期刊
ACTA NEUROPATHOLOGICA COMMUNICATIONS
卷 9, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s40478-021-01244-0
关键词
Blood-brain barrier; Blood-spinal cord barrier; TDP-43; ALS; Hemoglobin; Human
资金
- Marsden FastStart and Rutherford Discovery Fellowship from the Royal Society of New Zealand [15-UOA-157, 15-UOA-003]
- Health Research Council of NZ
- Sir Thomas and Lady Duncan Trust
- Coker Family Trust
- PaR NZ Golfing
- Motor Neuron Disease NZ
- Neurological Foundation of New Zealand
ALS is a fatal neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. In ALS patients, there is evidence of blood-spinal cord barrier leakage during life, but the regions with the most severe barrier damage do not correlate with the areas of most abundant TDP-43 accumulation. This suggests that BSCB leakage and TDP-43 pathology are independent pathologies in ALS.
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.
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