Accelerated brain aging among HIV-infected adults might be due in part to altered deep sleep patterns, new research suggests.
Using a measure known as the brain age index (BAI) — a machine-learning model that measures deviations in brain activity during sleep relative to healthy individuals — investigators identified 34 sleep electroencephalogram (EEG) features that were significantly altered by HIV infection. The most notable of these was the decline in slow wave activity during nonrapid eye movement (NREM) sleep, which has been previously associated with MRI markers of brain aging in healthy adults.
“One of the functions of slow wave sleep appears to be its association with the glymphatic system, which clears [metabolic] waste products and supports memory consolidation,” study coauthor Brandon Westover, MD, PhD, associate professor of neurology at Massachusetts General Hospital/Harvard Medical School, Boston, told Medscape Medical News. “It’s also believed to be associated with an accelerated risk for dementia and other cognitive issues.”
Previous work conducted at Johns Hopkins and other institutions confirm Westerson’s hypothesis. Charlene Gamaldo, MD, medical director of Johns Hopkins Sleep Disorders Center in Baltimore, pointed to other study findings in patients with neurodegenerative disease that have shown a link between predominant habitual sleep positions and dementia, potentially driven by inefficient glymphatic transport. Gamaldo was not involved in the current study.
Threefold Acceleration vs Healthy Volunteers
“We’ve been grappling with whether people with HIV on ART experience accelerated aging or accentuated aging,” coauthor Shibani Mukerji, MD, PhD, associate director of the neuro-infectious diseases unit at Massachusetts General, told Medscape Medical News. “We have yet to have biomarkers to address this question, and most of the tools are limited to invasive or expensive diagnostics. “In general, sleep and its influence on health have been understudied in the HIV population,” she said.
To address this question, the researchers retrospectively examined a Massachusetts General Hospital database of diagnostic sleep study participants from 2008 to 2018, identifying 3155 healthy, HIV-negative control subjects and 43 HIV-positive (HIV+) participants. Thirty-four (79%) of the HIV+ participants were men, 30 (70%) were white, and 38 (93%) were virally suppressed at the time of their sleep study. Four patients were taking efavirenz, 13 were taking an integrase strand transfer inhibitor (INSTI), and all were adherent to antiretroviral therapy (ART) at the time of their sleep study.
None of the HIV+ participants had a history of secondary brain infection or brain tumor, although one patient had recovered fully from a previous HIV-associated encephalitis.
The study findings, which were published online March 30 in Sleep, first showed that HIV+ participants had an average BAI of 3.19 years (standard error of the mean [SEM],1.43 years) compared with the control participants, who had an average BAI of –0.16 (SEM, 0.18 years).
These findings held after adjustment for potential confounders (age, sex, race, tobacco use disorder, and alcohol use disorder), yielding a total effect of HIV on BAI of 3.35 years (P < .01).
“Despite being well-controlled on ART, HIV-positive individuals who had participated in the sleep studies still had elevated brain age,” said Westover. “We didn’t have enough information to determine the pathways by which HIV increases the BAI, but chronic inflammation appears to be an important factor.”
The findings also demonstrated that comorbidities accounted for roughly a quarter of the effect of HIV on BAI. However, the lack of statistical significance (in part because of the limited sample size) precluded the ability to determine if treating or preventing them might influence the degree to which HIV affects BAI and, in turn, cognitive decline.
HIV, Sleep EEG, and Brain Aging
To estimate the effect of HIV on specific EEG features, the investigators again evaluated the total effect, this time replacing BAI with individual sleep EEG as the primary outcome. Among the 34 EEG features significantly altered by HIV, none were observed in the wake state and three were altered in REM (each associated with reduced delta band power). The rest were distributed in NREM sleep, most notably in the deepest phase, corresponding to relative reductions in delta wave power.
The study findings build on the investigators’ previous research, which demonstrated an association between greater mean BAI and dementia, psychotic disorders, and anxiety/mood disorders in HIV-negative subjects, all of which correlated to attenuated slow wave sleep.
More research is needed to determine if BAI, as it relates to sleep EEG, can effectively track the risk for cognitive decline among HIV+ people, and if certain confounders might attenuate or accelerate this risk.
“While our team has not specifically looked at BAI, the findings in this study seem perfectly in line with what we have found with our own research,” Gamaldo told Medscape Medical News. “Not only have we observed a robust association between minimal cognitive deficits and patients’ sleep complaints (despite being virally controlled), but also, the potential value of measuring the architectural sleep features by ambulatory EEG to identify HIV patients’ vulnerability to cognitive decline.” she said.
“BAI is a physiologic, easily repeatable measurement that can be used to track if an intervention is having a good effect,” Westover said. Mukerji concurred, adding that “having a tool that can be used in resource-challenged settings and also be incorporated into longitudinal studies in a patient population with substantial age-related comorbidities, like HIV, would be really helpful.”
Westover and Mukerji have disclosed no relevant financial relationships.. Gamaldo is a consultant for Jazz Pharmaceuticals, and has received author royalties from UpToDate and honoraria from Medscape CME for content contribution.
Sleep. Published online March 30, 2021. Abstract
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