Blood-spinal cord barrier leakage is independent of motor neuron pathology in ALS

Sarah Waters, Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand.
Molly E. Swanson, Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand.
Birger V. Dieriks, Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand.
Yibin B. Zhang, Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand.
Natasha L. Grimsey, Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand.
Helen C. Murray, Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand.
Clinton Turner, Centre for Brain Research, University of Auckland, Auckland, New Zealand.
Henry J. Waldvogel, Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand.
Richard L. Faull, Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand.
Jiyan An, Departments of Neurology and Neurobiology, Barrow Neurological Institute, Phoenix, ARI, 85013, USA.
Robert Bowser, Departments of Neurology and Neurobiology, Barrow Neurological Institute, Phoenix, ARI, 85013, USA.Follow
Maurice A. Curtis, Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand.
Mike Dragunow, Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand. m.dragunow@auckland.ac.nz.
Emma Scotter, Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand. emma.scotter@auckland.ac.nz.

Document Type

Article

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive degeneration of upper and lower motor neurons. The pattern of lower motor neuron loss along the spinal cord follows the pattern of deposition of phosphorylated TDP-43 aggregates. The blood-spinal cord barrier (BSCB) restricts entry into the spinal cord parenchyma of blood components that can promote motor neuron degeneration, but in ALS there is evidence for barrier breakdown. Here we sought to quantify BSCB breakdown along the spinal cord axis, to determine whether BSCB breakdown displays the same patterning as motor neuron loss and TDP-43 proteinopathy. Cerebrospinal fluid hemoglobin was measured in living ALS patients (n = 87 control, n = 236 ALS) as a potential biomarker of BSCB and blood-brain barrier leakage. Cervical, thoracic, and lumbar post-mortem spinal cord tissue (n = 5 control, n = 13 ALS) were then immunolabelled and semi-automated imaging and analysis performed to quantify hemoglobin leakage, lower motor neuron loss, and phosphorylated TDP-43 inclusion load. Hemoglobin leakage was observed along the whole ALS spinal cord axis and was most severe in the dorsal gray and white matter in the thoracic spinal cord. In contrast, motor neuron loss and TDP-43 proteinopathy were seen at all three levels of the ALS spinal cord, with most abundant TDP-43 deposition in the anterior gray matter of the cervical and lumbar cord. Our data show that leakage of the BSCB occurs during life, but at end-stage disease the regions with most severe BSCB damage are not those where TDP-43 accumulation is most abundant. This suggests BSCB leakage and TDP-43 pathology are independent pathologies in ALS.

Keywords

ALS, Blood-spinal cord barrier, Blood–brain barrier, Hemoglobin, Human, TDP-43

Publication Date

8-28-2021

Publication Title

Acta neuropathologica communications

E-ISSN

2051-5960

Volume

9

Issue

1

First Page

144

PubMed ID

34446086

Digital Object Identifier (DOI)

10.1186/s40478-021-01244-0

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