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Biomedical subjects

Igor Grant

Publications and source records attributed to Igor Grant.

At least 19 recordsLinked to original sources

Stress-related reduction in personal mastery is associated with reduced immune cell beta2-adrenergic receptor sensitivity.

BACKGROUND: A growing body of literature suggests that caregiving burden is associated with impaired immune system functioning, which may contribute to elevated morbidity and mortality risk among dementia caregivers. However, potential mechanisms linking these relationships are not well understood. The purpose of this study was to investigate whether stress-related experience of depressive symptoms and reductions in personal mastery were related to alterations in ss2-adrenergic receptor sensitivity. METHODS: Spousal Alzheimer's caregivers (N = 106) completed measures assessing the extent to which they felt overloaded by their caregiving responsibilities, experienced depressive symptoms, and believed their life circumstances were under their control. We hypothesized that caregivers reporting elevated stress would report increased depressive symptoms and reduced mastery, which in turn would be associated with reduced ss2- adrenergic receptor sensitivity on peripheral blood mononuclear cells (PBMC), as assessed by in vitro isoproterenol stimulation. RESULTS: Regression analyses indicated that overload was negatively associated with mastery (beta = -0.36, p = 0.001) and receptor sensitivity (beta = -0.24, p = 0.030), whereas mastery was positively associated with receptor sensitivity (beta = 0.29, p = 0.005). Finally, the relationship between overload and receptor sensitivity diminished upon simultaneous entry of mastery. Sobel's test confirmed that mastery significantly mediated some of the relationship between overload and receptor sensitivity (z = -2.02, p = 0.044). CONCLUSIONS: These results suggest that a reduced sense of mastery may help explain the association between caregiving burden and reduced immune cell ss2-receptor sensitivity.

Adaptation, Psychological↗

Lithium improves HIV-associated neurocognitive impairment.

OBJECTIVE: To determine the effects of low-dose oral lithium on the neuropsychological performance of individuals diagnosed with HIV-associated neurocognitive impairment. DESIGN AND METHODS: The project was a single-arm, open-label, 12-week pilot study at a university-based tertiary care center. The participants were adults who had been diagnosed with HIV-associated neurocognitive impairment and had been on stable antiretroviral therapy for at least 12 weeks. Conditions that could affect cognition, worsen adherence to study procedures, or increase the risk of lithium adverse reactions were excluded. Twenty-one individuals were screened and eight were enrolled, all of whom completed the study. Oral lithium was initiated at 300 mg daily and was titrated to maintain 12-h trough concentrations between 0.4 and 0.8 mEq/l. Global neuropsychological performance was assessed by the global deficit score. RESULTS: At baseline, all participants had impaired neuropsychological performance and most had reduced CD4 cell counts (median 292 cells/microl), and HIV RNA levels in plasma below 400 copies/mL (seven of eight). Titrated lithium doses ranged between 600 and 1200 mg/day. Performance improved in all eight individuals after 12 weeks, and became unimpaired in six. The study treatment was well tolerated with no grade 3 or 4 adverse events and no premature discontinuations. CONCLUSIONS: Lithium resulted in improved neuropsychological performance in antiretroviral-treated, impaired individuals in this small, open-label study. Based on published in vitro data, lithium may exert this effect by inhibiting neuronal glycogen synthase kinase-3beta.

Administration, Oral↗

Sexual risk behavior of HIV-positive methamphetamine-using men who have sex with men: the role of partner serostatus and partner type.

This study examined the role of partner serostatus and partner type in relation to the sexual risk behaviors and disclosure practices of HIV-positive methamphetamine (meth)-using men who have sex with men (MSM). The sample consisted of 132 HIV-positive meth-using MSM who reported having both serodiscordant (i.e., HIV-negative and unknown serostatus) and seroconcordant (i.e., HIV-positive) partners. HIV-positive meth-using MSM engaged in significantly fewer acts of anal sex with serodiscordant partners as compared to seroconcordant partners. However, mean levels of unprotected anal and oral sex were high, and mean levels of protected sex were low for both seroconcordant and serodiscordant partners. Oral sex was practiced twice as often as anal sex; however, both types of sex were primarily unprotected. This pattern of risky sexual behavior was reported for steady, casual, and anonymous partners, regardless of partner serostatus. Despite high rates of unprotected sex, rates of HIV serostatus disclosure were consistently high for HIV-positive and HIV-negative steady, casual, and anonymous partners. However, rates of disclosure to unknown serostatus partners were low, particularly in relation to anonymous partners. Future research should address the reasons why HIV-positive meth-using MSM engage in risky sexual activity with serodiscordant partners, and HIV prevention programs for this population should emphasize the risks associated with unprotected sex with seroconcordant partners.

Adult↗

Depression and suicidality in HIV/AIDS in China.

BACKGROUND: This pilot study examined rates of major depression and suicidality and their associations with daily functioning in HIV infected (HIV+) and uninfected (HIV-) persons in China. METHOD: HIV+ participants (N=28) and demographically matched HIV- controls (N=23) completed the Chinese Composite International Diagnostic Interview to determine lifetime rates of major depressive disorder (MDD) and suicidality. Current mood and suicidal ideation were assessed with the Beck Depression Inventory-I. The impact of depression and HIV infection on daily functioning was measured by an Activity of Daily Living questionnaire. RESULTS: Mean duration of known HIV+ status was 2 years. Almost 79% (n=22) of HIV+ but just 4% (n=1) of HIV- groups reported lifetime major depression. Of the 22 HIV+ individuals with lifetime MDD, only one had onset before learning of HIV status. The remainder developed MDD within 6 months after testing HIV positive. In those HIV+ subjects who met MDD criteria after HIV diagnosis, only two (9%) had received depression treatment, yet four (18%) had persisting active suicidal thoughts. Depression and HIV+ status independently predicted worse daily functioning. LIMITATIONS: Representativeness is limited in this small sample of convenience. CONCLUSION: This preliminary study presents evidence of high rates of major depression and suicidality in HIV-infected persons in China. Despite this, few had sought mental health assistance, suggesting a need to increase awareness of psychiatric comorbidity and access to mental health services.

Acquired Immunodeficiency Syndrome↗

Sexual compulsivity in a sample of HIV-positive methamphetamine-using gay and bisexual men.

Little research has been done on the relationship between sexual compulsivity and the sexual risk behaviors of methamphetamine (meth) users. This exploratory study sought to identify correlates of sexual compulsivity in a sample of 217 HIV-positive meth-using gay and bisexual men. Participants reported a mean score of 2.4 on the Sexual Compulsivity Scale (SCS) (SD=.76, range 1-4). Sexual compulsivity was positively associated with high-risk sexual behaviors (e.g., number of unprotected sex acts with anonymous partners, total number of HIV-negative or unknown serostatus partners). In multivariate analyses, higher scores on sexual compulsivity were associated with older age, meth use before or during sex, visits to sex clubs and street corners to find sex partners, lower self-efficacy for condom use, lower levels of self-esteem, higher scores on a measure of disinhibition, and a greater number of HIV-negative or unknown serostatus partners. The results suggest that more attention should be focused on sexual compulsivity and its correlates to determine how they may contribute to resistance to sexual behavior change in this high-risk population.

Bisexuality↗

Genetic attributes of cerebrospinal fluid-derived HIV-1 env.

HIV-1 often invades the CNS during primary infection, eventually resulting in neurological disorders in up to 50% of untreated patients. The CNS is a distinct viral reservoir, differing from peripheral tissues in immunological surveillance, target cell characteristics and antiretroviral penetration. Neurotropic HIV-1 likely develops distinct genotypic characteristics in response to this unique selective environment. We sought to catalogue the genetic features of CNS-derived HIV-1 by analysing 456 clonal RNA sequences of the C2-V3 env subregion generated from CSF and plasma of 18 chronically infected individuals. Neuropsychological performance of all subjects was evaluated and summarized as a global deficit score. A battery of phylogenetic, statistical and machine learning tools was applied to these data to identify genetic features associated with HIV-1 neurotropism and neurovirulence. Eleven of 18 individuals exhibited significant viral compartmentalization between blood and CSF (P < 0.01, Slatkin-Maddison test). A CSF-specific genetic signature was identified, comprising positions 9, 13 and 19 of the V3 loop. The residue at position 5 of the V3 loop was highly correlated with neurocognitive deficit (P < 0.0025, Fisher's exact test). Antibody-mediated HIV-1 neutralizing activity was significantly reduced in CSF with respect to autologous blood plasma (P < 0.042, Student's t-test). Accordingly, CSF-derived sequences exhibited constrained diversity and contained fewer glycosylated and positively selected sites. Our results suggest that there are several genetic features that distinguish CSF- and plasma-derived HIV-1 populations, probably reflecting altered cellular entry requirements and decreased immune pressure in the CNS. Furthermore, neurological impairment may be influenced by mutations within the viral V3 loop sequence.

Amino Acid Sequence↗

Cortical and subcortical neurodegeneration is associated with HIV neurocognitive impairment.

OBJECTIVE: To determine the association of markers of regional neurodegeneration (ND) at autopsy to degree of neurocognitive impairment in persons with HIV. DESIGN: In a prospectively followed cohort of HIV-infected individuals we examined the relationship between antemortem neuropsychological (NP) abilities and postmortem neuropathological data. METHODS: Twenty-seven HIV-infected individuals with both neuropsychological and neuropathological data were identified. Laser confocal scanning microscopy was used to determine the degree of ND based on: (1) microtubule-associated protein (MAP2; reflecting neuronal cell bodies and dendrites) and (2) synaptophysin (SYN; a measure of presynaptic terminals). A regional combined score, based on the distribution of percentage neuropil occupied by MAP2 and SYN and emphasizing severity of ND, was created for each brain region: midfrontal cortex, hippocampus, and putamen. RESULTS: The regional combined scores from each brain region studied were better correlated with level of global NP impairment than measures of SYN and MAP2 individually. In a regression, hippocampal and putamen regional combined scores were independent predictors of degree of antemortem NP impairment (F(3,23) = 6.17; P < 0.01; R2 = 0.45). The correlations among regional ND measures demonstrated that ND is unevenly distributed across multiple brain regions. CONCLUSIONS: As the anatomic distribution and temporal progression of neuropathologic changes appears to differ across individuals, it is important to consider both cortical and subcortical brain regions in studies of neuropathogenesis and treatment of HIV-related brain disease. Furthermore, combining information from several markers of neural injury provided the strongest association with degree of neurocognitive impairment during life.

Adult↗

Recency effects in HIV-associated dementia are characterized by deficient encoding.

The aim of the present study was to investigate the nature and cognitive mechanisms of serial position learning effects in HIV-associated dementia (HAD). Participants were 16 persons with HAD, 50 non-demented persons with HIV-infection, and 50 demographically comparable HIV-seronegative participants. HAD participants, relative to both comparison groups, exhibited reduced middle region (p<0.01) and elevated recency region (p<0.05) recall on the Hopkins Verbal Learning Test-Revised, but no primacy region effect (p>0.10). On recognition testing, the HAD group was impaired in discriminating targets from distractors (p<0.01) in all three serial position regions; however, they were not impaired on measures of retrieval (p>0.10) within these same regions. In sum, HAD participants relied disproportionately on recency regions of the list, indicating a passive recall style of echoing only the words within their auditory attention span. Interestingly, HAD participants did not evidence significant improvement on measures of recognition, a finding that suggests that the serial position effects are most consistent with a primary encoding deficit.

AIDS Dementia Complex↗

Additive deleterious effects of methamphetamine dependence and immunosuppression on neuropsychological functioning in HIV infection.

Methamphetamine (MA) dependence and HIV infection are independently associated with cerebral dysfunction, especially within frontal-basal ganglia circuits. Recent evidence indicates that MA dependence has an additive effect on neuropsychological (NP) deficits associated with HIV infection. This study extends prior findings by examining the combined effects of MA dependence (MA+) and immunosuppression (i.e., CD4 lymphocyte count <200) on NP functioning in 284 HIV+ individuals. Prevalence of NP impairment was examined in four demographically comparable groups: (1) MA+/CD4 < 200; (2) MA+/CD4 > or = 200; (3) MA-/CD4 < 200; and (4) MA-/CD4 > or = 200. Results revealed that both MA dependence and immunosuppression were significant predictors of NP impairment. More importantly, additive effects were evident whereby the MA+/CD4 < 200 group exhibited the highest rate of NP impairment. Findings indicate that MA dependence conveys an additive deleterious impact on NP status in immunosuppressed persons with HIV infection, perhaps reflecting the combined effects of neuropathophysiological mechanisms in fronto-striatal circuits.

Adult↗

Relationship of antiretroviral treatment to postmortem brain tissue viral load in human immunodeficiency virus-infected patients.

Human immunodeficiency virus (HIV)-1 invades the central nervous system (CNS) soon after infection and is partially protected there from host immunity and antiretroviral drugs (ARVs). Sanctuary from highly active antiretroviral therapy (HAART) in the CNS could result in ongoing viral replication, promoting the development of drug resistance and neurological disease. Despite the importance of these risks, no previous study has directly assessed HAART's effects on brain tissue viral load (VL). The authors evaluated 61 HIV-infected individuals for whom both histories of HAART treatment and postmortem brain tissue VL measurements were available. Two groups were defined based on HAART use in the 3 months prior to death: HAART(+) subjects had received HAART, and HAART(-) subjects had not received HAART. HIV RNA was quantified in postmortem brain tissue (log10 copies/10 microg total tissue RNA) and antemortem plasma (log10 copies/ml) by reverse transcriptase-polymerase chain reaction (RT-PCR). Brain tissue VLs were significantly lower among HAART(+) subjects compared to HAART(-) subjects (median 2.6 versus 4.1; P= .0007). These findings suggest that despite the limited CNS penetration of many antiretroviral medications, HAART is at least partially effective in suppressing CNS viral replication. Because some HAART regimens may be better than others in this regard, regimen selection strategies could be used to impede CNS viral activity, limit neuronal dysfunction, and prevent or treat clinical neurocognitive disorders in HIV-infected patients. Furthermore, such strategies might help to prevent the development of ARV resistance.

Adult↗

Valproic acid does not affect markers of human immunodeficiency virus disease progression.

Valproic acid (VPA) reduces latent human immunodeficiency virus (HIV) reservoirs by activating resting CD4+ cells. This retrospective case-control study (n = 30) examined effects of VPA on markers of HIV progression. VPA was not associated with changes in cerebrospinal fluid viral loads (VL), plasma VL, or neuropsychological performance. VPA patients had a trend towards lower CD4+ cells (P = .08) at follow-up. Concurrent antiretrovirals did not alter these relationships. VPA does not induce viremia or promote disease progression and may be safe for clinical intervention.

Adult↗

Action (verb) fluency predicts dependence in instrumental activities of daily living in persons infected with HIV-1.

Inspired by the hypothesized neural dissociation between the retrieval of nouns and verbs, several studies now support the construct validity of Action (verb) Fluency as a measure of frontostriatal systems function. Relative to traditional noun- and letter-cued verbal fluency tests, Action Fluency is more sensitive to HIV-1-associated neuropsychological impairment, which may reflect inefficiencies engaging motor representations during action retrieval in this population. Accordingly, impaired Action Fluency might adversely impact instrumental activities of daily living (IADL) by disrupting the production and organization of script-based action schemas upon which successful IADL performance depends. The present study thus sought to evaluate the ecological validity of Action Fluency as a predictor of IADL among persons with HIV-1 infection. Action, Letter (FAS), and Noun (animal) fluency were compared in 21 HIV-1-infected participants with self-reported IADL dependence relative to 76 demographically comparable HIV-1-infected participants who reported no IADL declines. Results revealed significant between-group differences in Action and Letter Fluency, but not Noun Fluency. Action Fluency achieved an overall hit rate of 76% and was more sensitive than Letter Fluency in classifying IADL dependent participants. Individuals with impaired Action Fluency performance had a fivefold risk of concurrent IADL dependence as compared to those who performed within normal limits. Findings suggest that Action Fluency may possess incremental ecological validity in the identification of HIV-1-associated neurocognitive disorders.

Activities of Daily Living↗

Prospective memory in HIV-1 infection.

The cognitive deficits associated with HIV-1 infection are thought to primarily reflect neuropathophysiology within the fronto-striato-thalamo-cortical circuits. Prospective memory (ProM) is a cognitive function that is largely dependent on prefronto-striatal circuits, but has not previously been examined in an HIV-1 sample. A form of episodic memory, ProM involves the complex processes of forming, monitoring, and executing future intentions vis-à-vis ongoing distractions. The current study examined ProM in 42 participants with HIV-1 infection and 29 demographically similar seronegative healthy comparison (HC) subjects. The HIV-1 sample demonstrated deficits in time- and event-based ProM, as well as more frequent 24-hour delay ProM failures and task substitution errors relative to the HC group. In contrast, there were no significant differences in recognition performance, indicating that the HIV-1 group was able to accurately retain and recognize the ProM intention when retrieval demands were minimized. Secondary analyses revealed that ProM performance correlated with validated clinical measures of executive functions, episodic memory (free recall), and verbal working memory, but not with tests of semantic memory, retention, or recognition discrimination. Taken together, these findings indicate that HIV-1 infection is associated with ProM impairment that is primarily driven by a breakdown in the strategic (i.e., executive) aspects of retrieving future intentions, which is consistent with a prefronto-striatal circuit neuropathogenesis.

Adult↗

Demographically adjusted normative standards for new indices of performance on the Paced Auditory Serial Addition Task (PASAT).

The Paced Auditory Serial Addition Task (PASAT) is a complex cognitive test sensitive to neuropsychological disorders. Its traditional Total Correct score seemingly reflects multiple cognitive abilities, including attention, working memory, and processing speed. Snyder, Aniskiewicz, and Snyder (1993) modified scoring guidelines for the PASAT to give credit only for "dyads." This method emphasizes working memory operations and has been found superior to Total Correct scores at detecting cognitive impairments in several investigations. To date, normative standards are not available for the "dyad" scoring method, thus limiting its utility in clinical and research settings. The current investigation provides demographically adjusted normative data based on a sample of 500 healthy adults of varied age, education, sex, and race (African American and Caucasian) for various indices of performance on the PASAT, including "Total Dyads" obtained across the four PASAT trials. In addition, we describe and present normative data on four other indices designed to quantify various aspects of performance on the PASAT: invalid responding, effects of varied information processing speed demands, and tendency to omit responses and to make arithmetic errors.

Abstracting and Indexing↗

Effect of Alzheimer caregiving stress and age on frailty markers interleukin-6, C-reactive protein, and D-dimer.

BACKGROUND: Elevated plasma levels of interleukin (IL)-6, C-reactive protein (CRP), and D-dimer belong to the biological alterations of the "frailty syndrome," defining increased vulnerability for diseases and mortality with aging. We hypothesized that, compatible with premature frailty, chronic stress and age are related in predicting inflammation and coagulation activity in Alzheimer caregivers. METHODS: Plasma IL-6, CRP, and D-dimer levels were measured in 170 individuals (mean age 73 +/- 9 years; 116 caregivers, 54 noncaregiving controls). Demographic factors, diseases, drugs, and lifestyle variables potentially affecting inflammation and coagulation were obtained by history and adjusted for as covariates in statistical analyses. RESULTS: Caregivers had higher mean levels of IL-6 (1.38 +/- 1.42 vs 1.00 +/- 0.92 pg/mL, p =.032) and of D-dimer (723 +/- 530 vs 471 +/- 211 ng/mL, p <.001) than controls had. CRP levels were similar between groups (p =.44). The relationship between caregiver status and D-dimer was independent of covariates (p =.037) but affected by role overload. Age accounted for much of the relationship with IL-6. After controlling for covariates, the interaction between caregiver status and age was significant for D-dimer (beta =.20, p =.029) and of borderline significance for IL-6 (beta =.17, p =.090). Post hoc regression analyses indicated that, among caregivers, age was significantly correlated with both D-dimer (beta =.50, p <.001) and IL-6 (beta =.38, p =.001). Among controls, however, no significant relationship was observed between age and either D-dimer or IL-6. CONCLUSIONS: The interaction between caregiving status and age for D-dimer and IL-6 suggests the possibility that older caregivers could be at risk of a more rapid transition to the frailty syndrome and clinical manifestations of cardiovascular diseases.

Age Factors↗

Sleep disturbance, norepinephrine, and D-dimer are all related in elderly caregivers of people with Alzheimer disease.

STUDY OBJECTIVE: Caregiving for a relative with Alzheimer disease has been associated with sympathoadrenal medullary arousal and morbidity and mortality. In this study, we examined if sleep disturbance of elderly caregivers was associated with physiologic markers of cardiovascular risk, including plasma norepinephrine, epinephrine, and the hemostasis marker D-dimer. DESIGN: Cross-sectional. SETTING: Community-based sample of elderly caregivers of spouses with Alzheimer disease assessed within their homes. PARTICIPANTS: A sample of 40 elderly spousal caregivers of patients with Alzheimer disease. MEASUREMENTS AND RESULTS: Participants underwent in-home full-night polysomnography and had plasma assayed for norepinephrine and epinephrine. Using multiple regression analyses and controlling for a number of cardiovascular risk factors (e.g., age, sex, blood pressure, body mass index), increased wake after sleep onset was positively associated with norepinephrine levels (beta = .35; t = 2.45, df = 32, p = .020) and plasma D-dimer (beta = .31; t = 2.18, df = 29, p = .038). Further, plasma norepinephrine was significantly associated with D-dimer (beta = .34; t = 2.11, df = 29, p = .044). Additional analyses indicated that norepinephrine accounted for 28% of the relationship between wake after sleep onset and D-dimer. No association was observed between sleep variables and epinephrine. CONCLUSIONS: These findings provide preliminary evidence that sleep disturbance may contribute to morbidity in caregivers through sympathoadrenal medullary arousal and downstream physiologic effects such as altering the hemostasis environment.

Aged↗

Avoidant coping partially mediates the relationship between patient problem behaviors and depressive symptoms in spousal Alzheimer caregivers.

OBJECTIVE: Caring for a loved one with Alzheimer disease is a highly stressful experience that is associated with significant depressive symptoms. Previous studies indicate a positive association between problem behaviors in patients with Alzheimer disease (e.g., repeating questions, restlessness, and agitation) and depressive symptoms in their caregivers. Moreover, the extant literature indicates a robust negative relationship between escape-avoidance coping (i.e., avoiding people, wishing the situation would go away) and psychiatric well-being. The purpose of this study was to test a mediational model of the associations between patient problem behaviors, escape-avoidance coping, and depressive symptoms in Alzheimer caregivers. METHODS: Ninety-five spousal caregivers (mean age: 72 years) completed measures assessing their loved ones' frequency of problem behaviors, escape-avoidance coping, and depressive symptoms. A mediational model was tested to determine if escape-avoidant coping partially mediated the relationship between patient problem behaviors and caregiver depressive symptoms. RESULTS: Patient problem behaviors were positively associated with escape-avoidance coping (beta = 0.38, p < 0.01) and depressive symptoms (beta = 0.26, p < 0.05). Escape-avoidance coping was positively associated with depressive symptoms (beta = 0.33, p < 0.01). In a final regression analysis, the impact of problem behaviors on depressive symptoms was less after controlling for escape-avoidance coping. Sobel's test confirmed that escape-avoidance coping significantly mediated the relationship between problem behaviors and depressive symptoms (z = 2.07, p < 0.05). CONCLUSION: Escape-avoidance coping partially mediates the association between patient problem behaviors and depressive symptoms among elderly caregivers of spouses with dementia. This finding provides a specific target for psychosocial interventions for caregivers.

Adaptation, Psychological↗

Dementia severity of the care receiver predicts procoagulant response in Alzheimer caregivers.

BACKGROUND: The procoagulant factor D-dimer has been shown to be associated with thrombus formation and degradation as seen with conditions such as myocardial infarction and unstable angina. Research has demonstrated that spousal dementia caregivers have elevated levels of D-dimer relative to their non-caregiving peers. OBJECTIVE: The objective of this study was to determine the relationship of basal level and laboratory stressor-induced concentration of D-dimer to severity of dementia in spousal care recipients. METHODS: Seventy-one elderly caregivers were compared with a comparison group of 37 non-caregivers (average age: 71 years). Clinical Dementia Rating (CDR), a global measure of dementia, was used to assess severity of spousal dementia. Plasma D-dimer was measured at baseline and in response to an acute speech stressor. RESULTS: Regression analysis revealed a significant positive association between severity of spousal dementia and caregiver D-dimer, both at baseline and in response to acute stress, while controlling for age. The model examined an exponential relationship, with D-dimer increasing progressively across the span of dementia stages. DISCUSSION: Dementia severity of the care recipient was associated with increasing hypercoagulability among elderly caregivers. Effect size estimates suggest that such D-dimer increases may have clinical implications, particularly among late-stage caregivers.

Aged↗