Rates of cognitive impairment in a South African cohort of people with HIV: variation by definitional criteria and lack of association with neuroimaging biomarkers.

There is wide variation in the reported prevalence of cognitive impairment in people with HIV (PWH). Part of this variation may be attributable to different studies using different methods of combining neuropsychological test scores to classify participants as either cognitively impaired or unimpaired. Our aim was to determine, in a South African cohort of PWH (N = 148), (a) how much variation in reported rates was due to method used to define cognitive impairment and (b) which method correlated best with MRI biomarkers of HIV-related brain pathology. Participants completed detailed neuropsychological assessment and underwent 3 T structural MRI and diffusion tensor imaging (DTI). We used the neuropsychological data to investigate 20 different methods of determining HIV-associated cognitive impairment. We used the neuroimaging data to obtain volumes for cortical and subcortical grey matter and total white matter and DTI metrics for several white matter tracts. Applying each of the 20 methods to the cognitive dataset resulted in a wide variation (20-97%) in estimated rates of impairment. Logistic regression models showed no method was associated with HIV-related neuroimaging abnormalities as measured by structural volumes or DTI metrics. We conclude that for the population from which this sample was drawn, much of the variation in reported rates of cognitive impairment in PWH is due to the method of classification used, and that none of these methods accurately reflects biological effects of HIV in the brain. We suggest that defining HIV-associated cognitive impairment using neuropsychological test performance only is insufficient; pre-morbid functioning, co-morbidities, cognitive symptoms, and functional impairment should always be considered.

Heterogeneity in neurocognitive change trajectories among people with HIV starting antiretroviral therapy in Rakai, Uganda.

Considerable heterogeneity exists in patterns of neurocognitive change in people with HIV (PWH). We examined heterogeneity in neurocognitive change trajectories from HIV diagnosis to 1-2 years post-antiretroviral therapy (ART). In an observational cohort study in Rakai, Uganda, 312 PWH completed a neuropsychological (NP) test battery at two-time points (ART-naïve, 1-2 years post-ART initiation). All NP outcomes were used in a latent profile analysis to identify subgroups of PWH with similar ART-related neurocognitive change profiles. In a subset, we examined subgroup differences pre-ART on cytokine and neurodegenerative biomarkers CSF levels. We identified four ART-related change subgroups: (1) decline-only (learning, memory, fluency, processing speed, and attention measures), (2) mixed (improvements in learning and memory but declines in attention and executive function measures), (3) no-change, or (4) improvement-only (learning, memory, and attention measures). ART-related NP outcomes that are most likely to change included learning, memory, and attention. Motor function measures were unchanged. Subgroups differed on eight of 34 pre-ART biomarker levels including interleukin (IL)-1ß, IL-6, IL-13, interferon-γ, macrophage inflammatory protein-1ß, matrix metalloproteinase (MMP)-3, MMP-10, and platelet-derived growth factor-AA. The improvement-only and mixed subgroups showed lower levels on these markers versus the no-change subgroup. These findings provide support for the need to disentangle heterogeneity in ART-related neurocognitive changes, to focus on higher-order cognitive processes (learning, memory, attention) as they were most malleable to change, and to better understand why motor function remained unchanged despite ART treatment. Group differences in pre-ART CSF levels provide preliminary evidence of biological plausibility of neurocognitive phenotyping.

Heterogeneity of Neuropsychological Impairment in HIV Infection: Contributions from Mild Cognitive Impairment.

Despite longstanding acknowledgement of the heterogeneity of HIV-associated neurocognitive disorders (HAND), existing HAND diagnostic methods classify according to the degree of impairment, without regard to the pattern of neuropsychological strengths and weaknesses. Research in mild cognitive impairment (MCI) has demonstrated that classifying individuals into subtypes by both their level and pattern of impairment, using either conventional or statistical methods, has etiologic and prognostic utility. Methods for characterizing the heterogeneity of MCI provide a framework that can be applied to other disorders and may be useful in clarifying some of the current challenges in the study of HAND. A small number of studies have applied these methods to examine the heterogeneity of neurocognitive function among individuals with HIV. Most have supported the existence of multiple subtypes of neurocognitive impairment, with some evidence for distinct clinicodemographic features of these subtypes, but a number of gaps exist. Following a review of diagnostic methods and challenges in the study of HAND, we summarize the literature regarding conventional and empirical subtypes of MCI and HAND and identify directions for future research regarding neurocognitive heterogeneity in HIV infection.

HIV-associated neurocognitive disorder in Australia: a case of a high-functioning and optimally treated cohort and implications for international neuroHIV research.

The Australian HIV-infected (HIV+) population is largely comprised of high-functioning men who have sex with men (MSM). Like other English-speaking countries, Australia mostly relies on US neuropsychological normative standards to detect and determine the prevalence of neurological disorders. Whether the US neuropsychological (NP) normative standards are appropriate in Australian HIV+ MSM has not been established. Ninety virally suppressed HIV+ and 49 HIV-uninfected (HIV-) men (respectively 86 and 85 % self-reported MSM; mean age 54 and 56 years, mean premorbid verbal IQ estimate 110 and 111) undertook standard NP testing. The raw neuropsychological data were transformed using the following: (1) US standards as uncorrected scaled scores and demographically corrected T scores (US norms); and (2) z scores (without demographic corrections) derived from Australian comparison group scaled scores (local norms). To determine HIV-associated neurocognitive disorder prevalence, we used a standard definition of impairment based upon a battery-wide summary score: the global deficit score (GDS). Impairment classification (GDS ≥ 0.5) based on the local norms was best at discriminating between the two groups (HIV- = 14.3 % vs. HIV+ = 53.3 %; p < 0.0001). This definition was significantly associated with age. Impairment classification based on the US norms yielded much lower impairment rate regardless of the HIV status (HIV- = 4.1 % vs. HIV+ = 14.7 %; p = 0.05), but was associated with historical AIDS, and not age. Both types of summary scores were associated with reduced independence in activities of daily living (p ≤ 0.03). Accurate neuropsychological classifications of high (or low) functioning individuals may need country-specific norms that correct for performance-based (e.g., reading) estimates of premorbid cognition in addition to the traditional demographic factors.

HIV-associated cognitive impairment in sub-Saharan Africa--the potential effect of clade diversity.

In the US, HIV dementia occurs in 10-15% of HIV-positive individuals with advanced infection. The prevalence of HIV dementia in sub-Saharan countries, where the vast majority of individuals with HIV reside, is largely unknown. This Review will summarize our current understanding of HIV-associated cognitive impairment in resource-limited settings, focusing specifically on the countries of sub-Saharan Africa. We will describe the frequency of HIV dementia and HIV-associated cognitive impairment from several case series in the sub-Saharan region. We will then summarize recent studies from Uganda and Ethiopia that included detailed neuropsychological assessments. The potential influence of clade diversity on HIV-associated cognitive impairment will be discussed. Differences between the results of the studies in Uganda and in Ethiopia raise the possibility that HIV subtypes might have different biological properties with respect to their capacity to cause HIV-associated cognitive impairment. Further studies are needed to determine the true prevalence of HIV dementia in sub-Saharan Africa and to establish whether specific clade subtypes might influence the presentation of neurological complications.

Ezrin immunoreactivity reveals specific astrocyte activation in cerebral HIV.

The actin-binding protein ezrin is associated with cellular shape changes, motility, tumor invasion, and lymphocyte activation. We have earlier shown that ezrin immunoreactivity (IR) is faintly present in normal astrocytes but increased in malignant human astrogliomas. We studied the role of ezrin in astrocyte activation, applying immunostaining on serial paraffin sections from human autopsied brain tissues (51 cases). Cerebral HIV infection was chosen as a model displaying consistent exemplary astrocyte activation. Semiquantitative ezrin-IR was compared with the common glial markers GFAP, ferritin, and HLA-DR in relation to clinical and morphologic criteria of HIV encephalopathy. In all cases with HIV infection, GFAP-, HLA-DR-, and ferritin-IR were elevated in comparison to normal brain tissues. In contrast, high ezrin-IR in HIV infection strictly correlated with additional HIV encephalopathy. HIV encephalopathy with particularly high ezrin-IR was correlated with neuronal apoptosis (TUNEL). Combined ezrin-IR and GFAP-IR thus reveals 2 distinct states of astrocytic activation. Normal ezrin-IR, when paralleled by upregulated GFAP, reflects astroglial activation not associated with neuronal apoptosis. High ezrin-IR indicates specific astrocyte stressors related to cellular damage within the central nervous system. Ezrin-IR might also provide a diagnostic tool for the classification of HIV encephalopathy.

Joint Data Harmonization and Group Cardinality Constrained Classification.

To boost the power of classifiers, studies often increase the size of existing samples through the addition of independently collected data sets. Doing so requires harmonizing the data for demographic and acquisition differences based on a control cohort before performing disease specific classification. The initial harmonization often mitigates group differences negatively impacting classification accuracy. To preserve cohort separation, we propose the first model unifying linear regression for data harmonization with a logistic regression for disease classification. Learning to harmonize data is now an adaptive process taking both disease and control data into account. Solutions within that model are confined by group cardinality to reduce the risk of overfitting (via sparsity), to explicitly account for the impact of disease on the inter-dependency of regions (by grouping them), and to identify disease specific patterns (by enforcing sparsity via the l0-'norm'). We test those solutions in distinguishing HIV-Associated Neurocognitive Disorder from Mild Cognitive Impairment of two independently collected, neuroimage data sets; each contains controls and samples from one disease. Our classifier is impartial to acquisition difference between the data sets while being more accurate in diseases seperation than sequential learning of harmonization and classification parameters, and non-sparsity based logistic regressors.

Recommendations for the classification of HIV associated neuromanifestations in the German DRG system.

HIV associated neuromanifestations are of growing importance in the in-patient treatment of HIV infected patients. In Germany, all in-patients have to be coded according to the ICD-10 classification and the German DRG-system. We present recommendations how to code the different primary and secondary neuromanifestations of HIV infection. These recommendations are based on the commentary of the German DRG procedures and are aimed to establish uniform coding of neuromanifestations.

Evidence for a change in AIDS dementia complex in the era of highly active antiretroviral therapy and the possibility of new forms of AIDS dementia complex.

This review will discuss emerging evidence for the possibility that AIDS dementia complex (ADC) has changed in the era of highly active antiretroviral therapy (HAART). The consequences of not considering these possibilities at the patient level and at the level of research are considerable. Data will be discussed that are derived from epidemiological studies, neuropsychological and positron emission tomography studies, as well as analyses from the abacavir ADC trial. These will then be assessed to develop the concept that there are now different forms of ADC: an inactive form, a chronic variety and a 'transformed' variant. Whereas the latter relates to the compounding influence of a number of other processes on ADC, such as hepatitis C, particular discussion will focus upon Alzheimer's disease and whether HIV may lead to Alzheimer-like changes. It is certainly recognized that some of the concepts discussed here are highly speculative.

Effect of the revised AIDS case definition on AIDS reporting in San Francisco: evidence of increased reporting in intravenous drug users.

To examine the effect of the revision of the US national AIDS case definition in September 1987, we compared demographic and clinical information for AIDS patients diagnosed and reported to the San Francisco Department of Public Health between 1 September 1987 and 31 October 1989. Of the 3167 patients diagnosed and reported during the study period, 584 (18%) met the revised case definition only, increasing AIDS case reporting in San Francisco by 23%. One hundred and thirty-four of these 584 patients (23%) subsequently developed diagnoses meeting the old definition. After adjusting for this proportion, the revised case definition increased reporting by 17%. The mean time between initial diagnosis with a disease meeting the revised definition and subsequent development of a disease meeting the old definition was 18.5 months. Patients who met the revised case definition only were slightly older and more likely to be Black, female, and intravenous drug users (IVDUs) than those meeting the old case definition. The majority of patients who met the revised case definition only had initial diagnoses of HIV wasting syndrome (26%), HIV encephalopathy (21%), and presumptive Pneumocystis carinii pneumonia (19%). The revised AIDS case definition has significantly increased the reporting of severe morbidity associated with HIV infection, particularly among IVDUs.

Variable progression of HIV-associated dementia.

A consecutive series of 71 patients diagnosed with HIV-associated dementia (HAD) (1984-1994) were studied to characterize the clinical course of HAD, and to identify predictive markers of rapid neurologic progression. Neurologic progression rate was determined from the change in the Memorial Sloan Kettering (MSK) dementia severity score from diagnosis to death. Those with the most rapid progression in neurologic disability were compared with those with slow or no progression. Autopsy material was immunostained for macrophage activation markers and gp41 in 30 individuals. Median survival was 3.3 months and 6.1 months for rapid-progression and no-progression patients, respectively. Rapid progression was associated with injection drug use but not with race, gender, or age. CD4+ cell counts were lower at diagnosis among rapid-progression than no-progression patients but no differences in AIDS-defining illnesses or patterns of antiretroviral therapy were found. At presentation, rapid-progression patients had more prominent symptoms of mental slowing than those with no progression; however, no other clinical features, CSF, or imaging features distinguished the groups. Less abundant macrophage activation in both basal ganglia and midfrontal gyrus regions, as judged by HAM56 immunostaining, was noted in 9 no-progression patients, compared with 12 rapid-progression patients. Neurologic progression and survival with HAD is highly variable. A significant proportion of individuals with dementia have prolonged survival of more than 12 months and remain cognitively stable. A history of injection drug use and presentation with prominent psychomotor slowing is associated with more rapid neurologic progression, and these patients tend to show more abundant macrophage activation within the CNS.

Differential receptive and expressive language functioning of children with symptomatic HIV disease and relation to CT scan brain abnormalities.

OBJECTIVES: To investigate the effect of HIV disease on the receptive and expressive language of children and the relationship between CT scan brain abnormalities and language functioning. METHODS: Thirty-six children (mean age, 5.5 years; range, 1 through 10 years; 75% vertical transmission; 58% classified as encephalopathic) with symptomatic HIV infection and 20 uninfected siblings (mean age, 7.8 years; range, 3 through 15 years) were administered an age-appropriate comprehensive language test assessing both receptive and expressive language (Reynell Developmental Language Scales or Clinical Evaluation of Language Fundamentals--Revised). Each HIV-infected child had a CT scan of the brain as part of the baseline evaluation, which was rated independently and blindly by two neurologists, for presence and severity of brain abnormalities using a semiquantitative rating system. RESULTS: Expressive language was significantly more impaired than receptive language in the overall sample of HIV-infected children. The encephalopathic children scored significantly lower than the non-encephalopathic children, however, the degree of discrepancy between mean receptive and expressive language scores was not significantly different between these two groups. The uninfected sibling control group did not have a significant discrepancy between receptive and expressive language, and they scored significantly higher than the infected patient group. Greater severity of CT scan abnormalities was significantly correlated with poorer receptive and expressive language functioning in the overall HIV-infected sample and a higher discrepancy between receptive and expressive language in the encephalopathic group. CONCLUSION: Pediatric HIV disease is associated with differential receptive and expressive language functioning in which expressive language is significantly more impaired than receptive language. The sibling data and CT scan correlations suggest that the observed language impairments are associated with the direct effects of HIV-related central nervous system disease.

Spontaneous eye blinking, a measure of dopaminergic function, in children with acquired immunodeficiency syndrome.

OBJECTIVE: To investigate possible alterations in dopaminergic function in children with acquired immunodeficiency syndrome by evaluating spontaneous eye blink rate, a putative measure of central dopaminergic function. DESIGN: Evaluation of previously videotaped test sessions of a consecutive case series of 50 children (mean age, 5.2 years; range, 2-12 years) with acquired immunodeficiency syndrome. SETTING: Government medical research center. RESULTS: Intrarater reliability was high, expected co-variation of blink rate with age and concurrent mental activity were confirmed, and obtained rates were similar to published data. Higher blink rates, suggestive of increased dopaminergic function, were associated with more severe cortical atrophy (P < .05) and white matter abnormality (P < .05) on computed tomographic brain scans. The presence or severity of basal ganglia calcifications did not seem to influence blink rate. In addition, higher blink rates were associated with higher ratings of depressed affect (P < .05) and lower ratings of hyperactive behaviors (P < .05) during other test activities. CONCLUSIONS: The higher blink rates in human immunodeficiency virus-infected children with more severe cortical abnormalities suggest increased central dopamine activity compared with that in children without cortical computed tomographic brain scan abnormalities. Thus, as a result of structural brain abnormalities, neurotransmitter levels in children with acquired immunodeficiency syndrome may vary and this may be reflected in their socioemotional functioning.

Neurodevelopmental outcomes of Ugandan infants with HIV infection: an application of growth curve analysis.

Neurodevelopmental outcomes of human immunodeficiency virus Type 1 (HIV-1)-infected infants of non-drug-using mothers were assessed in a controlled, prospective study from birth to 24 months with 3 groups: 61 infants of HIV-infected mothers, 234 uninfected infants of HIV-infected mothers (seroreverters), and 115 uninfected infants of uninfected mothers. Compared with seroreverters and uninfected infants, HIV-infected infants demonstrated lower mental and motor development on the Bayley Scales and greater deceleration in their rate of motor development. HIV-infected infants with abnormal neurologic exams had lower motor and mental test scores and lower rates of motor Bayley Scales scores than their HIV-infected counterparts with normal neurologic exams. Contrary to prediction, no group differences in mean performance or growth rates were found on visual information processing on the Fagan Test of Infant Intelligence.

HIV-related brain impairment from palliative care to rehabilitation.

Brain impairment is a distressing manifestation of human immunodeficiency virus (HIV) disease characterized by progressive cognitive impairment leading eventually to dementia and death. Patients with advanced brain impairment are clinically difficult to manage and usually require residential care. In 1997, a brain impairment unit opened at the Mildmay Hospital UK in London to meet the needs of this patient group. It began as a nurse-led unit, has adopted an interdisciplinary approach to care and aims to maximize the quality of life until death. In a study of patients admitted during its first year, it emerged that while the condition of many patients declined resulting in death, some patients improved sufficiently with rehabilitation and ongoing medical treatment to return to independent living. The possible reasons for this are discussed in this article. Study findings have not only affected the approach to care but have also highlighted some unexpected problems; the importance of adopting an interdisciplinary approach in caring for the group of patients becomes evident.

[HIV-1 cognitive and motor syndrome]. / Syndrome cognitif et moteur associé au VIH-1.

The central nervous system (CNS) is often affected by HIV-1 infection. Over 40% of AIDS cases present with neurological symptoms and CNS lesion are detected by anatomical and pathological studies in 80 to 90% of AIDS cases. There may be infections and tumors secondary to the immunodeficiency and pathologies may occur directly due to the neurotropism of the virus. Neurological problems associated with HIV-infection include encephalopathies, myelopathies, neuropathies and myopathies. HIV-1-induced encephalopathy may develop at any stages of HIV-1 infection and affects all risk groups equally. Its frequency worldwide is between 4 and 65% among individuals seropositive for HIV-1. The frequencies reported differ between studies due to differences in sampling methods, geographical factors, diagnostic criteria and investigative methods used. The pathogenesis of HIV-1-associated encephalopathy is not understood, but there are several hypotheses. The involvement of HIV-1 infected macrophages and microglial cells has been demonstrated. Indirect mechanisms such as release of lymphokines (tumor necrosis factor-TNF alpha- and interleukin-1) and neurotoxicity of the HIV envelope protein, gp 120, have also been suggested. This disorder is known as HIV-1-associated cognitive and motor syndrome. It presents clinically as a form of sub-cortical dementia with cognitive problems, motor deficits and behavioral disorders depending on the type and stage of HIV infection. The diagnosis can only be made after all other infections and tumors common in HIV-1 patients have been ruled out by appropriate investigations such as cerebrospinal fluid analysis, cerebral scan and magnetic resonance imaging. Electrophysiological studies, such as evoked responses and electroencephalograms, are particularly useful in its diagnosis. Anatomical examination shows diffuse paleness of the white matter, multi-nucleated giant cells and microglial nodes. Neuropsychological studies could be of value in diagnosis and in assessing the response to anti-retroviral treatment. There is currently no specific therapy for HIV-1-associated cognitive and motor syndrome. The use of new nucleoside analogue drugs in combination with existing drugs may provide new approaches to managing these patients.