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Research paper
TDP-43 frontotemporal lobar degeneration and autoimmune disease
  1. Zachary A Miller1,2,
  2. Katherine P Rankin1,2,
  3. Neill R Graff-Radford3,
  4. Leonel T Takada1,2,4,
  5. Virginia E Sturm1,2,
  6. Clare M Cleveland5,
  7. Lindsey A Criswell5,
  8. Philipp A Jaeger6,
  9. Trisha Stan6,7,
  10. Kristin A Heggeli3,
  11. Sandy Chan Hsu8,
  12. Anna Karydas1,2,
  13. Baber K Khan1,2,
  14. Lea T Grinberg1,2,
  15. Maria Luisa Gorno-Tempini1,2,
  16. Adam L Boxer1,2,
  17. Howard J Rosen1,2,
  18. Joel H Kramer1,2,
  19. Giovanni Coppola8,
  20. Daniel H Geschwind8,
  21. Rosa Rademakers9,
  22. William W Seeley1,2,
  23. Tony Wyss-Coray6,7,10,
  24. Bruce L Miller1,2
  1. 1UCSF Memory and Aging Center, University of California San Francisco, San Francisco, California, USA
  2. 2Department of Neurology, University of California San Francisco, San Francisco, California, USA
  3. 3Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA
  4. 4Department of Neurology, University of Sao Paulo Medical School, Brazil
  5. 5Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, University of California San Francisco, San Francisco, California, USA
  6. 6Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
  7. 7Immunology IDP Program, Stanford University School of Medicine, Stanford, California, USA
  8. 8Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, USA
  9. 9Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA
  10. 10Center for Tissue Regeneration, Repair and Restoration, Veterans Administration Palo Alto Health Care System, Palo Alto, California, USA
  1. Correspondence to Dr Zachary A Miller, UCSF Memory and Aging Center, University of California San Francisco, 675 Nelson Rising Lane, Suite 191D Box 1207 San Francisco, CA 94143-1207, USA; zmiller{at}


Background The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need to be explored.

Objective To describe the prevalence of systemic autoimmune disease in semantic variant primary progressive aphasia (svPPA), a clinical cohort, and in progranulin (PGRN) mutation carriers compared with neurologically healthy normal controls (NC) and Alzheimer's disease (AD) as dementia controls.

Design Case control.

Setting Academic medical centres.

Participants 129 svPPA, 39 PGRN, 186 NC and 158 AD patients underwent chart review for autoimmune conditions. A large subset of svPPA, PGRN and NC cohorts underwent serum analysis for tumour necrosis factor α (TNF-α) levels.

Outcome measures χ2 Comparison of autoimmune prevalence and follow-up logistic regression.

Results There was a significantly increased risk of autoimmune disorders clustered around inflammatory arthritides, cutaneous disorders and gastrointestinal conditions in the svPPA and PGRN cohorts. Elevated TNF-α levels were observed in svPPA and PGRN compared with NC.

Conclusions svPPA and PGRN are associated with increased prevalence of specific and related autoimmune diseases compared with NC and AD. These findings suggest a unique pattern of systemic inflammation in svPPA and PGRN and open new research avenues for understanding and treating disorders associated with underlying transactive response DNA-binding protein 43 aggregation.


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