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

  • Mikhail Popov
  • Samantha A. Molsberry
  • Fabrizio Lecci
  • Brian Junker
  • Lawrence A. Kingsley
  • Andrew Levine
  • Eileen Martin
  • Eric Miller
  • Cynthia A. Munro
  • Ann Ragin
  • Eric Seaberg
  • Ned Sacktor
  • James T. BeckerEmail author


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.


HIV Dementia Multiple imputation Brain structure Mixed membership trajectory 



The preparation of this manuscript and the collection of the MRI data were supported in part by funds from the NIH to J.T.B. (AG034852 and MH098745).

Data in this manuscript were collected by the Multicenter AIDS Cohort Study (MACS) with centers at Baltimore (U01-AI35042): The Johns Hopkins University Bloomberg School of Public Health: Joseph B. Margolick (PI), Jay Bream, Todd Brown, Adrian Dobs, Michelle Estrella, W. David Hardy, Lisette Johnson-Hill, Sean Leng, Anne Monroe, Cynthia Munro, Michael W. Plankey, Wendy Post, Ned Sacktor, Jennifer Schrack, Chloe Thio; Chicago (U01-AI35039): Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health Services: Steven M. Wolinsky (PI), Sheila Badri, Dana Gabuzda, Frank J. Palella, Jr., Sudhir Penugonda, John P. Phair, Susheel Reddy, Matthew Stephens, Linda Teplin; Los Angeles (U01-AI35040): University of California, UCLA Schools of Public Health and Medicine: Roger Detels (PI), Otoniel Martínez-Maza (PI), Peter Anton, Robert Bolan, Elizabeth Breen, Anthony Butch, Shehnaz Hussain, Beth Jamieson, John Oishi, Harry Vinters, Dorothy Wiley, Mallory Witt, Otto Yang, Stephen Young, Zuo Feng Zhang; Pittsburgh (U01-AI35041): University of Pittsburgh, Graduate School of Public Health: Charles R. Rinaldo (PI), James T. Becker, Phalguni Gupta, Kenneth Ho, Lawrence A. Kingsley, Susan Koletar, Jeremy J. Martinson, John W. Mellors, Anthony J. Silvestre, Ronald D. Stall; Data Coordinating Center (UM1-AI35043): The Johns Hopkins University Bloomberg School of Public Health: Lisa P. Jacobson (PI), Gypsyamber D’Souza (PI), Alison Abraham, Keri Althoff, Michael Collaco, Priya Duggal, Sabina Haberlen, Eithne Keelaghan, Heather McKay, Alvaro Muñoz, Derek Ng, Anne Rostich, Eric C. Seaberg, Sol Su, Pamela Surkan, Nicholas Wada. Institute of Allergy and Infectious Diseases: Robin E. Huebner; National Cancer Institute: Geraldina Dominguez. The MACS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional co-funding from the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH). Targeted supplemental funding for specific projects was also provided by the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute on Deafness and Communication Disorders (NIDCD). MACS data collection is also supported by UL1-TR001079 (JHU ICTR) from the National Center for Advancing Translational Sciences (NCATS) a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH), Johns Hopkins ICTR, or NCATS. The MACS website is located at

The members of the Neuropsychology Working Group include Francine Barrington, James T. Becker, Pim Brouwers, Velpandi Ayyavoo, Karl Goodkin, Robin Huebner, Eithne Keelaghan, Andrew J. Levine, Eileen M. Martin, Cynthia Munro, Ann Ragin, Leah Rubin, Ned Sacktor, Eric Seaberg, and Carlie Williams.


AG034852, MH098745, U01-AI35042, U01-AI35039, U01-AI35040, UM1-AI35043, U01-AI35041

Compliance with ethical standards

Conflict of interest


Ethical approval

This research was reviewed and approved by the Institutional Review Boards at all four MACS clinic sites – Johns Hopkins University, Northwestern University, University of California Los Angeles, and the University of Pittsburgh.

Informed consent

Each participant signed a written statement of informed consent prior to starting any research-related activities.


Eric N. Miller is the author of the reaction time software used in this study (CalCAP) and has a financial interest in the software.

Supplementary material

11682_2018_26_MOESM1_ESM.doc (310 kb)
ESM 1 (DOC 309 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Mikhail Popov
    • 1
    • 2
  • Samantha A. Molsberry
    • 1
    • 3
  • Fabrizio Lecci
    • 4
    • 5
  • Brian Junker
    • 4
  • Lawrence A. Kingsley
    • 6
  • Andrew Levine
    • 7
  • Eileen Martin
    • 8
  • Eric Miller
    • 9
  • Cynthia A. Munro
    • 10
    • 11
  • Ann Ragin
    • 12
  • Eric Seaberg
    • 13
  • Ned Sacktor
    • 11
  • James T. Becker
    • 1
    • 14
    • 15
    Email author return OK on get
  1. 1.Department of PsychiatryUniversity of PittsburghPittsburghUSA
  2. 2.Wikimedia FoundationSan FranciscoUSA
  3. 3.Population Health SciencesHarvard UniversityCambridgeUSA
  4. 4.Department of StatisticsCarnegie Mellon UniversityPittsburghUSA
  5. 5.UberNew YorkUSA
  6. 6.Department of Infectious Diseases and MicrobiologyUniversity of PittsburghPittsburghUSA
  7. 7.Department of NeurologyUniversity of California Los AngelesLos AngelesUSA
  8. 8.Department of PsychiatryRush Medical SchoolChicagoUSA
  9. 9.Department of PsychiatryUniversity of California Los AngelesLos AngelesUSA
  10. 10.Department of PsychiatryThe Johns Hopkins University School of MedicineBaltimoreUSA
  11. 11.Department of NeurologyThe Johns Hopkins University School of MedicineBaltimoreUSA
  12. 12.Department of RadiologyNorthwestern UniversityEvanstonUSA
  13. 13.Department of EpidemiologyThe Johns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  14. 14.Department of NeurologyUniversity of PittsburghPittsburghUSA
  15. 15.Department of PsychologyUniversity of PittsburghPittsburghUSA

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