Frances L. Wilkie

Aging and neuro-AIDS conditions and the changing spectrum of HIV-1-associated morbidity and mortality

Older individuals (>50 years of age) now comprise over 11% of patients with AIDS in the United States. This percentage is expected to continue to grow, due both to the improved longevity of patients prescribed highly active antiretroviral therapy (HAART) and to new infections among older individuals. This review focuses on the neuropsychiatric and neurological conditions that are most likely to be affected by advancing age-HIV-1-associated cognitive-motor disorder, peripheral neuropathy, progressive multifocal leukoencephalopathy, primary CNS lymphoma, and risk for cerebrovascular accident. Age associations with incidence of these disorders and with treatment foci are specified. Implications for future changes in management are discussed.

Neuropsychological deficits in human immunodeficiency virus type 1 clade C-seropositive adults from South India

Most studies of cognitive functioning in human immunodeficiency virus type 1 (HIV-1)-seropositive (HIV-1+) subjects have been done in the United States and Europe, where clade B infections predominate. However, in other parts of the world such as South India, where clade C HIV is most common, the prevalence of HIV-1 is increasing. Standardized neuropsychological tests were used to assess cognitive functioning in a sample of 119 adults infected with clade C HIV-1 who were not on antiretroviral medications. The subjects did not have neurological or psychiatric illness and were functioning adequately. Neuropsychological test performance was compared with gender-, age-, and education-matched normative data derived from a sample of 540 healthy volunteers and a matched cohort of 126 healthy, HIV-1-seronegative individuals. Among the seropositive subjects, 60.5% had mild to moderate cognitive deficits characterized by deficits in the domains of fluency, working memory, and learning and memory. None of the subjects had severe cognitive deficits. The HIV-1+ sample was classified into groups according to the level of immune suppression as defined by CD4 count (<200, 201–499, and >500 cells/mm3) and viral load (<5000, 5001–30,000, 30,001–99,999, 100,000–1,000,000, and >1,000,001 copies). Although the most immunosuppressed group (CD4 count <200 cells/mm3 or viral load >1,000,001 copies) was small, their rate of impairment in visual working memory was greater when compared to groups with better immune functioning. Mild to moderate cognitive deficits can be identified on standardized neuropsychological tests in clade C-infected HIV-1+ adults who do not have any clinically identifiable functional impairment. The prevalence of cognitive deficits is similar to that reported in antiretroviral treatment-naïve individuals infected with clade B virus in the western world.

Older age and plasma viral load in HIV-1 infection.

Background: The purpose of the study was to examine the relationship between age and plasma viral load in HIV-1-infected individuals. Design: The experimental method was to recruit older (> 50 years of age) and younger (18–39 years of age) HIV-1-infected individuals. The plasma viral load was measured using the Roche Molecular Systems UltraSensitive Roche HIV-1 Monitor test reflexively with the standard Amplicor HIV Monitor test to quantify viral load in the range of 50–750 000 copies of HIV-1 RNA/ml plasma. Subjects: A total of 135 HIV-1-seropositive individuals (at Centers for Disease Control and Prevention early symptomatic stage B or late symptomatic stage/AIDS C) were enrolled as part of a larger cohort also consisting of HIV-1-seronegative individuals. Results: A generalized linear models statistical analysis was conducted in order to evaluate age category as a predictor of plasma viral load. The result was a significant effect of age category, with older age associated with a lower plasma viral load. The association held controlling for antiretroviral therapy usage, disease stage, antiretroviral medication adherence, HIV-1 serostatus duration, alcohol and substance use, recent sexually transmitted disease, and sociodemographics (except income). Conclusion: Older age was associated with lower levels of HIV-1 replication in this sample, independent of antiretroviral therapy usage, regimen adherence, and disease stage. It is suggested that the effect may be caused by changes in viral evolution or immunological monitoring specific to older individuals with HIV-1 infection.

Neurocognitive Aspects of Medication Adherence in HIV-Positive Injecting Drug Users

Cognitive deficits are associated with nonadherence to HIV medications. HIV-positive injecting drug users (IDUs) are at particular risk for nonadherence and cognitive barriers to adherence specific to this population should therefore be identified. The present study assessed the relation of three domains of cognitive functioning, executive functions, memory, and psychomotor speed, to self-reported antiretroviral adherence in a sample of HIV-positive IDUs. Depression, use of alcohol, heroin, cocaine/crack, or marijuana in the last week were also included in the models. Logistic regression analyses showed that only psychomotor slowing was significantly associated with nonadherence. Executive functions, memory, depression, and active alcohol and substance use were unrelated to adherence. No other studies to date have exclusively linked psychomotor slowing to nonadherence in HIV infection. Psychomotor slowing among our study sample was severe and suggests that when evident, such slowing may be a valuable determinant for antiretroviral adherence among IDUs.

Cognitive functioning in younger and older HIV-1-infected adults.

Summary: In young adults, a major neurologic complication of HIV‐1 infection is cognitive motor impairment. Epidemiologic findings suggest that increasing age is a significant risk factor for HIV‐1‐associated dementia as the AIDS‐defining illness. Findings from the few studies that have directly measured cognition in younger and older HIV‐1‐infected adults, however, have been mixed, in part, because of small sample sizes and other methodologic differences between studies. The authors present preliminary findings on cognitive functioning in symptomatic HIV‐1‐infected younger (aged 20‐39 years) and older (aged 50 years or older) adults. Independent of age, HIV‐1 infection was accompanied by learning and memory retrieval deficits, which were significantly associated with high plasma viral loads in the young adults. Relative to the younger and older HIV‐1‐negative (HIV‐1‐) groups, only the younger HIV‐1positive (HIV‐1+)group had significantly longer reaction times (RTs). Within the older HIV‐1+ group, however, longer simple and choice RTs were significantly correlated with higher viral loads and lower CD4 cell counts. Although HIV‐1 infection affects cognition independent of age, longitudinal studies involving large numbers of older individuals are needed to determine whether there are age differences in the prevalence, nature, and severity of HIV‐1‐associated cognitive dysfunction.

The occurrence of different intrusive errors in patients with Alzheimer's disease, multiple cerebral infarctions, and major depression

Recent evidence suggests that specific types of intrusive errors may occur more often in the protocols of Alzheimers disease (AD) patients than in those of patients diagnosed with other types of dementia. Using the FULD Object Memory Evaluation, we documented the occurrence of five qualitatively different types of intrusive errors for mildly and moderately impaired patients with AD and multiple cerebral infarctions (MCI). Depressed and normal elderly controls were also studied. Despite an equivalent degree of impairment on a broad array of neuropsychological measures, mildly impaired AD patients evidenced greater deficits on a measure tapping retrieval from semantic memory and demonstrated a higher occurrence of specific types of intrusive errors relative to their mildly impaired MCI counterparts. Further, both of these measures were highly correlated, suggesting that these indices may be particularly sensitive to semantic dysfunction associated with early AD.

Psychological Burden in the Era of Haart: Impact of Selenium Therapy

Objective: To determine the impact of nutritional (selenium) chemo-prevention on levels of psychological burden (anxiety, depression, and mood state) in HIV/AIDS. Method: A randomized, double-blind, placebo-controlled selenium therapy (200 μ/day) trial was conducted in HIV+ drug users from 1998–2000. Psychosocial measures (STAI-State and Trait anxiety, BDI-depression, and POMS- mood state), clinical status (CD4 cell count, viral load), and plasma selenium levels were determined at baseline and compared with measurements obtained at the 12-month evaluation in 63 participants (32 men, 31 women). Results: The majority of the study participants reported elevated levels of both State (68%) and Trait (70%) anxiety. Approximately 25% reported overall mood distress (POMS >60) and moderate depression (BDI > 20). Psychological burden was not influenced by current drug use, antiretroviral treatment, or viral load. At the 12-month evaluation, participants who received selenium reported increased vigor (p = 0.004) and had less anxiety (State, p = 0.05 and Trait, p = 0.02), compared to the placebo-treated individuals. No apparent selenium-related affect on depression or distress was observed. The risk for state anxiety was almost four times higher, and nearly nine times greater for trait anxiety in the placebo-treated group, controlling for antiretroviral therapy, CD4 cell decline (> 50 cells) and years of education. Conclusions: Selenium therapy may be a beneficial treatment to decrease anxiety in HIV+ drug users who exhibit a high prevalence of psychological burden.

Cobalamin level is related to self-reported and clinically rated mood and to syndromal depression in bereaved HIV-1+ and HIV-1- homosexual men

OBJECTIVE An examination of the relationship of plasma cobalamin (vitamin B(12)) level to overall psychological distress, specific mood states, and major depressive disorder was conducted in 159 bereaved men (90 HIV-1(+) and 69 HIV-1(-)). METHODS The relationship of a continuous measure of cobalamin level to psychological distress was examined, while controlling for HIV-1 serostatus, life stressors, social support, and coping styles. RESULTS Of this sample, 23.9% were either overtly or marginally cobalamin deficient; however, the deficiency rate was not significantly different by HIV-1 serostatus. Cobalamin level was inversely related to self-reported overall distress level and specifically to depression, anxiety, and confusion subscale scores, as well as to clinically rated depressed and anxious mood. Lower plasma cobalamin levels also were associated with the presence of symptoms consistent with major depressive disorder. CONCLUSION These findings suggest that cobalamin level may be physiologically related to depressed and anxious mood level, as well as to syndromal depression.

The importance of cognitive self-report in early HIV-1 infection: Validation of a cognitive functional status subscale

Background The Medical Outcomes Study HIV (MOS-HIV) Health Survey is a widely used instrument to assess quality of life in HIV-1-infected individuals. Its cognitive functional status subscale measures functional status owing to neuropsychological (NP) impairment. Objectives To determine the concurrent validity of the Dutch four-item MOS-HIV cognitive functional status subscale and its clinical significance in predicting NP test performance. Design Cross-sectional analysis of baseline data collected between October, 1994, and March, 1997, in the Netherlands and in Flanders, Belgium. Subjects A total of 85 HIV-1-infected homosexual men who participated in an ongoing longitudinal research project designed to study the effects of a support group. Results The MOS-HIV cognitive functional status subscale showed significant associations with NP test performance overall and, specifically, with the domains of abstraction, language and visuospatial abilities, controlling for CD4 cell count and Centers for Disease Control and Prevention (CDC) clinical disease stage. A trend toward significance was also found in the memory domain. Conclusions To our knowledge, this is the first report of a cognitive functional status subscale used with HIV-1-infected subjects in a language other than English. The MOS-HIV cognitive functional status subscale seems particularly sensitive to changes in NP test performance in early HIV-1 infection. These results suggest the potential for clinical utility of a brief functional status self-report measure related to cognitive abilities in early HIV-1 infection for the screening and diagnosis of HIV-1 associated cognitive-motor disorders.

Cognitive Effects of HIV-1 Infection.

The major neurological complication of human immunodeficiency virus type 1 (HIV-1) infection is cognitive impairment, which can range in severity from a mild subclinical cognitive inefficiency to a severe dementing illness. Mild to moderate cognitive impairment is identified primarily by neuropsychological tests. The prevalence and severity of cognitive impairment associated with HIV-1 infection increases as the disease progresses. Deficits in attention, information processing speed, memory, and motor abilities can occur early in the course of HIV-1 infection, with deficits in abstraction and executive functions observed in later stages of infection. The nature of the cognitive impairment observed is thought to reflect the effects of HIV-1 infection on the integrity of subcortical or frontostriatal brain systems. Issues related to the detection of subclinical to severe cognitive impairment are discussed, along with the clinical significance of mild cognitive impairment as a significant risk factor for mortality in HIV-1 infection. The need to control for possible confounding factors that can influence test performance is also reviewed.