TDP-43 frontotemporal lobar degeneration and autoimmune disease

J Neurol Neurosurg Psychiatry. 2013 Sep;84(9):956-62. doi: 10.1136/jnnp-2012-304644. Epub 2013 Mar 30.


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: χ(2) 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.


Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Alzheimer Disease / pathology
  • Aphasia, Primary Progressive / pathology
  • Autoimmune Diseases / epidemiology
  • Autoimmune Diseases / pathology*
  • Autoimmune Diseases / psychology
  • Cohort Studies
  • Educational Status
  • Female
  • Frontotemporal Lobar Degeneration / epidemiology
  • Frontotemporal Lobar Degeneration / pathology*
  • Frontotemporal Lobar Degeneration / psychology
  • Humans
  • Inflammation / pathology
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Logistic Models
  • Male
  • Middle Aged
  • Mutation / physiology
  • Neuropsychological Tests
  • Prevalence
  • Progranulins
  • Psychiatric Status Rating Scales
  • TDP-43 Proteinopathies / epidemiology
  • TDP-43 Proteinopathies / pathology*
  • Tumor Necrosis Factor-alpha / metabolism


  • GRN protein, human
  • Intercellular Signaling Peptides and Proteins
  • Progranulins
  • Tumor Necrosis Factor-alpha