| |
HIV Remodels Brain Function Study Suggests - also: illicit drug use history, comorbidities
|
| |
| |
Download the PDF here
Brain/Vascular function remodeled suggests study - in HIV+ neurofunction worse / affected by HIV, drug use history, comorbidities
"we studied markers of vascular remodeling, PP pulse pressure, and neurocognitive function among older (≥50 years of age) HIV-infected (HIV+, n = 72) and HIV-seronegative (HIV-, n = 36) adults, patients had history of psych disorders, illicit drug use and comorbidities......HIV+ participants had worse neurocognitive function [global T-score = 45.8 (SD 7.0)] than HIV- participants [global T-score = 49.9 (SD 6.4)] (P = 0.004).
.....In our cohort of older HIV+ and HIV- adults, markers of vascular remodeling and arterial stiffness were associated with neurocognitive function. HIV interacted with biomarkers of vascular remodeling (ie, Tie-2 and VEGF) on neurocognitive function.....these findings indicate that both vascular remodeling and altered cerebral blood flow autoregulation contribute to neurocognitive function. These effects seem to be driven by the neurocognitive domains of fine motor functioning, SIP, executive functioning, and learning ......The interactions between vascular remodeling (ie, Tie-2 and VEGF) and HIV on neurocognitive function suggest that HIV is interacting with the aging brain to affect neurologic function.....In our cohort of older HIV+ and HIV- adults, markers of vascular remodeling and arterial stiffness were associated with neurocognitive function..........Consistent with previous studies involving older HIV+ adults, we found that diabetes mellitus emerged as an independent predictor of neurocognitive function......The etiology of HIV-associated NCI in the cART era is multifactorial and may be related to both direct and indirect consequences of HIV, the immune response, and comorbid factors,59 such as subclinical CVD. Delineating the relative contribution of CVD risk factors, such as vascular remodeling and PP, in the pathogenesis of HIV-associated NCI may allow for the identification of adjunct therapies aimed at improving health outcomes for persons aging with HIV/AIDS.....HIV disease, which is characterized by chronic inflammation, may confer risk for increased arterial stiffness.12-15 Arterial stiffening is a complex process involving structural and functional changes in the arterial wall that occurs with normal aging16 and is accelerated by chronic inflammatory conditions, such as diabetes mellitus and hypertension.....Multivariable linear regression analyses were conducted to test for potential interacting effects of HIV and biomarkers of vascular remodeling on neurocognitive function. Of the covariates listed in Tables 1 and 2, pulse, diabetes, antidepressant prescription, current MDD, lifetime MDD [depression], and the Medical Outcome Study physical health composite were associated with global T-scores (P values < 0.10)."
HIGH PREVALENCE of COMORBIDITIES among STUDY PARYICIPANTS but also drug use, psych disorders - About 44 vs. 36% of HIV+ and HIV- groups were hypertensive, respectively, and of whom 81% vs. 62% were taking antihypertensive medications. The HIV+ group had more non-Hispanic white participants (84.7% vs. 63.9%, P = 0.01), men (84.7% vs. 61.1%, P = 0.006), hyperlipidemia (59.7% vs. 30.6%, P = 0.004), and lifetime MDD (55.6% vs. 27.8%, P = 0.006)......major depressive disorder (MDD)
HIV-associated neurocognitive impairment (NCI) remains highly prevalent in the current era of combination antiretroviral therapy (cART),1 although the severity of impairment tends to be milder than in the pre-cART era.1,2 Even mild forms of NCI can be associated with poor everyday functioning.3,4 The burden of HIV-associated NCI is projected to increase as persons living with HIV (HIV+) age.5 In addition, older age-related diseases that affect the general population, such as cardiovascular disease (CVD), are increasingly observed in HIV+ persons6-8 and are anticipated to increase in the future.7 With the increased incidence and prevalence of CVD, there is a growing body of evidence demonstrating the detrimental effect of CVD risk factors on neurocognitive function among HIV+ persons.9-11
Among the HIV+ participants (n = 72), the mean estimated duration of HIV infection was 17.3 years, the mean duration of exposure to cART was 11.9 years, the median current CD4+ T-cell count was 654 cells per cubic millimeter, and the median nadir CD4+ T-cell count was 180 cells per cubic millimeter. HIV disease-related characteristics of the HIV+ sample are presented in Table 2.
HIV+ participants had worse neurocognitive function [global T-score = 45.8 (SD 7.0)] than HIV- participants [global T-score = 49.9 (SD 6.4)] (P = 0.004).
The sample consisted of 108 participants who were predominantly middle-aged [mean 58.5 (SD 6.3) years] non-Hispanic white (77.8%) men (76.9%) with some college education [mean 14.5 (SD 2.6) years].
Abstract
Background: HIV is associated with elevated markers of vascular remodeling that may contribute to arterial fibrosis and stiffening and changes in pulse pressure (PP). These changes may, in turn, deleteriously affect autoregulation of cerebral blood flow and neurocognitive function.
Methods: To evaluate these mechanisms, we studied markers of vascular remodeling, PP, and neurocognitive function among older (≥50 years of age) HIV-infected (HIV+, n = 72) and HIV-seronegative (HIV-, n = 36) adults. Participants completed standardized neurobehavioral and neuromedical assessments. Neurocognitive functioning was evaluated using a well-validated comprehensive battery. Three plasma biomarkers of vascular remodeling (ie, angiopoietin 2, Tie-2, and vascular endothelial growth factor, VEGF) were collected.
Results: HIV+ and HIV- participants had similar levels of plasma angiopoietin 2 (P = 0.48), Tie-2 (P = 0.27), VEGF (P = 0.18), and PP (P = 0.98). In a multivariable regression model, HIV interacted with Tie-2 (β = 0.41, P < 0.01) and VEGF (β = -0.43, P = 0.01) on neurocognitive function, such that lower Tie-2 and higher VEGF values were associated with worse neurocognitive function for HIV+ participants. Greater Tie-2 values were associated with increased PP (r = 0.31, P < 0.01). In turn, PP demonstrated a quadratic association with neurocognitive function (β = -0.33, P = 0.01), such that lower and higher, relative to mean sample, PP values were associated with worse neurocognitive function.
Conclusions: These findings indicate that vascular remodeling and altered cerebral blood flow autoregulation contribute to neurocognitive function. Furthermore, HIV moderates the association between vascular remodeling and neurocognitive function but not the association between PP and neurocognitive function.
CONCLUSION: In our cohort of older HIV+ and HIV- adults, markers of vascular remodeling and arterial stiffness were associated with neurocognitive function. HIV interacted with biomarkers of vascular remodeling (ie, Tie-2 and VEGF) on neurocognitive function. For HIV+ adults, lower Tie-2 values and higher VEGF values were associated with worse neurocognitive function. Vascular remodeling, as measured by higher Tie-2 values, was associated with greater PP values. In turn, PP had a quadratic relationship with neurocognitive function. Relative to the sample mean, lower and higher values of PP were associated with worse neurocognitive function. Together, these findings indicate that both vascular remodeling and altered cerebral blood flow autoregulation contribute to neurocognitive function. These effects seem to be driven by the neurocognitive domains of fine motor functioning, SIP, executive functioning, and learning. .....The interactions between vascular remodeling (ie, Tie-2 and VEGF) and HIV on neurocognitive function suggest that HIV is interacting with the aging brain to affect neurologic function......The etiology of HIV-associated NCI in the cART era is multifactorial and may be related to both direct and indirect consequences of HIV, the immune response, and comorbid factors,59 such as subclinical CVD. Delineating the relative contribution of CVD risk factors, such as vascular remodeling and PP, in the pathogenesis of HIV-associated NCI may allow for the identification of adjunct therapies aimed at improving health outcomes for persons aging with HIV/AIDS.
Consistent with previous studies involving older HIV+ adults,10,53 we found that diabetes mellitus emerged as an independent predictor of neurocognitive function. Diabetes mellitus has shown an association with NCI in HIV+ adults older than 55 years.10 Likely mechanisms for the effect of diabetes mellitus on neurocognitive function may include direct damage to the brain from hyperglycemia, brain exposure to higher levels of glucose given disruption of the blood-brain barrier by HIV,54 and/or increased risk for cerebral atherosclerosis. Imaging studies demonstrate an association between diabetes mellitus and morphological changes in the brain that are predominantly subcortical, which is similar to the subcortical effects of HIV.55-57
HIV disease, which is characterized by chronic inflammation, may confer risk for increased arterial stiffness.12-15 Arterial stiffening is a complex process involving structural and functional changes in the arterial wall that occurs with normal aging16 and is accelerated by chronic inflammatory conditions, such as diabetes mellitus and hypertension.17,18 Arterial remodeling is influenced by multiple biological pathways, including vascular endothelial growth factor (VEGF) and angiopoietin pathways.19 VEGF and angiopoietins are considered to work in concert during vascular remodeling, such that VEGF is expressed during the earliest stages of vascular remodeling and the angiopoietin pathway plays a larger role in vessel maturation.20 With increased arterial stiffening, changes in blood pressure (BP) occur such that systolic BP (SBP) increases, diastolic BP (DBP) decreases, and pulse pressure (PP)—defined as the difference between SBP and DBP readings—increases.16 PP is a surrogate marker of arterial stiffness, and elevation of PP is an independent risk factor for future cardiovascular events and cerebrovascular disease.21-25 Markers of arterial stiffness are associated with neurocognitive performance and decline in relatively healthy middle-aged adults.26,27 On the other end of the spectrum, poor cerebral perfusion related to low PP is associated with increased risk of NCI.28
The neurologic consequences of vascular remodeling and arterial stiffness in the context of chronic HIV disease remain unclear and warrant investigation. The first aim of this study is to examine the relation of vascular remodeling with neurocognitive function. Angiogenic growth factors were examined because of their role in vascular remodeling.19,29 Second, we aim to investigate the association of vascular remodeling with PP. We hypothesize that biomarkers associated with vascular remodeling will be related to greater PP. Lastly, we aim to evaluate the association between neurocognitive function and PP. We hypothesize that PP will have a quadratic relationship with neurocognitive function, such that lower and higher PP values (relative to sample mean PP) will be associated with worse neurocognitive function.
DISCUSSION
In our cohort of older HIV+ and HIV- adults, markers of vascular remodeling and arterial stiffness were associated with neurocognitive function. HIV interacted with biomarkers of vascular remodeling (ie, Tie-2 and VEGF) on neurocognitive function. For HIV+ adults, lower Tie-2 values and higher VEGF values were associated with worse neurocognitive function. Vascular remodeling, as measured by higher Tie-2 values, was associated with greater PP values. In turn, PP had a quadratic relationship with neurocognitive function. Relative to the sample mean, lower and higher values of PP were associated with worse neurocognitive function. Together, these findings indicate that both vascular remodeling and altered cerebral blood flow autoregulation contribute to neurocognitive function. These effects seem to be driven by the neurocognitive domains of fine motor functioning, SIP, executive functioning, and learning.
Our investigation explored the association of angiogenic growth factors with both PP and neurocognitive function given their crucial role in vascular remodeling.19,29 A complex interplay of the angiopoietins, Tie-2, VEGF, and other pro- or antiangiogenic factors contribute to angiogenesis and vascular remodeling.36 Angiopoietins bind to the endothelial tyrosine kinase receptor Tie-2 to exert context-dependent biological functions,36 and circulating levels of Ang-2 and Tie-2 have been associated with CVD risk factors (eg, hypertension, diabetes mellitus, and abdominal obesity).37 Ang-2 has previously been found to have a positive association with PP.36 Our study did not find an association between PP and Ang-2; however, we found a positive association between PP and Tie-2. Given the cross-sectional design of this study, we are unable to infer whether this association reflects a dysregulation of VEGFs that contribute to microvascular rarefaction (ie, a deficiency in mature small vessels)36 or PP-induced vascular remodeling.36 Future research, particularly studies employing longitudinal designs, may tease apart the temporal association between vascular remodeling, PP, and cerebrovascular disease in the context of HIV disease.
The interactions between vascular remodeling (ie, Tie-2 and VEGF) and HIV on neurocognitive function suggest that HIV is interacting with the aging brain to affect neurologic function. VEGF is generally considered to have neuroprotective effects,38 whereas upregulated levels of Tie-2 may reflect pathological angiogenesis.39For HIV- adults, we found that higher Tie-2 and lower VEGF values were associated with worse neurocognitive function. Counterintuitively, lower Tie-2 values and higher VEGF values were associated with worse neurocognitive function for HIV+ adults. One potential interpretation of these counterintuitive associations is that the neuroprotective effect of VEGF is attenuated within our HIV+ sample, given that they demonstrate good immunologic and virologic status. Emerging evidence indicates that the neuroprotective effect of VEGF may be the most robust among adults with greater risk factors for Alzheimer disease (AD).38 It is possible that our HIV serostatus groups differ in regard to AD risk factors that, in turn, may be influencing the effect of VEGF on neurocognitive function. Alternatively, the association between lower Tie-2 values and worse neurocognitive function observed among the HIV+ sample may reflect pathological angiogenesis.
Pathological angiogenesis shares many cellular and molecular processes with physiological angiogenesis (eg, sprouting of new blood vessels and recruitment of inflammatory cells to sites of inflammation); however, pathological angiogenesis is characterized by a highly disorganized vascular network.39 Given that HIV is characterized by chronic inflammation, HIV+ adults may be particularly vulnerable to pathological angiogenic processes.
Despite not finding an interacting effect of HIV and PP on neurocognitive function, our results show an association between PP and neurocognitive function that holds in the overall sample. Arterial stiffness may lead to neurocognitive decline because of augmented pressure pulses that penetrate and cause damage to the smaller blood vessels of the brain.40 Previous research indicates that cerebrovascular disease may be a key underpinning in HIV-associated NCI.41 We found a quadratic association between PP and neurocognitive function. This is consistent with literature demonstrating a U-shaped relationship between PP and risk of AD and dementia, whereby both lower and higher ends of the PP spectrum confer risk.28 Alternatively, the association between PP and neurocognitive function may reflect normal brain arterial aging. A recent histopathologic study showed that with age, the arteries of the brain undergo degenerative changes characterized by arterial thickening, even in the absence of atherosclerosis.42 These degenerative changes are hypothesized to be the downstream effect of mechanical forces of blood flow.42 Thus, it is possible that PP is indexing arterial stiffening that may be occurring in the periphery and brain.
Our sample of older HIV+ adults did not demonstrate different levels of arterial stiffness relative to older HIV- adults. This finding is in agreement with studies finding no differences in arterial stiffness by HIV serostatus,12 although there have been reports of increased arterial stiffness in the context of HIV.43 Divergent results among studies may be related to differences in cohort characteristics. For example, among HIV+ persons, commonly reported determinants of arterial stiffness are low nadir CD4 T-cell counts (eg, <350 cells per microliter), age, hypertension, and high cholesterol levels.43-51 Given that our HIV+ sample demonstrated good immunologic and virologic status, potential effects of HIV-related characteristics on PP may be greatly diminished. Discerning differences in PP among HIV+ adults on suppressive cART as compared with HIV- adults requires careful selection of the appropriate HIV- comparison group.52 Our HIV+ and HIV- samples were largely comparable across many characteristics (eg, age and prevalence of medical comorbidities and lifetime substance-use disorders). Thus, our failure to detect differences in PP may indicate that HIV+ persons do not have greater arterial stiffening when compared with an HIV- sample with a comparable prevalence of comorbidities.
Consistent with previous studies involving older HIV+ adults,10,53 we found that diabetes mellitus emerged as an independent predictor of neurocognitive function. Diabetes mellitus has shown an association with NCI in HIV+ adults older than 55 years.10 Likely mechanisms for the effect of diabetes mellitus on neurocognitive function may include direct damage to the brain from hyperglycemia, brain exposure to higher levels of glucose given disruption of the blood-brain barrier by HIV,54 and/or increased risk for cerebral atherosclerosis. Imaging studies demonstrate an association between diabetes mellitus and morphological changes in the brain that are predominantly subcortical, which is similar to the subcortical effects of HIV.55-57
Limitations of the study include its cross-sectional design and the high likelihood of selection bias, given that the parent study aimed to investigate "successful aging" with HIV and thus may have biased our sample toward a group of HIV+ patients demonstrating good immunologic and virologic profiles. Given our small sample size, we did not test whether the effect of vascular remodeling on neurocognitive function is mediated by PP given the likelihood of type II error. Our study collected resting BP rather than ambulatory BP, which may potentially demonstrate a different association with neurocognitive function or reveal differing BP profiles between HIV+ and HIV- individuals. Our study used a proxy measure of arterial stiffness, whereas pulse wave analysis is a more direct and noninvasive method of assessing large artery or aortic stiffness.58 Although vascular remodeling and PP were found to have associations with neurocognitive function, the clinical utility of these markers depends on the availability of efficacious treatments to reduce pathological angiogenesis and arterial stiffness and whether treatment-induced reductions of these processes translate to improved neurocognitive outcomes.58
The etiology of HIV-associated NCI in the cART era is multifactorial and may be related to both direct and indirect consequences of HIV, the immune response, and comorbid factors,59 such as subclinical CVD. Delineating the relative contribution of CVD risk factors, such as vascular remodeling and PP, in the pathogenesis of HIV-associated NCI may allow for the identification of adjunct therapies aimed at improving health outcomes for persons aging with HIV/AIDS.
|
|
| |
| |
|
|
|
