Módulo 3 – Curso pós-graduado – VIH e Envelhecimento

Neurocognitive Disorders in HIV Infected Patients

Risk factors for neurocognitive disorders in the setting of HIV infection

Autor: Prof. DoutorVictorValcour, MD PhD (Memory and Aging Center, University of California, San Francisco, USA)

Mechanistic and age-related factors

Other mechanistic risk factors may be involved in the development of cognitive impairment. Garvey et al. have observed increased microglia activation in a series of 7 asymptomatic HIV patients receiving ART.10 Using a specific positron emission tomography (PET) marker, he found activation of the microglia and the amount of activation correlated with poor performance on executive functioning tests. Hence, even though patients were asymptomatic, it seems possible to correlate the degree of microglial activation to performance on cognitive tests, which may be worrisome since many patients are asymptomatic. Microglia activation seems to be chronic, despite ART. Many patients are inefficient (they slow down) in their ability to do things, especially when they try to do two or three tasks at the same time; yet, they may not fully meet criteria for HAND, suggesting some limitations in this diagnostic approach. This aspect is different from what we see in age-associated neurodegenerative disorders, such as Alzheimer’s disease, where a relentless progression is standard.

Another aspect is the presence of intracellular HIV DNA at the CNS and circulating in blood but linked to cognition. Even with treatment, HIV-infected monocytes may be activated in the blood and possibly in the brain. In fact, HIV DNA in peripheral blood reduces markedly with early ART but still is detected in about half people that had been suppressed for many years.11, 12 Furthermore, the amount of HIV DNA measurable in circulating monocytes correlates well with HAND and the effect of ART on HIV reservoir size is smaller in those HIV patients with dementia.12, 13

The monocyte activation markers (soluble CD14 and sCD163) also correlate to cognitive impairment. Imp et al. describe this correlation in a group of 600 women in the US who were suppressed for a number of years.14 In the presence of monocyte activation, sCD14 and sCD163 are released in the blood and can be measured. In this study, monocyte activation was associated with worse cognitive performance, and associations persisted despite viral suppression, probably due to persistent inflammatory mechanisms related to monocytes.

In the setting of an aging HIV population, other risk factors should also be addressed. Age itself is an important competing risk, with older patients (>50 years) presenting more MND and HAD.15 For people aged more than 70, when an appreciable background risk for Alzheimer’s disease occurs, how can we tell the difference between HIV dementia and Alzheimer’s? Are HIV patients at higher risk for Alzheimer’s? Answers to these questions remain largely unknown.

Other age-related phenomenon are important to consider, for example polypharmacy. Greene et al. have found that more than 90% of patients over age 60 received more than three medicines and, even when accounting for antiretroviral medication, the rate was still 75%, approximately.16 In addition, drug-drug interactions were identified in over 60%, and, regarding elderly patients, about 50% received inappropriate medicines that increase risk for falls and cognitive impairment.

The increasing number of comorbidities with age is also a risk factor for cognitive impairment. For instance, the literature shows that the likelihood of showing symptoms of Alzheimer’s disease goes up if patient has another disease (namely cerebrovascular disease), a condition called mixed dementia. In people with HIV infection, it is reasonable to consider that patients will also have an increased risk for cognitive impairment when having comorbidities.

The apolipoprotein E (ApoE) ε4 marker is linked to Alzheimer’s disease but is also a vulnerability marker, linked to head injuries, worse cognitive outcomes, and even seizures. In HIV patients over 60, expression of ApoE ε4 is associated with increased risk of cognitive impairment, as well as being correlated with the amount of atrophy, particularly in the thalamus, the deep gray matter, and expansion of the ventricle which is central atrophy. In addition, patients with ApoE ε4 have marked differences in diffusion tensor imaging, reflecting worse integrity of the brain.17

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