Assessment of Tau Tangles and Amyloid-β Plaques Among Super Agers Using PET Imaging | Dementia and Cognitive Impairment | JAMA Network Open | JAMA Network
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Figure.  Global and Regional Tau Tangles and Amyloid β Plaques for the Super Ager, Normal Ager, and Mild Cognitive Impairment (MCI) Groups
Global and Regional Tau Tangles and Amyloid β Plaques for the Super Ager, Normal Ager, and Mild Cognitive Impairment (MCI) Groups

A and B, All brain projections represent the contrast of the respective group against the younger healthy cognitively normal group (P < .0001, uncorrected). C and D, Box plots show significant differences between regional standard uptake value ratios (SUVRs) of the 4 groups. Lines within boxes denote medians, tops and bottoms of boxes denote 75th and 25th percentiles, error bars denote 95% CIs, and circles denote outliers. Benjamini Hochberg corrected P value threshold was P ≤ .022 for tau burden and P ≤ .007 for amyloid burden.

aComparison of respective group vs younger healthy control group.

bComparison of super agers vs normal agers.

Table.  Demographic Characteristics of the Studied Groups
Demographic Characteristics of the Studied Groups
1.
Rogalski  E, Gefen  T, Mao  Q,  et al.  Cognitive trajectories and spectrum of neuropathology in superagers: the first 10 cases.   Hippocampus. 2019;29(5):458-467. doi:10.1002/hipo.22828PubMedGoogle ScholarCrossref
2.
Gefen  T, Peterson  M, Papastefan  ST,  et al.  Morphometric and histologic substrates of cingulate integrity in elders with exceptional memory capacity.   J Neurosci. 2015;35(4):1781-1791. doi:10.1523/JNEUROSCI.2998-14.2015PubMedGoogle ScholarCrossref
3.
Dang  C, Yassi  N, Harrington  KD,  et al; AIBL Research Group.  Rates of age- and amyloid β-associated cortical atrophy in older adults with superior memory performance.   Alzheimers Dement (Amst). 2019;11(1):566-575. doi:10.1016/j.dadm.2019.05.005PubMedGoogle ScholarCrossref
4.
Dekhtyar  M, Papp  KV, Buckley  R,  et al.  Neuroimaging markers associated with maintenance of optimal memory performance in late-life.   Neuropsychologia. 2017;100:164-170. doi:10.1016/j.neuropsychologia.2017.04.037PubMedGoogle ScholarCrossref
5.
Crane  PK, Carle  A, Gibbons  LE,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Development and assessment of a composite score for memory in the Alzheimer’s Disease Neuroimaging Initiative (ADNI).   Brain Imaging Behav. 2012;6(4):502-516. doi:10.1007/s11682-012-9186-zPubMedGoogle ScholarCrossref
6.
Benjamini  Y, Hochberg  Y.  Controlling the false discovery rate: a practical and powerful approach to multiple testing.   J Royal Stat Soc. 1995;57(1):289-300.Google Scholar
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    Research Letter
    Neurology
    December 11, 2020

    Assessment of Tau Tangles and Amyloid-β Plaques Among Super Agers Using PET Imaging

    Author Affiliations
    • 1Research Center Juelich, Institute for Neuroscience and Medicine II, Molecular Organization of the Brain, Juelich, Germany
    • 2Department of Nuclear Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
    • 3Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
    • 4German Center for Neurodegenerative Diseases, Bonn, Germany
    JAMA Netw Open. 2020;3(12):e2028337. doi:10.1001/jamanetworkopen.2020.28337
    Introduction

    Little is known about the presence and extent of amyloid-β plaques and tau tangles in individuals who preserve exceptional cognitive function despite advanced age,1 also known as super agers. Although lower expression of these hallmarks of neurodegeneration may be expected in this group,2-4 in vivo evidence of tau tangles in particular is still lacking. Using positron emission tomography (PET) imaging data, we therefore studied the tau tangle and amyloid-β plaque burdens in a super ager (SA) group, normal ager (NA) group, and a patient group with mild cognitive impairment (MCI). Because tau tangles are closely associated with cognitive decline, we hypothesized that the SA group would have fewer tau tangles than the NA and MCI groups.

    Methods

    In this cross-sectional study, we included data (retrieved in June 2019) of 3 age- and education-matched patient groups of 25 SAs, 25 NAs, and 25 patients with MCI, all aged 80 years or older (Table) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. A group of younger amyloid-negative controls (YC group) served as the reference. Ethical approval was obtained by the ADNI investigators at each participating site. All participants provided written informed consent.

    We categorized the SA, NA, and MCI groups according to the ADNI memory score from the ADNI neuropsychological test battery.5 We focused on at least 4 ADNI memory score measurements within a 4-year period leading back from the [18F]AV-1451 PET acquisition. Individuals with a mean ADNI memory z score greater than 1.25 were defined as the SA group, those with a mean z score between 0.5 and 1.25 during the study period were defined as the NA group, and those with a mean z score of less than 0 were defined as the MCI group.

    Regional group differences in tau tangles and amyloid-β plaques were compared between the YC group and the other 3 groups using normalized and intensity-standardized (reference: cerebellum) [18F]AV-1451 (tau) and [18F]AV-45 (amyloid) PET scans in a voxelwise (P < .0001, uncorrected) and a region-of-interest (ROI) approach, including sex as covariate. The ROI approach included 5 meta-ROIs (entorhinal cortex, inferior temporal, middle occipital, precuneus, and orbitofrontal gyrus) and was corrected for multiple comparisons (Bejamini Hochberg correction).6 Statistical testing was 2-sided with P < .05 considered statistically significant and analysis of covariance corrected for sex. Final statistical analysis was performed using SPSS version 25 (IBM Corp) in September 2020.

    Results

    There were 94 participants, including 48 women (51.06%). The mean (SD) age was 85.21 (3.51) years for the SA group, 84.52 (3.49) years for the NA group, 84.77 (3.93) years for the MCI group, and 63.60 (2.76) years for the YC group.

    The results of the voxelwise analysis (Figure, A) yielded no differences in tau tangles and amyloid-β plaques when comparing the SA group with the YC group. In contrast, the NA group presented with higher tau burden in medial temporal regions but no differences in amyloid burden compared with YC group. The MCI group demonstrated both elevated amyloid and tau burden. Significant differences of the ROI analysis surviving multiple comparison correction (Figure, B) accorded with the results of the voxelwise analysis. The NA group had more tau tangles in entorhinal (F1,40 = 19.808; P < .001), inferior temporal (F1,40 = 22.461; P < .001), and orbitofrontal (F1,40 = 5.698; P = .02) regions, and the MCI group presented overall greater pathogenic burden (P = .01) except tau tangles in the orbitofrontal region (F1,40 = 2.128; P = .15) and amyloid plaques in the entorhinal region (F1,40 = 3.484; P = .07) compared with the YC group. Direct comparison of NAs vs SAs yielded significantly higher inferior temporal (F1,45 = 7.45; P = .009) and precuneal (F1,45 = 7.74; P = .008) tau tangles in the NA group.

    Discussion

    The in vivo findings of this cross-sectional study suggest that the phenomenon of super aging may be associated with higher brain resistance against the buildup of both tau tangles and amyloid-β plaques, which could prevent neurodegeneration, as previously hypothesized.1,3 Normal aging, in contrast, appears to be associated with tau tangles but not amyloid plaques, pointing to a role of isolated tau accumulation in age-related cognitive decline, whereas synergistic effects of both proteinopathies seem to accelerate the unsuccessful aging process as seen in MCI.

    A limitation of this study was the small sample size. Despite the small sample size and the cross-sectional design, this study may stimulate future longitudinal assessments in larger, less selective cohorts also examining the role of lifestyle and molecular pathways, to decipher causal factors associated with successful aging. Overall, the characterization of individuals who remain resistant to these aging-associated proteinopathies, may inspire novel concepts for cognitive preservation in older age and therapy of neurodegeneration.

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    Article Information

    Accepted for Publication: October 6, 2020.

    Published: December 11, 2020. doi:10.1001/jamanetworkopen.2020.28337

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Hoenig MC et al. JAMA Network Open.

    Corresponding Author: Merle C. Hoenig, PhD, Research Center Juelich, Institute for Neuroscience and Medicine II, Molecular Organization of the Brain, Wilhelm-Johnen-Straße 1, 52428 Juelich, Germany (m.hoenig@fz-juelich.de).

    Author Contributions: Dr Hoenig had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: All authors.

    Acquisition, analysis, or interpretation of data: Hoenig, Willscheid, van Eimeren, Drzezga.

    Drafting of the manuscript: Hoenig, Willscheid, Drzezga.

    Critical revision of the manuscript for important intellectual content: Hoenig, Bischof, van Eimeren, Drzezga.

    Statistical analysis: Hoenig, Willscheid, Bischof, Drzezga.

    Administrative, technical, or material support: Willscheid, van Eimeren, Drzezga.

    Supervision: Bischof, van Eimeren, Drzezga.

    Conflict of Interest Disclosures: Dr van Eimeren reported receiving consulting and lecture fees from Lundbeck A/S, Lilly Germany, and Shire Germany and research funding from the German Research Foundation (DFG), the Leibniz Association, and the EU-joint program for neurodegenerative disease research (JPND). Dr Drzezga reported receiving research support and speaker honoraria by Life Molecular Imaging, AVID/Lilly Radiopharmaceuticals, Siemens Healthineers, and GE Healthcare. No other disclosures were reported.

    Funding/Support: Dr Bischof received funding from the Alzheimer Forschung Initiative e.V. for the interpretation of the data and review of the manuscript. In addition, this study was supported by the German Research Foundation (DFG, DR 445/9-1) for the analysis and interpretation of the data. Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica Inc; Biogen; Bristol-Myers Squibb Company; CereSpir Inc; Cogstate; Eisai Inc; Elan Pharmaceuticals Inc; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech Inc; Fujirebio; GE Healthcare; IXICO Ltd; Janssen Alzheimer Immunotherapy Research & Development, LLC; Johnson & Johnson Pharmaceutical Research & Development LLC; Lumosity; Lundbeck; Merck & Co Inc; Meso Scale Diagnostics, LLC; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health. The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Alzheimer’s Disease Neuroimaging Initiative: Part A: Leadership and Infrastructure. Principal Investigator: Michael Weiner, MD, University of California (UC) San Francisco. ADCS PI and Director of Coordinating Center Clinical Core: Paul Aisen, MD, UC San Diego. Executive Committee: Michael Weiner, MD, UC San Francisco; Paul Aisen, MD, UC San Diego; Ronald Petersen, MD, PhD, Mayo Clinic, Rochester; Clifford R. Jack Jr, MD, Mayo Clinic, Rochester; William Jagust, MD, UC Berkeley; John Q. Trojanowki, MD, PhD, University of Pennsylvania; Arthur W. Toga, PhD, UCLA; Laurel Beckett, PhD, UC Davis; Robert C. Green, MD, MPH, Brigham and Women’s Hospital/ Harvard Medical School; Andrew J. Saykin, PsyD, Indiana University; John Morris, MD, Washington University St Louis. ADNI 2 Private Partner Scientific Board (PPSB) Chair: Enchi Liu, PhD, Janssen Alzheimer Immunotherapy. Data and Publication Committee (DPC): Robert C. Green, MD, MPH, Brigham and Women’s Hospital/Harvard Medical School (Chair). Resource Allocation Review Committee: Tom Montine, MD, PhD, University of Washington (Chair). Clinical Core Leaders: Ronald Petersen, MD, PhD, Mayo Clinic, Rochester (Core PI); Paul Aisen, MD, UC San Diego. Clinical Informatics and Operations: Anthony Gamst, PhD, UC San Diego; Ronald G. Thomas, PhD, UC San Diego; Michael Donohue, PhD, UC San Diego; Sarah Walter, MSc, UC San Diego; Devon Gessert, UC San Diego; Tamie Sather, UC San Diego. Biostatistics Core Leaders and Key Personnel: Laurel Beckett, PhD, UC Davis (Core PI); Danielle Harvey, PhD, UC Davis; Anthony Gamst, PhD, UC San Diego; Michael Donohue, PhD, UC San Diego; John Kornak, PhD, UC Davis. MRI Core Leaders and Key Personnel: Clifford R. Jack Jr, MD, Mayo Clinic, Rochester (Core PI); Anders Dale, PhD, UC San Diego; Matthew Bernstein, PhD, Mayo Clinic, Rochester; Joel Felmlee, PhD, Mayo Clinic, Rochester; Nick Fox, MD, University of London; Paul Thompson, PhD, UCLA School of Medicine; Norbert Schuff, PhD, UCSF MRI; Gene Alexander, PhD, Banner Alzheimer’s Institute; Charles DeCarli, MD, UC Davis. PET Core Leaders and Key Personnel: William Jagust, MD, UC Berkeley (Core PI); Dan Bandy, MS, CNMT, Banner Alzheimer’s Institute; Robert A. Koeppe, PhD, University of Michigan; Norm Foster, MD, University of Utah; Eric M. Reiman, MD, Banner Alzheimer’s Institute; Kewei Chen, PhD, Banner Alzheimer’s Institute; Chet Mathis, MD, University of Pittsburgh. Neuropathology Core Leaders: John Morris, MD, Washington University St Louis; Nigel J. Cairns, PhD, Washington University St Louis; Lisa Taylor-Reinwald, BA, HTL, Washington University St Louis (ASCP). Biomarkers Core Leaders and Key Personnel: J. Q. Trojanowki, MD, PhD, University of Pennsylvania (UPenn) School of Medicine (Core PI); Les Shaw, PhD, UPenn School of Medicine Virginia; M. Y. Lee, PhD, MBA, UPenn School of Medicine; Magdalena Korecka, PhD, UPenn School of Medicine. Informatics Core Leaders and Key Personnel: Arthur W. Toga, PhD, UCLA (Core PI); Karen Crawford, UCLA; Scott Neu, PhD, UCLA. Genetics Core Leaders and Key Personnel: Andrew J. Saykin, PsyD, Indiana University; Tatiana M. Foroud, PhD, Indiana University; Steven Potkin, MD, UC, UC Irvine; Li Shen, PhD, Indiana University. Early Project Development: Zaven Kachaturian, PhD, Khachaturian, Radebaugh & Associates (KRA) Inc, Alzheimer's Association's Ronald and Nancy Reagan's Research Institute; Richard Frank, MD, PhD, General Electric; Peter J. Snyder, PhD, University of Connecticut. NIA: Susan Molchan, PhD, National Institute on Aging, National Institutes of Health.

    Part B: Investigators by Site: FULL ADNI Investigator Lists. Oregon Health and Science University: Jeffrey Kaye, MD; Joseph Quinn, MD; Betty Lind, BS; Sara Dolen, BS – Past Investigator. University of Southern California: Lon S. Schneider, MD; Sonia Pawluczyk, MD; Bryan M. Spann, DO, PhD. University of California, San Diego: James Brewer, MD, PhD; Helen Vanderswag, RN. University of Michigan: Judith L. Heidebrink, MD, MS; Joanne L. Lord, LPN, BA, CCRC. Mayo Clinic, Rochester: Ronald Petersen, MD, PhD; Kris Johnson, RN. Baylor College of Medicine: Rachelle S. Doody, MD, PhD; Javier Villanueva-Meyer, MD; Munir Chowdhury, MBBS, MS. Columbia University Medical Center: Yaakov Stern, PhD; Lawrence S. Honig, MD, PhD; Karen L. Bell, MD. Washington University, St Louis: John C. Morris, MD; Beau Ances, MD; Maria Carroll, RN, MSN; Sue Leon, RN, MSN; Mark A. Mintun, MD – Past Investigator; Stacy Schneider, APRN, BC, GNP – Past Investigator. University of Alabama - Birmingham: Daniel Marson, JD, PhD; Randall Griffith, PhD, ABPP; David Clark, MD. Mount Sinai School of Medicine: Hillel Grossman, MD; Effie Mitsis, PhD; Aliza Romirowsky, BA. Rush University Medical Center: Leyla deToledo-Morrell, PhD; Raj C. Shah, MD. Wein Center: Ranjan Duara, MD; Daniel Varon, MD; Peggy Roberts, CNA. Johns Hopkins University: Marilyn Albert; Chiadi Onyike; Stephanie Kielb. New York University: Henry Rusinek, PhD; Mony J de Leon, EdD; Lidia Glodzik, MD, PhD. Duke University Medical Center: P. Murali Doraiswamy, MD; Jeffrey R. Petrella, MD; R. Edward Coleman, MD. University of Pennsylvania: Steven E. Arnold, MD; Jason H. Karlawish, MD; David Wolk, MD. University of Kentucky: Charles D. Smith, MD; Greg Jicha, MD; Peter Hardy, PhD. University of Pittsburgh: Oscar L. Lopez, MD; MaryAnn Oakley, MA; Donna M. Simpson, CRNP, MPH. University of Rochester Medical Center: Anton P. Porsteinsson, MD; Bonnie S. Goldstein, MS, NP; Kim Martin, RN; Kelly M. Makino, BS – Past Investigator; M. Saleem Ismail, MD – Past Investigator; Connie Brand, RN – Past Investigator. University of California, Irvine: Ruth A. Mulnard, DNSc, RN, Gaby Thai, MD; Catherine Mc-Adams-Ortiz, MSN, RN, A/GNP. University of Texas Southwestern Medical School: Ramon Diaz-Arrastia, MD, PhD; Kristen Martin-Cook, MA; Michael DeVous, PhD. Emory University: Allan I. Levey, MD, PhD; James J. Lah, MD, PhD; Janet S. Cellar, DNP, PMHCNS-BC. University of Kansas, Medical Center: Jeffrey M. Burns, MD; Heather S. Anderson, MD; Russell H. Swerdlow, MD. University of California, Los Angeles: Liana Apostolova, MD; Po H. Lu, PsyD; George Bartzokis, MD – Past Investigator; Daniel H. S. Silverman, MD, PhD – Past Investigator. Mayo Clinic, Jacksonville: Neill R Graff-Radford, MBBCH (London); Francine Parfitt, MSH, CCRC; Heather Johnson, MLS, CCRP. Indiana University: Martin Farlow, MD; Scott Herring, RN; Ann M. Hake, MD. Yale University School of Medicine: Christopher H. van Dyck, MD; Richard E. Carson, PhD; Martha G. MacAvoy, PhD. McGill Univ, Montreal-Jewish General Hospital: Howard Chertkow, MD; Howard Bergman, MD; Chris Hosein, MEd. Sunnybrook Health Sciences, Ontario: Sandra Black, MD; Dr Bojana Stefanovic Curtis Caldwell, PhD. U.B.C. Clinic for AD & Related Disorders: Ging-Yuek Robin Hsiung, MD, MHSc; Howard Feldman, MD; Michele Assaly, MA. Cognitive Neurology - St Joseph's, Ontario: Andrew Kertesz, MD; John Rogers, MD; Dick Trost, PhD. Cleveland Clinic Lou Ruvo Center for Brain Health: Charles Bernick, MD; Donna Munic, PhD. Northwestern University: Diana Kerwin, MD; Marek-Marsel Mesulam, MD; Kristina Lipowski, BA; Chuang-Kuo Wu, MD, PhD – Past Investigator; Nancy Johnson, PhD – Past Investigator. Premiere Research Inst (Palm Beach Neurology): Carl Sadowsky, MD; Walter Martinez, MD; Teresa Villena, MD. Georgetown University Medical Center: Raymond Scott Turner, MD, PhD; Kathleen Johnson, NP; Brigid Reynolds, NP. Brigham and Women's Hospital: Reisa A. Sperling, MD; Keith A. Johnson, MD; Gad Marshall, MD; Meghan Frey – Past Investigator. Stanford University: Allyson Rosen, PhD; Jared Tinklenberg, MD. Banner Sun Health Research Institute: Marwan Sabbagh, MD, CCRI; Christine Belden, PsyD; Sandra Jacobson, MD. Boston University: Neil Kowall, MD; Ronald Killiany, PhD; Andrew E. Budson, MD; Alexander Norbash, MD – Past Investigator; Patricia Lynn Johnson, BA – Past Investigator. Howard University: Thomas O. Obisesan, MD, MPH; Saba Wolday, MSc; Salome K. Bwayo, PharmD – Past Investigator. Case Western Reserve University: Alan Lerner, MD; Leon Hudson, MPH; Paula Ogrocki, PhD. University of California, Davis – Sacramento: Evan Fletcher, PhD; Owen Carmichael, PhD; John Olichney, MD; Charles DeCarli, MD – Past Investigator. Neurological Care of CNY: Smita Kittur, MD. Parkwood Hospital: Michael Borrie, MD; T-Y. Lee, PhD; Dr Rob Bartha, PhD. University of Wisconsin: Sterling Johnson, PhD; Sanjay Asthana, MD; Cynthia M. Carlsson, MD. University of California, Irvine - BIC: Steven G. Potkin, MD; Adrian Preda, MD; Dana Nguyen, PhD. Banner Alzheimer's Institute: Pierre Tariot, MD; Adam Fleisher, MD; Stephanie Reeder, BA. Dent Neurologic Institute: Vernice Bates, MD; Horacio Capote, MD; Michelle Rainka, PhD; Barry A. Hendin, MD. Ohio State University: Douglas W. Scharre, MD; Maria Kataki, MD, PhD. Albany Medical College: Earl A. Zimmerman, MD; Dzintra Celmins, MD; Alice D. Brown – Past Investigator. Hartford Hosp, Olin Neuropsychiatry Research Center: Godfrey D. Pearlson, MD; Karen Blank, MD; Karen Anderson, RN. Dartmouth-Hitchcock Medical Center: Andrew J. Saykin, PsyD; Robert B. Santulli, MD; Eben S. Schwartz, PhD. Wake Forest University Health Sciences: Kaycee M. Sink, MD, MAS; Jeff D. Williamson, MD, MHS; Pradeep Garg, PhD; Franklin Watkins, MD – Past Investigator. Rhode Island Hospital: Brian R. Ott, MD; Henry Querfurth, MD; Geoffrey Tremont, PhD. Butler Hospital: Stephen Salloway, MD, MS; Paul Malloy, PhD; Stephen Correia, PhD. UC San Francisco: Howard J. Rosen, MD; Bruce L. Miller, MD. Medical University South Carolina: Jacobo Mintzer, MD, MBA; Crystal Flynn Longmire, PhD; Kenneth Spicer, MD, PhD.

    Additional Information: Data used in preparation of this article were obtained from the ADNI database (http://adni.loni.usc.edu/). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at http://adni.loni.usc.edu/wpcontent/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

    References
    1.
    Rogalski  E, Gefen  T, Mao  Q,  et al.  Cognitive trajectories and spectrum of neuropathology in superagers: the first 10 cases.   Hippocampus. 2019;29(5):458-467. doi:10.1002/hipo.22828PubMedGoogle ScholarCrossref
    2.
    Gefen  T, Peterson  M, Papastefan  ST,  et al.  Morphometric and histologic substrates of cingulate integrity in elders with exceptional memory capacity.   J Neurosci. 2015;35(4):1781-1791. doi:10.1523/JNEUROSCI.2998-14.2015PubMedGoogle ScholarCrossref
    3.
    Dang  C, Yassi  N, Harrington  KD,  et al; AIBL Research Group.  Rates of age- and amyloid β-associated cortical atrophy in older adults with superior memory performance.   Alzheimers Dement (Amst). 2019;11(1):566-575. doi:10.1016/j.dadm.2019.05.005PubMedGoogle ScholarCrossref
    4.
    Dekhtyar  M, Papp  KV, Buckley  R,  et al.  Neuroimaging markers associated with maintenance of optimal memory performance in late-life.   Neuropsychologia. 2017;100:164-170. doi:10.1016/j.neuropsychologia.2017.04.037PubMedGoogle ScholarCrossref
    5.
    Crane  PK, Carle  A, Gibbons  LE,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Development and assessment of a composite score for memory in the Alzheimer’s Disease Neuroimaging Initiative (ADNI).   Brain Imaging Behav. 2012;6(4):502-516. doi:10.1007/s11682-012-9186-zPubMedGoogle ScholarCrossref
    6.
    Benjamini  Y, Hochberg  Y.  Controlling the false discovery rate: a practical and powerful approach to multiple testing.   J Royal Stat Soc. 1995;57(1):289-300.Google Scholar
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