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HIV prematurely ages the brain - new study & Commentary
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Download the PDF here
Download the PDF here
How much evidence, how long will it take for researchers to tell HHS, OAR, NIH that we need services for patients including Geriatric Clinics, not more studies but actual services!!!
"Older age was significantly associated with lower performance in all five neuropsychological domains tested (working memory, episodic memory, motor function, executive function, and information processing speed; p<0⋅0001 for all comparisons)...... results should spur the development of geriatric medicine into an integrated multidisciplinary model of care for ageing patients with HIV.....large studies are needed to address whether ageing people with HIV are at increased risk of age-associated neurodegenerative disorders, such as vascular cognitive impairment6, 7 and perhaps Alzheimer's disease.....results support the general clinical need to screen HIV-infected individuals for HIV-associated neurocognitive disorders and to do so particularly intensively for older HIV-infected individuals, ideally with tests sensitive to deficits in the episodic memory and motor domains"
"As expected, we noted a primary effect of ageing across models, which consistently showed lower performance with older age on all five neurocognitive domains......subsample in which these data were available in the MACS cohort showed higher performance with longer duration of HIV infection in information processing speed, episodic memory, and executive function, the results clearly show that controlling for the specific factor of time since infection separately from age has an effect of major importance......A greater than expected effect of ageing on episodic memory and motor function with advanced stages of HIV infection suggests that these two domains are most susceptible to the progression of neurocognitive impairment caused by ageing in individuals with HIV. This deficit pattern suggests differential damage to the hippocampus and basal ganglia (specifically nigrostriatal pathways). Older individuals with HIV infection should be targeted for regular screening for HIV-associate neurocognitive disorder, particularly with tests referable to the episodic memory and motor domains.......results should spur the development of geriatric medicine into an integrated multidisciplinary model of care for ageing patients with HIV.....most patients are older than 50 years.....studies have not accounted for - the age-duration effect. The age-duration effect is supported by increasing evidence that duration of HIV infection is important in establishing the effect of advancing age, although this hypothesis is not universally accepted.5 For example, if in a study of 60-year-old people with HIV, some participants were infected aged 20 years but others were infected at ages 40 or 50 years, results will probably be conflicting if all patients are analysed together.....using data from the Multicenter AIDS Cohort Study....Older age was significantly associated with lower performance in all five neuropsychological domains tested (working memory, episodic memory, motor function, executive function, and information processing speed; p<0⋅0001 for all comparisons). Furthermore, the effects were related to the degree of advancement of HIV disease as assessed by US Centers for Disease Control and Prevention clinical disease staging, and duration of HIV infection was significantly associated with worse performance on information processing speed, working memory, and executive function......age-stage and age-duration variables should be incorporated into prospective large cohort studies to ensure meaningful results. Second, large studies are needed to address whether ageing people with HIV are at increased risk of age-associated neurodegenerative disorders, such as vascular cognitive impairment6, 7 and perhaps Alzheimer's disease"
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Comment
Does HIV prematurely age the brain?
14 July 2017 Lancet HIV
Bruce J Brew, Lucette Cysique
Departments of Neurology and HIV Medicine, Peter Duncan Neurosciences Unit, St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, 390 Victoria St, Darlinghurst, Sydney, NSW, Australia 2010
In an Article in The Lancet HIV,1 Karl Goodkin and colleagues answer the controversial question of whether chronic HIV infection leads to premature ageing in the combination antiretroviral therapy (ART) era: it does.
With the success of ART leading to durable viral suppression, the average age of patients with HIV has increased, and in some countries most patients are older than 50 years. Life expectancy in people with HIV is nearly the same as that in the general population, except for in some important minority groups (eg, African Americans).2
[from Jules: not true - life expectancy is worse in HIV+: AGING CRISIS: Comorbidities Shorten Life & HALE: Healthy Years of Life Expectancy - (05/02/17)]
Counterbalanced against this momentous step forward is the fact that chronic HIV infection, even in people with long-lasting viral suppression, is still characterised by chronic inflammation, albeit at a lower level than that in those who are not virally suppressed.3 Such chronic inflammation is linked, probably at least partly in a causal manner, to several diseases associated with advancing age and with ageing itself.3, 4
It is therefore unsurprising that researchers have tried to address the issue of whether chronic HIV infection leads to premature ageing of the brain. The results of these efforts have, however, not been definitive. The reasons are numerous: small sample size, inclusion of young patients (ie, younger than 50 years), inclusion of patients with varying degrees of infection severity (something we have termed as the age-stage effect), cross-sectional rather than prospective design, inclusion of confounding factors such as substance use, the lack of appropriate controls (especially for age-related comorbidities), and lack of accounting for what has been termed the age-duration effect. The age-duration effect is supported by increasing evidence that duration of HIV infection is important in establishing the effect of advancing age, although this hypothesis is not universally accepted.5 For example, if in a study of 60-year-old people with HIV, some participants were infected aged 20 years but others were infected at ages 40 or 50 years, results will probably be conflicting if all patients are analysed together.
By using data from the Multicenter AIDS Cohort Study, Goodkin and colleagues have largely overcome these issues. Their study included the largest sample so far: 5086 participants (2278 of whom had HIV) and 47 886 visits (20 477 of which were contributed by people with HIV). The sample size ensured an adequate proportion of participants aged older than 50 years and even beyond 65 years. They also excluded people with major neurological and psychiatric disorders, including current, severe alcohol or substance use disorders. More minority participants were in the HIV-seropositive group than in the seronegative group. Older age was significantly associated with lower performance in all five neuropsychological domains tested (working memory, episodic memory, motor function, executive function, and information processing speed; p<0⋅0001 for all comparisons). Furthermore, the effects were related to the degree of advancement of HIV disease as assessed by US Centers for Disease Control and Prevention clinical disease staging, and duration of HIV infection was significantly associated with worse performance on information processing speed, working memory, and executive function.
As noted by the authors, their study had several limitations, chief among which is the fact that the cohort was entirely male. However, these limitations do not detract from the results, which will hopefully be extended (particularly to women) and better understood by further studies. The design of the study did not allow for analyses of HIV-specific variables such as CD4 cell count nadir, plasma HIV load, treatment adherence, or ART central nervous system penetration effectiveness scores. Furthermore, Goodkin and colleagues did not test for complex effects such as interactions between age, education, and ethnicity interactions. Finally, data for cholesterol and triglyceride concentration, renal and hepatic function, and indices of general nutritional status were insufficient. But diabetes, hypertension, body-mass index, and total bodyweight were associated with poor neuropsychological performance.
Goodkin and colleagues' results have important implications for future work. First, age-stage and age-duration variables should be incorporated into prospective large cohort studies to ensure meaningful results. Second, large studies are needed to address whether ageing people with HIV are at increased risk of age-associated neurodegenerative disorders, such as vascular cognitive impairment6, 7 and perhaps Alzheimer's disease in people who are genetically predisposed.4, 8 Third, investigators will need to establish whether the same findings of accelerated ageing apply to patients who have been chronically virally suppressed and have no history of advanced HIV disease. In other words, will early adoption of ART negate premature ageing or will it contribute to ageing through potential toxic effects?
[from Jules: in my opinion starting ART very early or early may slow premature aging process but will not eliminate it because inflammation persists regardless of viral load & HIV enters the brain & causes inflammation shortly after infection & never leaves the brain AND of note although Guidelines recommend ART immediately many people do NOT start early because they remain undiagnosed, are not engaged in care, or treatment is delayed].
Finally, and most importantly, Goodkin and colleagues' results should spur the development of geriatric medicine into an integrated multidisciplinary model of care for ageing patients with HIV.
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Effect of ageing on neurocognitive function by stage of HIV infection: evidence from the Multicenter AIDS Cohort Study
Karl Goodkin, Eric N Miller, Christopher Cox, Sandra Reynolds, James T Becker, Eileen Martin, Ola A Selnes, David G Ostrow, Ned C Sacktor, for the Multicenter AIDS Cohort Study
Summary
Background
The demographics of the HIV epidemic in the USA have shifted towards older age. We aimed to establish the relationship between the processes of ageing and HIV infection in neurocognitive impairment.
Methods
With longitudinal data from the Multicenter AIDS Cohort Study, a long-term prospective cohort study of the natural and treated history of HIV infection among men who have sex with men in the USA, we examined the effect of ageing, HIV infection (by disease stage), and their interaction on five neurocognitive domains: information processing speed, executive function, episodic memory, working memory, and motor function. We controlled for duration of serostatus in a subanalysis, as well as comorbidities and other factors that affect cognition. Analyses were by linear mixed models for longitudinal data.
Findings
5086 participants (47 886 visits) were included in the analytic sample (2278 HIV-seropositive participants contributed 20 477 visits and 2808 HIV-seronegative control participants contributed 27 409 visits). In an a-priori multivariate analysis with control variables including comorbidities and time since seroconversion, significant, direct negative effects of ageing were noted on all neurocognitive domains (p<0⋅0001 for all). Similar effects were noted for late-stage HIV disease progression on information processing speed (p=0⋅002), executive function (p<0⋅0001), motor function (p<0⋅0001), and working memory (p=0⋅001). Deleterious interaction effects were also noted in the domains of episodic memory (p=0⋅03) and motor function (p=0⋅02).
Interpretation
A greater than expected effect of ageing on episodic memory and motor function with advanced stages of HIV infection suggests that these two domains are most susceptible to the progression of neurocognitive impairment caused by ageing in individuals with HIV. This deficit pattern suggests differential damage to the hippocampus and basal ganglia (specifically nigrostriatal pathways). Older individuals with HIV infection should be targeted for regular screening for HIV-associate neurocognitive disorder, particularly with tests referable to the episodic memory and motor domains.
Funding
National Institute of Mental Health.
Discussion
As expected, we noted a primary effect of ageing across models, which consistently showed lower performance with older age on all five neurocognitive domains. Likewise, we noted a primary effect of systemic HIV disease severity (ie, HIV disease stage) consistently on all domains, with the lowest performance predominantly in the late symptomatic stage. The control variables (ethnicity, education, income, ART era, diabetes, hypertension, depressed mood level, pain, fatigue, body-mass index, total bodyweight, and history of hepatitis C virus infection) were predominantly consistently in the expected directions across the outcome domains. In the model 1 analysis, interactions of age with HIV disease stage were present in all domains but episodic memory and motor function. The direction of these interactions suggested that older HIV-seropositive individuals showed higher neurocognitive performance than their younger counterparts, with respect to how older HIV-seronegative controls compared with their younger counterparts, except in the motor domain. Similar positive interactions of age with HIV disease stage have been reported previously in models in which duration of HIV serostatus could not be controlled.9
The addition of the highlighted control for time since seroconversion to this model in a subsample in which these data were available in the MACS cohort showed higher performance with longer duration of HIV infection in information processing speed, episodic memory, and executive function. Such an effect might be driven by variance in the lower end of the range of this period related to effective suppression of viral load on antiretroviral regimens and the associated greater immune reconstitution. In this analytic model, the significant interactions of ageing with HIV disease stage suggesting higher performance in older HIV-seropositive participants on information processing speed and executive function were eliminated. The non-significant interaction for episodic memory became significant and shifted to a negative direction. Motor function still showed lower performance, and working memory showed higher performance but decreasing associations toward late stage disease. Thus, with serostatus duration controlled, the results yielded the anticipated ageing interaction effect (ie, the lowest performance occurred with older age and late disease stage) in the specific domains of motor function and episodic memory, along with a similar direction by stage of disease in working memory. One limitation of the study is that participants undergoing neuropsychological testing could have experienced intercurrent medical events that affected their neurocognitive function between visits; however, our analytic model would have controlled for the effect of many of these events, and such events were recorded and uncommon. Overall, the results clearly show that controlling for the specific factor of time since infection separately from age has an effect of major importance. Furthermore, our results suggest that chronological age represents not only simply time since birth but also the onset of a specific physiological process of ageing, which has a debilitating neurocognitive effect beginning at about age 50 years in HIV infection.
This evidence showing an increased effect of ageing by HIV disease stage on motor function and episodic memory performance has specific neuroanatomical referents. For motor function, the neuroanatomical referent is the basal ganglia, which is affected early in HIV brain infection.4 Of note, parkinsonism has been reported in individuals with HIV and is related to lowered dopamine concentrations in the cerebrospinal fluid and brain tissue.25For episodic memory, the neuroanatomical referent is the hippocampus, in which dysfunction and atrophy occur independently with both ageing26 and HIV infection27 and with a deleterious interaction between ageing and HIV infection.28 Several studies have shown these regions to be of particular concern for damage in the setting of older individuals with HIV infection. The authors of a critical review29 reported that HIV infection was associated with greater than age-related brain atrophy in the basal ganglia and hippocampus. This finding has been supported by those from a study30 of brain morphometry in an older cohort with HIV. According to the critical review, functional MRI studies showed evidence for greater effects than those expected from ageing alone in individuals with HIV by brain region, although these effects varied when other neuroimaging techniques were used. In another neuroimaging study,31 longitudinal analysis showed evidence for a greater-than-expected effect of ageing on selected brain regions over a period of 6 months to 8 years within a cohort of individuals with HIV infection who were in good overall health and did not have clinical evidence for dementia. Another relevant study32 showed age-dependent changes in brain activation in response to tasks of increasing attentional load that differed among three groups, with HIV infection and ageing acting synergistically (ie, interactively) to exacerbate brain activation abnormalities in different brain regions. These results suggest that a neurologically adaptive mechanism in the attention network could be operating to compensate for decreased neural efficiency. Along a separate line, the protective role of neurocognitive reserve in older individuals with HIV infection also merits further study.33
In summary, our results show evidence for region-specific increases of deleterious ageing effects with worsening systemic stage of HIV infection. These results are supported by other studies in which changes in brain tissue were examined by neuroimaging. Our neuropsychological results provide evidence that there is a differential worsening of the deleterious effect of ageing on neurocognitive function when patients have a higher level of systemic HIV disease progression, most specifically on the neurocognitive domains of episodic memory and motor performance. That is, the magnitude of the impairment in these domains is greater than the sum of the independent, negative effects of age and HIV disease stage. Our results support the general clinical need to screen HIV-infected individuals for HIV-associated neurocognitive disorders and to do so particularly intensively for older HIV-infected individuals, ideally with tests sensitive to deficits in the episodic memory and motor domains.
Introduction
Until the advent of effective antiretroviral therapy (ART) in the mid-1990s, the prevalence of older adults (ie, aged 50 years or older) living with HIV was low. By 2010, however, older adults accounted for more than 50% of AIDS cases in San Francisco (CA, USA), a pattern expected to be seen nationwide by 2020. Older age continues to be predictive of excess mortality, despite suggestions that increasing age might be associated with higher antiretroviral adherence,1 and despite adjustment for natural ageing, which accounts for more than 50% of mortality in individuals aged 45 years or older with HIV.2 The prevalence of HIV-associated neurocognitive disorders seems to have increased too, primarily as a function of increased survival and ageing in the ART era, although the number of newly infected older adults is also increasing.3 Studies of neurocognitive dysfunction among older individuals with HIV have increased in number in the past 15 years, but results have been inconsistent. Neurocognitive dysfunction and HIV-associated neurocognitive disorders in older individuals with HIV have been focused upon as high priorities in the field, and thus systematic attempts to identify and resolve the sources of these inconsistencies are needed.
A substantial body of evidence shows that older age is associated with an increased likelihood of HIV-associated neurocognitive disorders, particularly of HIV-associated dementia and, less so, of mild neurocognitive disorder and HIV-associated neurocognitive impairment generally (across systemic HIV disease stages).4, 5 During the transitional period to effective ART, Hardy and colleagues6reported that, in a sample of 257 men with HIV, older men (aged 37 years or older; mean age 44⋅5 years) showed lower performance than younger men (aged 36 years or younger; mean age 31⋅5 years) on several neuropsychological tests. As expected, men in the late symptomatic stage of HIV (ie, AIDS) showed lower performance than those with earlier-stage disease. Subsequently, Hinkin and coauthors7 used data adapted from Hardy and colleagues' study6 to investigate the interaction between age (<40 years, 40-49 years, ≥50 years) and HIV disease category (HIV seronegative, HIV seropositive [non-AIDS], and HIV seropositive [AIDS]), and showed that age was a significant risk factor for HIV-associated neurocognitive impairment in late-stage systemic disease. Furthermore, as in Hardy and colleagues' study,6 neurocognitive impairment was more common in individuals aged 50 years or older who had progressed to AIDS than in those in younger groups with and without AIDS. In a subsequent study by Hardy and colleagues,8 HIV-associated neurocognitive impairment was not consistently more frequent with age across domains, and a large inter-individual variation in neuropsychological performance was noted among older individuals with HIV. Longer follow-up and increased use of control variables for neuropsychological performance, particularly for medical comorbidities, depressed mood, and alcohol or substance use, could help to decrease inter-individual variation in older individuals and improve the consistency of results. Another influence of concern that has been noted but not generally assessed as a specific type of control is the duration of HIV infection (as opposed to the effect of ageing itself).9
Research in context
Evidence before this study
We searched PubMed with the terms "aging", "HIV", and "cognition disorders" as medical subject heading terms for human studies published in any language between Jan 1, 1985 (soon after the initiation of the Multicenter AIDS Cohort Study), and March 22, 2017 (the date of our final search). In place of "cognition disorders", we also used ["cognition" (all fields) and "disorders" (all fields)] or ["cognitive" (all fields) and "impairment" (all fields)] or ["cognitive impairment" (all fields)]. We included studies of participants aged 65 or older and those of participants aged 45-64 years, because "older age" in HIV infection has been generally defined as age 50 years or older. This designation is partly because of the epidemiological rationale of the US Centers for Disease Control and Prevention. Notably, most older individuals living with HIV are aged 50-64 years. The biological rationale that age 50 years is typically when age-associated neurocognitive deficits and immunological deficits are first noted in the general population also plays a part. We identified reports of ageing and HIV infection affecting neurocognitive function beginning in 1994. Results of studies identified by our strategy varied widely, with some showing no significant effect of ageing, others showing an additive effect of ageing and HIV infection, and others showing a truly synergistic, interactive effect of ageing and HIV infection on the designated neurocognitive outcomes. We also identified studies of outcomes associated with neurocognitive deficits, such as cerebrospinal fluid parameters of CNS injury, structural and functional neuroimaging findings, magnetic resonance spectroscopic findings of brain tissue metabolites by brain region, and neuropathological outcomes. Weaknesses in published research include a lack of control for both medical and psychiatric comorbidities and other factors that might affect cognition. Additionally, almost no studies in which duration of infection (eg, as length of HIV-positive serostatus) was separately assessed have been reported, partly because this variable is generally acknowledged to be difficult to ascertain.
Added value of this study
To our knowledge no other studies in this area have been active for as long as the Multicenter AIDS Cohort Study, and the breadth of data allowed us to explore the effects of ageing in HIV more fully longitudinally. Our study also adds to the methodological rigour of published work through its controls for medical and psychiatric comorbidities and other factors that can affect cognition. Furthermore, this study shows the importance of controlling for duration of HIV infection, which had significant effects that accounted for otherwise apparently anomalous statistical interactions between ageing and HIV infection on cognition.
Implications of all the available evidence
Our results show that future studies of ageing and HIV infection should include controls that account for the recognised effects of medical and psychiatric comorbidities and other factors that affect cognition. Attempts to control for duration of HIV infection might be required to separate the effect of ageing from that of the longevity of the infectious process, irrespective of age. An overall, categorical differentiation of an additive but independent pattern versus a synergistic, interactive pattern of results of ageing and HIV infection on cognition might be an oversimplification. These relationships might vary by the specific domains of neurocognitive function analysed. Episodic memory and motor function, which have been prominent among the areas of cognitive function affected by HIV infection, show a pattern of synergistic, interactive effects. Older individuals with HIV should be regularly screened for HIV-associated neurocognitive disorder with tests aimed at the episodic memory and motor function domains.
In summary, limitations of the work published so far include the truncation of the oldest age range and the incomplete use of controls for other possible influences on neurocognitive function beyond education, ethnicity, and stage of HIV disease. The need to control for additional factors, such as medical comorbidities common in the general population that affect cognition (eg, diabetes, hypertension, coronary artery disease, cerebrovascular disease, thyroid disease), has been increasingly acknowledged. Furthermore, controls for depressed mood, use of alcohol, psychoactive substances, or psychotropic drugs, history of hepatitis C virus infection, pain, and fatigue also need to be considered routinely. Thus, we aimed to examine the hypothesis that ageing interacts with the effect of HIV infection on neurocognitive impairment and simultaneously to address the limitations of published work by using the Multicenter AIDS Cohort Study (MACS) dataset.
Results
Our sample comprised 5086 participants, 2278 of whom were HIV seropositive and 2808 of whom were HIV seronegative (table 1). We analysed 47 886 visits, 20 477 of which were by HIV-seropositive individuals and 27 409 by HIV-seronegative individuals. On initial recruitment, 10% of HIV-seronegative participants and 5% of HIV-seropositive participants were aged 50 years or older (table 1). Most of the HIV-seropositive participants aged 50 years or older were in their mid-50s, with very few participants older than 65 years (data not shown). More participants in the seropositive group than in the seronegative group had an educational level of high school or less (table 1). Similarly, university-level education or higher was more common in the HIV-seronegative subsample, and particularly in the older HIV-seronegative group, than in the seropositive sample (table 1). Significantly more participants in the HIV-seropositive group than in the seronegative group were of non-white ethnicity (table 1), as expected from national demographics. HIV disease stage differed significantly by age at baseline, and more patients in the older age group had stage C disease than in the younger age group (table 1). CD4 cell nadir and concurrent CD4 cell counts were significantly higher in the older HIV-seropositive subgroup than in the younger subgroup (table 1), although these differences were probably not clinically important. The frequency of detectable plasma viral load was similar between age groups (table 1).
Neuropsychological domain scores were generally lower (but not always significantly so) in HIV-seropositive participants than in HIV-seronegative participants (table 2). However, when HIV disease stage was accounted for, lower performance on all five neuropsychological domain scores was significantly associated with advanced disease stage (table 2).
The full model on full sample (model 1) results showed that older age was significantly associated with lower performance in all five neuropsychological outcome domains (p<0⋅0001 for all; table 3). Deleterious HIV disease stage effects were maintained (table 3). We noted a significant age-by-disease-stage interaction in information processing speed, executive functioning, and working memory (table 3). In the reduced model on the entire sample (model 2), elimination of non-significant control variables recapitulated the results of the full models, including the effect of controls, which were in the expected directions (data not shown). Each control was significant in the analyses, except for cannabis use and lifetime history of hepatitis B virus infection (table 3).
The full model with the subsample analysis adding time since seroconversion as a special focus for control (model 3) included 4234 participants, 1638 of whom were HIV seropositive and 2596 of whom were seronegative. Of the seropositive participants, 1120 were seroprevalent at study baseline and 518 seroconverted while enrolled in the study. For seroprevalent participants, we conservatively used date of study baseline as time since seroconversion. Time since seroconversion was significant for information processing speed, episodic memory, and executive function (table 3). The negative effects of ageing from the full model were maintained in model 3 (table 3). The effect of HIV disease stage on neuropsychological performance was greater in the expected negative direction in this model than in the original model. The age-by-HIV-disease-stage interactions were eliminated for information processing speed and executive function (table 3). The interactions in this model (figure) between age and disease stage were significant and negative for motor function and episodic memory (which had changed in direction from positive to negative). A significant positive interaction was noted for working memory (table 3), but the directions of the changes noted with progression from HIV disease stages A to C were in the negative pattern consistently, as predicted. Analysis of this subsample with the full model (ie, the fourth model, without including time since seroconversion) showed that results predominantly reverted to those of model 1 (data not shown), which, as anticipated, were once again contrary to prediction in the directions of the age by HIV disease stage interactions.
Plots of adjusted domain scores and fitted regression lines from multivariable models for relationships between age and episodic memory in the full model on the full sample (A) and model including time since seroconversion (B); and between age and motor function in the full model (C) and model including time since seroconversion (D). The AIDS and HIV-seronegative subsamples were selected to display the results from the opposite poles of the spectrum of HIV disease. In the model adding time since seroconversion, participants with AIDS did worse at older ages than HIV-seronegative control participants in both domains. The absence of any pattern in the residual error scattergrams of both groups (aside from the downward trends consistent with the regression on age) supports the validity of the analytic models used.
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