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Reduced Region-Specific Corpus Callosum Volumes Correlate with Low Nadir CD4 an Decreased Cognition in HIV-Infected Carriers of the ApoE4 Allele
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Reported by Jules Levin
CROI 2013
Kalpana J Kallianpur*1, Aaron McMurtray1, Victor Valcour1,2,Bruce Shiramizu1 and Cecilia Shikuma1
1 Hawaii AIDS Clinical Research Program, University of Hawaii; 2 University of California-San Francisco
ABSTRACT
Background: Low nadir CD4 cell count and apolipoprotein E4 (ApoE4) allele are known risk factors for HIV- related neurocognitive impairment. ApoE4 is also predictive of development or progression of Alzheimer's disease (AD). The severity of dementia in HIV infection has been correlated to diffusion alterations within the corpus callosum, and in AD, with regionally specific atrophy of the same structure. We hypothesize that volumetric changes in callosal regions may correlate with nadir CD4, presence of an ApoE4 allele, and neurocognitive deficits.
Methods: Seventeen HIV-seropositive men over age 50 (8 with at least one ApoE4 allele; 9 without ApoE4) underwent T1-weighted structural magnetic resonance imaging at 3.0 Tesla, clinical and neuropsychological tests, and ApoE4 genotyping. Nadir CD4 count was determined by patient self-report and confirmed as possible. We utilized FreeSurfer software to parcellate corpus callosum into five segments. Analysis of covariance was used to study the effects of callosal volumes on cognitive domains where neuropsychological test performance differed significantly (p<.05) between ApoE4-positive and non-ApoE4 groups. Independent variables were age, education, ApoE4 group status, and callosal segment volume. Regional volumes that were associated with cognitive deficit were examined for correlation with nadir CD4.
Results: Education and viral load did not differ significantly between ApoE4-positive and non-ApoE4 groups. Reduction of normalized total and regional callosal volumes in ApoE4 carriers did not reach significance. Significant ApoE4-associated impairment included diminished visuospatial function and non-verbal memory, which showed effects at significant or trend (p<.1) levels of splenium (posterior), genu (anterior), and central callosal volume. Age and education did not contribute significantly to the model. Lower nadir CD4 correlated with decreased splenium (p=0.048, R=0.712) and genu (p=0.040, R=0.730) volume in ApoE4 carriers only.
Conclusions: HIV-seropositive individuals possessing at least one ApoE4 allele are more vulnerable to effects of low nadir CD4 count, which may contribute to region-specific corpus callosum atrophy and thereby to cognitive impairment. Early antiretroviral therapy may be more vital for these patients than for those without the allele.
BACKGROUND
Apolipoprotein E is essential to the metabolism and transport of serum lipids, and mediates cholesterol metabolism in the brain. The E4 isoform (ApoE4) has been linked to impaired cognitive function in the non- demented elderly·, to vascular dementia·, and to increased vulnerability to late-onset Alzheimer's Disease (AD)·. Inheritance of a single ApoE4 allele nearly doubles an individual's lifetime risk of developing AD4. Diffusion tensor imaging has revealed compromised white matter integrity in the posterior corpus callosum of healthy non-demented ApoE4 carriers5; and even in healthy, cognitively normal older individuals, presence of the allele has been shown to affect implicit learning6.
Region-specific atrophy of the corpus callosum has been implicated in AD, mild neurocognitive impairment, and cognitive complaints of older adults with intact neuropsychological functioning7. When impairment is slight the posterior callosal region may be the most affected, with atrophy progressing to other regions as dementia grows more severe. Callosal atrophy has also been linked to impaired cognitive and motor function in healthy elderly subjects with age-related white matter changes8.
As previously reported by our group, HIV-infected patients who are over 50 years of age and heterozygous for ApoE4 have a higher risk of developing HIV-associated dementia than do non-carriers of the allele9. Nadir CD4 count has been proposed as a predictor of current cognitive and neurological status10. A recent comparison of four nadir CD4 cutoff points (200 to 350 cell/ml) found a trend toward a higher prevalence of impairment as CD4 nadir decreased, along with significantly greater deficits in attention, working memory and executive function11. Relative to HIV-seronegative controls, non-demented AIDS patients show a trend toward lower total callosal volume as well as significantly reduced thickness throughout the region, with the thinning in anterior sections correlated to CD4 T-cell decline12. Diffusion abnormalities detected in the genu and splenium have been associated with cognitive and motor speed effects of HIV infection13,14. The present study investigates the relationship among neurocognitive test performance, corpus callosum volume, nadir CD4 and presence of an ApoE4 allele.
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