[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes, and multiple sclerosis. These data suggest that these plasma protein levels may constitute informative endophenotypes for these complex traits. We found three potential pleiotropic genes: ABO for plasma SELE and ACE levels, FUT2 for CA19-9 and CEA plasma levels, and APOE for ApoE and CRP levels. We also found multiple independent signals in loci associated with plasma levels of ApoH, CA19-9, FetuinA, IL6r, and LPa. Our study highlights the power of biological traits for genetic studies to identify genetic variants influencing clinically relevant traits, potential pleiotropic effects, and complex disease associations in the same locus.
Full-text · Article · Jan 2016 · Scientific Reports
[Show abstract][Hide abstract] ABSTRACT: Both HIV disease and advanced age have been associated with alterations to cerebral white matter, as measured with white matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), and more recently with diffusion tensor imaging (DTI). This study investigates the combined effects of age and HIV serostatus on WMH and DTI measures, as well as the relationships between these white matter measures, in 88 HIV seropositive (HIV+) and 49 seronegative (HIV-) individuals aged 23-79 years. A whole-brain volumetric measure of WMH was quantified from FLAIR images using a semi-automated process, while fractional anisotropy (FA) was calculated for 15 regions of a whole-brain white matter skeleton generated using tract-based spatial statistics (TBSS). An age by HIV interaction was found indicating a significant association between WMH and older age in HIV+ participants only. Similarly, significant age by HIV interactions were found indicating stronger associations between older age and decreased FA in the posterior limbs of the internal capsules, cerebral peduncles, and anterior corona radiata in HIV+ vs. HIV- participants. The interactive effects of HIV and age were stronger with respect to whole-brain WMH than for any of the FA measures. Among HIV+ participants, greater WMH and lower anterior corona radiata FA were associated with active hepatitis C virus infection, a history of AIDS, and higher current CD4 cell count. Results indicate that age exacerbates HIV-associated abnormalities of whole-brain WMH and fronto-subcortical white matter integrity.
No preview · Article · Oct 2015 · Journal of NeuroVirology
[Show abstract][Hide abstract] ABSTRACT: The Trail Making Test Part B (TMT-B) is widely used in clinical and research settings as a measure of executive function. Standard administration allows a maximal time score (i.e., floor score) of 300 s. This practice potentially masks performance variability among cognitively impaired individuals who cannot complete the task. For example, performances that are nearly complete receive the same 300-s score as a performance of only a few moves. Such performance differences may have utility in research and clinical settings. To address this, we propose a new TMT-B efficiency metric designed to capture clinically relevant performance variability below the standard administration floor. Our metric takes into account time, correct moves, and errors of commission and omission. We demonstrate that the metric has concurrent validity, permits statistical analysis of performances that fall below the test floor, and captures clinically relevant performance variability missed by alternative methods.
Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
No preview · Article · Jul 2015 · Archives of Clinical Neuropsychology
[Show abstract][Hide abstract] ABSTRACT: Executive function (EF) and cognitive processing speed (CPS) are two cognitive performance domains that decline with advanced age. Reduced EF and CPS are known to correlate with age-related frontal-lobe volume loss. However, it remains unclear whether white matter microstructure in these regions is associated with age-related decline in EF and/or CPS. We utilized quantitative tractography metrics derived from diffusion-tensor MRI to investigate the relationship between the mean fiber bundle lengths (FBLs) projecting to different lobes, and EF/CPS performance in 73 healthy aging adults. We measured aspects of EF and CPS with the Trail Making Test (TMT), Color-Word Interference Test, Letter-Number Sequencing (L-N Seq), and Symbol Coding. Results revealed that parietal and occipital FBLs explained a significant portion of variance in EF. Frontal, temporal, and occipital FBLs explained a significant portion of variance in CPS. Shorter occipital FBLs were associated with poorer performance on the EF tests TMT-B and CWIT 3. Shorter frontal, parietal, and occipital FBLs were associated with poorer performance on L-N Seq and Symbol Coding. Shorter frontal and temporal FBLs were associated with lower performance on CPS tests TMT-A and CWIT 1. Shorter FBLs were also associated with increased age. Results suggest an age-related FBL shortening in specific brain regions related to poorer EF and CPS performance among older adults. Overall, results support both the frontal aging hypothesis and processing speed theory, suggesting that each mechanism is contributing to age-related cognitive decline.
Full-text · Article · Nov 2014 · Brain Imaging and Behavior
[Show abstract][Hide abstract] ABSTRACT: HIV-infected individuals frequently exhibit brain dysfunction despite antiretroviral treatment. The neuropathological mechanisms underlying these abnormalities remain unclear, pointing to the importance of identifying biomarkers sensitive to brain dysfunction. We examined 74 medically stable HIV-infected individuals using T1-weighted MRI. Volumes of the cortical grey matter (GM), white matter (WM), caudate, putamen, globus pallidus, thalamus, hippocampus, amygdala, and ventricles were derived using automated parcellation. A panel of plasma cytokines was measured using multiplexed bead array immunoassay. A model selection algorithm was used to select the combination of clinical and cytokine markers that best predicted each brain volumetric measure in a series of linear regression models. Higher CD4 nadir, shorter HIV infection duration, and antiretroviral treatment were significantly related to higher volumes of the putamen, thalamus, hippocampus, and WM. Older age was related to lower volumes in most brain regions and higher ventricular volume. Higher IFN-γ, MCP-1, and TNF-α were related to higher volumes of the putamen, pallidum, amygdala, GM, and WM. Higher IL-1β, IL-6, IL-16, IL-18, IP-10, MIP-1β, and SDF-1α were related to lower volumes of the putamen, pallidum, thalamus, hippocampus, amygdala, GM, and WM; and higher ventricular volume. The current findings provide evidence linking smaller brain volumes to HIV disease history, antiretroviral treatment, and advanced age. Cytokine markers, especially IL-6 and IL-16, showed robust association with brain volumes even after accounting for other clinical variables, demonstrating their utility in examining the mechanisms of HIV-associated brain abnormalities.
No preview · Article · Oct 2014 · Journal of Neuroimmune Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Objective: To examine cognitive predictors of functional performance and dexterity using an advanced upper-limb prosthetic
device. Method: Veterans (n = 14) with upper-limb amputation (transradial, transhumeral, or full-arm) underwent tests of neuropsychological functioning
and dexterity (Jebsen-Taylor Hand Function Test [JTHF]), and a clinician-based functional rating (Activities Measure for Upper-Limb
Amputees [AM-ULA]) using the prosthetic device at study baseline. Prosthetic measures were repeated after a variable in-laboratory
prosthetic training period. Results: Multiple linear regression showed Wechsler Adult Intelligence Scale-IV Digit Span (DS)
and oral Trails B (TMT-B) performance explained 54% of the variance in JTHF light items per second (R2 = .54, F(2, 10) = 5.89, p < .02) and 40% of the variance in JTHF heavy items per second (R2 = .38, F(2.10) = 3.17, p < .09). DS, TMT-B, and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Story Recall explained 77%
of the variance in AM-ULA (R2 = .77, F(3, 9) = 10.07, p < .00). Cognitive predictors remained significant after accounting for age and education. Dexterity performance was significantly
better in the transradial group versus all others for JTHF light and heavy items. Conclusion(s): Measures of attention and
working memory significantly predict post-training performance on tests of dexterity and functional ability using an advanced
upper-limb prosthetic device. Results underscore the predictive value of neuropsychological assessment for short-term prosthetic
proficiency, allowing improved individualized training. Ongoing work on this project will examine cognitive predictors of
No preview · Article · Sep 2014 · Archives of Clinical Neuropsychology
[Show abstract][Hide abstract] ABSTRACT: 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.
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 revealed significantly shorter FBLs in the anterior thalamic radiation for every 1-year increase over the age of 50 years.
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.
[Show abstract][Hide abstract] ABSTRACT: Major imaging biomarkers of Alzheimer's disease include amyloid deposition [imaged with [(11)C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [(18)F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer's disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.
Full-text · Article · Nov 2013 · Proceedings of the National Academy of Sciences
[Show abstract][Hide abstract] ABSTRACT: Chronic systemic immune activation and inflammatory processes have been linked to brain dysfunction in medically stable HIV-infected people. We investigated the association between verbal memory performance and plasma concentrations of 13 cytokines measured using multiplexed bead array immunoassay in 74 HIV-seropositive individuals and 50 HIV-seronegative controls. Memory performance was positively related to levels of IL-8 and IFN-γ, and negatively related to IL-10 and IL-18 and to hepatitis C infection. Memory performance was not significantly related to HIV disease markers. The results indicate the importance of systemic immune and inflammatory markers to neurocognitive function in chronic and stable HIV disease.
Full-text · Article · Sep 2013 · Journal of neuroimmunology
[Show abstract][Hide abstract] ABSTRACT: To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network.
Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO).
We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO.
Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Mar 2013 · Brain Imaging and Behavior
[Show abstract][Hide abstract] ABSTRACT: Objective: Presentation of an unusual case of amnesic syndrome following a suspected AVM. The subject was a 14-year-old female (N) who suffered a large right temporo-parietal intra-parenchymal hemorrhage with extension into the ventricular system requiring surgical evacuation. She presented with a significant anterograde amnesic disorder that was generalized and not circumscribed to the visual domain. A neuropsychological assessment was recommended to investigate the nature and extent of her amnesic symptoms. Two aspects were found to be fundamental in this case, firstly, the inconsistency between the image findings of acute cerebral injury and her general amnesic disorder, and secondly, her capacity to keep up with academic demands despite persisting memory impairment. Method: N was assessed on four occasions over a period of 4 years to monitor her recovery. The initial assessment was comprehensive and covered intellectual functions, attention, processing speed, general memory, and executive functions. The subsequent reviews targeted for the most part the areas of impairment to evaluate the recovery process. Follow-up MRI findings were also reviewed. Results: The initial neuropsychological findings 5-6 weeks post-injury confirmed the presence of a moderate to severe impairment in general memory. Subsequent reviews indicated some gains overall, but she demonstrated persisting mild memory dysfunctions particularly in the area of visual memory. Conclusions: Ns general memory impairment was surprising given her right hemispheric injury. Her profile suggested some probable left hemispheric injury. Ns grades at school indicated that her mild memory impairments were not affecting her ability to keep up academically at a level that was consistent with her intellectual ability. The etiology of her memory impairment as well as the course of recovery over time will discussed.