Amyotrophic lateral sclerosis: Is the spinal fluid pathway involved in seeding and spread?  Richard Smith, Kathleen Myers, John Ravits, Robert Bowser  Medical Hypotheses  Volume 85, Issue 5, Pages 576-583 (November 2015) DOI: 10.1016/j.mehy.2015.07.014 Copyright © 2015 The Authors Terms and Conditions

Fig. 1 Key anatomical features of the cerebrospinal fluid pathway. The cerebrospinal fluid communicates with broad regions of the central nervous system, filling two lateral ventricles (A), the 3rd ventricle (B), and the 4th ventricle (C) in the brain’s interior. CSF eventually flows from the ventricles into the subarachnoid space and its cisterns, and from there into sulci overlying the cortical surface, as well as the spinal cord’s central canal (D). There is also a CSF “microcirculation” which originates at the pial surface and carries molecules into brain tissue via transport through the perivascular, or Virchow–Robin spaces, of penetrating blood vessels. CSF is primarily secreted by the choroid plexus (E), a structure that is essentially an extension of the ependymal cell layer of the ventricular wall. The tight junctions between the epithelial cells of the choroid plexus are the basis of the blood cerebrospinal fluid barrier (BCSFB), since the endothelial cells within the CP vasculature itself do not possess tight junctions. Endothelial cells in cerebral capillaries, however, are joined by tight junctions that constitute the blood brain barrier (BBB). The 5th, 7th, 9th, 10th, and 12th cranial nerve nuclei are frequently involved in ALS, as of course are motor neurons in the spinal cord. The proximity of the 5th, 7th, 10th, and 12th nerves to the CSF is illustrated. (F) 5th cranial (trigeminal) nerve nucleus; (G) 7th cranial (facial) nerve nucleus; (H) 12th cranial (hypoglossal) nucleus; (I) dorsal motor nucleus of 10th cranial nerve (vagus); (J) motor neurons of the anterior horn of the spinal cord. The relative proximity of spinal motor neurons to surrounding spinal fluid in the subarachnoid space (K) as well as in the central canal (D) is shown. Medical Hypotheses 2015 85, 576-583DOI: (10.1016/j.mehy.2015.07.014) Copyright © 2015 The Authors Terms and Conditions

Fig. 2 Uptake of intra-ventricularly injected macromolecules into neurons. (A) Immunofluorescent microscopy depicting the presence of antibody within spinal neurons 2weeks after their intracerebroventricular infusion in mice. Anti-choline acetyltransferase (ChAT) (red) was used to label motor neurons in tissue sections obtained from the lumbar spinal cord, and a fluorescently conjugated rabbit anti-mouse secondary antibody (green) was used to detect the infused primary antibody. Adapted with permission from Gros-Louis et al. [80]. (B) A chemically-modified 20-mer antisense oligonucleotide was infused into the right lateral ventricle of a normal rat for 14days, after which tissues were collected and localization of the oligonucleotide was determined by immunostaining with an antibody that specifically recognizes the oligonucleotide. Immunostaining was noted at all levels of the spinal cord, with prominent uptake in the ventral horn. The arrow in the panel highlights uptake by a neuronal cell. Oligonucleotide was also found to be distributed to non-neuronal cells, including astrocytes and microglia, and was shown to be localized in brain parenchyma relevant to neurodegenerative diseases, including the hippocampus, substantia nigra, pons, and cerebellum [81]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) Medical Hypotheses 2015 85, 576-583DOI: (10.1016/j.mehy.2015.07.014) Copyright © 2015 The Authors Terms and Conditions