Original Paper

Acta Neuropathologica

, Volume 114, Issue 3, pp 221-229

First online:

Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases

  • Hanae Nakashima-YasudaAffiliated withDepartment of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine
  • , Kunihiro UryuAffiliated withDepartment of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine
  • , John RobinsonAffiliated withDepartment of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine
  • , Sharon X. XieAffiliated withDepartment of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine
  • , Howard HurtigAffiliated withDepartment of Neurology, University of Pennsylvania School of Medicine
  • , John E. DudaAffiliated withDepartment of Neurology, University of Pennsylvania School of MedicineParkinson’s Disease Research, Education and Clinical Center, Philadelphia VAMC
  • , Steven E. ArnoldAffiliated withDepartment of Psychiatry, University of Pennsylvania School of Medicine
  • , Andrew SiderowfAffiliated withDepartment of Neurology, University of Pennsylvania School of Medicine
  • , Murray GrossmanAffiliated withDepartment of Neurology, University of Pennsylvania School of Medicine
    • , James B. LeverenzAffiliated withDepartment of Psychiatry and Behavioral Sciences, University of WashingtonDepartment of Neurology, University of WashingtonMental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care SystemParkinson’s Disease Research, Education, and Clinical Center, VA Puget Sound Health Care System
    • , Randy WoltjerAffiliated withDepartment of Pathology, University of Washington
    • , Oscar L. LopezAffiliated withDepartment of Neurology, University of Pittsburgh
    • , Ronald HamiltonAffiliated withDepartment of Pathology, University of Pittsburgh
    • , Debby W. TsuangAffiliated withDepartment of Psychiatry and Behavioral Sciences, University of WashingtonParkinson’s Disease Research, Education, and Clinical Center, VA Puget Sound Health Care System
    • , Douglas GalaskoAffiliated withDepartment of Neuroscience, University of California-San Diego
    • , Eliezer MasliahAffiliated withDepartment of Neuroscience, University of California-San DiegoDepartment of Pathology, University of California-San Diego
    • , Jeffrey KayeAffiliated withDepartment of Neurology, Oregon Health & Sciences University
    • , Christopher M. ClarkAffiliated withDepartment of Neurology, University of Pennsylvania School of Medicine
    • , Thomas J. MontineAffiliated withDepartment of Pathology, University of Washington
    • , Virginia M. -Y. LeeAffiliated withDepartment of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine
    • , John Q. TrojanowskiAffiliated withDepartment of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of MedicineInstitute on Aging, University of Pennsylvania School of Medicine Email author 

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Abstract

Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson’s disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer’s disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.

Keywords

Frontotemporal lobar degeneration TDP-43 Dementia with Lewy bodies Parkinson’s disease