Will people with HIV be at increased risk of Alzheimer's- or Parkinson's-like diseases as they age?

Neurologists should not assume that all signs of dementia in people with HIV are related to HIV, researchers warned at a recent international meeting on HIV and the brain. As people with HIV age, neurologists will need to keep a careful eye out for the early onset of degenerative disorders like Alzheimer's or Parkinson’s disease.

“Dementia and neuropathy are more common in older patients with HIV,” said Dr Victor Valcour of UCSF, describing data from a cohort of patients with HIV he followed while at the University of Hawaii. He stressed that the causes of cognitive impairment in older patients are quite heterogeneous with risk factors such as apolipoprotein E4 allele status (associated with a risk of Alzheimer's), diabetes, blood pressure and cerebrovascular risk factors all appearing to influence cognition in older patients.

A number of researchers at the recent Evolving Mechanisms of HIV Neuropathogenesis in the HAART era: Domestic and Global Issues meeting in Venice, Italy also noted that as people age, there is a decrease in the neuroprotective mechanisms, such as neurotrophins in the brain. Several were also worried that as people living with HIV survive into older age, they could be at increased risk of neurodegeneration with Alzheimer's or Parkinson’s-like syndromes developing, possibly as early as their 50’s or 60’s.

“We should not jump to saying patients have HIV-associated dementia in this population. And I am worried about neurodegenerative pathology [such as Alzheimer's], we don’t really know if there is a possibility for added or synergistic effects of HIV, although I suspect that one or the other is true,” Dr Valcour said.

“Successful HAART obviously means that people are living longer, quite a bit longer,” said Dr Valcour. “In Hawaii most of our patients who are living with HIV are over 50 years of age and the US Senate Committee on aging predicts that by 2015 half of the people in the Unites States living with HIV/AIDS will be over 50 years of age. So this really is a growing phenomenon.”

Dr Valcour conducted a study while at the University of Hawaii comparing a variety of neurocognitive parameters in 128 younger people with HIV (under 40) compared to 159 older people with HIV (average age 54.5) along with a similar number of age, gender, ethnicity, and education matched HIV-negative controls. Neurological assessments were comprehensive and subjects were categorised as to whether they had dementia, minor cognitive motor disorder (MCMD), neuropsychiatrically abnormal or normal.

“The early data that we found, indicated that in fact dementia was more common in the older patients compared to the younger patients, as well as MCMD being more common in the older versus younger patients,” he said. However, they also noted that a greater proportion of cases were categorised as possible disease (which was probably impacted by co-morbidities) as opposed to probable disease.

“We designed this model thinking that [there] were decreasing [brain] reserves in older patients due to a number of different factors that were occurring and then increasing the susceptibility to HIV infection,” he said. But their findings made them question whether the comorbidities might actually be just as important as HIV — and that much of the dementia in older people with HIV should perhaps be called dementia in the context of HIV rather than HIV dementia.

“It allowed us in fact to turn this whole model on its head a bit and think about HIV disease perhaps increasing the possibility of someone having Alzheimer’s or showing the effects of cerebrovascular disease. With regard to HIV-associated dementia, you can certainly understand changes in immune status as aging occurs, changes in astrocytic function and BBB function as people age, thus increasing their risk of HIV-associated dementia. But as well you may consider co-morbid disease and particularly neuro degenerative cerebrovascular disease which can contribute to a phenotype of dementia in a population. It may not necessarily be HIV that’s causing the changes or perhaps more importantly, that HIV alone is causing the changes.

How common a problem early Alzheimer's or other forms of senile degeneration might be is unclear, but Dr Valcour described one example of a case he has seen. He was a 67 year old Caucasian male, a retired teacher who lived alone. He complained mostly about memory problems: “typical things like leaving the stove on, getting lost while driving,” said Dr. Valcour.

He had been HIV-infected since the 1980s and his CD4 nadir (74) occurred in the 1990s. When he presented to Dr Valcour, he was on a standard regimen, with a CD4 cell count over 400, viral load was undetectable both in plasma and CSF, and his cholesterol/glucose was under control.

However, they knew from a research protocol that he carried apolipoprotein E4 allele, and both his parents had Alzheimer’s disease in their 70’s and 80’s. His MRI indicated some white matter hyper-intensity that might be mistaken as being HIV-related in a younger person with HIV, but in an older patient with long-standing hypertension would probably be attributed to other causes.

“When you look at his neuropsychological profile over the four years we followed him, he had a striking amount of verbal recall problems, whereby he could only remember four numbers when he started and it decreased over time to the point where he was not recalling any of them."

"He had visual spatial skill abnormalities which really made me think of posterior regions of the brain being affected, both in his recall as well as his visual spatial skill copy, and then he had some of the psychomotor abnormalities that you would expect in group pegboard and so forth - so really a mixed picture."

"But I think it would be very hard for people in this room to just quickly call this HIV-associated dementia. We may be seeing these patients more and more frequently as we follow this epidemic.”

So they looked at the apolipoprotein E4 allele status in a small study and found that 40% (10 out of 25) older HAD participants had at least one E4 allele, compared to 17% (2 out of 12) younger patients with HAD, offering some support for Dr Valcour's suspicion that Alzheimer's may be implicated in the emergence of dementia in HIV-positive people.

Data on abnormal protein deposition which occurs in people with neurodegeneration related to Parkinson's or Alzheimer's disease have been less clear. For instance, there have been some reports of abnormal amyloid deposition (which forms part of the plaques which occur in the brains of people with Alzheimer's) occurring in some patients with HIV — but Valcour has been unable to find any evidence of this in his patients.

“There is a tendency in autopsy material with the increasing age of the individuals for an increased number of lesions that are associated either with Parkinson’s disease or Alzheimer’s disease,” said Dr. Eliezer Masliah of the University of California, San Diego.

“In terms of the disorders associated with Parkinson’s disease, we have seen an increase in accumulation of alpha-synuclein in aging individuals with HIV in the nervous system. We also have observed these very peculiar amyloid deposits as well as these intracellular amyloid immuno-reactive structures associated with HIV in these elderly individuals (older than 50 years old).”

Another researcher, Dr Cristian Achim from the University of Pittsburgh presented imaging studies that detected abnormal protein deposition in the brains of people living with HIV. These commonly included intraneuronal amyloid, extracellular plaques, tau and oligomers. This could be related to disrupted protein processing described by Dr Benjamin Gelman (see related article).

While researchers have not seen anything in the brains of aging people with HIV quite like Alzheimer's in terms of numbers of plaques and types of plaques, this clearly warrants keeping an eye on, as growing numbers of people living with HIV survive into old age.