The hallmark of HIV infection is the virus’ impact on the cellular immune system via its attack on CD4 cells—but the virus also directly affects functions of the brain, spinal cord, and peripheral nervous system, some evidence suggests, at higher rates than in the general population. For people living with HIV (PLWH), the complex of neurologic complications observed is known as HIV-associated neurocognitive disorder, or HAND, and may include deficits in attention, language, motor skills, memory, and other aspects of cognitive function. While, according to multiple studies over the past decade, the advent of effective antiretroviral therapy (ART) has dramatically improved cognitive outcomes among PLWH, it is estimated that more than 45% of HIV-positive individuals nevertheless experience some form of HAND.
HAND or aMCI? It’s Complicated
In clinical research and practice, HAND is categorized into three subtypes, including asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). The cognitive impairment associated with ANI does not interfere with everyday functioning at home, work, school, or in social settings. With MND, there is at least mild interference in daily functioning. And with HAD, there is marked impairment of day-to-day functioning.
While rates of HAND increase with age, older PLWH, like those without HIV, are also at increased risk for Alzheimer’s disease (AD), as well as for its precursor, amnestic mild cognitive impairment (aMCI). Certain kinds of memory deficits that are characteristic of aMCI are also common in HAND; for example, deficits in episodic, or long-term, memory. Thus, distinguishing between aMCI and HAND-related cognitive impairment represents a major challenge and an area of concern for health care clinicians. Consequently, it is often the case that clinicians attribute memory deficits in PLWH solely to HAND based on their HIV status, when they, in fact, may be experiencing aMCI or AD.
This is a problem for clinical care, because aMCI is a more progressive condition than HAND and requires early intervention to maximize the opportunity to delay or alter the course of AD. Given the aging of the population living with HIV—more than half of PLWH are aged 50 or older—and the overlapping cognitive profiles of HAND, Alzheimer’s, and aMCI, it’s clear that health care providers need reliable methods for distinguishing HAND from aMCI or Alzheimer’s.
What the Nose Knows
The study of olfactory function, aka the sense of smell, is one promising area of research scientists are exploring to address the complexities of distinguishing between aMCI—a sign that an individual may be on a path to developing Alzheimer’s—and HAND. Impaired sense of smell is one of the earliest deficits seen in AD, likely due to the fact that the beta amyloid plaques (abnormal clusters of brain protein fragments) and neurofibrillary tangles (dead and dying nerve cells) characteristic of the disease occur initially in regions of the brain responsible for smell, including the entorhinal cortex and the orbitofrontal cortex.
Smell deficits have also been observed among people with aMCI, as well as among adults with normal cognitive function who are at risk for AD based on family history or the presence of the apolipoprotein E4 allele, the main genetic determinant of AD risk. In addition, studies using magnetic resonance imagery (MRI) and positron emission tomography (PET) have found associations between AD biomarkers and olfactory deficits.
Like neurocognitive impairment, olfactory impairment is common among PLWH. Moreover, numerous studies over the past 30 years have shown that olfactory deficits among PLWH are linked to HAND. The question, though, is whether impaired sense of smell among PLWH points clearly to aMCI. To unravel this question, researchers from the University of California and San Diego State University conducted an observational cohort study among 81 PLWH aged 50 years and older (participants were 83% men and 65% white). The study’s findings were published in March in the journal AIDS. The study participants came from the California site of the National NeuroAIDS Tissue Consortium, a tissue donation program established to collect a wide range of samples from people both with and without HIV for use in research projects into so-called neuroAIDS disorders, a group of neurologic disorders associated with HIV-related damage to the central and peripheral nervous systems.
The participants completed the University of Pennsylvania Smell Identification Test (UPSIT), a standard research tool. On the UPSIT, a higher score indicates better smell identification. The researchers used standard cognitive assessments to determine whether participants met the criteria for HAND or aMCI risk. Of the participants, 57 (70%) were classified with HAND, and 35 (43%) were classified as high aMCI risk.
Consistent with numerous other studies among PLWH, researchers observed mild olfactory deficits across all aMCI and HAND groups. Mean UPSIT scores fell below the normative cut-score for mild microsmia (reduced ability to smell and to detect odors) and exhibited a significant positive correlation with memory function. That is to say, the data from this study confirm what has been known for years—that mild olfactory dysfunction is common among PLWH, regardless of their cognitive status.
More severe olfactory deficits, however, correlated with aMCI, but not with HAND. The study found significantly lower (worse) UPSIT score among those at high risk for aMCI compared to those at low aMCI risk (F (1,76) = 10.04, P = 0.002); by contrast, UPSIT scores did not differ by HAND status (F (1,76) = 0.62, P = 0.43).
Sniffing for Earlier AD Diagnoses
The study’s results support the conclusion that assessing olfactory function may be a useful tool in distinguishing aMCI/AD from HAND in older PLWH—thereby facilitating timely and appropriate medical intervention. The difference in UPSIT scores by aMCI risk was even greater among a subgroup of participants age 60 and older, suggesting that olfactory function may be an even more important discriminating factor with increasing age, which corresponds to increasing aMCI/AD risk.
This was a small study, and further research is warranted to confirm these results in larger cohorts with longer-term follow-up. Also useful would be studies comparing olfactory findings with other biomarkers related to AD, so as to further refine clinicians’ ability to identify aMCI among PLWH.