA models examined independent and interactive effects of HIV and binge drinking on neurocognitive outcomes, adjusting for overall alcohol consumption, lifetime substance use, sex, and age. Subsequent multiple linear regressions examined whether HIV/Binge group moderated the relationship between age and neurocognition. RESULTS: HIV+/Binge+ participants had worse global neurocognition, processing speed, delayed recall, and working memory than HIV-/Binge- participants (p's < .05). While there were significant main effects of HIV and binge drinking, their interaction did not predict any of those neurocognitive outcomes (p's > .05). Significant interactions between age and HIV/Binge group showed that HIV+/Binge+ participants demonstrated steeper negative relationships between age and neurocognitive outcomes of learning, delayed recall, and motor skills compared to HIV-/Binge- participants (p's < .05). CONCLUSIONS: Results showed adverse additive effects of HIV and binge drinking on neurocognitive functioning, with older adults demonstrating the most vulnerability to these effects. Findings support the need for interventions to reduce binge drinking, especially among older PWH.

Identification of Youthful Neurocognitive Trajectories in Adults Aging with HIV: A Latent Growth Mixture Model.

Despite the neurocognitive risks of aging with HIV, initial cross-sectional data suggest a subpopulation of older people with HIV (PWH) possess youthful neurocognition (NC) characteristic of SuperAgers (SA). Here we characterize longitudinal NC trajectories of older PWH and their convergent validity with baseline SA status, per established SuperAging criteria in PWH, and baseline biopsychosocial factors. Growth mixture modeling (GMM) identified longitudinal NC classes in 184 older (age ≥ 50-years) PWH with 1-5 years of follow-up. Classes were defined using 'peak-age' global T-scores, which compare performance to a normative sample of 25-year-olds. 3-classes were identified: Class 1Stable Elite (n = 31 [16.8%], high baseline peak-age T-scores with flat trajectory); Class 2Quadratic Average (n = 100 [54.3%], intermediate baseline peak-age T-scores with u-shaped trajectory); Class 3Quadratic Low (n = 53 [28.8%], low baseline peak-age T-scores with u-shaped trajectory). Baseline predictors of Class 1Stable Elite included SA status, younger age, higher cognitive and physiologic reserve, and fewer subjective cognitive difficulties. This GMM analysis supports the construct validity of SuperAging in older PWH through identification of a subgroup with longitudinally-stable, youthful neurocognition and robust biopsychosocial health.

RESUMEN: A pesar de los riesgos neurocognitivos de envejecer con VIH, datos transversales iniciales sugieren que una subpoblación de personas con VIH (PCV) de edad mayor posee neurocognición (NC) juvenil, característica de los Súper-Ancianos (SA). Aquí nosotros caracterizamos trayectorias longitudinales de NC en PCV mayores y su validez convergente con su status de referencia de SA, según los criterios establecidos en PCV, y factores biopsicosociales en la base de referencia. El modelo de mezclas Gaussianas (GMM) identificó clases longitudinales de NC en 184 PCV mayores (edad ≥ 50-años) con 1­5 años de seguimiento. Las clases fueron definidas utilizando puntuaciones-T (T-scores) globales de "edad pico", que comparan el desempeño con una muestra normativa de personas de 25 años de edad. 3-clases fueron identificadas: Clase 1Élite Estable (n = 31 [16.8%], puntuaciones-T de edad pico de referencia altas con trayectoria plana; Clase 2Promedio Cuadrático (n = 100 [54.3%], puntuaciones-T de edad pico de referencia intermedias con trayectoria en forma de u); Clase 3Cuadrática Baja (n = 53 [28.8%], %], puntuaciones-T de edad pico de referencia bajas con trayectoria en forma de u). Los predictores de referencia de la Clase 1Élite Estable incluyen estatus de SA, edad mas joven, reserva cognitiva y fisiológica superior, y menos dificultades cognitivas subjetivas. Este análisis GMM apoya la validez del constructo de Súper-Envejecimiento en PCV mayores mediante la identificación de un subgrupo longitudinalmente estable, neurocognición juvenil y una robusta salud biopsicosocial.

Use of digital health technologies to examine subjective and objective sleep with next-day cognition and daily indicators of health in persons with and without HIV.

Most previous studies investigating sleep's association with health outcomes have relied on averaged sleep quality and laboratory-based health measures. This study examines the dynamic within-person relationships between subjective (Ecological Momentary Assessment) and objective sleep (actigraphy) on next-day cognition (subjective and objective), mood, and engagement in daily activities using linear mixed-effects regression modeling. Participants included 94 individuals (59 people with HIV, 35 HIV-) aged 50-74, assessed daily for 14 consecutive days/nights. Subjective and objective sleep were well correlated and were both associated with subjective ratings of cognition, but not objective cognition. Worse subjective sleep was associated with next-day lower happiness and higher depressed mood, and more pain, but was not related to next-day daily activities. Objective sleep was associated with next-day depressed mood and feelings of worry, and was positively associated with next-day television watching. Results provide evidence to support the utility of real-time assessment for sleep and functional outcomes that may lead to potential personalized interventions for individuals with and without HIV.

Chronically elevated depressive symptoms interact with acute increases in inflammation to predict worse neurocognition among people with HIV.

We examined the joint effects of depressive symptoms (Beck Depression Inventory-II (BDI-II)) and systemic inflammation (plasma C-reactive protein (CRP)) on longitudinal profiles of neurocognition in a cohort of 143 people with HIV (PWH) on antiretroviral therapy. Global neurocognition, processing speed, motor skills, and attention/working memory all worsened as CRP increased but only among PWH who, on average, exhibited moderate to severe depressive symptoms (BDI-II > 22). Findings suggest that some PWH with chronically elevated depressive symptoms may have an inflammatory subtype of depression and a particular vulnerability to neurocognitive changes that may respond to drugs targeting inflammation or its neural sequelae.

Increased Social Interactions Reduce the Association Between Constricted Life-Space and Lower Daily Happiness in Older Adults With and Without HIV: A GPS and Ecological Momentary Assessment Study.

OBJECTIVE: Older persons with human immunodeficiency virus (HIV) (PWH) are particularly susceptible to life-space restrictions. The aims of this study included: 1) using global positioning system (GPS) derived indicators as an assessment of time spent at home among older adults with and without HIV; 2) using ecological momentary assessment (EMA) to examine real-time relationships between life-space, mood (happiness, sadness, anxious), fatigue, and pain; and 3) determining if number of daily social interactions moderated the effect of life-space on mood. METHODS: Eighty-eight older adults (PWH n = 54, HIV-negative n = 34) completed smartphone-based EMA surveys assessing mood, fatigue, pain, and social interactions four times per day for two weeks. Participants' smartphones were GPS enabled throughout the study. Mixed-effects regression models analyzed concurrent and lagged associations among life-space and behavioral indicators of health. RESULTS: PWH spent more of their time at home (79% versus 70%, z = -2.08; p = 0.04) and reported lower mean happiness (3.2 versus 3.7; z = 2.63; p = 0.007) compared to HIV-negative participants. Controlling for covariates, more daily social interactions were associated with higher ratings of real-time happiness (b = 0.12; t = 5.61; df = 1087.9; p< 0.001). Similar findings were seen in lagged analyses: prior day social interactions (b = 0.15; t = 7.3; df = 1024.9; p < 0.0001) and HIV status (b = -0.48; t = -2.56; df = 1026.8; p = 0.01) attenuated the effect of prior day time spent at home on happiness. CONCLUSION: Accounting for engagement in social interactions reduced the significant effect of time spent at home and lower happiness. Interventions targeting social isolation within the context of constricted life-space may be beneficial for increasing positive mood in older adults, and especially relevant to older PWH.

Genetic variation in alcohol dehydrogenase is associated with neurocognition in men with HIV and history of alcohol use disorder: preliminary findings.

The co-occurrence of HIV and alcohol use disorder (AUD) amplifies risk for neural injury and neurocognitive deficits. However, the substantial neurocognitive heterogeneity across HIV+/AUD+ individuals suggests inter-individual differences in vulnerability to the neurotoxicity of comorbid HIV/AUD. Genetic variation in alcohol dehydrogenase (ADH), which metabolizes ethanol, may contribute to inter-individual neurocognitive variability. We evaluated associations between five ADH single-nucleotide polymorphisms (SNPs) and neurocognition in men stratified by HIV and lifetime AUD status. Neurobehavioral assessments were administered to 153 men. Three-way ANOVAs examined the interaction of HIV, AUD, and ADH SNPs on global and domain-specific demographically corrected T scores. Follow-up ANCOVAs adjusted for age, estimated verbal IQ, depression, and remote non-alcohol substance use disorders. HIV/AUD groups differed globally and for verbal fluency, working memory, executive function, and processing speed T scores specifically, with HIV+/AUD+ exhibiting the poorest performance. ADH4 (rs1126671) was associated with large effects on working memory (d = - 1.16, p = .001) and executive function (d = - 0.77, p = .028) selectively in HIV+/AUD+, which remained significant in ANCOVA models. ADH1A (rs3819197) moderated the deleterious effects of HIV+/AUD+ on processing speed such that HIV+/AUD+ related to slower information processing in A allele carriers but not GG homozygotes (ps < 0.03). Preliminary findings suggest genetic variation in the ADH pathway moderates the deleterious neurocognitive effects of comorbid HIV/AUD. Differential metabolism of heavy ethanol exposure may compromise neurocognition under conditions of neurobiological stress, such as in HIV infection. The functional effects on ethanol metabolism of ADH SNPs examined in this study remain poorly understood, warranting further examination of pharmacokinetic mechanisms mediating ADH gene-neurobehavior relationships in HIV.

Pre-frailty predicts cognitive decline at 2-year follow-up in persons living with HIV.

Both HIV disease and frailty syndrome are risk factors for neurocognitive impairment. Longitudinal research among individuals of the general population suggests that frailty predicts future cognitive decline; however, there is limited evidence for these longitudinal relationships among people living with HIV (PLWH). The current study evaluated and compared rates of cognitive decline over 2 years among HIV serostatus and frailty status groups. Participants included 50 PLWH and 60 HIV-uninfected (HIV-) participants who were evaluated at baseline and 2-year follow-up visits. Baseline frailty status (non-frail, pre-frail, and frail) was determined using fried frailty phenotype criteria. Neurocognitive functioning was measured using practice-effect corrected scaled scores derived from a comprehensive neuropsychological battery covering seven cognitive domains. Repeated measures analysis was used to estimate rates of global and domain-specific cognitive change from baseline to 2-year follow-up among each of six HIV/frailty status groups. Among PLWH, the pre-frail group demonstrated consistent declines in global cognitive functioning (B = - 0.029, p = 0.034), processing speed (B = - 0.047, p = 0.031), and motor functioning (B = - 0.048, p = 0.038). Among HIV- participants, pre-frail individuals also declined in global cognitive functioning and processing speed (ps ≤ 0.05). HIV- non-frail participants also declined in the cognitive domains of learning, delayed recall, and motor functioning; however, these declines appeared to be driven by relatively higher baseline scores among this group. Notably, 38% of PLWH changed in frailty status from baseline to follow-up, and those with stable pre-frailty demonstrated higher likelihood for cognitive decline; change in depressive symptoms did not relate to change in frailty status. Current findings highlight pre-frailty as an important clinical syndrome that may be predictive of cognitive decline among PLWH. Interventions to prevent or reduce frailty among vulnerable PLWH are needed to maintain optimal cognitive health.

Lower CSF homovanillic acid relates to higher burden of neuroinflammation and depression in people with HIV disease.

BACKGROUND: HIV-related neuroinflammation has been proposed as a catalyst for dopaminergic dysregulation in mesocortical pathways, which may contribute to the pathogenesis of depression. Abnormalities in dopaminergic neurotransmission and depression are common in people with HIV (PWH), however the link between dopamine (DA) and depression in PWH is poorly characterized. This study investigated CSF dopaminergic biomarkers, specifically DA and its metabolite, homovanillic acid (HVA), and examined their relationship with depressive symptoms and CSF neuroinflammatory markers in PWH and HIV-seronegative (HIV-) individuals. METHODS: Participants were 102 HIV- individuals and 123 PWH (mean age = 42) who underwent neuropsychiatric evaluations and lumbar puncture. Current depression severity was classified using the Beck Depression Inventory-II (BDI-II). CSF was assayed for DA and HVA using high performance liquid chromatography and neuroinflammatory markers using immunoassays. Linear regressions modelled BDI-II scores as a function of HIV, dopaminergic biomarker z-scores, and their interaction, controlling for psychosocial factors. Correlational analyses examined dopaminergic and neuroinflammatory relationships. RESULTS: PWH had significantly higher BDI-II scores than HIV- participants. DA and HVA were not associated with HIV status but both significantly moderated the effect of HIV on BDI-II scores, such that PWH exhibited higher depressive symptoms than HIV- participants only at lower concentrations of HVA (z ≤ 0.06) and DA (z ≤ 0.11). In PWH only, lower HVA significantly correlated with higher BDI-II scores and higher neuroinflammation, including higher MCP-1 and IP-10. CONCLUSIONS: Results suggest that the pathophysiology of depression in PWH differs from that in HIV- individuals. Specifically, lower central dopaminergic activity was selectively associated with greater depressive symptoms and neuroinflammation in PWH. With the rise in consideration of DA agonists for the treatment of depression, these results suggest that PWH may show a greater response to these agents than their HIV- peers.

The Effects of Low-Risk Drinking on Neurocognition Among Older Persons Living With HIV as Compared to Those Without HIV.

BACKGROUND: Heavy alcohol use negatively impacts neurocognition, but some studies report neurocognitive benefits associated with light drinking among HIV-seronegative (HIV-) older persons, suggesting a nonlinear or an inverted "J-shaped" association of alcohol consumption on neurocognition. Alcohol use is common among people with HIV (PWH); however, the association between recent "low-risk" alcohol consumption and neurocognition among PWH is poorly understood. METHODS: Participants included 310 PWH and 89 HIV- older (≥50 years) adults who reported alcohol abstinence or "low-risk" drinking, defined per the National Institute on Alcohol Abuse and Alcoholism criteria (i.e., ≥15 drinks/wk or ≥5 drinks/d for men; ≥8 drinks/wk or ≥4 drinks/d for women). Neurocognition was measured using global and domain-specific demographically corrected T-scores. Multiple linear regressions examined the interaction between total drinks in the last 30 days (linear and quadratic terms) and HIV serostatus on neurocognition, covarying for age, sex, lifetime major depressive disorder, lifetime nonalcohol substance use disorders, and lifetime alcohol use disorder. RESULTS: Total drinks consumed in the last 30 days did not differ by HIV serostatus (p = 0.202). Among HIV- older adults, quadratic effects of total drinks on neurocognition occurred such that optimal neurocognition (i.e., global function, executive function, learning, delayed recall, and motor skills) was detected at intermediate levels of "low-risk" drinking (~20 to 40 drinks), with poorer performance at the lower and higher ranges of "low-risk" consumption. In PWH, total drinks did not exhibit linear or quadratic associations with neurocognition. CONCLUSIONS: In HIV- "low-risk" drinkers, intermediate levels of recent alcohol use were associated with better neurocognition, consistent with the inverted J-shaped association. The same nonlinear effect of recent alcohol consumption on neurocognition was absent in PWH, indicating there may be no beneficial or deleterious effects of low-risk alcohol consumption on neurocognition among PWH. Future research is warranted to examine associations between alcohol consumption and HIV-related biopsychosocial disadvantages that may supersede the neurocognitive benefits of alcohol.

Conditional Effects of Lifetime Alcohol Consumption on Methamphetamine-Associated Neurocognitive Performance.

OBJECTIVES: Methamphetamine (MA) dependence contributes to neurotoxicity and neurocognitive deficits. Although combined alcohol and MA misuse is common, how alcohol consumption relates to neurocognitive performance among MA users remains unclear. We hypothesized that alcohol and MA use would synergistically diminish neurocognitive functioning, such that greater reported alcohol consumption would exert larger negative effects on neurocognition among MA-dependent individuals compared to MA-nonusing persons. METHODS: Eighty-seven MA-dependent (MA+) and 114 MA-nonusing (MA-) adults underwent neuropsychological and substance use assessments. Linear and logistic regressions examined the interaction between MA status and lifetime average drinks per drinking day on demographically corrected global neurocognitive T scores and impairment rates, controlling for recent alcohol use, lifetime cannabis use, WRAT reading performance, and lifetime depression. RESULTS: MA+ displayed moderately higher rates of impairment and lower T scores compared to MA-. Lifetime alcohol use significantly interacted with MA status to predict global impairment (ORR = 0.70, p = .003) such that greater lifetime alcohol use increased likelihood of impairment in MA-, but decreased likelihood of impairment in MA+. Greater lifetime alcohol use predicted poorer global T scores among MA- (b = -0.44, p = .030) but not MA+ (b = 0.08, p = .586). CONCLUSIONS: Contrary to expectations, greater lifetime alcohol use related to reduced risk of neurocognitive impairment among MA users. Findings are supported by prior research identifying neurobiological mechanisms by which alcohol may attenuate stimulant-driven vasoconstriction and brain thermotoxicity. Replication and examination of neurophysiologic mechanisms underlying alcohol use in the context of MA dependence are warranted to elucidate whether alcohol confers a degree of neuroprotection.

Neurocognitive SuperAging in Older Adults Living With HIV: Demographic, Neuromedical and Everyday Functioning Correlates.

OBJECTIVES: Studies of neurocognitively elite older adults, termed SuperAgers, have identified clinical predictors and neurobiological indicators of resilience against age-related neurocognitive decline. Despite rising rates of older persons living with HIV (PLWH), SuperAging (SA) in PLWH remains undefined. We aimed to establish neuropsychological criteria for SA in PLWH and examined clinically relevant correlates of SA. METHODS: 734 PLWH and 123 HIV-uninfected participants between 50 and 64 years of age underwent neuropsychological and neuromedical evaluations. SA was defined as demographically corrected (i.e., sex, race/ethnicity, education) global neurocognitive performance within normal range for 25-year-olds. Remaining participants were labeled cognitively normal (CN) or impaired (CI) based on actual age. Chi-square and analysis of variance tests examined HIV group differences on neurocognitive status and demographics. Within PLWH, neurocognitive status differences were tested on HIV disease characteristics, medical comorbidities, and everyday functioning. Multinomial logistic regression explored independent predictors of neurocognitive status. RESULTS: Neurocognitive status rates and demographic characteristics differed between PLWH (SA=17%; CN=38%; CI=45%) and HIV-uninfected participants (SA=35%; CN=55%; CI=11%). In PLWH, neurocognitive groups were comparable on demographic and HIV disease characteristics. Younger age, higher verbal IQ, absence of diabetes, fewer depressive symptoms, and lifetime cannabis use disorder increased likelihood of SA. SA reported increased independence in everyday functioning, employment, and health-related quality of life than non-SA. CONCLUSIONS: Despite combined neurological risk of aging and HIV, youthful neurocognitive performance is possible for older PLWH. SA relates to improved real-world functioning and may be better explained by cognitive reserve and maintenance of cardiometabolic and mental health than HIV disease severity. Future research investigating biomarker and lifestyle (e.g., physical activity) correlates of SA may help identify modifiable neuroprotective factors against HIV-related neurobiological aging. (JINS, 2019, 25, 507-519).

Age of Last Alcohol Use Disorder Relates to Processing Speed Among Older Adults Living with HIV.

AIMS: Older persons living with HIV (PLWH) and past alcohol use disorder (AUD) are at higher risk for neurocognitive deficits compared to those with either condition alone; however, factors underlying this relationship are unknown. Given that aging potentiates multi-system damage from alcohol misuse, the current study examined whether neurocognitive functioning among older adults relates to the age at which they last met criteria for AUD (i.e. 'age of last AUD'), and whether this relationship differed by HIV serostatus. METHODS: All participants (aged between 50 and 75 years) were grouped by HIV/AUD status: 345 HIV+/AUD+, 148 HIV-/AUD+, 273 HIV+/AUD-, and 206 HIV-/AUD-. Neurocognitive functioning was assessed globally and within seven domains. Among only the two AUD+ groups, multivariable linear regressions examined the interaction between age of last AUD and HIV status on neurocognitive functioning, controlling for demographics and clinical characteristics. RESULTS: Older age of last AUD related to worse processing speed among PLWH (b = -0.03; P = 0.006); however, this relationship was not significant among persons without HIV (b = 0.01; P = 0.455). The interaction between age of last AUD and HIV status did not predict neurocognitive functioning in other domains. Processing speed appeared clinically important, as slower speed related to worse everyday functioning, including more reported cognitive difficulties (r = -0.26, P < 0.001) and higher rates of functional dependence (OR = 0.87, 95%CI = 0.80-0.95, P = 0.002). CONCLUSIONS: Our novel findings, demonstrating slower processing speed when a past AUD occurred at an older age in PLWH, highlight the value in assessing older PLWH for processing speed deficits, even if other cognitive domains appear to be intact.