PT  - JOURNAL ARTICLE
AU  - Sarah Waters
AU  - Birger V. Dieriks
AU  - Molly E. V. Swanson
AU  - Yibin Zhang
AU  - Natasha L. Grimsey
AU  - Helen C. Murray
AU  - Clinton Turner
AU  - Henry J. Waldvogel
AU  - Richard L.M. Faull
AU  - Jiyan An
AU  - Robert Bowser
AU  - Maurice A. Curtis
AU  - Mike Dragunow
AU  - Emma L. Scotter
TI  - Blood-spinal cord barrier leakage is not caused by neurodegeneration in amyotrophic lateral sclerosis
AID  - 10.1101/704270
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 704270
4099  - http://biorxiv.org/content/early/2019/07/26/704270.short
4100  - http://biorxiv.org/content/early/2019/07/26/704270.full
AB  - Objective Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive degeneration of upper and lower motor neurons. Both lower motor neuron loss and the deposition of phosphorylated TDP-43 inclusions display regional patterning along the spinal cord. The blood-spinal cord barrier (BSCB) ordinarily restricts entry into the spinal cord parenchyma of blood components that are neurotoxic, but in ALS there is evidence for barrier breakdown. Here we sought to examine whether BSCB breakdown, motor neuron loss, and TDP-43 proteinopathy display the same regional patterning across and along the spinal cord.Methods We measured cerebrospinal fluid (CSF) hemoglobin in living ALS patients (n=87 controls, n=299 ALS) as a potential biomarker of BSCB and blood-brain barrier leakage. We then immunostained cervical, thoracic, and lumbar post mortem spinal cord tissue (n=5 controls, n=13 ALS) and employed semi-automated imaging and analysis to quantify and map lower motor neuron loss and phosphorylated TDP-43 inclusion load against hemoglobin leakage.Results 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 ventral grey (lamina IX) of the cervical and lumbar cord. In contrast, hemoglobin leakage was observed along the ALS spinal cord axis but was most severe in the dorsal grey and white matter in the thoracic spinal cord.Interpretation Our data show that leakage of the blood-spinal cord barrier occurs during life but at end-stage its distribution is independent from the major motor neuron pathology in ALS.