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Cited by 481Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

TDP-43 is a key player in the clinical features associated with Alzheimer’s disease

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Josephs, Keith A., Whitwell, Jennifer L., Weigand, Stephen D., Murray, Melissa E., Tosakulwong, Nirubol, Liesinger, Amanda M., Petrucelli, Leonard, Senjem, Matthew L. +8 more·2014·Acta Neuropathologica
DOI 10.1007/s00401-014-1269-zPMC PMC4172544
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Abstract

The aim of this study was to determine whether the TAR DNA-binding protein of 43 kDa (TDP-43) has any independent effect on the clinical and neuroimaging features typically ascribed to Alzheimer's disease (AD) pathology, and whether TDP-43 pathology could help shed light on the phenomenon of resilient cognition in AD. Three-hundred and forty-two subjects pathologically diagnosed with AD were screened for the presence, burden and distribution of TDP-43. All had been classified as cognitively impaired or normal, prior to death. Atlas-based parcellation and voxel-based morphometry were used to assess regional atrophy on MRI. Regression models controlling for age at death, apolipoprotein ε4 and other AD-related pathologies were utilized to explore associations between TDP-43 and cognition or brain atrophy, stratified by Braak stage. In addition, we determined whether the effects of TDP-43 were mediated by hippocampal sclerosis. One-hundred and ninety-five (57%) cases were TDP-positive. After accounting for age, apolipoprotein ε4 and other pathologies, TDP-43 had a strong effect on cognition, memory loss and medial temporal atrophy in AD. These effects were not mediated by hippocampal sclerosis. TDP-positive subjects were 10× more likely to be cognitively impaired at death compared to TDP-negative subjects. Greater cognitive impairment and medial temporal atrophy were associated with greater TDP-43 burden and more extensive TDP-43 distribution. TDP-43 is an important factor in the manifestation of the clinico-imaging features of AD. TDP-43 also appears to be able to overpower what has been termed resilient brain aging. TDP-43 therefore should be considered a potential therapeutic target for the treatment of AD.

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  • As TDP-43 distribution increases from limbic regions to other parts of the brain, it is associated with worsening cognition and medial temporal atrophy on antemortem brain imaging.

    “As the distribution of TDP-43 increases from limbic regions to other parts of the brain, it is associated with worsening cognition and with medial temporal atrophy on antemortem brain imaging [130, 132, 133].”

    From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [133]

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Research works printed but not linked: 38

  1. [1]Agresti A Categorical Data Analysis 2002 City Wiley-Interscience
  2. [3]Amador-Ortiz C Lin WL Ahmed Z TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease Annals of neurology 2007 61 435 445 17469117 PMC2677204
  3. [4]Arai T Mackenzie IR Hasegawa M Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies Acta neuropathologica 2009 117 125 136 19139911
  4. [6]Ashburner J Friston KJ Voxel-based morphometry--the methods NeuroImage 2000 11 805 821 10860804
  5. [7]Ashburner J Friston KJ Unified segmentation NeuroImage 2005 26 839 851 15955494
  6. [8]Bigio EH Mishra M Hatanpaa KJ TDP-43 pathology in primary progressive aphasia and frontotemporal dementia with pathologic Alzheimer disease Acta neuropathologica 2010 120 43 54 20361198 PMC2903745
  7. [10]Brenowitz WD Monsell SE Schmitt FA Kukull WA Nelson PT Hippocampal Sclerosis of Aging is a Key Alzheimer's Disease Mimic: Clinical-Pathologic Correlations and Comparisons with both Alzheimer's Disease and Non-Tauopathic Frontotemporal Lobar Degeneration J Alzheimers Dis 2014 39 691 702 24270205 PMC3946156
  8. [11]Buratti E Brindisi A Pagani F Baralle FE Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance American journal of human genetics 2004 74 1322 1325 15195661 PMC1182100
  9. [12]Corder EH Saunders AM Strittmatter WJ Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families Science 1993 261 921 923 8346443
  10. [13]Crook R Hardy J Duff K Single-day apolipoprotein E genotyping Journal of neuroscience methods 1994 53 125 127 7823614
  11. [14]Davidson YS Raby S Foulds PG TDP-43 pathological changes in early onset familial and sporadic Alzheimer's disease, late onset Alzheimer's disease and Down's syndrome: association with age, hippocampal sclerosis and clinical phenotype Acta neuropathologica 2011 122 703 713 21968532
  12. [16]Dickson DW Davies P Bevona C Hippocampal sclerosis: a common pathological feature of dementia in very old (>or = 80 years of age) humans Acta neuropathologica 1994 88 212 221 7810292
  13. [17]Folstein MF Folstein SE McHugh PR "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician J Psychiatr Res 1975 12 189 198 1202204
  14. [18]Gosche KM Mortimer JA Smith CD Markesbery WR Snowdon DA Hippocampal volume as an index of Alzheimer neuropathology: findings from the Nun Study Neurology 2002 58 1476 1482 12034782
  15. [19]Hu WT Josephs KA Knopman DS Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease Acta neuropathologica 2008 116 215 220 18592255 PMC3404722
  16. [20]Jack CR Jr Dickson DW Parisi JE Antemortem MRI findings correlate with hippocampal neuropathology in typical aging and dementia Neurology 2002 58 750 757 11889239 PMC2745935
  17. [21]Jack CR Jr Lowe VJ Senjem ML 11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment Brain: a journal of neurology 2008 131 665 680 18263627 PMC2730157
  18. [22]Janocko NJ Brodersen KA Soto-Ortolaza AI Neuropathologically defined subtypes of Alzheimer's disease differ significantly from neurofibrillary tangle-predominant dementia Acta neuropathologica 2012 124 681 692 22968369 PMC3483034
  19. [23]Josephs KA Tsuboi Y Cookson N Watt H Dickson DW Apolipoprotein E epsilon 4 is a determinant for Alzheimer-type pathologic features in tauopathies, synucleinopathies, and frontotemporal degeneration Archives of neurology 2004 61 1579 1584 15477512
  20. [24]Josephs KA Whitwell JL Knopman DS Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype Neurology 2008 70 1850 1857 18401022 PMC2779031
  21. [25]Josephs KA Whitwell JL Parisi JE Argyrophilic grains: a distinct disease or an additive pathology? Neurobiology of aging 2008 29 566 573 17188783 PMC2727715
  22. [26]Josephs KA Murray ME Whitwell JL Staging TDP-43 pathology in Alzheimer's disease Acta neuropathologica 2014 127 441 450 24240737 PMC3944799
  23. [28]Kaufer DI Cummings JL Ketchel P Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory The Journal of neuropsychiatry and clinical neurosciences 2000 12 233 239 11001602
  24. [30]Mirra SS Heyman A McKeel D The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease Neurology 1991 41 479 486 2011243
  25. [31]Morris JC The Clinical Dementia Rating (CDR): current version and scoring rules Neurology 1993 43 2412 2414 8232972
  26. [34]Neumann M Sampathu DM Kwong LK Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science 2006 314 130 133 17023659
  27. [35]Pao WC Dickson DW Crook JE Finch NA Rademakers R Graff-Radford NR Hippocampal sclerosis in the elderly: genetic and pathologic findings, some mimicking Alzheimer disease clinically Alzheimer Dis Assoc Disord 2011 25 364 368 21346515 PMC3107353
  28. [38]Rojo MG Garcia GB Mateos CP Garcia JG Vicente MC Critical comparison of 31 commercially available digital slide systems in pathology Int J Surg Pathol 2006 14 285 305 Doi 14/4/285 [pii]10.1177/1066896906292274 17041192 · DOI
  29. [39]Snowdon DA Greiner LH Mortimer JA Riley KP Greiner PA Markesbery WR Brain infarction and the clinical expression of Alzheimer disease. The Nun Study Jama 1997 277 813 817 9052711
  30. [40]Sullivan SG Greenland S Bayesian regression in SAS software Int J Epidemiol 2013 42 308 317 23230299
  31. [41]Thal DR Schultz C Botez G The impact of argyrophilic grain disease on the development of dementia and its relationship to concurrent Alzheimer's disease-related pathology Neuropathol Appl Neurobiol 2005 31 270 279 15885064
  32. [42]Tzourio-Mazoyer N Landeau B Papathanassiou D Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain NeuroImage 2002 15 273 289 11771995
  33. [43]Uryu K Nakashima-Yasuda H Forman MS Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies Journal of neuropathology and experimental neurology 2008 67 555 564 18520774 PMC3659339
  34. [44]Whitwell JL Josephs KA Murray ME MRI correlates of neurofibrillary tangle pathology at autopsy: a voxel-based morphometry study Neurology 2008 71 743 749 18765650 PMC2676950
  35. [45]Whitwell JL Jack CR Jr Przybelski SA Temporoparietal atrophy: A marker of AD pathology independent of clinical diagnosis Neurobiology of aging 2009 PMC2888989 19914744
  36. [46]Whitwell JL Dickson DW Murray ME Neuroimaging correlates of pathologically defined subtypes of Alzheimer's disease: a case-control study Lancet neurology 2012 11 868 877 PMC3490201 22951070
  37. [47]WorkingGroup Consensus recommendation for the postmortem diagnosis of Alzheimer's disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for Neuropathologic Assessment of Alzheimer's Disease Neurobiology of aging 1997 18 Supp1 S1 S2 9330978
  38. [48]Zhang YJ Xu YF Cook C Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity Proceedings of the National Academy of Sciences of the United States of America 2009 106 7607 7612 19383787 PMC2671323

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Authors
Josephs, K. A., Whitwell, J. L., Weigand, S. D., Murray, M. E., Tosakulwong, N., Liesinger, A. M., Petrucelli, L., Senjem, M. L., Knopman, D. S., Boeve, B. F., Ivnik, R. J., Smith, G. E., Jack, C. R., Parisi, J. E., Petersen, R. C., & Dickson, D. W.
Affiliations
  • Mayo Clinic (US)
  • Mayo Clinic in Florida (US)
Corresponding author
Josephs, Keith A.
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2014-03-23
Volume
127
Issue
6
Pages
811-824
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-014-1269-z
PMC
PMC4172544
OpenAlex
W2154520196
Cited by
481
References
8
Citations by year
2026: 46 · 2025: 61 · 2024: 47 · 2023: 35 · 2022: 55 · 2021: 33 · 2020: 53 · 2019: 33 · 2018: 27 · 2017: 24 · 2016: 28 · 2015: 27 · 2014: 12
FWCI
23.16
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Acta Neuropathologica (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Mayo Clinic
  • National Institute on Aging (R21AG038736, R01AG011378, R01AG037491, P50AG016574)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
TDP-43, Alzheimer's disease, cognitive impairment, medial temporal lobe atrophy, hippocampal sclerosis, Braak stages, brain atrophy, therapeutic target
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Atrophy, Brain, Cognition, DNA-Binding Proteins, Female, Humans, Immunohistochemistry, Magnetic Resonance Imaging, Male, Memory Disorders, Middle Aged, Regression Analysis, Sclerosis, Severity of Illness Index, Apolipoprotein E4

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