Microglial Activation Correlates with Disease Progression and Upper Motor Neuron Clinical Symptoms in Amyotrophic Lateral Sclerosis
Open accessAbstract
BACKGROUND/AIMS: We evaluated clinicopathological correlates of upper motor neuron (UMN) damage in amyotrophic lateral sclerosis (ALS), and analyzed if the presence of the C9ORF72 repeat expansion was associated with alterations in microglial inflammatory activity. METHODS: Microglial pathology was assessed by IHC with 2 different antibodies (CD68, Iba1), myelin loss by Kluver-Barrera staining and myelin basic protein (MBP) IHC, and axonal loss by neurofilament protein (TA51) IHC, performed on 59 autopsy cases of ALS including 9 cases with C9ORF72 repeat expansion. RESULTS: Microglial pathology as depicted by CD68 and Iba1 was significantly more extensive in the corticospinal tract (CST) of ALS cases with a rapid progression of disease. Cases with C9ORF72 repeat expansion showed more extensive microglial pathology in the medulla and motor cortex which persisted after adjusting for disease duration in a logistic regression model. Higher scores on the clinical UMN scale correlated with increasing microglial pathology in the cervical CST. TDP-43 pathology was more extensive in the motor cortex of cases with rapid progression of disease. CONCLUSIONS: This study demonstrates that microglial pathology in the CST of ALS correlates with disease progression and is linked to severity of UMN deficits.
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ALS patients carrying C9orf72 mutations display microglial activation that correlates with disease progression.
“ALS patients carrying C9orf72 mutations display microglial activation that correlates with disease progression [438].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [438]
Postmortem and in vivo PET studies revealed widespread cerebral microglial activation in patients with ALS and even in pre-symptomatic ALS-related mutation carriers.
“Postmortem studies308–310 and in vivo PET studies311–313 revealed widespread cerebral microglial activation in patients with ALS,308–312 and even in pre-symptomatic ALS-related mutation carriers.309,313”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [309]
Microglial activation in the corticospinal tract of ALS correlated with neuronal and axonal loss and more severe upper motor neuron symptoms.
“Microglial activation in the corticospinal tract of ALS correlated with neuronal and axonal loss and more severe upper motor neuron symptoms.309”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [309]
Decreased C9orf72 expression in C9-ALS led to altered microglial function and increased microglial activation.
“Transcriptome and histologic analyses of postmortem tissue from patients with ALS carrying the C9orf72 expansion (C9-ALS) found that decreased C9orf72 expression in C9-ALS led to altered microglial function and increased microglial activation.309,361”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [309]
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- Authors
- Brettschneider, J., Toledo, J. B., Van Deerlin, V. M., Elman, L., McCluskey, L., Lee, V. M.-Y., & Trojanowski, J. Q.
- Affiliations
- Universität Ulm (DE)
- University of Pennsylvania (US)
- Corresponding author
- Brettschneider, Johannes
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-06-14
- Volume
- 7
- Issue
- 6
- Pages
- e39216
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3375234
- OpenAlex
- W1974485241
- Cited by
- 268
- References
- 68
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 23 · 2023: 27 · 2022: 24 · 2021: 25 · 2020: 24 · 2019: 24 · 2018: 15 · 2017: 22 · 2016: 10 · 2015: 13 · 2014: 12 · 2013: 13 · 2012: 2
- FWCI
- 8.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (AG10124)
- National Institutes of Health (AG 10 124, AG 17586)
- National Institute on Aging (AG033101, AG-32953, P30AG010124, P01AG017586, AG17586, AG-10124, K08AG033101, P01AG032953)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- amyotrophic lateral sclerosis, microglial activation, upper motor neuron lesion, corticospinal tract, C9orf72 repeat expansion, disease progression, TDP-43 pathology, demyelination, axonal loss, neuroinflammation, motor cortex, medulla
- MeSH terms
- Aged, Amyotrophic Lateral Sclerosis, Axons, Base Sequence, Female, Humans, Male, Middle Aged, Motor Neurons, Cohort Studies, Polymerase Chain Reaction, Open Reading Frames, Microglia, DNA Primers, Disease Progression
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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