INTERACTIONS BETWEEN AGEING, ALZHEIMER’S PATHOLOGY AND HIV

As noted in the chapter, the increased life expectancy of HIV patients has led to concern that chronic difficulties in cognitive performance may interact with cognitive symptoms associated with age-related conditions (e.g. Alzheimer’s disease; AD). The population of treated HIV patients is ageing, with nearly 1/3 of patients being older than 50 in some countries. Advanced age is the primary risk factor for AD, and therefore longer lifespan with HIV is expected to increase the risk of comorbid conditions including AD. It remains unclear, however, whether the presence of HIV synergistically interacts with disease mechanisms of neurodegeneration to increase the risk of AD or whether the presence of HIV in the brain lowers the age at which AD symptoms are manifest behaviourally. Evidence in favour of some level of interaction focuses on neuroinflammation, which, as described in the chapter, represents the primary mechanism associated with neuronal injury in the brain of individuals diagnosed with HIV. Cysique et al. [1] recently demonstrated that increased age and elevated risk factors for cerebrovascular disease are both independently linked to abnormal markers of inflammation in the brain. Inflammation has also been implicated as a primary mechanism of initial neuronal damage in AD [2], suggesting that HIV-mediated inflammation in the brain could lead to an increased risk, or earlier expression, of AD.

Empirical data supporting an HIV–AD interaction are limited. A recent study did not confirm excessive amyloid deposition in the brains of older HIV patients [3]. In addition, cerebrospinal fluid (CSF) studies of common AD biomarkers in HIV patients indicate alternate disease pathways for AD and HIV-associated dementia (HAD) [4]. These studies suggest that despite chronic inflammation in the brain, the characteristic amyloid plaques present in AD are not present in older HIV patients to a degree greater than that in age-matched seronegative individuals.

Studies of neuropsychological patterns associated with HIV have not identified a shift from the classic ‘subcortical’ pattern of deficits referenced in the chapter to a more cortical pattern characteristic of AD. The cortical pattern typical of AD is most commonly characterized by difficulties with anomia, apraxia, aphasia and amnesia. Older HIV patients do have memory impairments; however, these impairments do not manifest in the classic pattern of cortical dysfunction associated with hippocampal damage and AD neuropathology.

Relatedly, whilst some studies have reported increased cognitive impairment in older HIV patients compared to older seronegative controls, not all studies have reported similar outcomes. In a well-controlled study of older HIV patients, Valcour et al. [5] did not identify an increased risk of cognitive impairment amongst seropositive individuals after controlling for demographic confounds. When combined with the lack of enhanced AD neuropathology amongst older HIV patients compared to age-matched controls, there is converging evidence that HIV and AD follow independent paths.

In terms of clinical care, it is likely that a subset of older HIV patients, particularly those above age 65, when AD is more common, will experience memory loss consistent with sporadic AD. In these cases, neuropsychological testing may reveal subcortical deficits consistent with HIV (poor motor speed, etc.) as described in the chapter, in addition to memory retention loss common in AD, supporting a comorbid diagnosis. This is similar to cases of mixed vascular and AD dementia when there is neuroimaging evidence of white matter abnormalities along with a neuropsychological pattern of both subcortical and cortical deficits. As in the case with HIV and ageing, there is potential interaction between disease mechanisms, but the diagnosis should include mixed etiologies.

DIFFERENCES BETWEEN HIV SUBTYPES AND HAND

Another driver of the heightened appreciation for brain-related research associated with HIV is the realization that neurocognitive disorders are present across genetic variants of the disease. Previous studies suggested that neurocognitive symptoms associated with HIV were rare in subtypes outside of North America, including subtype C, which accounts for the majority of HIV cases globally. However, evidence that neurocognitive disorders exist across all subtypes implicates HIV as a leading cause of brain dysfunction amongst young adults when considered on a global basis.

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