The Blood-CSF-Brain Route of Neurological Disease: The Indirect Pathway into the Brain

Oliver Cousins; Angela Hodges; Julia Schubert; Mattia Veronese; Federico Turkheimer; Jaleel Miyan; Britta Engelhardt; Federico Roncaroli

doi:10.1111/nan.12789

The Blood-CSF-Brain Route of Neurological Disease: The Indirect Pathway into the Brain

Oliver Cousins, Angela Hodges, Julia Schubert, Mattia Veronese, Federico Turkheimer, Jaleel Miyan, Britta Engelhardt, Federico Roncaroli

Neuroimaging Department
IoPPN Genomics and Biomarker Core
King's College London
Professor of Old Age Psychiatry, Department of Old age Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, United Kingdom Email: dag.aarsland@kcl.ac.uk.
Manchester Centre for Audiology and Deafness, The University of Manchester, Manchester M13 9PL, UK; Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
Support Centre for Advanced Neuroimaging (SCAN), Institute for Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. Electronic address: manuela.pastore-wapp@insel.ch.

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

Abstract

The brain is protected by the endothelial blood-brain-barrier (BBB) that limits the access of micro-organisms, tumour cells, immune cells and autoantibodies to the parenchyma. However, the classic model of disease spread across a disrupted BBB does not explain the focal distribution of lesions seen in a variety of neurological diseases and why lesions are frequently adjacent to the cerebrospinal fluid (CSF) spaces. We have critically reviewed the possible role of a blood-CSF-brain route as a disease entry pathway into the brain parenchyma. The initial step of this pathway is the transfer of pathogens or immune components from the blood into the CSF at the choroid plexuses, where the blood-CSF-barrier (BCSFB) is located. The flow of CSF results in disease dissemination throughout the CSF spaces. Access to the brain parenchyma from the CSF, can then occur across the ependymal layer at the ventricular surface, or across the pial-glial barrier of the subarachnoid space and the Virchow-Robin spaces. We have reviewed the anatomy and physiology of the blood-CSF-brain pathway and the brain barriers controlling this process. We then summarised the evidence supporting this brain entry route in a cross-section of neurological diseases including neuromyelitis optica, multiple sclerosis, neurosarcoidosis, neuropsychiatric lupus, cryptococcal infection, and both solid and haematological tumours. This summary highlights the conditions that share the blood-CSF-brain pathway as a pathogenetic mechanism. These include the characteristic proximity of lesions to CSF, evidence of disruption of the brain barriers, and the identification of significant pathology within the CSF. An improved understanding of pathological transfer through the CSF and across all brain barriers will inform on more effective and targeted treatments of primary and secondary disease of the central nervous system.

Original language	English
Article number	e12789
Journal	Neuropathology and Applied Neurobiology
Volume	48
Issue number	4
Early online date	13 Jan 2022
DOIs	https://doi.org/10.1111/nan.12789
Publication status	Published - Jun 2022

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10.1111/nan.12789

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@article{591e802f678449c891bd707e3a8f30f6,

title = "The Blood-CSF-Brain Route of Neurological Disease: The Indirect Pathway into the Brain",

abstract = "The brain is protected by the endothelial blood-brain-barrier (BBB) that limits the access of micro-organisms, tumour cells, immune cells and autoantibodies to the parenchyma. However, the classic model of disease spread across a disrupted BBB does not explain the focal distribution of lesions seen in a variety of neurological diseases and why lesions are frequently adjacent to the cerebrospinal fluid (CSF) spaces. We have critically reviewed the possible role of a blood-CSF-brain route as a disease entry pathway into the brain parenchyma. The initial step of this pathway is the transfer of pathogens or immune components from the blood into the CSF at the choroid plexuses, where the blood-CSF-barrier (BCSFB) is located. The flow of CSF results in disease dissemination throughout the CSF spaces. Access to the brain parenchyma from the CSF, can then occur across the ependymal layer at the ventricular surface, or across the pial-glial barrier of the subarachnoid space and the Virchow-Robin spaces. We have reviewed the anatomy and physiology of the blood-CSF-brain pathway and the brain barriers controlling this process. We then summarised the evidence supporting this brain entry route in a cross-section of neurological diseases including neuromyelitis optica, multiple sclerosis, neurosarcoidosis, neuropsychiatric lupus, cryptococcal infection, and both solid and haematological tumours. This summary highlights the conditions that share the blood-CSF-brain pathway as a pathogenetic mechanism. These include the characteristic proximity of lesions to CSF, evidence of disruption of the brain barriers, and the identification of significant pathology within the CSF. An improved understanding of pathological transfer through the CSF and across all brain barriers will inform on more effective and targeted treatments of primary and secondary disease of the central nervous system.",

author = "Oliver Cousins and Angela Hodges and Julia Schubert and Mattia Veronese and Federico Turkheimer and Jaleel Miyan and Britta Engelhardt and Federico Roncaroli",

note = "Funding Information: We would like to thank Federico Baratto for his support with the figures. Publisher Copyright: {\textcopyright} 2021 British Neuropathological Society.",

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T1 - The Blood-CSF-Brain Route of Neurological Disease

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AU - Cousins, Oliver

AU - Hodges, Angela

AU - Schubert, Julia

AU - Veronese, Mattia

AU - Turkheimer, Federico

AU - Miyan, Jaleel

AU - Engelhardt, Britta

AU - Roncaroli, Federico

PY - 2022/6

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N2 - The brain is protected by the endothelial blood-brain-barrier (BBB) that limits the access of micro-organisms, tumour cells, immune cells and autoantibodies to the parenchyma. However, the classic model of disease spread across a disrupted BBB does not explain the focal distribution of lesions seen in a variety of neurological diseases and why lesions are frequently adjacent to the cerebrospinal fluid (CSF) spaces. We have critically reviewed the possible role of a blood-CSF-brain route as a disease entry pathway into the brain parenchyma. The initial step of this pathway is the transfer of pathogens or immune components from the blood into the CSF at the choroid plexuses, where the blood-CSF-barrier (BCSFB) is located. The flow of CSF results in disease dissemination throughout the CSF spaces. Access to the brain parenchyma from the CSF, can then occur across the ependymal layer at the ventricular surface, or across the pial-glial barrier of the subarachnoid space and the Virchow-Robin spaces. We have reviewed the anatomy and physiology of the blood-CSF-brain pathway and the brain barriers controlling this process. We then summarised the evidence supporting this brain entry route in a cross-section of neurological diseases including neuromyelitis optica, multiple sclerosis, neurosarcoidosis, neuropsychiatric lupus, cryptococcal infection, and both solid and haematological tumours. This summary highlights the conditions that share the blood-CSF-brain pathway as a pathogenetic mechanism. These include the characteristic proximity of lesions to CSF, evidence of disruption of the brain barriers, and the identification of significant pathology within the CSF. An improved understanding of pathological transfer through the CSF and across all brain barriers will inform on more effective and targeted treatments of primary and secondary disease of the central nervous system.

AB - The brain is protected by the endothelial blood-brain-barrier (BBB) that limits the access of micro-organisms, tumour cells, immune cells and autoantibodies to the parenchyma. However, the classic model of disease spread across a disrupted BBB does not explain the focal distribution of lesions seen in a variety of neurological diseases and why lesions are frequently adjacent to the cerebrospinal fluid (CSF) spaces. We have critically reviewed the possible role of a blood-CSF-brain route as a disease entry pathway into the brain parenchyma. The initial step of this pathway is the transfer of pathogens or immune components from the blood into the CSF at the choroid plexuses, where the blood-CSF-barrier (BCSFB) is located. The flow of CSF results in disease dissemination throughout the CSF spaces. Access to the brain parenchyma from the CSF, can then occur across the ependymal layer at the ventricular surface, or across the pial-glial barrier of the subarachnoid space and the Virchow-Robin spaces. We have reviewed the anatomy and physiology of the blood-CSF-brain pathway and the brain barriers controlling this process. We then summarised the evidence supporting this brain entry route in a cross-section of neurological diseases including neuromyelitis optica, multiple sclerosis, neurosarcoidosis, neuropsychiatric lupus, cryptococcal infection, and both solid and haematological tumours. This summary highlights the conditions that share the blood-CSF-brain pathway as a pathogenetic mechanism. These include the characteristic proximity of lesions to CSF, evidence of disruption of the brain barriers, and the identification of significant pathology within the CSF. An improved understanding of pathological transfer through the CSF and across all brain barriers will inform on more effective and targeted treatments of primary and secondary disease of the central nervous system.

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JF - Neuropathology and Applied Neurobiology

IS - 4

M1 - e12789

ER -

The Blood-CSF-Brain Route of Neurological Disease: The Indirect Pathway into the Brain

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