Evidence map›Paper›PMID 34259858›Full record

ArticleBrain : a journal of neurology2021

Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe.

Paul A Yushkevich, Mónica Muñoz López, María Mercedes Iñiguez de Onzoño Martin, Ranjit Ittyerah, Sydney Lim, Sadhana Ravikumar, Madigan L Bedard, Stephen Pickup, Weixia Liu, Jiancong Wang and 30 more

Open access · bronzeAbstract read
In one paragraph

Article in Brain : a journal of neurology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.

0numbers the graph read from it
0cells of the map it votes in
58citing papers in PubMed
8.0field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

58 citing papers in PubMed, 80 citations in OpenAlex.

  1. Using CA1 rather than the whole hippocampus to capture tau-PET Braak stage II.European journal of nuclear medicine and molecular imaging · 2026
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  8. [Progress on prognostic assessment methods for mild cognitive impairment].Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2026
    Review
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  16. Brain and retina in Alzheimer's disease: Pathological intersections and estimates from imaging.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Review
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  19. Article
  20. Impact of amygdala functional connectivity on cognitive impairment in Alzheimer's disease.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025
    Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

40 authors at 4 institutions in 4 countries.

Paul A YushkevichDepartment of Radiology, University of Pennsylvania, Philadelphia, USA.ORCID 0000-0001-8543-4016
Mónica Muñoz LópezHuman Neuroanatomy Laboratory, Neuromax CSIC Associated Unit, University of Castilla-La Mancha, Albacete, Spain.
María Mercedes Iñiguez de Onzoño MartinHuman Neuroanatomy Laboratory, Neuromax CSIC Associated Unit, University of Castilla-La Mancha, Albacete, Spain.
Ranjit IttyerahDepartment of Radiology, University of Pennsylvania, Philadelphia, USA.
Sydney LimDepartment of Radiology, University of Pennsylvania, Philadelphia, USA.
Sadhana RavikumarDepartment of Radiology, University of Pennsylvania, Philadelphia, USA.ORCID 0000-0002-9858-4731
Madigan L BedardDepartment of Radiology, University of Pennsylvania, Philadelphia, USA.ORCID 0000-0001-6731-0853
Stephen PickupDepartment of Radiology, University of Pennsylvania, Philadelphia, USA.
Weixia LiuDepartment of Radiology, University of Pennsylvania, Philadelphia, USA.
Jiancong WangDepartment of Radiology, University of Pennsylvania, Philadelphia, USA.
Ling Yu HungDepartment of Radiology, University of Pennsylvania, Philadelphia, USA.
Jade LasserveDepartment of Radiology, University of Pennsylvania, Philadelphia, USA.
Nicolas VergnetDepartment of Radiology, University of Pennsylvania, Philadelphia, USA.
Long XieDepartment of Radiology, University of Pennsylvania, Philadelphia, USA.
Mengjin DongDepartment of Radiology, University of Pennsylvania, Philadelphia, USA.
Salena CuiDepartment of Neurology, University of Pennsylvania, Philadelphia, USA.
Lauren McCollumDepartment of Neurology, University of Pennsylvania, Philadelphia, USA.
John L RobinsonDepartment of Pathology, University of Pennsylvania, Philadelphia, USA.
Theresa SchuckDepartment of Pathology, University of Pennsylvania, Philadelphia, USA.
Robin de FloresInstitut National de la Santé et de la Recherche Médicale (INSERM), Caen, France.
Murray GrossmanDepartment of Neurology, University of Pennsylvania, Philadelphia, USA.
M Dylan TisdallDepartment of Radiology, University of Pennsylvania, Philadelphia, USA.ORCID 0000-0002-0454-3112
Karthik PrabhakaranDepartment of Neurology, University of Pennsylvania, Philadelphia, USA.
Gabor MizseiDepartment of Radiology, University of Pennsylvania, Philadelphia, USA.
Sandhitsu R DasDepartment of Neurology, University of Pennsylvania, Philadelphia, USA.
Emilio Artacho-PérulaHuman Neuroanatomy Laboratory, Neuromax CSIC Associated Unit, University of Castilla-La Mancha, Albacete, Spain.
Marı'a Del Mar Arroyo JiménezHuman Neuroanatomy Laboratory, Neuromax CSIC Associated Unit, University of Castilla-La Mancha, Albacete, Spain.ORCID 0000-0002-8390-5352
Marı'a Pilar Marcos RabaHuman Neuroanatomy Laboratory, Neuromax CSIC Associated Unit, University of Castilla-La Mancha, Albacete, Spain.
Francisco Javier Molina RomeroHuman Neuroanatomy Laboratory, Neuromax CSIC Associated Unit, University of Castilla-La Mancha, Albacete, Spain.
Sandra Cebada SánchezHuman Neuroanatomy Laboratory, Neuromax CSIC Associated Unit, University of Castilla-La Mancha, Albacete, Spain.ORCID 0000-0001-9547-9277
José Carlos Delgado GonzálezHuman Neuroanatomy Laboratory, Neuromax CSIC Associated Unit, University of Castilla-La Mancha, Albacete, Spain.
Carlos de la Rosa-PrietoHuman Neuroanatomy Laboratory, Neuromax CSIC Associated Unit, University of Castilla-La Mancha, Albacete, Spain.
Marta Córcoles ParadaHuman Neuroanatomy Laboratory, Neuromax CSIC Associated Unit, University of Castilla-La Mancha, Albacete, Spain.
Edward B LeeDepartment of Pathology, University of Pennsylvania, Philadelphia, USA.ORCID 0000-0002-4589-1180
John Q TrojanowskiDepartment of Pathology, University of Pennsylvania, Philadelphia, USA.
Daniel T OhmDepartment of Neurology, University of Pennsylvania, Philadelphia, USA.
Laura E M WisseDepartment of Diagnostic Radiology, University of Lund, Lund, Sweden.
David A WolkDepartment of Neurology, University of Pennsylvania, Philadelphia, USA.
David J IrwinDepartment of Neurology, University of Pennsylvania, Philadelphia, USA.
Ricardo InsaustiHuman Neuroanatomy Laboratory, Neuromax CSIC Associated Unit, University of Castilla-La Mancha, Albacete, Spain.
University of Pennsylvania · USUniversity of Castilla-La Mancha · ESInserm · FRLund University · SE

Funding

Transgenic Mouse Models of Tau PathologiesP01AG017586 · NIA · UNIVERSITY OF PENNSYLVANIA · PI LEE, VIRGINIA M · 2000 to 2021
$37.3M
UPenn ADCC Biomarker CoreP30AG010124 · NIA · UNIVERSITY OF PENNSYLVANIA · PI XIE, SHARON XIANGWEN · 1991 to 2020
$35.1M
Research Education ComponentP30AG072979 · NIA · UNIVERSITY OF PENNSYLVANIA · PI DAVID A WOLK · 2021 to 2026
$24.8M
Understanding Environmental Contributions to Heterogeneity in bvFTD.P01AG066597 · NIA · UNIVERSITY OF PENNSYLVANIA · PI David John Irwin, Corey T McMillan · 2020 to 2026
$18.8M
Ex Vivo Imaging of the Aging Brain to Discover Morphology/Pathology AssociationsR01AG056014 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Paul A. Yushkevich · 2017 to 2026
$4.5M
Microscopic and Large-Scale Networks of Molecular Pathology in Frontotemporal Lobar DegenerationR01NS109260 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI IRWIN, DAVID JOHN · 2019 to 2023
$3.8M
Modulators of Medial Temporal Lobe Subregion Structure and Function in Normal and Pathological AgingR01AG055005 · NIA · UNIVERSITY OF PENNSYLVANIA · PI WOLK, DAVID A · 2017 to 2021
$3.3M
Adaptive Large-Scale Framework for Automatic Biomedical Image SegmentationR01EB017255 · NIBIB · UNIVERSITY OF PENNSYLVANIA · PI YUSHKEVICH, PAUL A. · 2014 to 2018
$3.0M
NIA NIH HHS P01 AG017586NIA NIH HHS P01 AG066597NIA NIH HHS P30 AG010124NIA NIH HHS P30 AG072979NIA NIH HHS R01 AG055005NIA NIH HHS R01 AG056014NIBIB NIH HHS R01 EB017255NINDS NIH HHS R01 NS109260
6 · The paper itself

Abstract

Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer's disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, range 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangles were measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer's disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.

Indexed as

AgedAged, 80 and overBrain MappingCohort StudiesFemaleHumansImaging, Three-DimensionalMagnetic Resonance ImagingMaleMiddle AgedNeurofibrillary TanglesTemporal LobeAlzheimer’s diseasemedial temporal lobeneurodegenerationneurofibrillary tangles

Identifiers

PMID34259858
PMCPMC8783607
OpenAlexW3178386347

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.