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Cited by 354Barrier Structure and Function StudiesAmyotrophic Lateral Sclerosis ResearchSpinal Cord Injury Research

Blood–spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis

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Winkler, Ethan A., Sengillo, Jesse D., Sullivan, John S., Henkel, Jenny S., Appel, Stanley H., Zlokovic, Berislav V.·2013·Acta Neuropathologica
DOI 10.1007/s00401-012-1039-8PMC PMC3535352
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Abstract

The blood-brain barrier and blood-spinal cord barrier (BSCB) limit the entry of plasma components and erythrocytes into the central nervous system (CNS). Pericytes play a key role in maintaining blood-CNS barriers. The BSCB is damaged in patients with amyotrophic lateral sclerosis (ALS). Moreover, transgenic ALS rodents and pericyte-deficient mice develop BSCB disruption with erythrocyte extravasation preceding motor neuron dysfunction. Here, we studied whether BSCB disruption with erythrocyte extravasation and pericyte loss are present in human ALS. We show that 11 of 11 cervical cords from ALS patients, but 0 of 5 non-neurodegenerative disorders controls, possess perivascular deposits of erythrocyte-derived hemoglobin and hemosiderin typically 10-50 μm in diameter suggestive of erythrocyte extravasation. Immunostaining for CD235a, a specific marker for erythrocytes, confirmed sporadic erythrocyte extravasation in ALS, but not controls. Quantitative analysis revealed a 3.1-fold increase in perivascular hemoglobin deposits in ALS compared to controls showing hemoglobin confined within the vascular lumen, which correlated with 2.5-fold increase in hemosiderin deposits (r = 0.82, p < 0.01). Spinal cord parenchymal accumulation of plasma-derived immunoglobulin G, fibrin and thrombin was demonstrated in ALS, but not controls. Immunostaining for platelet-derived growth factor receptor-β, a specific marker for CNS pericytes, indicated a 54 % (p < 0.01) reduction in pericyte number in ALS patients compared to controls. Pericyte reduction correlated negatively with the magnitude of BSCB damage as determined by hemoglobin abundance (r = -0.75, p < 0.01). Thus, the BSCB disruption with erythrocyte extravasation and pericyte reductions is present in ALS. Whether similar findings occur in motor cortex and affected brainstem motor nuclei remain to be seen.

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Crossref · 10.1007/s00401-012-1039-8

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  • Many neurodegenerative diseases are associated with loss of pericytes.

    “Many neurodegenerative diseases were found to be associated with the loss of pericytes.495,496”

    From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [495]

    The Results section ('Reduction of spinal cord pericyte population in ALS'; page unavailable) reports fewer spinal-cord pericytes in people with ALS than in controls. That supports the claim for ALS, but the cited paper does not establish pericyte loss across many neurodegenerative diseases. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In sporadic and familial amyotrophic lateral sclerosis, immunohistochemical analysis found pericyte degeneration and loss associated with blood-spinal cord barrier breakdown and fibrinogen and IgG perivascular deposits.

    “Immunohistochemical analysis for pericyte biomarkers on the spinal cord capillaries from patients with sporadic and familial ALS found pericyte degeneration and loss that is associated with BSCB breakdown and fibrinogen and IgG perivascular deposits (652).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [652]

    The Human subjects section includes both sporadic and familial ALS cases. The Results report reduced pericyte number and coverage associated with BSCB damage, while the BSCB results show extravascular IgG and fibrin. The paper does not establish pericyte degeneration, and it describes fibrin accumulation rather than specifically identifying fibrinogen deposits. Page numbers are unavailable in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • A few post mortem studies revealed BBB disruption with red blood cell extravasation, pericyte reductions, and reduced levels of tight junction proteins in the spinal cord of ALS patients with both familial and sporadic form of disease.

    “A few post mortem studies revealed BBB disruption with red blood cells (RBCs) extravasation, pericyte reductions, and reduced levels of TJ proteins in the spinal cord of ALS patients with both familial and sporadic form of disease (243, 652).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [652]

  • A subset of amyotrophic lateral sclerosis patients shows increased Qalb ratio and elevated CSF levels of several blood-derived proteins.

    “A subset of ALS patients shows increased Qalb ratio and elevated CSF levels of several blood-derived proteins (79, 652).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [652]

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Sorted by citations

Authors
Winkler, E. A., Sengillo, J. D., Sullivan, J. S., Henkel, J. S., Appel, S. H., & Zlokovic, B. V.
Affiliations
  • University of Southern California (US)
  • Houston Methodist (US)
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2012-09-01
Volume
125
Issue
1
Pages
111-120
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-012-1039-8
PMC
PMC3535352
OpenAlex
W2080353159
Cited by
354
References
14
Citations by year
2026: 26 · 2025: 28 · 2024: 34 · 2023: 25 · 2022: 27 · 2021: 40 · 2020: 37 · 2019: 26 · 2018: 22 · 2017: 21 · 2016: 22 · 2015: 17 · 2014: 18 · 2013: 9 · 2012: 2
FWCI
7.41
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Acta Neuropathologica (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • ALS Association
  • National Institute on Aging (R01AG039452, AG039452, RF1AG039452)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
Keywords
amyotrophic lateral sclerosis, blood-spinal cord barrier, blood-brain barrier disruption, pericytes, erythrocyte extravasation, hemosiderin, glycophorin A, PDGFRβ, cervical spinal cord
MeSH terms
Aged, Amyotrophic Lateral Sclerosis, Blood-Brain Barrier, Capillary Permeability, Female, Humans, Male, Middle Aged, Motor Neurons, Spinal Cord, Tight Junctions, Pericytes, Endothelial Cells

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