Objective The apolipoprotein E (genotyping were performed in 139 subjects [70 seronegative controls (SN); 69 clinically-stable HIV subjects]. inversion recovery (FLAIR) to assess for possible brain pathology. Image analyses FreeSurfer 4.3.1 http://surfer.nmr.mgh.harvard.edu was used for automated reconstruction and labeling of subcortical and cortical regions. was used for automated reconstruction and labeling of cortical and subcortical regions.} Brain structures were extracted from the skull and registered to an existing brain template prior to segmentation of each structure. Regional volumes were determined automatically in each hemisphere for amygdala caudate hippocampus globus pallidus putamen thalamus and global cerebral and cerebellar cortex and white matter (Figure 1). All regions of interest (ROIs) were visually inspected to ensure accurate segmentation. Segmented volumes were manually edited only when they were identified as outliers and caused by program errors. An estimated total intracranial volume (eTIV) was also computed based on the determinant of the transformation matrix used to register the brain with the template (Buckner et al. 2004 Figure 1 Center panel: Top medial and lateral views of averaged MRIs from all subjects with an overlay of MLN4924 colorized three-dimensionally rendered subcortical brain structures evaluated (see corresponding color blocks shown in the vertical axes of the bar-graphs). … Statistical Analyses Statistical analyses were performed using SAS 9.1 (SAS Institute Inc. Cary NC). One-way analysis of variance (ANOVA) was used to compare all clinical characteristics cognitive domains and brain volumes between HIV and SN subjects with and without APOEε4 allele(s) and contrasts were generated for pair-wise comparisons. {All analyses of brain volumes included age and eTIV as covariates.|All analyses of brain volumes included eTIV and age as covariates.} {Two way- or three-way ANOVA was used to test the independent and MLN4924 interactive effects of HIV status|Two way- or three-way ANOVA was used to test the interactive and independent effects of HIV status} … On MAPK6 linear regression analyses most regions studied showed age-related decreases in brain MLN4924 volumes. All HIV and SN subjects were combined in the correlation analysis since there were no significant HIV status-by-age interactions. The greatest age-related declines were observed in the thalamus (left/right: ?6/?5% per decade r=?0.47/?0.41 p<0.001/<0.001) and cerebral cortex (?4% per decade r=?0.43 p<0.001 for left and right). After Simes correction regions that remained significant for age-related decreases include cerebellar cortex (left/right: r=?0.38/?0.39; ?4% per decade and p<0.001 for both) putamen (left/right: ?5/4% per decade r=?0.38/?0.31 p<0.001 for MLN4924 both) pallidus (left/right: ?5/?3% per decade r=?0.37/?0.27 p<0.001/<0.002) hippocampus (left/right: ?2/?3% per decade r=?0.25/?0.34 p=0.003/<0.001) and amygdala (left/right: r=?0.22/?0.26 p=0.009/0.002; ?3% per decade for both). However when the subject groups were evaluated for age-related volume decline and stratified by presence of polymorphism on brain structures of HIV-infected subjects with and without HAND. In this group of relatively young subjects (average age < 50 years) the presence of genetic background also were reported in cell culture studies (Vitek et al. 2009 The enhanced neuro-inflammatory response in younger HIV or MS patients may be even stronger than the neuro-inflammatory changes that occur with normal aging which in turn may interact with the protein is predominantly expressed by astrocytes (Pitas et al. {1987 and involved in the delivery of cholesterol and lipids from astrocytes to repair injured neurons.|1987 and involved in the delivery of lipids and cholesterol from astrocytes to repair injured neurons.} However glial activation associated with ongoing HIV infection may down-regulate the expression as found in rodent studies (Arora et al. 2009 while the decreased clearance of the neurotoxic APOEε4-protein may lead to brain injury by enhancing β-amyloid induced oxidative damage (Lauderback et al. 2002 and by facilitating the aggregation and deposition of β-amyloid fibrils (Ma et al. 1994 as found in neuropathology studies of HIV patients (Green et al. {2005 All of these mechanisms may further enhance the neuro-inflammatory response.|2005 All of these mechanisms may enhance the neuro-inflammatory response further.} There are some limitations to the current study. First despite the use of a well-validated automated brain segmentation technique FreeSurfer to evaluate brain morphometric changes in of a group of HIV patients without other major co-morbid neurological conditions or illicit drug or alcohol dependence we relied on an eTIV to normalize the brain volumes. {However the eTIV may not be as accurate as using a three-dimensional T2-weighted image to determine the ICV.|However the eTIV might MLN4924 not be as accurate as using a three-dimensional T2-weighted image to determine the ICV.}.