To the Editors:
Despite the widespread use of combination antiretroviral therapy (ART), cognitive impairment remains prevalent in persons living with HIV infection (PLWH) and is associated with decreased adherence1,2 and quality of life.3 Increasing attention has been paid to the contribution of cardiovascular disease including stroke, rates of which are higher in PLWH compared with age-matched uninfected individuals,4–7 to HIV-associated neurocognitive disorders. In PLWH, white matter hyperintensities (WMHs), a radiologic marker of cerebral small vessel disease, are common,8,9 even among individuals with sustained virologic suppression,10 and increase with age.11 WMHs have been linked to worse cognitive function,12,13 as has cerebral small vessel disease at autopsy.14 Impaired cerebral vasoreactivity, a dynamic measure of cerebrovascular endothelial function15–18 associated with large artery atherosclerotic stroke and cerebral small vessel disease,19–22 may precede the development of end-stage cerebral ischemic pathology23 and could potentially identify individuals at risk of cognitive dysfunction or decline before irreversible damage (ie, WMH or other cerebral small vessel injury) has occurred.
The goal of this pilot study was to estimate the association between cerebral vasoreactivity and cognitive function in a cross-section of PLWH, as a first step toward investigating the utility of cerebral vasoreactivity as a predictor of longitudinal cognitive decline. We hypothesized that PLWH with higher cerebral vasoreactivity and, thus, better cerebrovascular endothelial function would perform better on cognitive testing.
We recruited PLWH followed in an HIV clinic at Peking Union Medical College Hospital in Beijing, China, between January and May 2015. Clinic patients on ART with undetectable plasma HIV RNA were invited to participate in a parent study investigating cerebrovascular endothelial function using transcranial Doppler ultrasound (TCD).24 Participants interested in undergoing a cognitive screening test on the same day as the TCD were enrolled in this substudy. To assess cerebrovascular endothelial function, we measured cerebral vasoreactivity in response to a breath-holding challenge, defined as the average change in mean flow velocities of the bilateral middle cerebral arteries in response to a 30-second period of breath holding,19 which has been shown to have good short- and long-term reproducibility.25–27 Lower cerebral vasoreactivity is indicative of worse cerebrovascular endothelial function. The primary outcome for cerebral vasoreactivity was the breath-holding index (BHI), which expresses the change in mean flow velocities from baseline to the conclusion of breath holding per second. Normal BHI values for adults aged 30–60 years range from 1.3 to 1.4 with a SD of 0.3.28 Results from 2 trials were averaged.
Cognitive evaluation was performed on the same day as the TCD using the Montreal Cognitive Assessment (MoCA, Chinese Beijing version), a cognitive screening test commonly used in the clinical setting for mild cognitive impairment accompanying cerebrovascular disease, Alzheimer-type dementia, and HIV-associated cognitive impairment.29–31 Demographics, cardiovascular risk, and HIV-specific factors were collected with a medical questionnaire and through chart review. Fasting lipid panel, serum inflammatory markers [high sensitivity C-reactive protein (hsCRP) and IL-6], and CD4 count were collected on the day of the TCD. We constructed linear regression models to estimate the association between cerebral vasoreactivity and cognitive function, with MoCA score as the dependent variable.
Informed consent was obtained from all study participants. The Peking Union Medical College Hospital Ethics Committee and University of California, San Francisco Committee on Human Research approved the study.
The mean age of 46 participants was 41 years (SD 11 years), and 13% were women. Thirty-one percent had a high school education or less. The most prevalent cardiovascular risk factors were dyslipidemia (18%) and smoking (27%). Less than 10% of participants had hypertension or diabetes mellitus. More than one-quarter of participants (27%) reported current alcohol consumption, most of whom had 1–4 alcoholic drinks per week [median 1 drink per week among current drinkers, interquartile range (IQR) 1–4 drinks per week]. No participants had a history of substance abuse.
The mean CD4 count was 467 cells/mm3 (SD 186 cells/mm3). Participants had been diagnosed with HIV for a median of 4 years (IQR 3–5) and on ART for a median of 3 years (IQR 2–5). Most participants were on a regimen of tenofovir or zidovudine, lamivudine and efavirenz (53%), nevirapine (35%) or lopinavir/ritonavir (7%). The median hsCRP was 1.12 mg/L (IQR 0.61–2.40 mg/L).
Mean BHI was 1.07 (SD 0.33). Among those with a high school education or less, the mean MoCA score was 24 (out of 30) compared with 28 for individuals with more than a high school level of education. In education-adjusted models, being a woman (2 points lower MoCA score compared with men, P = 0.039), longer duration since HIV diagnosis (0.3 points lower MoCA score per year) and higher hsCRP (0.1 point lower MoCA score per 1 mg/L higher hsCRP) were associated with worse cognitive performance. There was no statistically significant effect of any traditional cardiovascular risk factors on the MoCA.
After adjusting for education, age, and sex, higher cerebral vasoreactivity was associated with better MoCA performance (0.8 points higher MoCA score per 1 SD increase in cerebral vasoreactivity, P = 0.027). The magnitude and significance of the main effect of cerebral vasoreactivity on MoCA performance were relatively unchanged after controlling for individual cardiovascular and HIV-related risk factors (Table 1). In a multivariable model adjusting for education, demographics, and covariates reaching P < 0.10 significance in univariable models (hsCRP, duration since HIV diagnosis), higher cerebral vasoreactivity remained associated with better MoCA performance (1 point higher MoCA score per 1 SD increase in cerebral vasoreactivity, P = 0.005).
In this urban HIV population with well-controlled infection and no history of substance abuse, higher cerebral vasoreactivity, indicative of better cerebrovascular endothelial function, was associated with better performance on the MoCA. Although the modest sample size limited our ability to control for multiple factors simultaneously, this relationship was independent of cardiovascular and HIV-related factors, suggesting that cerebrovascular endothelial function, which is reduced in PLWH compared with HIV-uninfected individuals,32 may provide additional information on risk of cognitive impairment in PLWH.
Cognitive impairment in HIV may be mediated, in part, by cerebral small vessel injury,12 which is prevalent in PLWH.9,10,13 In the AGEhIV cohort, virologically suppressed men living with HIV had a greater burden of WMH—a cerebral small vessel disease marker—compared with HIV-uninfected men.12 An observed association between HIV and worse cognition was attenuated with addition of WMH to a multivariable model. In the general population, lower cerebral vasoreactivity, which is associated with clinical and subclinical cerebral small vessel disease,21,22,33–35 has been observed in individuals with cognitive impairment and those at risk of cognitive decline.36–40 In a cross-sectional study using the BHI and the MoCA to assess cerebral vasoreactivity and cognitive impairment, respectively, individuals with mild cognitive impairment had a significantly lower BHI compared with those without cognitive impairment [BHI 0.69 (SD 0.3) versus 1.35 (SD 0.31), P < 0.05].39 In a longitudinal study of patients with Alzheimer disease, a decrement of 0.10 in the BHI was associated with approximately 2.4-fold higher odds of cognitive decline over 1 year.40
The results from this pilot study provide preliminary evidence that cerebrovascular endothelial dysfunction may independently contribute to cognitive impairment in PLWH. Limitations of the study include the cross-sectional design, modest sample size, and use exclusively of the MoCA to evaluate cognitive function, which can provide meaningful clinical data but is not recommended as the sole instrument to screen for or diagnose HIV-associated neurocognitive disorders.41–43 Although we used the Chinese Beijing version of the MoCA, we were not able to standardize results using population-based normative data. Finally, our study lacked an HIV-uninfected comparator group to investigate whether the relationship between cerebral vasoreactivity and cognitive impairment differs by HIV status. In addition to validating our findings in a larger study with comprehensive neuropsychological testing, an essential next step will be to evaluate whether impaired cerebral vasoreactivity can identify PLWH at risk of longitudinal cognitive decline and whether targeting endothelial function may prevent or retard cognitive decline in HIV infection.
The authors are grateful to the study participants who made this work possible.
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