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.

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.

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.

Spanish validation of the HIV dementia scale in women.

HIV infection is increasing in minority groups, particularly in African American and Hispanic women. Although the incidence of HIV dementia has decreased since the advent of highly active antiretroviral treatment, prevalence of neurocognitive complications has increased as patients are now living longer. This study's purpose was to determine the psychometric properties of the Spanish-language HIV Dementia Scale (HDS) in a group of HIV-infected women. We recruited 96 women: 60 HIV-seropositive and 36 HIV-seronegative. Modification of the HDS into a Spanish-language version consisted of translating the instructions, substituting four words in Spanish (gato, media, azul, piña), increasing 1 second in the psychomotor speed because the Spanish alphabet has more letters than the English alphabet, and not offering clues for memory recall. Cognitive impairment (CI) was defined according to the modified American Academy of Neurology HIV-dementia criteria including an asymptomatic CI group. Statistical analysis consisted of analysis of variance to determine group differences and receiver operator characteristics (ROC) to determine the optimal cutoff point for the screening of CI. HDS-Spanish total score and subscores for psychomotor speed and memory recall showed significant differences between HIV-seronegative and women with HIV-dementia (p < 0.001) and between HIV-seropositive women with normal cognition and those with HIV-dementia (p < 0.001). The optimal cutoff point of 13 or less had performance characteristics of 87% sensitivity and 46% specificity for HIV-associated CI (50.0% positive predictive value, 85.0% negative predictive value). The HDS-Spanish translation offers a useful screening tool with value for the identification of Hispanic women at risk of developing HIV-associated symptomatic neurocognitive disturbances.

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.

[Clinical features, diagnosis and treatment of HIV-induced neuropsychiatric disorders]. / Klinik, Diagnostik und Therapie HIV-induzierter neuropsychiatrischer Störungen.

Since the acquired immune deficiency syndrome (AIDS) was first recognized in 1981, more than 25 million individuals have died from complications of the human immunodeficiency virus (HIV) infection. The introduction of highly active antiretroviral therapy (HAART) in 1995 has resulted in a significantly decreased incidence rate of AIDS in the developed world. As HAART led to considerable improvements in survival for patients with HIV infection, HIV-neurotropically associated neuropsychiatric disorders have become an increasingly important challenge for clinical medicine. This article gives an overview of epidemiology, clinical features, diagnosis, and therapy of HIV-induced cognitive-motor impairments including HIV-associated dementia complex, organic mood disorders and psychosis.

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.

Neurological manifestations of HIV infection in Kwazulu-Natal South Africa.

South Africa has one of the fastest growing HIV epidemics in the world and KwaZulu-Natal, one of its nine provinces, is the epicentre of the epidemic. Of the estimated 5.3 million people infected with HIV in South Africa, 1.2 million reside in KwaZulu-Natal. Transmission of HIV is almost exclusively heterosexual, intravenous drug misuse does not occur and the patients attending state hospitals are antiretroviral drug naive. The neurological complications of HIV infection include bacterial and fungal meningitis, intracranial mass lesions, acute disseminated encephalomyelitis, a variety of spinal cord disorders, and peripheral nerve dysfunction. Tuberculous meningitis, especially that due to multidrug resistant organisms has a high mortality rate. Toxoplasmosis is the most frequent cause of intracranial mass lesions. These cases are successfully treated with cotrimoxazole alone. Multiple bacterial abscesses and tuberculomata are other important causes whilst primary central nervous system lymphoma is rare. The spinal cord disorders include co-infection with HTLV-I, tuberculosis and syphilis. Intramedullary tuberculomata, often multiple, and spinal epidural tuberculous abscess without bony disease are seen more commonly than in the pre HIV era. Peripheral nerve dysfunction include Gillian Barre Syndrome, chronic inflammatory demyelinating polyneuropathy and mononeuritis multiplex. Until the antiretroviral therapy roll out programme is well established the above HIV related neurological complications will continue to be seen for several years.

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 combination antiretroviral therapy on cerebrospinal fluid HIV RNA, HIV resistance, and clinical manifestations of encephalopathy.

OBJECTIVES: This study evaluated the effect of treatment with abacavir/lamivudine/zidovudine versus lamivudine/zidovudine on cerebrospinal fluid (CSF) human immunodeficiency virus (HIV) RNA and clinical manifestations of HIV encephalopathy in children. STUDY DESIGN: HIV-infected children 7 months to 10 years of age (n = 23) were studied. CSF and plasma were obtained at baseline and weeks 8, 16, and 48. Genotype analysis of HIV was attempted at baseline and week 48. Neurologic evaluations were performed at baseline and weeks 16, 32, and 48. RESULTS: At baseline, 83% of children had >2.00 log(10) copies/mL HIV RNA in CSF, but only 10% had HIV RNA measurable at week 48. Among children in whom paired genotyping of HIV was possible, 8 of 11 had identical patterns in both CSF and plasma at baseline, whereas at week 48, only 1 of 9 children had similar patterns. Neurologic abnormalities were observed in 83% of children at baseline but only 35% of children at week 48 (P =.004), suggesting a benefit of treatment. CONCLUSIONS: Antiretroviral therapy was associated with a decline in CSF HIV RNA and an improvement in neurologic status. The development of genotypic mutations was different in CSF and plasma, suggesting discordant viral evolution. These results suggest that antiretroviral treatment in children should include agents with activity in the CNS.

Analyses of nursing home residents with HIV and dementia using the minimum data set.

OBJECTIVE: The objective of this paper is to profile nursing home residents with HIV who also have dementia at the time of admission, using the Minimum Data Set (MDS). In addition, this paper compares HIV residents with dementia with other residents with HIV. These resident profiles contain sociodemographic characteristics, health status measures, treatments, and procedures. STUDY SUBJECTS: There are 1,074 admission assessments for HIV residents with dementia and 4,040 admission assessments for other residents with HIV in the MDS between June 22, 1998 and January 17, 2000; these were analyzed for this study. RESULTS: Other residents with HIV were twice as likely to be physically independent as HIV residents with dementia. Only 1 of 5 HIV residents with dementia was independent in cognitive skills for daily decision making compared with 3 of 5 other residents with HIV who were independent in these skills. Significantly greater percentages of HIV residents with dementia also had anemia, depression, schizophrenia, cognitive and memory problems, hepatitis, renal failure, and cancer than other residents with HIV. CONCLUSIONS: These analyses demonstrate that HIV residents with dementia were significantly more likely to have other diseases, infections, and health care conditions than other residents with HIV.

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.

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.

[Routine electroencephalogram in follow-up of patients with HIV infections of different stages. A long-term study]. / Das Routineelektroenzephalogramm zur Verlaufsdokumentation bei Patienten mit HIV-Infektion unterschiedlicher Stadien. Eine Langzeituntersuchung.

Electroencephalography (EEG) is a well-tolerated non-invasive method and is therefore well suited for repetitive examinations. We performed serial EEG's on 117 HIV patients without any clinical signs of secondary neuromanifestation in order to document electroencephalographic changes in the course of HIV infection. Clinical signs of HIV-associated encephalopathy presented 18 patients at the first examination and 23 at reexamination. EEGs were analyzed visually; there was a mean interval of 20.3 +/- 13.7 months between the first and the second examination. Significant slowing of background activity occurred in the course of the disease; the alpha rhythm decreased from 10.7 +/- 2.3 Hz to 10.0 +/- 2.4 Hz (P < 0.05) with an increase in amplitudes from 60.9 +/- 24.6 microV to 69.5 +/- 33.7 microV (p < 0.05). The percentage of spontaneous dysrhythmias also increased from 30.7% to 41.8% (P < 0.05); pathological findings provoked by hyperventilation increased from 13.6% to 18.2%. Foci occurred rarely and did not increase in frequency with time. CD4 cell counts decreased from 294.2 +/- 209.5/microliter to 188.7 +/- 208.3/microliter (P < 0.01). The results of this study indicate progressive CNS dysfunction with worsening of the immunostatus.

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.

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.