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

TDP-43 Frontotemporal Lobar Degeneration and Autoimmune Disease

Free PMC article

TDP-43 Frontotemporal Lobar Degeneration and Autoimmune Disease

Zachary A Miller et al. J Neurol Neurosurg Psychiatry. .
Free PMC article


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.



Figure 1
Figure 1
Prevalence of Autoimmune Disease among Diagnostic Groups. Abbreviations: AD = Alzheimer’s disease; NC = normal controls; PGRN = progranulin; svPPA = semantic variant primary progressive aphasia. Retrospective chart review of autoimmune conditions in AD, NC, PGRN, and svPPA subjects. Other Autoimmune refers to all other autoimmune conditions on the collection instrument that were not thyroid disease. When an individual had a thyroid disorder and another autoimmune disease they were assigned to the Other Autoimmune category, so as to avoid being counted twice. Thyroid Only refers to those who had only thyroid spectrum disorders affecting subjects. Nothing Mentioned refers to individuals where there was no mention of any condition found within the screening collection instrument. * ** Two patients in the collection overlapped between the PGRN and svPPA cohort (one had type 1 diabetes and thyroid disease and the other had no mentioned autoimmune disorder).
Figure 2
Figure 2
TNF-α Levels in NC, PGRN, and svPPA. Abbreviations: NC = normal control; PGRN = progranulin; svPPA = semantic variant primary progressive aphasia; TNF-α = tumor necrosis factor alpha. Samples from NC (37), PGRN (24), and svPPA (26) were analyzed for plasma TNF-α levels. * ** Statistical differences in TNF-α levels were found between NC and PGRN as well as NC and svPPA (p = 0.0075 and p = 0.012, respectively; t test)..
Figure 3
Figure 3
Model of Relative Increased TNF-α Signaling in TDP-43 Disease, Via PGRN Depletion or TNF-α Elevation. Abbreviations: PGRN = progranulin; TDP-43 = transactive response DNA-binding protein 43; TNF-α = tumor necrosis factor alpha. Proposed unifying schema for TDP-43 disease pathology mediated through the effects of TNF-α signaling. Above, (A) represents primary PGRN and secondary TNF-α mediated mechanisms while (B) represents a primary TNF-α mediated mechanism of TDP-43 disease. These two mechanisms likely interact with each other.

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