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Cited by 142Amyotrophic Lateral Sclerosis ResearchNeuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatments

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

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Brettschneider, Johannes, Libon, David J., Toledo, Jon B., Xie, Sharon X., McCluskey, Leo, Elman, Lauren, Geser, Felix, Lee, Virginia M.-Y., Grossman, Murray, Trojanowski, John Q.·2012·Acta Neuropathologica
DOI 10.1007/s00401-011-0932-xPMC PMC3595560
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Abstract

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.

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  • Neuroinflammation has also been observed in patients with ALS, in which inflammatory microglial hyperactivity in these patients has been linked to disease progression.

    “Neuroinflammation has also been observed in patients with ALS, in which inflammatory microglial hyperactivity in these patients has been linked to disease progression [50,54].”

    From Head Injury and Amyotrophic Lateral Sclerosis: Population-Based Study from the National ALS Registry (2025) · cites this paper as [50]

    The Discussion reports microglial activation in ALS and links it to executive deficits and neuronal loss. It does not establish a link to disease progression: the Results section on disease duration and clinical phenotype reports no significant trend in microglial activation with disease duration and no correlation between any pathology and ALSFRS-R scores. (LLM, conf=0.88)

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Metadata

Authors
Brettschneider, J., Libon, D. J., Toledo, J. B., Xie, S. X., McCluskey, L., Elman, L., Geser, F., Lee, V. M.-Y., Grossman, M., & Trojanowski, J. Q.
Affiliations
  • University of Pennsylvania (US)
  • Drexel University (US)
  • Universität Ulm (DE)
Corresponding author
Trojanowski, John Q.
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2012-01-01
Volume
123
Issue
3
Pages
395-407
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-011-0932-x
PMC
PMC3595560
OpenAlex
W2137199534
Cited by
142
References
11
Citations by year
2026: 8 · 2025: 11 · 2024: 11 · 2023: 14 · 2022: 8 · 2021: 8 · 2020: 11 · 2019: 7 · 2018: 9 · 2017: 9 · 2016: 10 · 2015: 7 · 2014: 13 · 2013: 8 · 2012: 7
FWCI
5.43
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Acta Neuropathologica (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Aging (P30AG010124, P01AG017586, K08AG033101, P01AG032953)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords
amyotrophic lateral sclerosis, executive dysfunction, microglial activation, TDP-43 pathology, cognitive impairment, frontotemporal lobar degeneration, Alzheimer's disease pathology, tau pathology, amyloid-beta pathology, neuroinflammation, frontal and temporal cortex, CD68, Iba1
MeSH terms
Aged, Amyotrophic Lateral Sclerosis, Brain, DNA-Binding Proteins, Female, Humans, Male, Middle Aged, Neurons, Neuropsychological Tests, tau Proteins, Microglia, Executive Function

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