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1.  Impact of the AGTR1 A1166C polymorphism on subcortical hyperintensities and cognition in healthy older adults 
Age  2014;36(4):9664.
Vascular aging consists of complex and multifaceted processes that may be influenced by genetic polymorphisms of the renin-angiotensin system. A polymorphism in the angiotensin II type 1 receptor gene (AGTR1/rs5186) has been associated with an increased risk for arterial stiffness, hypertension, and ischemic stroke. Despite these identified relationships, the impact of AGTR1 A1166C on white matter integrity and cognition is less clear in a healthy aging population. The present study utilized indices of neuroimaging and neuropsychological assessment to examine the impact of the A1166C polymorphism on subcortical hyperintensities (SH) and cognition in 49 healthy adults between ages 51–85. Using a dominant statistical model (CC + CA (risk) vs. AA), results revealed significantly larger SH volume for individuals with the C1166 variant (p < 0.05, partial eta2 = 0.117) compared with those with the AA genotype. Post hoc analyses indicated that increased SH volume in C allele carriers could not be explained by vascular factors such as pulse pressure or body mass index. In addition, cognitive performance did not differ significantly between groups and was not significantly associated with SH in this cohort. Results suggest that presence of the C1166 variant may serve as a biomarker of risk for suboptimal brain integrity in otherwise healthy older adults prior to changes in cognition.
doi:10.1007/s11357-014-9664-x
PMCID: PMC4150909  PMID: 24981111
AGTR1; A1166C; Cerebrovascular aging; Subcortical hyperintensities; Cognition
2.  White matter changes with age utilizing quantitative diffusion MRI 
Neurology  2014;83(3):247-252.
Objective:
To investigate the relationship between older age and mean cerebral white matter fiber bundle lengths (FBLs) in specific white matter tracts in the brain using quantified diffusion MRI.
Methods:
Sixty-three healthy adults older than 50 years underwent diffusion tensor imaging. Tractography tracings of cerebral white matter fiber bundles were derived from the diffusion tensor imaging data.
Results:
Results revealed significantly shorter FBLs in the anterior thalamic radiation for every 1-year increase over the age of 50 years.
Conclusions:
We investigated the effects of age on FBL in specific white matter tracts in the brains of healthy older individuals utilizing quantified diffusion MRI. The results revealed a significant inverse relationship between age and FBL. Longitudinal studies of FBL across a lifespan are needed to examine the specific changes to the integrity of white matter.
doi:10.1212/WNL.0000000000000597
PMCID: PMC4117364  PMID: 24928121
3.  Impact of human immunodeficiency virus on neurocognition and risky behaviors in young adults 
Journal of neurovirology  2014;20(5):466-473.
Previous studies have identified cognitive impairments due to human immunodeficiency virus (HIV) in adults. However, few studies have examined the impact of HIV on cognition in young adults (18-24 years old). Yet, this group is one of the largest populations of individuals with new HIV infection. Young adulthood is also an important developmental window as the brain has not fully matured and individuals are prone to engage in risky behavior. The purpose of the present study was to examine the impact of HIV on neurocognition and risky behaviors. We hypothesized that HIV+ young adults (n=23) would exhibit greater cognitive impairment and risky behaviors compared to seronegative controls (n=21). In addition, we predicted that self-reported risky behavior as assessed by the Risk Assessment Battery (RAB) would covary with cognitive performances. Results revealed poorer executive function in HIV+ young adults compared to seronegative controls. HIV+ young adults also exhibited significantly greater risk scores on the RAB (p < 0.01) compared to HIV- young adults. However, there were no relationships between risky behavior and cognitive performance. Overall, our results suggest that HIV is associated with poorer cognition and increased risky behaviors in young adults.
doi:10.1007/s13365-014-0264-4
PMCID: PMC4305333  PMID: 24970235
HIV; Cognition; Risky Behavior; Neuropsychology; Executive Function
4.  HIV Clades B and C are Associated With Reduced Brain Volumetrics 
Journal of neurovirology  2013;19(5):10.1007/s13365-013-0202-x.
Objective
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 anti-retroviral therapy (HAART) naïve HIV-B and HIV-C participants.
Design
Thirty-four HAART-naïve HIV-infected (HIV+) participants [(17 HIV-B (United States); 17 HIV-C (South Africa)] and 34 age and education-matched HIV-uninfected (HIV−) participants were evaluated.
Methods
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 (grey and white matter) structures. A linear model that included HIV status, region, and their interaction assessed the effects of the virus on brain volumetrics.
Results
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, and corpus callosum and cortical grey and white matter compared to respective HIV− controls. Both HIV-clades B and C are associated with similar volumetric declines when compared to matched HIV− controls.
Conclusions
HIV-B and 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.
doi:10.1007/s13365-013-0202-x
PMCID: PMC3845807  PMID: 24078556
HIV clade; brain volumetrics; magnetic resonance imaging; neuropsychological performance
5.  Neuronal fiber bundle lengths in healthy adult carriers of the ApoE4 allele: A quantitative tractography DTI study 
Brain imaging and behavior  2013;7(3):10.1007/s11682-013-9225-4.
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.
doi:10.1007/s11682-013-9225-4
PMCID: PMC3726531  PMID: 23475756
ApoE; ApoE4; Tractography; DTI; White matter; Fiber bundle lengths; Aging
6.  Impact of body mass index on neuronal fiber bundle lengths among healthy older adults 
Brain imaging and behavior  2013;7(3):10.1007/s11682-013-9230-7.
Increased body mass index (BMI) has been linked to various detrimental health outcomes, including cognitive dysfunction. Recent work investigating associations between obesity and the brain has revealed decreased white matter microstructural integrity in individuals with elevated BMI, independent of age or comorbid health conditions. However, the relationship between high BMI and white matter fiber bundle length (FBL), which represents a novel metric of microstructural brain integrity, remains unknown. The present study utilized quantitative tractography based on diffusion tensor imaging (DTI) to investigate the relationship between BMI and FBL in 72 otherwise healthy older adults (24 males, 48 females). All participants were between 51 and 85 years of age (M = 63.26, SD = 8.76). Results revealed that elevated BMI was associated with shorter FBL in the temporal lobe, independent of age (p < .01). In addition, increased age was associated with shorter frontal, temporal, and whole brain FBL (all p values < .01). These findings indicate that, while increased age is an important factor associated with reduced FBL, high BMI is uniquely associated with reduced FBL in the temporal lobe. These data offer evidence for additive adverse effects of high BMI on the brain, especially in areas already vulnerable to aging processes and age-related neurodegenerative diseases. Further research is necessary to determine the physiological mechanisms associated with the shortening of FBL in individuals with high BMI.
doi:10.1007/s11682-013-9230-7
PMCID: PMC3830712  PMID: 23564371
Tractography; BMI; DTI; White Matter; Fiber Bundle Length; Aging
7.  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) and four educational levels (no education or primary education, less than secondary certificate, high school/associates degree, Bachelor’s degree or greater). The Thai cohort was compared (using 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<0.001) and memory (p<0.001), and measures of psychomotor speed (p<0.001). Education was a more powerful predictor of performance in the Thai cohort compared to 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.
doi:10.1080/13803395.2012.733682
PMCID: PMC3682786  PMID: 23113809
8.  The Effects of HIV and Combination Antiretroviral Therapy on White Matter Integrity 
AIDS (London, England)  2012;26(12):1501-1508.
HIV preferentially affects white matter (WM) in the brain. While combination antiretroviral therapy (cART) reduces HIV viral load within the brain, continued inflammation can persist. Diffusion tensor imaging (DTI) provides a non-invasive method to assess WM structural integrity in the cART era. We examined the impact of HIV and cART on WM integrity within the corpus callosum (CC) and centrum semiovale (CSO) using DTI. Neuropsychological testing and DTI scans were acquired for a cross-sectional cohort consisting of 63 individuals that were divided into one of three groups: 21 HIV-uninfected (HIV-) controls, 21 HIV-infected (HIV+) subjects naïve to cART (HIV+/cART-), and 21 HIV+ subjects receiving stable cART (HIV+/cART+). DTI measures (fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD)) were obtained for the genu, splenium, and body of the CC as well as the CSO. A subset of the HIV+/cART- individuals (n=10) were also longitudinally assessed immediately before and approximately 6 months after receiving stable therapy. Differences among the cross-sectional groups were assessed using an ANOVA while paired t-tests evaluated longitudinal changes. The HIV+/cART- participants had significantly lower MD, AD, and RD for each CC region and the CSO compared to HIV- controls and HIV+/cART+ individuals. Observed decreases in DTI parameters could reflect the presence of inflammatory cells or cytotoxic edema in the WM of HIV+/cART- subjects. No significant difference existed between HIV- controls and HIV+/cART+ subjects. In some HIV+ subjects, initiation of cART led to significant increases in MD, RD, and AD but not FA in the CC and CSO regions. Observed changes in DTI parameters in the WM after initiating cART could reflect reduced neuro-inflammation. Future DTI studies may be useful in evaluating the efficacy of cART regimens with higher brain penetration.
doi:10.1097/QAD.0b013e3283550bec
PMCID: PMC3752399  PMID: 22546990
HIV; Diffusion Tensor Imaging (DTI); Combination Antiretroviral Therapy (cART); Corpus Callosum (CC); Centrum Semiovale (CSO)
9.  Neuroimaging markers of Human Immunodeficiency Virus infection in South Africa 
Journal of neurovirology  2012;18(3):151-156.
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<.01), thalamus (p<.01) and total gray matter (inclusive of cortical and subcortical regions, p<.01). The current 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 ARVs are necessary to understand the development of HIV-related neurocognitive disorders in South Africa.
doi:10.1007/s13365-012-0090-5
PMCID: PMC3715135  PMID: 22528474
10.  Independent Effects of HIV, Aging, and HAART on Brain Volumetric Measures 
Background
Neurocognitive impairment remains prevalent in HIV infected (HIV+) individuals despite highly active anti-retroviral 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 (NPZ-4). Volumetrics were evaluated for the amygdala, caudate, thalamus, hippocampus, putamen, corpus callosum, cerebral grey and white matter. A three-group one 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 to 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 MRI studies, especially within older HIV+ participants, are required.
doi:10.1097/QAI.0b013e318249db17
PMCID: PMC3302928  PMID: 22269799
HIV; HAART; aging; brain volume
11.  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.
doi:10.1093/arclin/acr017
PMCID: PMC3142949  PMID: 21642663
Mild cognitive impairment; Neuroimaging (structural)

Results 1-11 (11)