Jodi M. Heaps

Independent Effects of HIV, Aging, and HAART on Brain Volumetric Measures

Background:Neurocognitive impairment remains prevalent in HIV-infected (HIV+) individuals despite highly active antiretroviral therapy (HAART). We assessed the impact of HIV, HAART, and aging using structural neuroimaging. Methods:Seventy-eight participants [HIV− (n = 26), HIV+ on stable HAART (HIV+/HAART+; n = 26), HIV+ naive to HAART (HIV+/HAART−; n = 26)] completed neuroimaging and neuropsychological testing. A subset of HIV+ subjects (n = 12) performed longitudinal assessments before and after initiating HAART. Neuropsychological tests evaluated memory, psychomotor speed, and executive function, and a composite neuropsychological score was calculated based on normalized performances (neuropsychological summary Z score, NPZ-4). Volumetrics were evaluated for the amygdala, caudate, thalamus, hippocampus, putamen, corpus callosum, and cerebral gray and white matter. A 3-group 1-way analysis of variance assessed differences in neuroimaging and neuropsychological indices. Correlations were examined between NPZ-4 and volumetrics. Exploratory testing using a broken-stick regression model evaluated self-reported duration of HIV infection on brain structure. Results:HIV+ individuals had significant reductions in brain volumetrics within select subcortical regions (amygdala, caudate, and corpus callosum) compared with HIV− participants. However, HAART did not affect brain structure as regional volumes were similar for HIV+/HAART− and HIV+/HAART+. No association existed between NPZ-4 and volumetrics. HIV and aging were independently associated with volumetric reductions. Exploratory analyses suggest caudate atrophy due to HIV slowly occurs after self-reported seroconversion. Conclusions:HIV associated volumetric reductions within the amygdala, caudate, and corpus callosum occurs despite HAART. A gradual decline in caudate volume occurs after self-reported seroconversion. HIV and aging independently increase brain vulnerability. Additional longitudinal structural magnetic resonance imaging studies, especially within older HIV+ participants, are required.

The Effects of HIV and Combination Antiretroviral Therapy on White Matter Integrity

Objective:HIV preferentially affects white matter in the brain. Although combination antiretroviral therapy (cART) reduces HIV viral load within the brain, continued inflammation can persist. We investigated the effect of HIV and cART on white matter integrity. Design:We used diffusion tensor imaging (DTI) to examine the effects of HIV and cART on white matter integrity within the corpus callosum and centrum semiovale (CSO). Methods:Neuropsychological testing and DTI measures (fractional anisotropy, mean diffusivity, axial diffusivity, radial diffusivity) were obtained from 21 HIV-uninfected controls, 21 HIV-infected patients naive to cART (HIV+/cART−), and 21 HIV+ patients receiving stable cART (HIV+/cART+). A subset of the HIV+/cART− individuals (n = 10) was assessed before and 6 months after receiving medications. Differences among the cross-sectional groups were assessed using an analysis of variance, whereas paired t-tests evaluated longitudinal changes. Results:HIV+/cART− participants had significantly lower mean diffusivity, axial diffusivity, and radial diffusivity for the corpus callosum and CSO compared to HIV− controls and HIV+/cART+ individuals. No significant difference existed between HIV− controls and HIV+/cART+ patients. cART initiation significantly improved mean diffusivity, radial diffusivity, and axial diffusivity, but not fractional anisotropy, in the corpus callosum and CSO in some HIV-infected patients. Conclusion:Observed decreases in DTI parameters between HIV+/cART+ and HIV+/cART− individuals could reflect the presence of inflammatory cells or cytotoxic edema in HIV+/cART− patients. Initiating cART could lead to a reduction in neuro-inflammation and improvement in DTI measures. Future DTI studies may be useful for evaluating the efficacy higher brain penetrating cART regimens.

Neuroimaging signatures and cognitive correlates of the montreal cognitive assessment screen in a nonclinical elderly sample.

The Montreal Cognitive Assessment (MoCA) screen was developed as a brief instrument to identify mild cognitive impairment and dementia among older individuals. To date, limited information is available regarding the neuroimaging signatures associated with performance on the scale, or the relationship between the MoCA and more comprehensive cognitive screening measures. The present study examined performances on the MoCA among 111 non-clinical older adults (ages 51-85) enrolled in a prospective study of cognitive aging. Participants were administered the MoCA, Mini-Mental State Exam (MMSE), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). A subset of participants (N = 69) underwent structural 3 T magnetic resonance imaging (MRI) to define the volumes of total frontal gray matter, total hippocampus, T2-weighted subcortical hyperintensities (SH), and total brain volume. The results revealed significant correlations between the total score on the MoCA and total score on the RBANS and MMSE, though the strength of the correlations was more robust between the MoCA and the RBANS. Modest correlations between individual subscales of the MoCA and neuroimaging variables were evident, but no patterns of shared variance emerged between the MoCA total score and neuroimaging indices. In contrast, total brain volume correlated significantly with total score on the RBANS. These results suggest that additional studies are needed to define the significance of MoCA scores relative to brain integrity among an older population.

Brain structure and cognitive correlates of body mass index in healthy older adults.

Obesity, commonly measured with body mass index (BMI), is associated with numerous deleterious health conditions including alterations in brain integrity related to advanced age. Prior research has suggested that white matter integrity observed using diffusion tensor imaging (DTI) is altered in relation to high BMI, but the integrity of specific white matter tracts remains poorly understood. Additionally, no studies have examined white matter tract integrity in conjunction with neuropsychological evaluation associated with BMI among older adults. The present study examined white matter tract integrity using DTI and cognitive performance associated with BMI in 62 healthy older adults (20 males, 42 females) aged 51-81. Results revealed that elevated BMI was associated with lower fractional anisotropy (FA) in the uncinate fasciculus, though there was no evidence of an age by BMI interaction relating to FA in this tract. No relationships were observed between BMI and other white matter tracts or cognition after controlling for demographic variables. Findings suggest that elevated BMI is associated with lower structural integrity in a brain region connecting frontal and temporal lobes and this alteration precedes cognitive dysfunction. Future studies should examine biological mechanisms that mediate the relationships between BMI and white matter tract integrity, as well as the evolution of these abnormalities utilizing longitudinal designs.

Neuroimaging markers of human immunodeficiency virus infection in South Africa

Previous studies have reported cognitive deficits among HIV-positive individuals infected with clade C virus. However, no study has examined whether individuals predominately infected with clade C virus exhibit brain atrophy relative to healthy controls. This study examined volumetric differences between 28 HIV+ individuals and 23 HIV− controls from South Africa. Volumetric measures were obtained from six regions of interest — caudate, thalamus, corpus callosum, total cortex, total gray matter, and total white matter. HIV+ participants had significantly lower volumes in the total white matter (p < 0.01), thalamus (p < 0.01) and total gray matter (inclusive of cortical and subcortical regions,p < 0.01). This study is the first to provide evidence of brain atrophy among HIV+ individuals in South Africa, where HIV clade C predominates. Additional research that integrates neuroimaging, comprehensive neuropsychological testing, genetic variance in clade-specific proteins, and the impact of treatment with Antiretrovirals (ARV) are necessary to understand the development of HIV-related neurocognitive disorders in South Africa.

HIV clades B and C are associated with reduced brain volumetrics

The human immunodeficiency virus (HIV) has multiple genetic clades with varying prevalence throughout the world. Both HIV clade C (HIV-C) and HIV clade B (HIV-B) can cause cognitive impairment, but it is unclear if these clades are characterized by similar patterns of brain dysfunction. We examined brain volumetrics and neuropsychological performance among highly active antiretroviral therapy (HAART)-naïve HIV-B and HIV-C participants. Thirty-four HAART-naïve HIV-infected (HIV+) participants [17 HIV-B (USA); 17 HIV-C (South Africa)] and 34 age- and education-matched HIV-uninfected (HIV−) participants were evaluated. All participants underwent similar laboratory, neuropsychological, and neuroimaging studies. Brain volume measures were assessed within the caudate, putamen, amygdala, thalamus, hippocampus, corpus callosum, and cortical (gray and white matter) structures. A linear model that included HIV status, region, and their interaction assessed the effects of the virus on brain volumetrics. HIV− and HIV+ individuals were similar in age. On laboratory examination, HIV-C participants had lower CD4 cell counts and higher plasma HIV viral loads than HIV-B individuals. In general, HIV+ participants performed significantly worse on neuropsychological measures of processing speed and memory and had significantly smaller relative volumetrics within the thalamus, hippocampus, corpus callosum, and cortical gray and white matter compared to the respective HIV− controls. Both HIV-B and HIV-C are associated with similar volumetric declines when compared to matched HIV− controls. HIV-B and HIV-C were associated with significant reductions in brain volumetrics and poorer neuropsychological performance; however, no specific effect of HIV clade subtype was evident. These findings suggest that HIV-B and HIV-C both detrimentally affect brain integrity.

Longitudinal Change in Performance on the Montreal Cognitive Assessment in Older Adults

Objective: The Montreal Cognitive Assessment (MoCA) is a brief screening measure commonly used to determine cognitive status among older adults. Despite the popularity of the MoCA, there has been little research into how performance on the MoCA changes over time in healthy older adults. Methods: The present study examined a sample of older adults (n = 53) recruited for a longitudinal study of healthy aging. Change in total MoCA score at three time points (baseline, 12 months, and 48 months) and scores from the Repeatable Battery for the Assessment of Neuropsychological Status at five time points (RBANS; baseline 12 months, 24 months, 36 months, and 48 months) were assessed using repeated measures analyses. Results: Total MoCA score significantly increased across time, particularly between the first and second administrations. Scores did not significantly differ between the second (12 month) and third (48 month) administrations. When grouped by baseline performance, individuals who scored low at baseline significantly improved performance at 12-month testing, but had little change between 12- and 48-month testing. Conversely, individuals who scored high at baseline did not significantly change between baseline and 12-month testing, but improved between 12- and 48-month testing. RBANS scores did not significantly change over time. Conclusions: These results suggest that the MoCA may be susceptible to practice effects, particularly between the first and second administrations. These practice effects should be taken into consideration when repeatedly employing the MoCA to screen for cognitive status in healthy older adults.

Impact of the HIV Tat C30C31S dicysteine substitution on neuropsychological function in patients with clade C disease.

Previous animal studies have identified a C31S residue substitution in the C30C31 dicysteine motif of the Tat protein that is associated with reduced neurovirulence in clade C human immunodeficiency virus (HIV). However, clinical studies of patients infected with clade C HIV have reported significant levels of cognitive impairment. To date, no study has specifically examined cognitive function in clade C-infected patients as a function of the presence or absence of the Tat C31 substitution. The present study investigated the impact of the Tat C30C31S genetic substitution among individuals residing in South Africa infected with clade C HIV that either exhibited the C30C31 motif (n = 128) or the C31S motif (n = 46). A control group of seronegative individuals was included to examine the overall impact of HIV on cognitive performance. All individuals completed a comprehensive neuropsychological battery consisting of tests sensitive to HIV. Results revealed that clade C-infected individuals performed significantly worse across cognitive tests compared to seronegative controls. However, there were no significant differences in cognitive performances between individuals with the C31S motif versus those without the C31S substitution. Proximal CD4 cell count and plasma viral load were unrelated to cognitive performances for either group. Results confirm that the C31S dicysteine motif substitution of the Tat protein does not appreciably moderate neuropsychological outcomes in clade C. Further, these findings highlight the importance of clinical management of cognitive symptoms among individuals infected with this viral clade worldwide.

Development of normative neuropsychological performance in Thailand for the assessment of HIV-associated neurocognitive disorders

International studies of HIV-associated neurocognitive disorder (HAND) are needed to determine the viral and host factors associated with cognitive impairment particularly as more than 80% of HIV+ subjects reside in resource-limited settings. Recent diagnostic nomenclature of HAND requires comparison of cognitive performance specifically to local normative data. To evaluate this need for local norms, we compared normative data obtained locally in Thailand to Western norms. The current study examined cognitive performance in 477 seronegative Thai participants (male = 211, female = 266) who completed a battery of tests sensitive to cognitive changes in HIV. The cohort was divided into three age brackets (20–34; 35–49; 50–65 years) and four educational levels (no education or primary education, less than secondary certificate, high-school/associates degree, bachelors degree or greater). The Thai cohort was compared (using analysis of covariance, ANCOVA) on a number of measures to a seronegative US cohort (n = 236; male = 198, female = 38) to examine cultural differences in performance. Normative data are provided with age and education stratification. The Thai and US groups performed significantly differently on all neuropsychological measures with the exception of verbal fluency. The Thai group performed better on measures of verbal learning (p < .001) and memory (p < .001) and measures of psychomotor speed (p < .001). Education was a more powerful predictor of performance in the Thai cohort than in the US group. These results highlight the continued need for the development of normative data within local populations. The use of Western norms as a comparison group could lead to inaccurate identification of HAND in culturally distinct groups.

Neuronal fiber bundle lengths in healthy adult carriers of the ApoE4 allele: A quantitative tractography DTI study

The epsilon 4 (e4) isoform of apolipoprotein E (ApoE) is a known genetic risk factor for suboptimal brain health. Morphometry studies of brains with Alzheimer’s disease have reported significant alterations in temporal lobe brain structure of e4 carriers, yet it remains unclear if the presence of an e4 allele is associated with alterations in the microstructure of white matter fiber bundles in healthy populations. The present study used quantitative tractography based on diffusion tensor imaging (qtDTI) to examine the influence of the e4 allele on temporal lobe fiber bundle lengths (FBLs) in 64 healthy older adults with at least one e4 allele (carriers, N = 23) versus no e4 allele (non-carriers, N = 41). Subtests from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were also analyzed to examine memory performance between groups. Analyses revealed shorter FBLs in the left uncinate fasciculus (UF) (p = .038) of e4 carriers compared to non-carriers. By contrast, neither FBLs specific to the temporal lobe nor memory performances differed significantly between groups. Increased age correlated significantly with shorter FBL in the temporal lobe and UF, and with decreased performance on tests of memory. This is the first study to utilize qtDTI to examine relationships between FBL and ApoE genotype. Results suggest that FBL in the UF is influenced by the presence of an ApoE e4 allele (ApoE4) in healthy older adults. Temporal lobe FBLs, however, are more vulnerable to aging than the presence of an e4 allele.