J Neurol DOI 10.1007/s00415-015-7783-7
JOURNAL CLUB
HIV-associated neurocognitive disorders Katharine E. Harding1 • Neil P. Robertson1
Ó Springer-Verlag Berlin Heidelberg 2015
Since the first description of HIV and AIDS, it has been clear that cognitive impairment can be a common and early clinical feature of disease. Although anti-retroviral therapy has significantly reduced the frequency of HIV-associated dementia, mild cognitive impairment still affects up to 40 % of HIV-positive patients. However, the biological mechanisms underlying this clinical phenomenon remain poorly understood. A detailed understanding of the pathophysiology leading to HIV-associated neurocognitive disorders, and the temporal evolution of clinical manifestations of these deficits would be of great value in developing neuroprotective strategies. It would also be helpful in the early identification of patients with HIVassociated cognitive impairment, and allow the prompt use of targeted therapies. In this month’s journal club, we examine three recent papers investigating cognition and HIV. The first is a large, longitudinal study of men at risk of HIV which utilises novel statistical methods to model trajectory of cognitive decline over time and investigates the relative contribution of factors including HIV status, AIDS, depression and other comorbidities. The second paper is from a more recently established cohort of women with HIV, using a cross-sectional design to compare neuropsychological measures in HIV-positive and -negative women and assess the relative impact of HIV on cognition. The final paper is a study of CSF markers of neuronal degeneration and inflammation in patients with HIV-associated neurocognitive
& Neil P. Robertson [email protected] 1
Department of Neurology, University Hospital of Wales, Cardiff, UK
disorders, and may represent a promising early investigation of relevant biological mechanisms.
Mixed membership trajectory models of cognitive impairment in the multicenter AIDS cohort study The multicentre AIDS cohort study was established in the 1980s, and recruited gay and bisexual men in order to study the natural and treated history of HIV and AIDS. A total of 6972 men were recruited in three separate phases (1984–1985, 1987–1991, 2001–2003), and have been followed up regularly ever since. This sub-study included 3892 men who underwent regular neuropsychological assessments and were either HIV-positive at recruitment or have remained HIV-negative throughout follow-up (i.e. patients who sero-converted at some point after recruitment were excluded, in order to avoid modelling two different time-varying variables). The researchers then employed a novel statistical modelling method to examine trajectory of change in cognitive function over time. Three theoretical pathways were developed: normal ageing, premature ageing, and unhealthy. The effect of seven variables (HIV-positive, AIDS, recruitment cohort, race, hepatitis C, depression, and other comorbidities) on the probability of moving from one trajectory to another was then analysed. HIV-positive status tended to move patients away from the healthy profile towards the premature ageing profile, as did having AIDS and hepatitis C. HIV-positive status and AIDS were both more likely to be found in patients closer to the premature ageing profile than the unhealthy profile. Confounding medical conditions and depression were more likely to move patients towards the unhealthy profile. Finally, the trajectories of five individual study participants
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J Neurol
with different combinations of risk factors were plotted to illustrate the models. Comment. Long-term natural history studies such as these are extremely informative and provide a rich source of data. The size of this study and the detail of the cognitive assessments are unparalleled. The statistical methods that have been used are novel and the authors go to some lengths to explain them. The finding that HIV and AIDS are more likely to lead towards a premature ageing profile, i.e. a higher risk of cognitive impairment, but less likely than depression and other comorbidities to lead to significant levels of cognitive impairment is an interesting one. For clinical practice it would be useful to know whether HIV means that patients are more vulnerable to cognitive impairment from other causes, or whether these effects are independent. Molsberry SA et al. (2015) AIDS 29:713–721.
Cognitive function in women with HIV: findings from the Women’s Interagency HIV Study This is a cross-sectional study comparing a cohort of 1019 HIV-positive women with 502 HIV-negative women, recruited from multiple centres in the USA. The study recruited women in two phases, first in 1994–1996, and then in 2001–2002. Cognitive testing of the entire cohort was carried out over the course of 2 years by trained test administrators. Neuropsychological tests included Hopkins Verbal Learning Test-Revised (HVLT-R); Stroop Test; Trail Making Test Parts A and B; Symbol Digit Modalities Test (SDMT); Letter-Number Sequencing Test (LNS); Letter Fluency (F, A, S); Semantic Fluency (animals); and Grooved Pegboard. Results from HIV-negative women were used to generate demographically corrected normative standards to which the results from HIV-positive women were compared. Models were corrected for premorbid factors including age, ethnicity, education level, reading level, and current factors including antidepressant use, smoking status, use of recreational drugs, and hepatitis C status. In all patients, reading level was the strongest predictor of cognitive function. HIV-positive women performed less well on cognitive testing than HIV-negative women, but the effect of having HIV was relatively small. In addition, the effect on cognitive testing of having HIV was smaller than the effects of years of education, age, household income, ethnicity and reading level. Finally, interactions were noted between reading level and years of education, and HIV status: women with HIV who had a low reading level performed less well in the Stroop test, Trails B and the Grooved Pegboard tests than women with a similar reading level but who were HIV-negative, and among
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women with fewer than 9 years of education, those with HIV performed less well on semantic fluency testing than those without HIV. Comment. This study has been carefully designed to detect effects of HIV on cognition in a large cohort of women. One of the strengths of the study is the inclusion of HIV-negative women living in the same geographical area as controls, allowing effects of other adverse risk factors to be disentangled from the effects of HIV. It is perhaps not surprising that reading level and education were strong predictors of cognitive function, as this has been shown in other studies not specifically focussed on HIV. It is clear that HIV also has an effect on cognition in women, even where ability to carry out daily activities is not impaired, although the effect is small. It would be worth remembering to consider the possibility of cognitive dysfunction in male and female patients with HIV. The fact that this study is cross-sectional means that it was unable to assess the rate of change in cognition over time, which in light of the first study we have reviewed would be valuable. A longitudinal study in this cohort is planned, with cognitive assessments every 2 years. We await the results of this with interest. Maki PM et al (2015) Neurology 84:231–240.
Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders In this retrospective study, CSF biomarkers were studied to explore the relationship between CNS macrophage activation and neuronal damage, as well as relationships between the biomarkers and plasma CD4? count or HIV RNA viral load, and classification of cognitive status. The biomarkers that were included in the study were neurofilament light (NFL) and phosphorylated neurofilament high molecular weight (pNFH) as markers of neuronal damage; and sCD14 and sCD163 which are markers of monocyte and macrophage activation. Patients were classified as neurocognitively normal (n = 15), asymptomatic neurocognitive impairment (n = 15), mild neurocognitive disorder (n = 15), and HIV-associated dementia (n = 3). All patients were either anti-retroviral treatment naı¨ve, or off-treatment at the time of testing. A historical group of age-matched HIV-negative controls was also included. NFL was elevated in all groups of HIV-positive patients as compared to controls. NFL was also found to be higher in patients with HIV-associated dementia and CD4? count \200, but there were no other differences by cognitive classification alone or in combination with CD4? count. There was a strong positive correlation between CSF neurofilament markers and both sCD14 and sCD163, but
J Neurol
not with plasma sCD14 or sCD163. There was an inverse correlation between CSF NFL and peripheral CD4? count, and a positive correlation between CSF NFL and peripheral HIV RNA viral load, but there was no correlation of CSF pNFH with peripheral HIV markers. Comment. This is an early study with some promise of improving understanding of mechanisms of cognitive impairment in HIV, and suggests an association between CNS inflammation and neuronal damage. Neurofilament light has been identified as a marker of neuronal damage in other neurological disease including multiple sclerosis as well as
Alzheimer’s disease and vascular dementia, and so it is interesting to see a possible association with HIV-associated neurocognitive disorders as well. However, only small numbers of patients were included in this study, and so it would be of value to see it replicated in a larger sample. At present these biomarkers are not likely to affect clinical practice, but this may change in the future as we become more knowledgeable about the biological processes underlying neurodegeneration. McGuire JL et al. (2015) J Neurovirol. Epub ahead of print 17 March 2015. doi:10.1007/s13365-015-0333-3.
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JOURNAL CLUB
HIV-associated neurocognitive disorders Katharine E. Harding1 • Neil P. Robertson1
Ó Springer-Verlag Berlin Heidelberg 2015
Since the first description of HIV and AIDS, it has been clear that cognitive impairment can be a common and early clinical feature of disease. Although anti-retroviral therapy has significantly reduced the frequency of HIV-associated dementia, mild cognitive impairment still affects up to 40 % of HIV-positive patients. However, the biological mechanisms underlying this clinical phenomenon remain poorly understood. A detailed understanding of the pathophysiology leading to HIV-associated neurocognitive disorders, and the temporal evolution of clinical manifestations of these deficits would be of great value in developing neuroprotective strategies. It would also be helpful in the early identification of patients with HIVassociated cognitive impairment, and allow the prompt use of targeted therapies. In this month’s journal club, we examine three recent papers investigating cognition and HIV. The first is a large, longitudinal study of men at risk of HIV which utilises novel statistical methods to model trajectory of cognitive decline over time and investigates the relative contribution of factors including HIV status, AIDS, depression and other comorbidities. The second paper is from a more recently established cohort of women with HIV, using a cross-sectional design to compare neuropsychological measures in HIV-positive and -negative women and assess the relative impact of HIV on cognition. The final paper is a study of CSF markers of neuronal degeneration and inflammation in patients with HIV-associated neurocognitive
& Neil P. Robertson [email protected] 1
Department of Neurology, University Hospital of Wales, Cardiff, UK
disorders, and may represent a promising early investigation of relevant biological mechanisms.
Mixed membership trajectory models of cognitive impairment in the multicenter AIDS cohort study The multicentre AIDS cohort study was established in the 1980s, and recruited gay and bisexual men in order to study the natural and treated history of HIV and AIDS. A total of 6972 men were recruited in three separate phases (1984–1985, 1987–1991, 2001–2003), and have been followed up regularly ever since. This sub-study included 3892 men who underwent regular neuropsychological assessments and were either HIV-positive at recruitment or have remained HIV-negative throughout follow-up (i.e. patients who sero-converted at some point after recruitment were excluded, in order to avoid modelling two different time-varying variables). The researchers then employed a novel statistical modelling method to examine trajectory of change in cognitive function over time. Three theoretical pathways were developed: normal ageing, premature ageing, and unhealthy. The effect of seven variables (HIV-positive, AIDS, recruitment cohort, race, hepatitis C, depression, and other comorbidities) on the probability of moving from one trajectory to another was then analysed. HIV-positive status tended to move patients away from the healthy profile towards the premature ageing profile, as did having AIDS and hepatitis C. HIV-positive status and AIDS were both more likely to be found in patients closer to the premature ageing profile than the unhealthy profile. Confounding medical conditions and depression were more likely to move patients towards the unhealthy profile. Finally, the trajectories of five individual study participants
123
J Neurol
with different combinations of risk factors were plotted to illustrate the models. Comment. Long-term natural history studies such as these are extremely informative and provide a rich source of data. The size of this study and the detail of the cognitive assessments are unparalleled. The statistical methods that have been used are novel and the authors go to some lengths to explain them. The finding that HIV and AIDS are more likely to lead towards a premature ageing profile, i.e. a higher risk of cognitive impairment, but less likely than depression and other comorbidities to lead to significant levels of cognitive impairment is an interesting one. For clinical practice it would be useful to know whether HIV means that patients are more vulnerable to cognitive impairment from other causes, or whether these effects are independent. Molsberry SA et al. (2015) AIDS 29:713–721.
Cognitive function in women with HIV: findings from the Women’s Interagency HIV Study This is a cross-sectional study comparing a cohort of 1019 HIV-positive women with 502 HIV-negative women, recruited from multiple centres in the USA. The study recruited women in two phases, first in 1994–1996, and then in 2001–2002. Cognitive testing of the entire cohort was carried out over the course of 2 years by trained test administrators. Neuropsychological tests included Hopkins Verbal Learning Test-Revised (HVLT-R); Stroop Test; Trail Making Test Parts A and B; Symbol Digit Modalities Test (SDMT); Letter-Number Sequencing Test (LNS); Letter Fluency (F, A, S); Semantic Fluency (animals); and Grooved Pegboard. Results from HIV-negative women were used to generate demographically corrected normative standards to which the results from HIV-positive women were compared. Models were corrected for premorbid factors including age, ethnicity, education level, reading level, and current factors including antidepressant use, smoking status, use of recreational drugs, and hepatitis C status. In all patients, reading level was the strongest predictor of cognitive function. HIV-positive women performed less well on cognitive testing than HIV-negative women, but the effect of having HIV was relatively small. In addition, the effect on cognitive testing of having HIV was smaller than the effects of years of education, age, household income, ethnicity and reading level. Finally, interactions were noted between reading level and years of education, and HIV status: women with HIV who had a low reading level performed less well in the Stroop test, Trails B and the Grooved Pegboard tests than women with a similar reading level but who were HIV-negative, and among
123
women with fewer than 9 years of education, those with HIV performed less well on semantic fluency testing than those without HIV. Comment. This study has been carefully designed to detect effects of HIV on cognition in a large cohort of women. One of the strengths of the study is the inclusion of HIV-negative women living in the same geographical area as controls, allowing effects of other adverse risk factors to be disentangled from the effects of HIV. It is perhaps not surprising that reading level and education were strong predictors of cognitive function, as this has been shown in other studies not specifically focussed on HIV. It is clear that HIV also has an effect on cognition in women, even where ability to carry out daily activities is not impaired, although the effect is small. It would be worth remembering to consider the possibility of cognitive dysfunction in male and female patients with HIV. The fact that this study is cross-sectional means that it was unable to assess the rate of change in cognition over time, which in light of the first study we have reviewed would be valuable. A longitudinal study in this cohort is planned, with cognitive assessments every 2 years. We await the results of this with interest. Maki PM et al (2015) Neurology 84:231–240.
Central and peripheral markers of neurodegeneration and monocyte activation in HIV-associated neurocognitive disorders In this retrospective study, CSF biomarkers were studied to explore the relationship between CNS macrophage activation and neuronal damage, as well as relationships between the biomarkers and plasma CD4? count or HIV RNA viral load, and classification of cognitive status. The biomarkers that were included in the study were neurofilament light (NFL) and phosphorylated neurofilament high molecular weight (pNFH) as markers of neuronal damage; and sCD14 and sCD163 which are markers of monocyte and macrophage activation. Patients were classified as neurocognitively normal (n = 15), asymptomatic neurocognitive impairment (n = 15), mild neurocognitive disorder (n = 15), and HIV-associated dementia (n = 3). All patients were either anti-retroviral treatment naı¨ve, or off-treatment at the time of testing. A historical group of age-matched HIV-negative controls was also included. NFL was elevated in all groups of HIV-positive patients as compared to controls. NFL was also found to be higher in patients with HIV-associated dementia and CD4? count \200, but there were no other differences by cognitive classification alone or in combination with CD4? count. There was a strong positive correlation between CSF neurofilament markers and both sCD14 and sCD163, but
J Neurol
not with plasma sCD14 or sCD163. There was an inverse correlation between CSF NFL and peripheral CD4? count, and a positive correlation between CSF NFL and peripheral HIV RNA viral load, but there was no correlation of CSF pNFH with peripheral HIV markers. Comment. This is an early study with some promise of improving understanding of mechanisms of cognitive impairment in HIV, and suggests an association between CNS inflammation and neuronal damage. Neurofilament light has been identified as a marker of neuronal damage in other neurological disease including multiple sclerosis as well as
Alzheimer’s disease and vascular dementia, and so it is interesting to see a possible association with HIV-associated neurocognitive disorders as well. However, only small numbers of patients were included in this study, and so it would be of value to see it replicated in a larger sample. At present these biomarkers are not likely to affect clinical practice, but this may change in the future as we become more knowledgeable about the biological processes underlying neurodegeneration. McGuire JL et al. (2015) J Neurovirol. Epub ahead of print 17 March 2015. doi:10.1007/s13365-015-0333-3.
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