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Regional Amyloid-β Load and White Matter Abnormalities Contribute to Hypometabolism in Alzheimer’s Dementia

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Abstract

We investigated the association between amyloid-β deposition and white matter (WM) integrity as a determinant of brain glucose hypometabolism across the Alzheimer’s disease (AD) spectrum. We assessed ninety-six subjects (27 cognitively normal, 49 mild cognitive impairment, and 20 AD dementia) who underwent [18F]FDG and [18F]Florbetapir positron emission tomography (PET) as well as magnetic resonance imaging (MRI) with diffusion tensor imaging. Among the regions with reduced fractional anisotropy (FA) in the AD group, we selected a voxel of interest in the angular bundle bilaterally for subsequent analyses. Using voxel-based interaction models at voxel level, we tested whether the regional hypometabolism is associated with FA in the angular bundle and regional amyloid-β deposition. In the AD patients, [18F]FDG hypometabolism in the striatum, mesiobasal temporal, orbitofrontal, precuneus, and cingulate cortices were associated with the interaction between high levels of [18F]Florbetapir standard uptake value ratios (SUVR) in these regions and low FA in the angular bundle. We found that the interaction between, rather than the independent effects of, high levels of amyloid-β deposition and WM integrity disruption determined limbic hypometabolism in patients with AD. This finding highlights a more integrative model for AD, where the interaction between partially independent processes determines the glucose hypometabolism.

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Abbreviations

AD:

Alzheimer’s disease

ADNI:

Alzheimer’s disease neuroimaging initiative

CDR:

clinical dementia rating

CN:

cognitive normal

FA:

fractional anisotropy

LAB:

left angular bundle

[18F]FDG:

[18F]fluorodeoxyglucose

MCI:

mild cognitive impairment

MMSE:

mini-mental state examination

MRI:

magnetic resonance imaging

RAB:

right angular bundle

SD:

standard deviation

SUVR:

standardized uptake value ratio

VOI:

voxel of interest; WM white matter

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Acknowledgments

Consortia

Alzheimer’s Disease Neuroimaging Initiative Group:

Michael W. Weiner5, Paul Aisen6, Ronald Petersen7, Clifford R. Jack, Jr.8, William Jagust9, John Q. Trojanowki10, Arthur W. Toga11, Laurel Beckett12, Robert C. Green13, Andrew J. Saykin14, John Morris15, Leslie M. Shaw15, Jeffrey Kaye16, Joseph Quinn16, Lisa Silbert16, Betty Lind16, Raina Carter16, Sara Dolen16, Lon S. Schneider11, Sonia Pawluczyk11, Mauricio Beccera11, Liberty Teodoro11, Bryan M. Spann11, James Brewer17, Helen Vanderswag17, Adam Fleisher17, Judith L. Heidebrink18, Joanne L. Lord18, Sara S. Mason8, Colleen S. Albers8, David Knopman8, Kris Johnson8, Rachelle S. Doody19, Javier Villanueva-Meyer19, Munir Chowdhury19, Susan Rountree19, Mimi Dang19, Yaakov Stern20, Lawrence S. Honig20, Karen L. Bell20, Beau Ances15, John C. Morris15, Maria Carroll15, Mary L. Creech15, Erin Franklin15, Mark A. Mintun15, Stacy Schneider15, Angela Oliver15, Daniel Marson21, Randall Griffith21, David Clark21, David Geldmacher21, John Brockington21, Erik Roberson21, Marissa Natelson Love21, Hillel Grossman22, Effie Mitsis22, Raj C. Shah23, Leyla deToledo-Morrell23, Ranjan Duara24, Daniel Varon24, Maria T. Greig24, Peggy Roberts24, Marilyn Albert25, Chiadi Onyike25, Daniel D’Agostino25, Stephanie Kielb25, James E. Galvin26, Brittany Cerbone26, Christina A. Michel26, Dana M. Pogorelec26, Henry Rusinek26, Mony J de Leon26, Lidia Glodzik26, Susan De Santi26, P. Murali Doraiswamy27, Jeffrey R. Petrella27, Salvador Borges-Neto27, Terence Z. Wong27, Edward Coleman27, Charles D. Smith28, Greg Jicha28, Peter Hardy28, Partha Sinha28, Elizabeth Oates28, Gary Conrad28, Anton P. Porsteinsson29, Bonnie S. Goldstein29, Kim Martin29, Kelly M. Makino29, M. Saleem Ismail29, Connie Brand29, Ruth A. Mulnard30, Gaby Thai30, Catherine Mc-Adams-Ortiz30, Kyle Womack31, Dana Mathews31, Mary Quiceno31, Allan I. Levey32, James J. Lah32, Janet S. Cellar32, Jeffrey M. Burns33, Russell H. Swerdlow33, William M. Brooks33, Liana Apostolova34, Kathleen Tingus34, Ellen Woo34, Daniel H.S. Silverman34, Po H. Lu34, George Bartzokis34, Neill R Graff-Radford35, Francine Parfitt35, Tracy Kendall35, Heather Johnson35, Martin R. Farlow14, Ann Marie Hake14, Brandy R. Matthews14, Jared R. Brosch14, Scott Herring14, Cynthia Hunt14, Christopher H. van Dyck36, Richard E. Carson36, Martha G. MacAvoy36, Pradeep Varma36, Howard Chertkow37, Howard Bergman37, Chris Hosein37, Sandra Black38, Bojana Stefanovic38, Curtis Caldwell38, Ging-Yuek Robin Hsiung39, Howard Feldman39, Benita Mudge39, Michele Assaly39, Elizabeth Finger40, Stephen Pasternack40, Irina Rachisky40, Dick Trost40, Andrew Kertesz40, Charles Bernick41, Donna Munic41, Marek-Marsel Mesulam42, Kristine Lipowski42, Sandra Weintraub42, Borna Bonakdarpour42, Diana Kerwin42, Chuang-Kuo Wu42, Nancy Johnson42, Carl Sadowsky43, Teresa Villena43, Raymond Scott Turner44, Kathleen Johnson44, Brigid Reynolds44, Reisa A. Sperling45, Keith A. Johnson45, Gad Marshall45, Jerome Yesavage46, Joy L. Taylor46, Barton Lane46, Allyson Rosen46, Jared Tinklenberg46, Marwan N. Sabbagh47, Christine M. Belden47, Sandra A. Jacobson47, Sherye A. Sirrel47, Neil Kowall48, Ronald Killiany48, Andrew E. Budson48, Alexander Norbash48, Patricia Lynn Johnson48, Thomas O. Obisesan49, Saba Wolday49, Joanne Allard49, Alan Lerner50, Paula Ogrocki50, Curtis Tatsuoka50, Parianne Fatica50, Evan Fletcher51, Pauline Maillard51, John Olichney51, Charles DeCarli51, Owen Carmichael51, Smita Kittur52, Michael Borrie53, T-Y Lee53, Rob Bartha53, Sterling Johnson54, Sanjay Asthana54, Cynthia M. Carlsson54, Steven G. Potkin55, Adrian Preda55, Dana Nguyen55, Pierre Tariot56, Anna Burke56, Nadira Trncic56, Adam Fleisher56, Stephanie Reeder56, Vernice Bates57, Horacio Capote57, Michelle Rainka57, Douglas W. Scharre58, Maria Kataki58, Anahita Adeli58, Earl A. Zimmerman59, Dzintra Celmins59, Alice D. Brown59, Godfrey D. Pearlson60, Karen Blank60, Karen Anderson60, Laura A. Flashman61, Marc Seltzer61, Mary L. Hynes61, Robert B. Santulli61, Kaycee M. Sink62, Leslie Gordineer62, Jeff D. Williamson62, Pradeep Garg62, Franklin Watkins62, Brian R. Ott63, Henry Querfurth63, Geoffrey Tremont63, Stephen Salloway64, Paul Malloy64, Stephen Correia64, Howard J. Rosen65, Bruce L. Miller65, David Perry65, Jacobo Mintzer66, Kenneth Spicer66, David Bachman66, Nunzio Pomara67, Raymundo Hernando67, Antero Sarrael67, Norman Relkin67, Gloria Chaing68, Michael Lin68, Lisa Ravdin68, Amanda Smith69, Balebail Ashok Raj69, Kristin Fargher69.

5Magnetic Resonance Unit at the VA Medical Center and Radiology, Medicine, Psychiatry and Neurology, University of California, San Francisco, USA. 6San Diego School of Medicine, University of California, California, USA. 7Mayo Clinic, Minnesota, USA. 8Mayo Clinic, Rochester, USA. 9University of California, Berkeley, USA. 10University of Pennsylvania, Pennsylvania, USA. 11University of Southern California, California, USA. 12University of California, Davis, California, USA. 13MPH Brigham and Women’s Hospital/Harvard Medical School; Massachusetts, USA.14Indiana University, Indiana, USA. 15Washington University St. Louis, Missouri, USA. 16Oregon Health and Science University, Oregon, USA. 17University of California--San Diego, California, USA. 18University of Michigan, Michigan, USA. 19Baylor College of Medicine, Houston, State of Texas, USA. 20Columbia University Medical Center, South Carolina, USA. 21University of Alabama – Birmingham, Alabama, USA. 22Mount Sinai School of Medicine, New York, USA. 23Rush University Medical Center, Rush University, Illinois, USA. 24Wien Center, Florida, USA. 25Johns.

Hopkins University, Maryland, USA. 26New York University, NY, USA. 27Duke University Medical Center, North Carolina, USA. 28University of Kentucky, Kentucky, USA. 29University of Rochester Medical Center, NY, USA. 30University of California, Irvine, California, USA. 31University of Texas Southwestern Medical School, Texas, USA. 32Emory University, Georgia, USA. 33University of Kansas, Medical Center, Kansas, USA. 34University of California, Los Angeles, California, USA. 35Mayo Clinic, Jacksonville, USA. 36Yale University School of Medicine, Connecticut, USA. 37McGill University, Montreal-Jewish General Hospital, Canada. 38Sunnybrook Health Sciences, Ontario, USA. 39U.B.C. Clinic for AD & Related Disorders, Canada. 40Cognitive Neurology - St. Joseph’s, Ontario, USA. 41Cleveland Clinic Lou Ruvo Center for Brain Health, Ohio, USA. 42Northwestern University, USA. 43Premiere Research Inst (Palm Beach Neurology), USA. 44Georgetown University Medical Center, Washington D.C, USA. 45Brigham and Women’s Hospital, Massachusetts, USA. 46Stanford University, California, USA. 47Banner Sun Health Research Institute, USA. 48Boston University, Massachusetts, USA.49Howard University, Washington D.C, USA. 50Case Western Reserve University, Ohio, USA. 51University of California, Davis – Sacramento, California, USA. 52Neurological Care of CNY, USA. 53Parkwood Hospital, Pennsylvania, USA. 54University of Wisconsin, Wisconsin, USA. 55University of California, Irvine – BIC, USA. 56Banner Alzheimer’s Institute, USA. 57Dent Neurologic Institute, NY, USA. 58Ohio State University, Ohio, USA. 59Albany Medical College, NY, USA. 60Hartford Hospital, Olin Neuropsychiatry Research Center, Connecticut, USA. 61Dartmouth-Hitchcock Medical Center, New Hampshire, USA. 62Wake Forest University Health Sciences, North Carolina, USA. 63Rhode Island Hospital, state of Rhode Island, USA. 64Butler Hospital, Providence, Rhode Island, USA. 65University of California, San Francisco, USA. 66Medical University South Carolina, USA. 67Nathan Kline Institute, Orangeburg, New York, USA. 68Cornell University, Ithaca, New York, USA. 69USF Health Byrd Alzheimer’s Institute, University of South Florida, USA.

Author information

Authors and Affiliations

  1. Translational Neuroimaging Laboratory (TNL), McGill Center for Studies in Aging (MCSA), Douglas Mental Health Research Institute, 6825, boul. LaSalle Blvd., Montréal, QC, H4H1R3, Canada

    Lucas Porcello Schilling, Tharick A. Pascoal, Eduardo R. Zimmer, Sulantha Mathotaarachchi, Monica Shin, Serge Gauthier & Pedro Rosa-Neto

  2. Alzheimer’s Disease Research Unit, MCSA, Douglas Mental Health Research Institute, Montréal, Canada

    Lucas Porcello Schilling, Tharick A. Pascoal, Eduardo R. Zimmer, Serge Gauthier & Pedro Rosa-Neto

  3. Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil

    Lucas Porcello Schilling, Eduardo R. Zimmer, Carlos Roberto de Mello Rieder & André Palmini

  4. Department of Pharmacology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil

    Eduardo R. Zimmer

  5. Graduate Program in Biological Science: Biochemistry, UFRGS, Porto Alegre, Brazil

    Eduardo R. Zimmer

  6. Graduate Program in Biological Sciences: Pharmacology and Therapeutics, UFRGS, Porto Alegre, Brazil

    Eduardo R. Zimmer

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  1. Lucas Porcello Schilling
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  2. Tharick A. Pascoal
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  3. Eduardo R. Zimmer
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  5. Monica Shin
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  7. Serge Gauthier
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  8. André Palmini
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  9. Pedro Rosa-Neto
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Consortia

for the Alzheimer’s Disease Neuroimaging Initiative

  • Michael W. Weiner
  • , Paul Aisen
  • , Ronald Petersen
  • , Ronald Clifford R. Jack Jr
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  • , Robert C. Green
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  • , Maria Carroll
  • , Mary L. Creech
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  • , Jeffrey R. Petrella
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  • , Edward Coleman
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  • , Peter Hardy
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  • , Elizabeth Oates
  • , Gary Conrad
  • , Anton P. Porsteinsson
  • , Bonnie S. Goldstein
  • , Kim Martin
  • , Kelly M. Makino
  • , M. Saleem Ismail
  • , Connie Brand
  • , Ruth A. Mulnard
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  • , Catherine Mc-Adams-Ortiz
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  • , Michael Borrie
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  • , Nadira Trncic
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  • , Horacio Capote
  • , Michelle Rainka
  • , Douglas W. Scharre
  • , Maria Kataki
  • , Anahita Adeli
  • , Earl A. Zimmerman
  • , Dzintra Celmins
  • , Alice D. Brown
  • , Godfrey D. Pearlson
  • , Karen Blank
  • , Karen Anderson
  • , Laura A. Flashman
  • , Marc Seltzer
  • , Mary L. Hynes
  • , Robert B. Santulli
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Contributions

L.P.S., T.A.P., C.R.M.R., S.G., A.P., and P.R-N. performed the conception of the study. L.P.S., T.A.P., E.R.Z., S.M., and M.S. performed the processing and the quality control of the image data. L.P.S., T.A.P., S.M., and P.R-N. analyzed and interpreted the data. L.P.S., T.A.P., E.R.Z., C.R.M.R., A.P., and P.R-N. prepared the figures, the table, and drafted the manuscript.

Corresponding author

Correspondence to Pedro Rosa-Neto.

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Conflict of interest

The authors declare that they have no conflict of interest.

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Schilling, L.P., Pascoal, T.A., Zimmer, E.R. et al. Regional Amyloid-β Load and White Matter Abnormalities Contribute to Hypometabolism in Alzheimer’s Dementia. Mol Neurobiol 56, 4916–4924 (2019). https://doi.org/10.1007/s12035-018-1405-1

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  • DOI: https://doi.org/10.1007/s12035-018-1405-1

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