Publications by authors named "James T Becker"

192 Publications

Cerebral Blood Flow Predicts Conversion of Mild Cognitive Impairment into Alzheimer's Disease and Cognitive Decline: An Arterial Spin Labeling Follow-up Study.

J Alzheimers Dis 2021 ;82(1):293-305

Computer Science, State University of New York at Binghamton, Binghamton, NY, USA.

Background: This is the first longitudinal study to assess regional cerebral blood flow (rCBF) changes during the progression from normal control (NC) through mild cognitive impairment (MCI) and Alzheimer's disease (AD).

Objective: We aim to determine if perfusion MRI biomarkers, derived from our prior cross-sectional study, can predict the onset and cognitive decline of AD.

Methods: Perfusion MRIs using arterial spin labeling (ASL) were acquired in 15 stable-NC, 14 NC-to-MCI, 16 stable-MCI, and 18 MCI/AD-to-AD participants from the Cardiovascular Health Study (CHS) cognition study. Group comparisons, predictions of AD conversion and time to conversion, and Modified Mini-Mental State Examination (3MSE) from rCBF were performed.

Results: Compared to the stable-NC group: 1) the stable-MCI group exhibited rCBF decreases in the right temporoparietal (p = 0.00010) and right inferior frontal and insula (p = 0.0094) regions; and 2) the MCI/AD-to-AD group exhibited rCBF decreases in the bilateral temporoparietal regions (p = 0.00062 and 0.0035). Compared to the NC-to-MCI group, the stable-MCI group exhibited a rCBF decrease in the right hippocampus region (p = 0.0053). The baseline rCBF values in the posterior cingulate cortex (PCC) (p = 0.0043), bilateral superior medial frontal regions (BSMF) (p = 0.012), and left inferior frontal (p = 0.010) regions predicted the 3MSE scores for all the participants at follow-up. The baseline rCBF in the PCC and BSMF regions predicted the conversion and time to conversion from MCI to AD (p < 0.05; not significant after multiple corrections).

Conclusion: We demonstrated the feasibility of ASL in detecting rCBF changes in the typical AD-affected regions and the predictive value of baseline rCBF on AD conversion and cognitive decline.
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http://dx.doi.org/10.3233/JAD-210199DOI Listing
January 2021

Cardiac-induced cerebral pulsatility, brain structure, and cognition in middle and older-aged adults.

Neuroimage 2021 06 11;233:117956. Epub 2021 Mar 11.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, USA.

Changes of cardiac-induced regional pulsatility can be associated with specific regions of brain volumetric changes, and these are related with cognitive alterations. Thus, mapping of cardiac pulsatility over the entire brain can be helpful to assess these relationships. A total of 108 subjects (age: 66.5 ± 8.4 years, 68 females, 52 healthy controls, 11 subjective cognitive decline, 17 impaired without complaints, 19 MCI and 9 AD) participated. The pulsatility map was obtained directly from resting-state functional MRI time-series data at 3T. Regional brain volumes were segmented from anatomical MRI. Multidomain neuropsychological battery was performed to test memory, language, attention and visuospatial construction. The Montreal Cognitive Assessment (MoCA) was also administered. The sparse partial least square (SPLS) method, which is desirable for better interpreting high-dimensional variables, was applied for the relationship between the entire brain voxels of pulsatility and 45 segmented brain volumes. A multiple holdout SPLS framework was used to optimize sparsity for assessing the pulsatility-volume relationship model and to test the reliability by fitting the models to 9 different splits of the data. We found statistically significant associations between subsets of pulsatility voxels and subsets of segmented brain volumes by rejecting the omnibus null hypothesis (any of 9 splits has p < 0.0056 (=0.05/9) with the Bonferroni correction). The pulsatility was positively associated with the lateral ventricle, choroid plexus, inferior lateral ventricle, and 3rd ventricle and negatively associated with hippocampus, ventral DC, and thalamus volumes for the first pulsatility-volume relationship. The pulsatility had an additional negative relationship with the amygdala and brain stem volumes for the second pulsatility-volume relationship. The spatial distribution of correlated pulsatility was observed in major feeding arteries to the brain regions, ventricles, and sagittal sinus. The indirect mediating pathways through the volumetric changes were statistically significant between the pulsatility and multiple cognitive measures (p < 0.01). Thus, the cerebral pulsatility, along with volumetric measurements, could be a potential marker for better understanding of pathophysiology and monitoring disease progression in age-related neurodegenerative disorders.
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http://dx.doi.org/10.1016/j.neuroimage.2021.117956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145789PMC
June 2021

Longitudinal 5-year prediction of cognitive impairment among men with HIV disease.

AIDS 2021 05;35(6):889-898

Department of Psychiatry.

Background: Although combination antiretroviral therapy reduced the prevalence of HIV-associated dementia, milder syndromes persist. Our goals were to predict cognitive impairment of the Multicenter AIDS Cohort Study (MACS) participants 5 years ahead and from a large pool of factors, select the ones that mostly contributed to our predictions.

Design: Longitudinal, natural and treated history of HIV infection among MSM.

Methods: The MACS is a longitudinal study of the natural and treated history of HIV disease in MSM; the neuropsychological substudy aims to characterize cognitive disorders in men with HIV disease.

Results: We modeled on an annual basis the risk of cognitive impairment 5 years in the future. We were able to predict cognitive impairment at individual level with high precision and overperform default methods. We found that while a diagnosis of AIDS is a critical risk factor, HIV infection per se does not necessarily convey additional risk. Other infectious processes, most notably hepatitis B and C, are independently associated with increased risk of impairment. The relative importance of an AIDS diagnosis diminished across calendar time.

Conclusion: Our prediction models are a powerful tool to help clinicians address dementia in early stages for MACS paticipants. The strongest predictors of future cognitive impairment included the presence of clinical AIDS and hepatitis B or C infection. The fact that the pattern of predictive power differs by calendar year suggests a clinically critical change to the face of the epidemic.
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http://dx.doi.org/10.1097/QAD.0000000000002827DOI Listing
May 2021

Quantifying diagnostic accuracy improvement of new biomarkers for competing risk outcomes.

Biostatistics 2020 Feb 21. Epub 2020 Feb 21.

Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh, Pittsburgh, PA 15260, USA.

The net reclassification improvement (NRI) and the integrated discrimination improvement (IDI) were originally proposed to characterize accuracy improvement in predicting a binary outcome, when new biomarkers are added to regression models. These two indices have been extended from binary outcomes to multi-categorical and survival outcomes. Working on an AIDS study where the onset of cognitive impairment is competing risk censored by death, we extend the NRI and the IDI to competing risk outcomes, by using cumulative incidence functions to quantify cumulative risks of competing events, and adopting the definitions of the two indices for multi-category outcomes. The "missing" category due to independent censoring is handled through inverse probability weighting. Various competing risk models are considered, such as the Fine and Gray, multistate, and multinomial logistic models. Estimation methods for the NRI and the IDI from competing risk data are presented. The inference for the NRI is constructed based on asymptotic normality of its estimator, and the bias-corrected and accelerated bootstrap procedure is used for the IDI. Simulations demonstrate that the proposed inferential procedures perform very well. The Multicenter AIDS Cohort Study is used to illustrate the practical utility of the extended NRI and IDI for competing risk outcomes.
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http://dx.doi.org/10.1093/biostatistics/kxaa048DOI Listing
February 2020

Longitudinal multivariate normative comparisons.

Stat Med 2021 03 9;40(6):1440-1452. Epub 2020 Dec 9.

Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Motivated by the Multicenter AIDS Cohort Study (MACS), we develop classification procedures for cognitive impairment based on longitudinal measures. To control family-wise error, we adapt the cross-sectional multivariate normative comparisons (MNC) method to the longitudinal setting. The cross-sectional MNC was proposed to control family-wise error by measuring the distance between multiple domain scores of a participant and the norms of healthy controls and specifically accounting for intercorrelations among all domain scores. However, in a longitudinal setting where domain scores are recorded multiple times, applying the cross-sectional MNC at each visit will still have inflated family-wise error rate due to multiple testing over repeated visits. Thus, we propose longitudinal MNC procedures that are constructed based on multivariate mixed effects models. A test procedure is adapted from the cross-sectional MNC to classify impairment on longitudinal multivariate normal data. Meanwhile, a permutation procedure is proposed to handle skewed data. Through simulations we show that our methods can effectively control family-wise error at a predetermined level. A dataset from a neuropsychological substudy of the MACS is used to illustrate the applications of our proposed classification procedures.
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http://dx.doi.org/10.1002/sim.8850DOI Listing
March 2021

Differential Effects of an AIDS Defining Illness and Chronic HIV Infection on Gray Matter Volume.

Clin Infect Dis 2020 Oct 14. Epub 2020 Oct 14.

University of Pittsburgh School of Medicine, Department of Neurology, Pittsburgh PA.

Background: Age, HIV infection, illicit drug use, and CNS opportunistic infections all can affect brain structure, with the striatum being particularly sensitive to HIV effects. Nevertheless, the impact of non-CNS AIDS defining illness (ADI) on brain structure has been less investigated. We examined ADI and HIV effects on brain volume.

Methods: In a cross-sectional study, including 95 virally-suppressed seropositive and 84 demographically-matched, seronegative participants, we examined serostatus and ADI effects. Cortical and subcortical GMV ROIs were estimated with computational neuroanatomy techniques applied to high resolution, T1-weighted MRI data. Linear regression was used to model HIV serostatus and ADI effects on global and regional GMV, adjusting for age, sex, CD4 nadir, drug use and total intracranial volume.

Results: While HIV serostatus was associated with lower striatal volume (B = -0.59; 95% CI = [-1.08 - -0.10]), co-occurring ADI was independently associated with lower striatal volume (B=-0.73; 95% CI =[-1.36 - -0.09]). ADI was also associated with lower global (B = -19.35; 95% CI = [-32.42 - -6.29]) and regional GMV.

Conclusions: While HIV infection is associated with a localized effect on striatal structure, having a prior ADI is a strong predictor of smaller global and regional GMV. The lack of interaction between HIV serostatus or ADI with age suggests that chronic HIV infection and ADI have independent effects on brain structure, without associated accelerated lower volume with age. ADI history should be incorporated into statistical adjustments in HIV neuroimaging analysis. These findings also lend support to current HIV treatment guidelines urging prompt ART initiation after HIV diagnosis.
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http://dx.doi.org/10.1093/cid/ciaa1552DOI Listing
October 2020

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults.

Nat Commun 2020 09 22;11(1):4796. Epub 2020 Sep 22.

Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.
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http://dx.doi.org/10.1038/s41467-020-18367-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508833PMC
September 2020

Estrogen, brain structure, and cognition in postmenopausal women.

Hum Brain Mapp 2021 01 10;42(1):24-35. Epub 2020 Sep 10.

Imaging Genetics Center, Mark & Mary Stevens Institute for Neuroimaging & Informatics, Keck School of Medicine, University of Southern California, Marina del Rey, California, USA.

Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer's disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy (HT) where possible benefits include a delay in the onset of dementia-yet findings are inconsistent. Effects of HT may be mediated by estrogen receptors found throughout the brain. Effects may also depend on lifestyle factors, timing of use, and genetic risk. We studied the impact of self-reported HT use on brain volume in 562 elderly women (71-94 years) with mixed cognitive status while adjusting for aforementioned factors. Covariate-adjusted voxelwise linear regression analyses using a model with 16 predictors showed HT use as positively associated with regional brain volumes, regardless of cognitive status. Examinations of other factors related to menopause, oophorectomy and hysterectomy status independently yielded positive effects on brain volume when added to our model. One interaction term, HTxBMI, out of several examined, revealed significant negative association with overall brain volume, suggesting a greater reduction in brain volume than BMI alone. Our main findings relating HT to regional brain volume were as hypothesized, but some exploratory analyses were not in line with existing hypotheses. Studies suggest lower levels of estrogen resulting from oophorectomy and hysterectomy affect brain volume negatively, and the addition of HT modifies the relation between BMI and brain volume positively. Effects of HT may depend on the age range assessed, motivating studies with a wider age range as well as a randomized design.
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http://dx.doi.org/10.1002/hbm.25200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721237PMC
January 2021

Studying the neuropsychological sequelae of SARS-CoV-2: lessons learned from 35 years of neuroHIV research.

J Neurovirol 2020 12 3;26(6):809-823. Epub 2020 Sep 3.

Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh, Pittsburgh, PA, 15260, USA.

The virology of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the human immune response to the virus are under vigorous investigation. There are now several reports describing neurological symptoms in individuals who develop coronavirus disease 2019 (COVID-19), the syndrome associated with SARS-CoV-2 infection. The prevalence, incidence, and clinical course of these symptoms will become clearer in the coming months and years through epidemiological studies. However, the long-term neurological and cognitive consequence of SARS-CoV-2 infection will remain conjectural for some time and will likely require the creation of cohort studies that include uninfected individuals. Considering the early evidence for neurological involvement in COVID-19 it may prove helpful to compare SARS-CoV-2 with another endemic and neurovirulent virus, human immunodeficiency virus-1 (HIV-1), when designing such cohort studies and when making predictions about neuropsychological outcomes. In this paper, similarities and differences between SARS-CoV-2 and HIV-1 are reviewed, including routes of neuroinvasion, putative mechanisms of neurovirulence, and factors involved in possible long-term neuropsychological sequelae. Application of the knowledge gained from over three decades of neuroHIV research is discussed, with a focus on alerting researchers and clinicians to the challenges in determining the cause of neurocognitive deficits among long-term survivors.
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http://dx.doi.org/10.1007/s13365-020-00897-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471564PMC
December 2020

Hippocampal sclerosis, TDP-43, and the duration of the symptoms of dementia of AD patients.

Ann Clin Transl Neurol 2020 09 31;7(9):1546-1556. Epub 2020 Jul 31.

Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Objectives: To examine the relationship between duration of the cognitive symptoms, from the earliest reported symptom to death, and hippocampal sclerosis (HS) and TAR-DNA binding protein of 43kDA (TDP-43) in Alzheimer's disease (AD) patients.

Methods: The study was conducted in 359 cognitively impaired patients who met the pathological criteria for AD (NIA-Reagan intermediate or high). The mean age at onset was 69.5 ± 8.8 years (range 37-95) and the mean duration of the symptoms was 10.5 ± 4.2 years. The association between symptoms duration and HS and TDP-43 was examined with logistic regression analyses controlling for age at death, atherosclerosis in the Circle of Willis (CW), cerebral infarcts, gender, baseline Mini Mental State Examination scores, APOE-4 allele, and presence of Lewy bodies (LB).

Results: HS was present in 18% (n = 64) and TDP-43 in 51.5% (n = 185) of the patients. HS and TDP-43 were more frequent in patients whose symptoms lasted more than 10 years. LBs were present in 72% of the patients with HS and in 64% of the patients with TDP-43. Age at onset was not associated with TDP-43 or HS. HS was associated with duration of symptoms and LB, TDP-43, and atherosclerosis in the CW. TDP-43 was associated with duration of symptoms, LB, and HS.

Interpretation: HS and TDP-43 are present in early and late onset AD. However, their presence is mainly driven by the duration of symptoms and the presence of LB. This suggests that HS and TDP-43 are part of the later neuropathological changes in AD.
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http://dx.doi.org/10.1002/acn3.51135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480925PMC
September 2020

Cerebral Blood Flow Is Associated with Diagnostic Class and Cognitive Decline in Alzheimer's Disease.

J Alzheimers Dis 2020 ;76(3):1103-1120

Department of Computer Science, State University of New York at Binghamton, Binghamton, NY, USA.

Background: Reliable cerebral blood flow (CBF) biomarkers using a noninvasive imaging technique are sought to facilitate early diagnosis and intervention in early Alzheimer's disease (AD).

Objective: We aim to identify brain regions in which CBF values are affected and related to cognitive decline in early AD using a large cohort.

Methods: Perfusion MRIs using continuous arterial spin labeling were acquired at 1.5 T in 58 normal controls (NC), 50 mild cognitive impairments (MCI), and 40 AD subjects from the Cardiovascular Health Study Cognition Study. Regional absolute CBF and normalized CBF (nCBF) values, without and with correction of partial volume effects, were compared across three groups. Association between regional CBF values and Modified Mini-Mental State Examination (3MSE) were investigated by multiple linear regression analyses adjusted for cardiovascular risk factors.

Results: After correcting for partial volume effects and cardiovascular risk factors, ADs exhibited decreased nCBF with the strongest reduction in the bilateral posterior cingulate & precuneus region (p < 0.001) compared to NCs, and the strongest reduction in the bilateral superior medial frontal region (p < 0.001) compared to MCIs. MCIs exhibited the strongest nCBF decrease in the left hippocampus and nCBF increase in the right inferior frontal and insular region. The 3MSE scores within the symptomatic subjects were significantly associated with nCBF in the bilateral posterior and middle cingulate and parietal (p < 0.001), bilateral superior medial frontal (p < 0.001), bilateral temporoparietal (p < 0.02), and right hippocampus (p = 0.02) regions.

Conclusion: Noninvasive perfusion MRI can detect functional changes across diagnostic class and serve as a staging biomarker of cognitive status.
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http://dx.doi.org/10.3233/JAD-200034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970411PMC
June 2021

Long-term cognitive decline and mortality after carotid endarterectomy.

Clin Neurol Neurosurg 2020 07 6;194:105823. Epub 2020 Apr 6.

Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Electronic address:

Objectives: To date no studies have evaluated long term cognitive decline after carotid endarterectomy (CEA). We evaluated whether participants who had CEA were at increased risk of cognitive decline over participants who didn't undergo CEA.

Patients And Methods: The patients in the study were participants in the Cardiovascular Health Study (CHS), a study of 5201 men and women over the age of 65 who were recruited from four communities (Pittsburgh, Pennsylvania; Sacramento, California; Winston-Salem, North Carolina; Hagerstown, Maryland) in 1988-89. The outcomes measured were 1) Decline in 3MSE and digit symbol substitution test (DSST) scores after CEA compared to before CEA. 2) All-cause mortality in CHS cohort among participants who did and did not have CEA.

Results: CEA patients had significantly greater annual decrease in the DSST scores -2.43 (SD 4.21) compared to those who did not have a CEA -1.1 (SD 2.57) (p < 0.001) but this was not seen in the 3MSE scores. CEA patients had increased the risk of decline in DSST (OR 2.41, 95 % CI 1.49, 3.88) and 3MSE (OR 2.17, 95 % CI 1.35, 3.48) scores after adjusting for age, gender, race and educational status. CEA was associated with all-cause mortality in the long term with a HR of 2.72 (95 % CI 2.22, 3.34) after adjusting for covariates. Participants with lower baseline 3MSE scores HR 1.39 (1.27, 1.51), lower DSST scores <34 HR 1.69(1.54, 1.85) were more likely deceased.

Conclusions: CEA patients are at increased risk of lower scores on 3MSE and DSST testing in the long term. Mortality in the CHS cohort was higher in participants who underwent CEA. Further, lower 3MSE and DSST scores increased the risk of mortality.
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http://dx.doi.org/10.1016/j.clineuro.2020.105823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871212PMC
July 2020

Genetic architecture of subcortical brain structures in 38,851 individuals.

Nat Genet 2019 11 21;51(11):1624-1636. Epub 2019 Oct 21.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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http://dx.doi.org/10.1038/s41588-019-0511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055269PMC
November 2019

Preface.

Prog Mol Biol Transl Sci 2019 ;165:xiii

University of Pittsburgh, School of Medicine, Department of Psychiatry, Pittsburgh, PA, USA.

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http://dx.doi.org/10.1016/S1877-1173(19)30149-8DOI Listing
April 2020

Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE): Protocol.

Contemp Clin Trials 2019 10 26;85:105832. Epub 2019 Aug 26.

Department of Psychology, University of Pittsburgh, USA.

Despite the ubiquity of normal age-related cognitive decline there is an absence of effective approaches for improving neurocognitive health. Fortunately, moderate intensity exercise is a promising method for improving brain and cognitive health in late life, but its effectiveness remains a matter of skepticism and debate because of the absence of large, comprehensive, Phase III clinical trials. Here we describe the protocol for such a randomized clinical trial called IGNITE (Investigating Gains in Neurocognition in an Intervention Trial of Exercise), a study capable of more definitively addressing whether exercise influences cognitive and brain health in cognitively normal older adults. We are conducting a 12-month, multi-site, randomized dose-response exercise trial in 639 cognitively normal adults between 65 and 80 years of age. Participants are randomized to (1) a moderate intensity aerobic exercise condition of 150 min/week (N = 213), (2) a moderate intensity aerobic exercise condition at 225 min/week (N = 213), or (3) a light intensity stretching-and-toning control condition for 150 min/week (N = 213). Participants are engaging in 3 days/week of supervised exercise and two more days per week of unsupervised exercise for 12 months. A comprehensive cognitive battery, blood biomarkers and battery of psychosocial questionnaires is assessed at baseline, 6 and 12-months. In addition, brain magnetic resonance imaging, physiological biomarkers, cardiorespiratory fitness, physical function, and positron emission tomography of amyloid deposition are assessed at baseline and at the 12-month follow-up. The results from this trial could transform scientific-based policy and health care recommendations for approaches to improve cognitive function in cognitively normal older adults.
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http://dx.doi.org/10.1016/j.cct.2019.105832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815730PMC
October 2019

Cross-sectional analysis of cognitive function using multivariate normative comparisons in men with HIV disease.

AIDS 2019 11;33(14):2115-2124

aDepartment of Statistics bDepartment of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania cPopulation Health Sciences, Harvard University, Cambridge, Massachusetts dDepartment of Epidemiology eDepartment of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania fDepartment of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, California gDepartment of Psychiatry, Rush University School of Medicine, Chicago, Illinois hDepartment of Psychiatry iDepartment of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland jDepartment of Radiology, Northwestern University, Evanston, Illinois kDepartment of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland lDepartment of Psychiatry mDepartment of Neurology nDepartment of Psychology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Background: Prevalence estimates of cognitive impairment in HIV disease vary widely. Here we used multivariate normative comparison (MNC) with identify individuals with impaired cognition, and to compare the results with those using the Frascati and Gisslén criteria.

Methods: The current project used data collected before October 2014 from bisexual/gay men from the Multicenter AIDS Cohort Study. A total of 2904 men (mean age 39.7 years, 52.7% seropositive) had complete data in six cognitive domains at their first neuropsychological evaluation. T-scores were computed for each domain and the MNC was applied to detect impairment among seronegative and seropositive groups.

Results: The MNC classified 6.26% of seronegative men as being impaired using a predetermined 5% false discovery rate. By contrast, the Frascati and the Gisslén criteria identified 24.54 and 11.36% of seronegative men as impaired. For seropositive men, the percentage impairment was 7.45, 25.73, and 11.69%, respectively, by the MNC, Frascati and Gisslén criteria. When we used seronegative men without medical comorbidities as the control group, the MNC, the Frascati and the Gisslén criteria identified 5.05, 27.07, and 4.21% of the seronegative men, and 4.34, 30.95, and 4.48% of the seropositive men as having cognitive impairment. For each method, serostatus was not associated with cognitive impairment.

Conclusion: The MNC controls the false discovery rate and therefore avoids the low specificity that characterizes the Frascati and Gisslén criteria. More research is needed to evaluate the sensitivity of the MNC method in a seropositive population that may be sicker and older than the current study sample and that includes women.
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http://dx.doi.org/10.1097/QAD.0000000000002312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832818PMC
November 2019

Midlife adiposity predicts cognitive decline in the prospective Multicenter AIDS Cohort Study.

Neurology 2019 07 14;93(3):e261-e271. Epub 2019 Jun 14.

From the Departments of Neurology (L.H.R., C.A.M., N.S.), Psychiatry (C.A.M.), and Medicine (T.T.B.), Johns Hopkins University School of Medicine; Department of Epidemiology (L.H.R., L.Z., L.P.J.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Department of Neurology (D.G.), State University of New York Downstate Medical Center, Brooklyn; University of Colorado (K.L.H., K.M.E.), Aurora; Denver Public Health (K.L.H.), CO; Department of Neurology (J.T.B.), University of Pittsburgh, PA; Department of Medicine (J.E.L.), University of Texas Health Science Center at Houston; Department of Psychiatry (E.M.), Rush University Medical Center, Chicago, IL; and Department of Neurology (A.L.), David Geffen School of Medicine at the University of California, Los Angeles.

Objective: Obesity is a common, modifiable cardiovascular and cerebrovascular risk factor. Among people with HIV, obesity may contribute to multisystem dysregulation including cognitive impairment. We examined body mass index (BMI) and central obesity (waist circumference [WC]) in association with domain-specific cognitive function and 10-year cognitive decline in men with HIV infection (MWH) vs HIV-uninfected (HIV-) men.

Methods: A total of 316 MWH and 656 HIV- Multicenter AIDS Cohort Study participants ≥40 years at baseline, with neuropsychological testing every 2 years and concurrent BMI and WC measurements, were included. MWH were included if taking ≥2 antiretroviral agents and had HIV-1 RNA <400 copies/mL at >80% of visits. Mixed-effects models included all visits from 1996 to 2015, stratified by HIV serostatus, and adjusted for sociodemographic, behavioral, and clinical characteristics. At baseline and follow-up, 8% of MWH and 15% of HIV- men and 41% of MWH and 56% of HIV- men were ≥60 years, respectively.

Results: Cross-sectionally, higher BMI was inversely associated with motor function in MWH and HIV- men, and attention/working memory in HIV- men. WC was inversely associated with motor function in MWH and HIV- men. Longitudinal associations indicated an obese BMI was associated with a less steep decline in motor function in MWH whereas in HIV- men, obesity was associated with a greater decline in motor function, learning, and memory. WC, or central obesity, showed similar patterns of associations.

Conclusion: Higher adiposity is associated with lower cognition cross-sectionally and greater cognitive decline, particularly in HIV- men. Overweight and obesity may be important predictors of neurologic outcomes and avenues for prevention and intervention.
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http://dx.doi.org/10.1212/WNL.0000000000007779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656644PMC
July 2019

HIV infection and age effects on striatal structure are additive.

J Neurovirol 2019 08 26;25(4):480-495. Epub 2019 Apr 26.

Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, MD, USA.

The age of the HIV-infected population is increasing. Although many studies document gray matter volume (GMV) changes following HIV infection, GMV also declines with age. Findings have been inconsistent concerning interactions between HIV infection and age on brain structure. Effects of age, substance use, and inadequate viral suppression may confound identification of GMV serostatus effects using quantitative structural measures. In a cross-sectional study of HIV infection, including 97 seropositive and 84 seronegative, demographically matched participants, ages 30-70, we examined serostatus and age effects on GMV and neuropsychological measures. Ninety-eight percent of seropositive participants were currently treated with anti-retroviral therapies and all were virally suppressed. Gray, white, and CSF volumes were estimated using high-resolution T1-weighted MRI. Linear regression modeled effects of serostatus, age, education, comorbidities, and magnetic field strength on brain structure, using both a priori regions and voxel-based morphometry. Although seropositive participants exhibited significant bilateral decreases in striatal GMV, no serostatus effects were detected in the thalamus, hippocampus, or cerebellum. Age was associated with cortical, striatal, thalamic, hippocampal, and cerebellar GMV reductions. Effects of age and serostatus on striatal GMV were additive. Although no main effects of serostatus on neuropsychological performance were observed, serostatus moderated the relationship between pegboard performance and striatal volume. Both HIV infection and age were associated with reduced striatal volume. The lack of interaction of these two predictors suggests that HIV infection is associated with premature, but not accelerated, brain age. In serostatus groups matched on demographic and clinical variables, there were no observed differences in neuropsychological performance. Striatal GMV measures may be promising biomarker for use in studies of treated HIV infection.
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http://dx.doi.org/10.1007/s13365-019-00747-wDOI Listing
August 2019

Neuropsychological changes in efavirenz switch regimens.

AIDS 2019 07;33(8):1307-1314

University of Pittsburgh School of Medicine.

Background: Efavirenz is associated with side effects involving the central nervous system. However, it remains largely unknown whether switching off EFV improves neuropsychological performance.

Methods: We utilized data from the Multicenter AIDS Cohort Study (MACS). Participants were categorized by their use of EFV: never on EFV (No EFV), continuously on EFV (No Switch-OFF) and on EFV and then switched off (Switch-OFF). Baseline time points were defined as visits when first neuropsychological data were available. In Analysis 1, we compared neuropsychological and Center for Epidemiological Studies-Depression Scale (CES-D) scores before and after EFV switch in Switch-OFF group, aligning participants at the time of switch. Analysis 2 evaluated trajectory of neuropsychological/CES-D score among the three groups.

Results: This analysis included 1989 HIV-seropositive participants with neuropsychological data (1675 in No EFV, 44 in No Switch-OFF, and 270 in Switch-OFF group). At baseline, participants had a median age of 37 years, median CD4 cell count 442 cells/μl, and 22.9% viral suppression rate. In Analysis 1, neuropsychological and CES-D scores did not show clinically significant changes over 2 years prior to and 4 years after switch in Switch-OFF group. In Analysis 2, trends in neuropsychological and CES-D scores in the three different groups did not show significant differences during a median of 3.2 years of follow-up.

Conclusion: Discontinuation of EFV is not associated with changes in neuropsychological performance or severity of depression in men. Furthermore, we did not observe differences among participants who were never on EFV, continuously on EFV, and on EFV and then switched off.
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http://dx.doi.org/10.1097/QAD.0000000000002206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588288PMC
July 2019

Elevated Depressive Symptoms Are a Stronger Predictor of Executive Dysfunction in HIV-Infected Women Than in Men.

J Acquir Immune Defic Syndr 2019 07;81(3):274-283

Departments of Psychiatry and Psychology, University of Illinois at Chicago College of Medicine, Chicago, IL.

Background: HIV-infected (HIV+) women seem to be more vulnerable to neurocognitive impairment (NCI) than HIV+ men, perhaps in part due to mental health factors. We assessed the association between elevated depressive symptoms and NCI among HIV+ and HIV-uninfected (HIV-) women and men.

Setting: Women's Interagency HIV Study and Multicenter AIDS Cohort Study.

Methods: Eight hundred fifty-eight HIV+ (429 women; 429 men) and 562 HIV- (281 women; 281 men) completed the Center for Epidemiologic Studies Depression (16 cutoff) Scale and measures of psychomotor speed/attention, executive, and motor function over multiple visits (or time points). Women's Interagency HIV Study and Multicenter AIDS Cohort Study participants were matched according to HIV status, age, race/ethnicity, and education. Generalized linear mixed models were used to examine interactions between biological sex, HIV serostatus, and depression on impairment (T-scores <40) after covariate adjustment.

Results: Despite a higher frequency of depression among men, the association between depression and executive function differed by sex and HIV serostatus. HIV+ women with depression had 5 times the odds of impairment on a measure of executive control and inhibition versus HIV- depressed women and 3 times the odds of impairment on that measure versus HIV+ depressed men. Regardless of group status, depression was associated with greater impairment on processing speed, executive (mental flexibility), and motor function (P's < 0.05).

Conclusions: Depression contributes to NCI across a broad range of cognitive domains in HIV+ and HIV- individuals, but HIV+ depressed women show greater vulnerabilities in executive function. Treating depression may help to improve cognition in patients with HIV infection.
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http://dx.doi.org/10.1097/QAI.0000000000002029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254882PMC
July 2019

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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http://dx.doi.org/10.1038/s41588-019-0358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463297PMC
March 2019

Changes in cognition precede changes in HRQoL among HIV+ males: Longitudinal analysis of the multicenter AIDS cohort study.

Neuropsychology 2019 Mar;33(3):370-378

University of California.

Objectives: Despite treatment-related improvements in morbidity and mortality, HIV-1-infected (HIV+) individuals continue to face a wide range of HIV-associated medical and HIV-associated neurocognitive disorders. Little is known about the impact of cognitive impairment on patients' health-related quality of life (HRQoL). To address this, the current study examined the longitudinal relationship between cognitive functioning and HRQoL among HIV+ individuals.

Method: The sample consisted of 1,306 HIV+ men enrolled in the Multicenter AIDS Cohort Study. Participants received biannual assessments of cognitive functioning (including tests of processing speed, executive functioning, attention/working memory, motor functioning, learning, and memory) and completed questionnaires assessing HRQoL and depression. Multilevel models were used to examine the longitudinal and cross-lagged relationship between HRQoL and cognition, independent of depression and HIV disease severity.

Results: There was a significant relationship between HRQoL and cognitive functioning both between and within subjects. Specifically, individuals who reported better HRQoL reported better cognitive functioning, and longitudinal change in cognition was positively related to change in HRQoL. There was a significant unidirectional-lagged relationship; cognition predicted HRQoL at subsequent visits, but HRQoL did not predict cognitive functioning at subsequent visits. Furthermore, analyses of severity of neurocognitive impairment revealed that transition to a more severe stage of cognitive impairment was associated with a decline in HRQoL.

Conclusions: Overall, the current study suggests that changes in HRQoL are partially driven by changes in cognitive functioning. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/neu0000530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6666308PMC
March 2019

High-dimensional longitudinal classification with the multinomial fused lasso.

Stat Med 2019 05 30;38(12):2184-2205. Epub 2019 Jan 30.

Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania.

We study regularized estimation in high-dimensional longitudinal classification problems, using the lasso and fused lasso regularizers. The constructed coefficient estimates are piecewise constant across the time dimension in the longitudinal problem, with adaptively selected change points (break points). We present an efficient algorithm for computing such estimates, based on proximal gradient descent. We apply our proposed technique to a longitudinal data set on Alzheimer's disease from the Cardiovascular Health Study Cognition Study. Using data analysis and a simulation study, we motivate and demonstrate several practical considerations such as the selection of tuning parameters and the assessment of model stability. While race, gender, vascular and heart disease, lack of caregivers, and deterioration of learning and memory are all important predictors of dementia, we also find that these risk factors become more relevant in the later stages of life.
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http://dx.doi.org/10.1002/sim.8100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599683PMC
May 2019

Brain structural correlates of trajectories to cognitive impairment in men with and without HIV disease.

Brain Imaging Behav 2020 Jun;14(3):821-829

Department of Psychiatry, University of Pittsburgh, Suite 830, 3501 Forbes Avenue, Pittsburgh, PA, 15213, USA.

There are distinct trajectories to cognitive impairment among participants in the Multicenter AIDS Cohort Study (MACS). Here we analyzed the relationship between regional brain volumes and the individual trajectories to impairment in a subsample (n = 302) of the cohort. 302 (167 HIV-infected; mean age = 55.7 yrs.; mean education: 16.2 yrs.) of the men enrolled in the MACS MRI study contributed data to this analysis. We used voxel-based morphometry (VBM) to segment the brain images to analyze gray and white matter volume at the voxel-level. A Mixed Membership Trajectory Model had previously identified three distinct profiles, and each study participant had a membership weight for each of these three trajectories. We estimated VBM model parameters for 100 imputations, manually performed the post-hoc contrasts, and pooled the results. We examined the associations between brain volume at the voxel level and the MMTM membership weights for two profiles: one considered "unhealthy" and the other considered "Premature aging." The unhealthy profile was linked to the volume of the posterior cingulate gyrus/precuneus, the inferior frontal cortex, and the insula, whereas the premature aging profile was independently associated with the integrity of a portion of the precuneus. Trajectories to cognitive impairment are the result, in part, of atrophy in cortical regions linked to normal and pathological aging. These data suggest the possibility of predicting cognitive morbidity based on patterns of CNS atrophy.
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http://dx.doi.org/10.1007/s11682-018-0026-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616021PMC
June 2020

Intraindividual variability in neurocognitive performance: No influence due to HIV status or self-reported effort.

J Clin Exp Neuropsychol 2018 12 20;40(10):1044-1049. Epub 2018 Aug 20.

f Departments of Psychiatry, Neurology, and Psychology , University of Pittsburgh , Pittsburgh , PA , USA.

Introduction: HIV-associated neurocognitive disorders (HAND) are estimated to affect approximately 50% of infected individuals at any one time. Dispersion, a type of intraindividual variability in neurocognitive test performance, has been identified as a potential behavioral marker of HAND; however, the specificity of dispersion to HAND and how it is influenced by participant effort when taking neurocognitive tests remain unclear.

Method: Data were analyzed from 996 (474 HIV-, 522 HIV+) men enrolled in the Multicenter AIDS Cohort Study (MACS). Dispersion was calculated based on the standard deviation of an individual's test scores within a single assessment. Effort was determined using the Visual Analogue Effort Scale. Predictors of dispersion were determined using stepwise linear regression. Dispersion was compared between the HIV serostatus groups using analysis of covariance (ANCOVA), considering demographic and psychosocial variables that differed between the groups.

Results: Contrary to our hypothesis, dispersion was not influenced by effort. Instead, poorer neurocognitive ability and race were the sole predictors of dispersion. Dispersion did not differ between the serostatus groups.

Conclusions: Our results indicate that dispersion is a valid indicator of neurocognitive dysfunction that is not due to suboptimal effort; however, it is not specific to HIV and is therefore of limited utility as a behavioral marker of HIV-related neurocognitive impairment.
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http://dx.doi.org/10.1080/13803395.2018.1508554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294568PMC
December 2018

Differences in Cognitive Function Between Women and Men With HIV.

J Acquir Immune Defic Syndr 2018 09;79(1):101-107

Department of Psychiatry, Rush University Medical Center, Chicago, IL.

Background: Women may be more vulnerable to HIV-related cognitive dysfunction compared with men because of sociodemographic, lifestyle, mental health, and biological factors. However, studies to date have yielded inconsistent findings on the existence, magnitude, and pattern of sex differences. We examined these issues using longitudinal data from 2 large, prospective, multisite, observational studies of US women and men with and without HIV.

Setting: The Women's Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS).

Methods: HIV-infected (HIV+) and uninfected (HIV-) participants in the Women's Interagency HIV Study and Multicenter AIDS Cohort Study completed tests of psychomotor speed, executive function, and fine motor skills. Groups were matched on HIV status, sex, age, education, and black race. Generalized linear mixed models were used to examine group differences on continuous and categorical demographically corrected T-scores. Results were adjusted for other confounding factors.

Results: The sample (n = 1420) included 710 women (429 HIV+) and 710 men (429 HIV+) (67% non-Hispanic black; 53% high school or less). For continuous T-scores, sex by HIV serostatus interactions were observed on the Trail Making Test parts A & B, Grooved Pegboard, and Symbol Digit Modalities Test. For these tests, HIV+ women scored lower than HIV+ men, with no sex differences in HIV- individuals. In analyses of categorical scores, particularly the Trail Making Test part A and Grooved Pegboard nondominant, HIV+ women also had a higher odds of impairment compared with HIV+ men. Sex differences were constant over time.

Conclusions: Although sex differences are generally understudied, HIV+ women vs men show cognitive disadvantages. Elucidating the mechanisms underlying these differences is critical for tailoring cognitive interventions.
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http://dx.doi.org/10.1097/QAI.0000000000001764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092201PMC
September 2018

HIV disease and diabetes interact to affect brain white matter hyperintensities and cognition.

AIDS 2018 08;32(13):1803-1810

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Since the onset of combination antiretroviral therapy use, the incidence of HIV-associated dementia and of HIV encephalitis has fallen dramatically. The present study investigates the extent of white matter hyperintensities (WMHs) among individuals with HIV disease, and factors that predict their presence and their impact on psychomotor speed.

Methods: A total of 322 men participating in the Multicenter AIDS Cohort Study (185 HIV-infected, age: 57.5 ± 6.0) underwent MRI scans of the brain. T1-weighted magnetization-prepared rapid gradient-echo (MP-RAGE) and T2-weighted Fluid Attenuated Inversion Recovery (FLAIR) images were obtained and processed using an automated method for identifying and measuring WMHs. WMH burden was expressed as the log10 transformed percentage of total white matter.

Results: There were no significant associations between WMHs and HIV disease. However, the extent of WMHs was predicted by age more than 60 (β = 0.17), non-white race (β = 0.14), glomerular filtration rate (β = -0.11), and the presence of diabetes (β = 0.12). There were no interactions between HIV status and age (β = -0.03) or between age and diabetes (β = 0.07). However, the interaction between HIV infection and diabetes was significant (β = 0.26). The extent of WMHs was significantly associated with performance on measures of psychomotor speed (β = 0.15).

Conclusion: In today's therapeutic environment, in HIV-infected and HIV seronegative individuals, those factors which affect the cerebrovasculature are the best predictors of WMHs. Diabetes has a specific impact among HIV-infected, but not uninfected, men, suggesting the need for more aggressive treatment even in the prediabetes state, especially as WMHs affect cognitive functions.
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http://dx.doi.org/10.1097/QAD.0000000000001891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082131PMC
August 2018

Neuropsychological phenotypes among men with and without HIV disease in the multicenter AIDS cohort study.

AIDS 2018 07;32(12):1679-1688

Department of Psychiatry, University of Pittsburgh.

Objective: Mild forms of HIV-associated neurocognitive disorder (HAND) remain prevalent in the combination antiretroviral therapy (cART) era. This study's objective was to identify neuropsychological subgroups within the Multicenter AIDS Cohort Study (MACS) based on the participant-based latent structure of cognitive function and to identify factors associated with subgroups.

Design: The MACS is a four-site longitudinal study of the natural and treated history of HIV disease among gay and bisexual men.

Methods: Using neuropsychological domain scores, we used a cluster variable selection algorithm to identify the optimal subset of domains with cluster information. Latent profile analysis was applied using scores from identified domains. Exploratory and posthoc analyses were conducted to identify factors associated with cluster membership and the drivers of the observed associations.

Results: Cluster variable selection identified all domains as containing cluster information except for Working Memory. A three-profile solution produced the best fit for the data. Profile 1 performed below average on all domains, Profile 2 performed average on executive functioning, motor, and speed and below average on learning and memory, Profile 3 performed at or above average across all domains. Several demographic, cognitive, and social factors were associated with profile membership; these associations were driven by differences between Profile 1 and the other profiles.

Conclusion: There is an identifiable pattern of neuropsychological performance among MACS members determined by all domains except Working Memory. Neither HIV nor HIV-related biomarkers were related with cluster membership, consistent with other findings that cognitive performance patterns do not map directly onto HIV serostatus.
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http://dx.doi.org/10.1097/QAD.0000000000001865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082155PMC
July 2018

Impact of glycemic status on longitudinal cognitive performance in men with and without HIV infection.

AIDS 2018 08;32(13):1849-1860

Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University, Baltimore, Maryland, USA.

Objectives: To determine the relationship between glycemic status and cognitive performance in men living with HIV (MLWH) and without HIV infection.

Design: A prospective HIV/AIDS cohort study in four US cities between 1999 and 2016.

Methods: Glycemic status was categorized as normal glucose, impaired fasting glucose, controlled diabetes mellitus and uncontrolled diabetes mellitus at each semiannual visit. Cognitive performance was evaluated using nine neuropsychological tests which measure attention, constructional ability, verbal learning, executive functioning, memory and psychomotor speed. Linear mixed models were used to assess the association between glycemic status and cognition.

Results: Overall, 900 MLWH and 1149 men without HIV were included. MLWH had significantly more person-visits with impaired fasting glucose (52.1 vs. 47.9%) and controlled diabetes mellitus (58.2 vs. 41.8%) than men without HIV (P < 0.05). Compared with men with normal glucose, men with diabetes mellitus had significantly poorer performance on psychomotor speed, executive function and verbal learning (all P < 0.05). There was no difference in cognition by HIV serostatus. The largest effect was observed in individuals with uncontrolled diabetes mellitus throughout the study period, equivalent to 16.5 and 13.4 years of aging on psychomotor speed and executive function, respectively, the effect of which remained significant after adjusting for HIV-related risk factors. Lower CD4+ nadir was also associated with worse cognitive performance.

Conclusion: Abnormalities in glucose metabolism were more common among MLWH than men without HIV and were related to impaired cognitive performance. Metabolic status, along with advanced age and previous immunosuppression, may be important predictors of cognition in the modern antiretroviral therapy era.
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http://dx.doi.org/10.1097/QAD.0000000000001842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731964PMC
August 2018