Acta Neuropathologica

, Volume 123, Issue 3, pp 395–407 | Cite as

Microglial activation and TDP-43 pathology correlate with executive dysfunction in amyotrophic lateral sclerosis

  • Johannes Brettschneider
  • David J. Libon
  • Jon B. Toledo
  • Sharon X. Xie
  • Leo McCluskey
  • Lauren Elman
  • Felix Geser
  • Virginia M.-Y. Lee
  • Murray Grossman
  • John Q. Trojanowski
Original Paper


While cognitive deficits are increasingly recognized as common symptoms in amyotrophic lateral sclerosis (ALS), the underlying histopathologic basis for this is not known, nor has the relevance of neuroinflammatory mechanisms and microglial activation to cognitive impairment (CI) in ALS been systematically analyzed. Staining for neurodegenerative disease pathology, TDP-43, and microglial activation markers (CD68, Iba1) was performed in 102 autopsy cases of ALS, and neuropathology data were related to clinical and neuropsychological measures. ALS with dementia (ALS-D) and ALS with impaired executive function (ALS-Ex) patients showed significant microglial activation in middle frontal and superior or middle temporal (SMT) gyrus regions, as well as significant neuronal loss and TDP-43 pathology in these regions. Microglial activation and TDP-43 pathology in middle frontal and superior or middle temporal regions were highly correlated with measures of executive impairment, but not with the MMSE. In contrast, only one ALS-D patient showed moderate Alzheimer’s disease (AD) pathology. Tau and Aβ pathology increased with age. A lower MMSE score correlated with tau pathology in hippocampus and SMT gyrus, and with Aβ pathology in limbic and most cortical regions. Tau and Aβ pathology did not correlate with executive measures. We conclude that microglial activation and TDP-43 pathology in frontotemporal areas are determinants of FTLD spectrum dementia in ALS and correlate with neuropsychological measures of executive dysfunction. In contrast, AD pathology in ALS is primarily related to increasing age and associated with a poorer performance on the MMSE.


Amyotrophic lateral sclerosis Frontotemporal lobar degeneration Cognitive impairment TDP-43 Microglia 



We thank the many patients who contributed samples for this study. We thank John Robinson and Terry Schuck for their help in sorting out and reviewing slides. This work was supported by the NIH (AG033101, AG17586, AG10124, AG32953), the Wyncote Foundation, and the Koller Family Foundation. VMYL is the John H. Ware, 3rd, Professor of Alzheimer’s Disease Research. JQT is the William Maul Measey-Truman G. Schnabel, Jr., Professor of Geriatric Medicine and Gerontology. JB was supported by a grant of the Deutsche Forschungsgemeinschaft DFG (AOBJ586910). JBT is supported by a grant of the Fundación Alfonso Martin Escudero.

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Johannes Brettschneider
    • 1
    • 5
  • David J. Libon
    • 2
  • Jon B. Toledo
    • 1
  • Sharon X. Xie
    • 4
  • Leo McCluskey
    • 3
  • Lauren Elman
    • 3
  • Felix Geser
    • 5
  • Virginia M.-Y. Lee
    • 1
  • Murray Grossman
    • 3
  • John Q. Trojanowski
    • 1
  1. 1.Center for Neurodegenerative Disease Research (CNDR)University of Pennsylvania School of MedicinePhiladelphiaUSA
  2. 2.Department of NeurologyDrexel UniversityPhiladelphiaUSA
  3. 3.Department of NeurologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  4. 4.Department of Biostatistics and EpidemiologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA
  5. 5.Department of NeurologyUniversity of UlmUlmGermany

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