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Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis.

Brettschneider J, Toledo JB, Van Deerlin VM, Elman L, McCluskey L, Lee VM, Trojanowski JQ - PLoS ONE (2012)

Bottom Line: 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.TDP-43 pathology was more extensive in the motor cortex of cases with rapid progression of disease.This study demonstrates that microglial pathology in the CST of ALS correlates with disease progression and is linked to severity of UMN deficits.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America. Johannes.brettschneider@uni-ulm.de

ABSTRACT

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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Related in: MedlinePlus

Microglial pathology in ALS with/without C9ORF72 repeat expansion.Bar plot shows microglial pathology as detected by staining for CD68 (above) and Iba1 (below) in ALS patients with and without presence of a C9ORF72 repeat expansion. For the spinal cord sections, the grey matter examined was the anterior horn and the white matter examined was the anterior and lateral portion of the CST. Whiskers in bar plot indicate 95% confidence interval of mean. CSC  =  cervical spinal cord, gr  =  grey matter, LSC  =  lumbar spinal cord, Mot  =  motor cortex (gyrus praecentralis), Med  =  medulla oblongata, wh  =  white.
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pone-0039216-g004: Microglial pathology in ALS with/without C9ORF72 repeat expansion.Bar plot shows microglial pathology as detected by staining for CD68 (above) and Iba1 (below) in ALS patients with and without presence of a C9ORF72 repeat expansion. For the spinal cord sections, the grey matter examined was the anterior horn and the white matter examined was the anterior and lateral portion of the CST. Whiskers in bar plot indicate 95% confidence interval of mean. CSC  =  cervical spinal cord, gr  =  grey matter, LSC  =  lumbar spinal cord, Mot  =  motor cortex (gyrus praecentralis), Med  =  medulla oblongata, wh  =  white.

Mentions: As the presence of C9ORF72 repeat expansions in ALS was associated with alterations in clinical phenotype, we next asked if this was associated with changes in microglial pathology. To determine the extent and regional distribution of microglial pathology in the neuraxis of ALS, the pathology labeled by CD68 and Iba1 was rated on a semi-quantitative scale. ALS cases with a C9ORF72 repeat expansion showed a tendency towards more extensive microglial pathology in the grey and white matter of the neuraxis that reached statistical significance in the white matter of the medulla and the motor cortex (Figure 4). After adjusting for disease duration using logistic ordinal regression, the significance persisted for CD68 in the motor cortex (p = 0.04) and the medulla (p = 0.01) white matter as well as for Iba1 in the medulla white matter (p = 0.02), while it was lost for Iba1 in the motor cortex white matter (p = 0.11). No significant difference regarding the extent of TDP-43 pathology was observed between cases with and without C9ORF72 repeat expansion in the regions analyzed here.


Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis.

Brettschneider J, Toledo JB, Van Deerlin VM, Elman L, McCluskey L, Lee VM, Trojanowski JQ - PLoS ONE (2012)

Microglial pathology in ALS with/without C9ORF72 repeat expansion.Bar plot shows microglial pathology as detected by staining for CD68 (above) and Iba1 (below) in ALS patients with and without presence of a C9ORF72 repeat expansion. For the spinal cord sections, the grey matter examined was the anterior horn and the white matter examined was the anterior and lateral portion of the CST. Whiskers in bar plot indicate 95% confidence interval of mean. CSC  =  cervical spinal cord, gr  =  grey matter, LSC  =  lumbar spinal cord, Mot  =  motor cortex (gyrus praecentralis), Med  =  medulla oblongata, wh  =  white.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375234&req=5

pone-0039216-g004: Microglial pathology in ALS with/without C9ORF72 repeat expansion.Bar plot shows microglial pathology as detected by staining for CD68 (above) and Iba1 (below) in ALS patients with and without presence of a C9ORF72 repeat expansion. For the spinal cord sections, the grey matter examined was the anterior horn and the white matter examined was the anterior and lateral portion of the CST. Whiskers in bar plot indicate 95% confidence interval of mean. CSC  =  cervical spinal cord, gr  =  grey matter, LSC  =  lumbar spinal cord, Mot  =  motor cortex (gyrus praecentralis), Med  =  medulla oblongata, wh  =  white.
Mentions: As the presence of C9ORF72 repeat expansions in ALS was associated with alterations in clinical phenotype, we next asked if this was associated with changes in microglial pathology. To determine the extent and regional distribution of microglial pathology in the neuraxis of ALS, the pathology labeled by CD68 and Iba1 was rated on a semi-quantitative scale. ALS cases with a C9ORF72 repeat expansion showed a tendency towards more extensive microglial pathology in the grey and white matter of the neuraxis that reached statistical significance in the white matter of the medulla and the motor cortex (Figure 4). After adjusting for disease duration using logistic ordinal regression, the significance persisted for CD68 in the motor cortex (p = 0.04) and the medulla (p = 0.01) white matter as well as for Iba1 in the medulla white matter (p = 0.02), while it was lost for Iba1 in the motor cortex white matter (p = 0.11). No significant difference regarding the extent of TDP-43 pathology was observed between cases with and without C9ORF72 repeat expansion in the regions analyzed here.

Bottom Line: 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.TDP-43 pathology was more extensive in the motor cortex of cases with rapid progression of disease.This study demonstrates that microglial pathology in the CST of ALS correlates with disease progression and is linked to severity of UMN deficits.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America. Johannes.brettschneider@uni-ulm.de

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus