February 10, 2009
My name is Kalpana Kallianpur and I'm from the University of Hawaii, the Clinical AIDS Research Group there. My coauthors on this project are Aaron McMurtray, Victor Valcour, Bruce Shiramizu and Cecilia Shikuma. This work was an offshoot of a larger study by Aaron McMurtray. He used PET [positron emission tomography] scans to look at cortical metabolism in ApoE4 carriers and non-carriers. The carriers had at least one ApoE4 allele. He found, by the way, that the ApoE4 carriers had reduced metabolism in the frontal lobes and a subset of his patients had MRI [magnetic resonance imaging] scans, so those are the patients we're looking at in this study.1
Another paper by our group had found that in HIV infection, older patients who are heterozygous for the ApoE4 allele have a higher risk of developing HIV-associated dementia, so that's the connection between ApoE4 and HIV. They found this only for older patients. So we are also looking at patients over 50 years of age.
From looking at mild cognitive impairment and Alzheimer's disease the presence of the ApoE4 allele is associated with worse prognosis, worse performance on neuropsychological tests and so on.
How does one test for this?
It's a genotype testing, genotype determination. We had somebody in a genetics lab do it for us.
But is this sort of testing commonly practiced with HIV-infected patients now?
I don't believe it is, no. I think they might be able to get it if they wanted to ...
So this is investigational normally?
This is investigational, yes. Our goal was to study how nadir CD4 count and corpus callosum volume and neurocognitive impairment are related to each other in older HIV-positive patients --both with and without this ApoE4 allele -- because nadir CD4 count has also been proposed as a predictor of neurocognitive impairment.
We focused on eight carriers of the allele and we had nine non-carriers as our comparison group. Both our groups are patients with HIV. We don't have any HIV-negative patients in this study.
All the subjects had MRI scans, which we used to calculate volumes of the corpus callosum. The corpus callosum was parcellated into five regions: anterior, mid-anterior, central, mid-posterior, and posterior. Of course, the corpus callosum is the largest white matter tract in the brain and connects the hemispheres.
The patients also received a battery of neuropsychological tests. As we expected, all the carriers who had the ApoE4 allele did much worse on the cognitive tests than the other group.
We first looked at which regional callosal volume had an effect on the test scores, so we took into account the ApoE4 group category and also the effect of each callosal volume, each region of the corpus callosum.
Only the posterior region had a statistically significant effect. And that was a certain test called the "rey complex figure test," which was in an area of nonverbal memory and visual-spatial function. The anterior region was close to being statistically significant as having an effect on these test scores. I suspect that if we have a larger patient sample, that'll also turn out to be significant.
Then we checked whether on these corpus callosum volumes, do ApoE4 allele and nadir CD4 both have an effect? These results were not significant because the ApoE4 group had a significantly higher nadir CD4 count than the non-carriers did. But also, probably because we had such a small sample size. That's our biggest limitation here.
But we did see an interaction effect between nadir CD4 and ApoE4, which was close to being significant relatively. I mean, just P = to .1. So we looked at each group separately. We used linear regression to look at corpus callosum volume for each region and plotted that against nadir CD4 count.
Of course nadir CD4 count is the lowest CD4 count that a patient ever had. We find that the anterior and volumes of the corpus callosum are correlated with nadir CD4 for patients who have the ApoE4 allele. There's a fairly strong correlation, the r value is 0.7and it's not correlated in non-carriers. If this turns out to be verified, it would mean that the patients who have an ApoE4 allele are much more susceptible to bad effects of low nadir CD4 because low nadir CD4 count would be associated with reduced corpus callosum volumes. Then the reduced corpus callosum volumes, the atrophy, would be linked to neurocognitive impairment.
So we would need a much larger study population to verify this test because the cohort we used was not originally designed to look at nadir CD4 count, our two groups are very unbalanced in their nadir CD4. The non-carriers actually have a much lower value of nadir CD4, so in a future study, we'd want to balance that between the two groups.
But at this point, it looks as if people who have at least one ApoE4 allele are at risk of having reduced corpus callosum volume, which means atrophy of the corpus callosum if they have low nadir CD4 counts.
The clinical implication would be, as many other studies have found, you'd want to start treatment earlier if this turns out to be true because you don't want the CD4 count to drop, especially in these patients who have that allele.
So we think that this allele is caused or associated with a low CD4 count?
It looks like that here, yes. And this allele is related to a protein, ApoE4, that is responsible for cholesterol metabolism in the brain. So it's also been linked to Alzheimer's disease. This is well known -- development of Alzheimer's.
Okay, thank you.