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Cerebrovascular Contributions to Neurocognitive
Disorders in People Living With HIV
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JAIDS Sept 1 2021 - Jose Gutierrez, MP, MPH,a,b Tiffany N. Porras, MPH,c Moka Yoo-Jeong, BS,d Farid Khasiyev, MD,e Kay C. Igwe, BS,a Krystal K. Laing, BS,a Adam M. Brickman, PhD,a,b,f Marykay Pavol, PhD,a and Rebecca Schnall, RN, PhDg,h
From the aDepartment of Neurology, Columbia University Irving Medical Center, New York, NY; bVagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY; cDonald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY; dSchool of Nursing, Bouvé College of Health Sciences, Northeastern University, Boston, MA; eDepartment of Neurology, Saint Louis Univer-sity, Saint Louis, MI; fTaub Institute for Research on Alzheimer’sDisease and the Aging Brain, Columbia University Irving Medical Center, New York, NY; gSchool of Nursing, Columbia University Irving Medical Center, New York, NY; and hDepartment of Population and Family Health, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY.
INTRODUCTION
With the advent of combined antiretroviral therapy, people living with HIV (PLWH) are living longer. Yet the aging of the HIV population parallels a rise of dementia in this population.1,2 Differentiating dementia and other HIV-associated neurocognitive disorders (HAND) has not been well achieved in PLWH. For example, there is evidence that in PLWH with persistent immunosuppression due to HIV or PLWH who have had an AIDS diagnosis, HAND may be explained by direct brain damage from opportunistic infections, neoplasia, or stroke.3-6 On the other hand, direct central nervous system infection by HIV seems directly related to central nervous system inflammation7,8 and has been associated with HAND even with well-controlled HIV infection,9,10 suggesting that further investigation is warranted to understand the relationship between neurodegenerative disease and HIV.
In addition to neurodegenerative disease, PLWH are at a higher risk of cerebrovascular disease (CVD), overt (eg stroke) or covert (also known as silent or with no distinct symptoms). CVD is an important consideration in the context of neurodegenerative disease because in non-HIV-infected individuals, it is associated with a higher risk of dementia and poorer cognition. For example, people with intracranial large artery stenosis are at higher risk of dementia.11-13 Similarly, silent brain infarcts and white matter hyperintensities (WMHs) are markers of CVD and have been associated with dementia, poorer cognition, and neurodegeneration.14,15 People with stroke are at higher risk of dementia,16 and those with dementia are at higher risk of stroke.17 The mechanisms by which CVD contributes to dementia warrant further investigation. In fact, CVD may contribute to HAND, and markers of covert magnetic resonance imaging (MRI)-based CVD have been associated with HAND in PLWH.18,19
Most studies on the vascular contributions to HAND have not included brain arterial imaging. Because brain large artery disease, specifically intracranial large artery stenosis, is an important predictor of stroke and cognition in people without HIV, we hypothesize that intracranial large artery stenosis may contribute to HAND in addition to other covert MRI-based biomarkers of CVD. The purpose of this study was to investigate a comprehensive array of covert MRI-based biomarkers of CVD in a cohort of PLWH and relate them to cognitive performance.
Abstract
Background:
To investigate a comprehensive array of magnetic resonance imaging (MRI)-based biomarkers of cerebrovascular disease (CVD) in a cohort of people living with HIV (PLWH) and relate these imaging biomarkers to cognition.
Settings:
Cross-sectional, community-based study.
Methods:
Participants were PLWH in New York City, aged 50 years or older. They underwent a brain magnetic resonance angiography or MRI to ascertain 7 MRI markers of CVD: silent brain infarcts, dilated perivascular spaces, microhemorrhages, white matter hyperintensity volume, white matter fractional anisotropy and mean diffusivity (measures of white matter integrity), and intracranial large artery stenosis. Participants underwent a battery of neurocognitive tests to obtain individual and global cognitive scores representative of various aspects of cognition.
Results:
We included 85 participants (mean age 60 ± 6 years, 48% men, 78% non-Hispanic Black), most of them with well-controlled HIV (75% with CD4 cell count > 200 cells/mm3 and viral load < 400 copies/mL at or near the time of the MRI scan).
Silent brain infarcts, intracranial large artery stenosis, and poor white matter integrity were associated with poorer performance in at least one cognitive domain, but the sum of these 3 MRI markers of CVD was associated with lower working memory (B = -0.213, P = 0.028), list learning (B = -0.275, P = 0.019), and global cognition (B = -0.129, P = 0.007).
Conclusions:
We identified silent brain infarcts, intracranial large artery stenosis, and poor white matter integrity as exposures that may be modifiable and may, therefore, influence cognitive decline. In addition, these MRI markers of CVD may help in identifying PLWH at higher risk of cognitive decline, which may be more amenable to targeted therapies.
• the data from this study support the notion that silent brain infarcts are important determinants of poorer cognition in PLWH.
• The study examining intracranial large artery stenosis in PLWH is of great importance because ethnic minorities are at an increased risk of both intracranial large artery stenosis and HIV.
• The sample was composed of 85 participants (mean age 60 ± 6 years, 48% men, 78% non-Hispanic Black). Demographic characteristics are summarized in Table 1.. Most of them had hypertension (66%) and well-controlled HIV (75%, defined by CD4 cell count > 200 cells/mm3 and viral load < 400 copies/mL at or near the time of the MRI visit).
• One-third of the sample (33%) had evidence of silent brain infarcts, 5% of microhemorrhages, and 12% of intracranial large artery stenosis, and 44% had imaging evidence of abnormal white matter integrity as defined by a low FA and/or high MD.
• intense therapy of the 4 main modifiable vascular risks (eg, hypertension, diabetes, dyslipidemia, and smoking) is a goal that should be pursued regardless of whether or not these risk factors were related to poorer cognition.
• WMHs volume and/or integrity are imaging biomarkers of covert CVD frequently studied among PLWH. For example, WMHs have been associated with decreased frontal cortical volume,26 longer duration of HIV infection,40 and aging.41 Although we did not find any association between WMHs volume and cognition, markers of abnormal integrity in white matter such as low FA and high MD did show a trend toward poorer cognition, a finding replicated in some42,43 but not all studies.44 The etiology of white matter disease in people with HIV has been attributed to aging, hypertension, historical effects of AIDS (with gliosis, which seems white in FLAIR images), and ongoing neuroinflammation.41,43,44 Intensive blood pressure control reduces the risk of mortality, vascular events (including stroke), and cognitive impairment in people without HIV.45-49
• In the univariate analysis, silent brain infarcts and intracranial large artery stenosis were associated with poorer cognition in at least one cognitive domain (Table 2). The association between silent brain infarcts and poorer cognition attenuated after adjustment for vascular risk factors and demographic covariates, whereas the association between intracranial large artery stenosis and list learning remained significant. Abnormal white matter integrity was associated with poorer mental sequencing and global cognition only after adjusting for demographics and education. There was no statistical association or trends between WMHs volume, microhemorrhages, or perivascular spaces with cognitive performance.
• We presented data from a cross-sectional study of 85 PLWH who underwent a brain MRI to assess for MRI-based biomarkers of covert CVD and related these to cognitive performance. We found that the presence of silent brain infarcts, abnormal white matter integrity, and intracranial large artery stenosis relate to some aspects of cognition and that the cumulative prevalence of these 3 MRI biomarkers relates to poorer working memory, list learning, and global cognition. Compared with clinically overt CVD such as stroke, covert CVD is at least 3 to 4 times more frequent.24 Furthermore, covert CVD is a risk factor of stroke and dementia.14,25,26 Therefore, timely identification of covert CVD and understanding its role in stroke and dementia may help in identifying individuals at higher risk of future stroke and dementia, with the potential for intervention to prevent further decline. The study examining intracranial large artery stenosis in PLWH is of great importance because ethnic minorities are at an increased risk of both intracranial large artery stenosis and HIV.27-29
• Nonetheless, intense therapy of the 4 main modifiable vascular risks (eg, hypertension, diabetes, dyslipidemia, and smoking) is a goal that should be pursued regardless of whether or not these risk factors were related to poorer cognition.
• In post hoc analyses, we found that a composite score representing the cumulative prevalence of silent brain infarcts, white matter abnormal integrity, and intracranial large artery stenosis was associated with poorer cognition in PLWH. Cumulative brain injury may decrease brain plasticity and remodeling to allow for compensation in the expected cognitive deficit. The cumulative prevalence of these imaging biomarkers may also reflect more severe vascular disease, which in turn could represent an epiphenomenon of poorer vascular health.......the pathophysiology of the association remains uncertain, and there is partial evidence that intracranial large artery stenosis may decrease brain blood flow,36,37 which may trigger downstream mechanisms, leading to neurodegeneration in addition to increased risk of stroke. Other nonatherosclerotic arteriopathies such as dolichoectasia (consisting of dilated brain arteries) are associated with poorer cognition, higher risk of dementia, and, among PLWH, longer and deeper immunosuppression.11,31,38,39 Therefore, inclusion of brain MRA for systematic evaluation of such brain large artery phenotypes provides new insights into the role of brain large artery disease in HAND and other cerebral outcomes in PLWH.
• WMHs volume and/or integrity are imaging biomarkers of covert CVD frequently studied among PLWH. For example, WMHs have been associated with decreased frontal cortical volume,26 longer duration of HIV infection,40 and aging.41 Although we did not find any association between WMHs volume and cognition, markers of abnormal integrity in white matter such as low FA and high MD did show a trend toward poorer cognition, a finding replicated in some42,43 but not all studies.44 The etiology of white matter disease in people with HIV has been attributed to aging, hypertension, historical effects of AIDS (with gliosis, which seems white in FLAIR images), and ongoing neuroinflammation.41,43,44 Intensive blood pressure control reduces the risk of mortality, vascular events (including stroke), and cognitive impairment in people without HIV.45-49
These associations were independent of sex, age, ethnicity, education, viral suppression, vascular risk factors, and ApoE4. Expectedly, higher education attainment was associated with better overall cognition. Findings from this study identified the following: (1) vascular exposures that may be modifiable and may, therefore, influence cognition in PLWH; and (2) PLWH at higher risk of cognitive decline for testing targeted treatment.
The sample was composed of 85 participants (mean age 60 ± 6 years, 48% men, 78% non-Hispanic Black). Demographic characteristics are summarized in Table 1.. Most of them had hypertension (66%) and well-controlled HIV (75%, defined by CD4 cell count > 200 cells/mm3 and viral load < 400 copies/mL at or near the time of the MRI visit). One-third of the sample (33%) had evidence of silent brain infarcts, 5% of microhemorrhages, and 12% of intracranial large artery stenosis, and 44% had imaging evidence of abnormal white matter integrity as defined by a low FA and/or high MD.
In the univariate analysis, silent brain infarcts and intracranial large artery stenosis were associated with poorer cognition in at least one cognitive domain (Table 2). The association between silent brain infarcts and poorer cognition attenuated after adjustment for vascular risk factors and demographic covariates, whereas the association between intracranial large artery stenosis and list learning remained significant. Abnormal white matter integrity was associated with poorer mental sequencing and global cognition only after adjusting for demographics and education. There was no statistical association or trends between WMHs volume, microhemorrhages, or perivascular spaces with cognitive performance.
In a post hoc analysis, we created a score that reflected the cumulative burden of MRI-based biomarkers of covert CVD in PLWH (CVD score) by adding on the covert MRI-based biomarkers of CVD that scored at least a trend of an association with any of the 5 cognitive domains. We used silent brain infarcts, abnormal white matter integrity, and intracranial large artery stenosis to create the score (range 0-3) based on the results described in Table 2. The CVD score was 0 in 36% of participants, 1 in 46%, 2 in 13%, and 3 in 5%. In the adjusted models for age, sex, ethnicity, education attainment, vascular risk factors, ApoE4, and status of HIV infection, CVD score was associated with lower working memory (B = -0.213, P = 0.028), list learning (B = -0.275, P = 0.019), global cognition (B = -0.129, P = 0.007), and a trend toward lower mental sequencing (B = -0.099, P = 0.08). Other predictors of cognitive performance in these models are reported in Table 3.
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