Ma Q, Ineichen BV, Detmar M, Proulx ST.
Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice.
Nat Commun. 2017 Nov 10;8(1):1434.
PubMed.
In this paper, Ma et al. report that the outflow of cerebrospinal fluid in mice is predominantly through lymphatic vessels, and is reduced with aging. They hypothesize that the lymphatic system may represent a target for age-associated neurological conditions.
The presence of lymphatics in human dura mater was first described by Mascagni in 1787 in his famous book “Vasorum lymphaticorum corporis humani historia et ichonographia.” Since then, his observations, in human subjects, were confirmed by a number of authors who studied connections between subarachnoid space and cervical lymph nodes (Schwalbe 1869; Key and Retzius, 1875; Zwillinger, 1912; Weed, 1914). In 1953, Lecco reported that, during a histological examination of the dura mater of 30 humans, lymphatic structures were found in only four of them. He concluded that lymphatics probably develop in the dura mater of humans for some unknown functional reason and independent of age. In 1964, Földi et al. reported that in human meninges, vessels with the characteristic morphology of lymphatics appeared only in the dura, particularly in regions close to the jugular foramen. In 2015, Aspelund et al. reported that in mice, dural lymphatics were more abundant in the basal than in the apical region.
Currently, we lack:
Comparative and phylogenetic research on the presence and regional distribution of lymphatics of dura mater, with particular attention to the role that the bipodalic evolution could have determined (e.g., what, if any, role could gravity have played in the localization of lymphatics in dura mater?).
Studies in large human populations of the presence and distribution of lymphatics in human dura, with particular attention to a statistical relationship with age, sex, work, lifestyle, morbidities, and other biological parameters that could have an influence.
We want to stress that the present report of Ma et al. did not confute the dogma that lymphatics are absent from in the central nervous system. In fact, dura mater is not, from both an anatomical and embryological point of view, a component of the neuraxis but one of its covers, along with the other meningeal layers.
Moreover, the blood–brain barrier prevents the formation of transudate (interstitial fluid) in the nervous tissue, thus preventing any change in the volume of these structures that would interfere with the functioning of neurons. Since transudate does not form, it is not necessary to have any lymphatic vessel here, as we already reported (Bucchieri et al., 2015).
References:
Schwalbe G.
Der Arachnoidealraum, ein Lymphraum und sein Zusammenhang mit dem Perichorioidealraum.
Z med Wiss 7, 465- (1869).
Key A, Retzius G.
Studien in der Anatomie des Nervensystems und des Bindegewebes.
Samson und Wallin, 1875
Zwillinger H.
Die Lymphbahnen des oberen Nasalschnittes und deren Beziehungen zu den perimeningealen Lymphraumen.
Arch Laryngol und Rhinol 26, 66-78 (1912).
Weed LH.
Studies on Cerebro-Spinal Fluid. No. IV : The dual Source of Cerebro-Spinal Fluid.
J Med Res. 1914 Sep;31(1):93-118.11.
PubMed.
LECCO V.
[Probable modification of the lymphatic fissures of the walls of the venous sinuses of the dura mater].
Arch Ital Otol Rinol Laringol. 1953 May-Jun;64(3):287-96.
PubMed.
Földi M, Gellért A, Kozma M, Poberai M, Zoltán OT, Csanda E.
New contributions to the anatomical connections of the brain and the lymphatic system.
Acta Anat (Basel). 1966;64(4):498-505.
PubMed.
Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K.
A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules.
J Exp Med. 2015 Jun 29;212(7):991-9. Epub 2015 Jun 15
PubMed.
Bucchieri F, Farina F, Zummo G, Cappello F.
Lymphatic vessels of the dura mater: a new discovery?.
J Anat. 2015 Nov;227(5):702-3. Epub 2015 Sep 18
PubMed.
This is a detailed study of CSF drainage. Its novel techniques include pegylated and small-molecule near-infrared (NIR) tracers and lymphatic-specific reporter mice, combined with stereo microscopy and quantitative measurements of tracers in venous blood. From their studies in mice, the authors suggest that the major route for CSF drainage is by perineural pathways, including the olfactory nerves. They found no drainage of tracer along lymphatics in the dura and detected no drainage of CSF directly into venous blood through arachnoid villi. Furthermore, the authors detected reduced clearance of CSF in aged mice, which may have relevance for Alzheimer's disease.
The elegant techniques are a step forward in resolving some of the problems associated with the dynamics of CSF drainage. The authors confirmed many findings from previous studies, and the imaging and quantitation of tracers in venous blood improve our understanding of the physiology of CSF drainage that complements the anatomical studies.
One primary hypothesis tested was that CSF does not flow directly into the venous blood via arachnoid villi. The authors’ results suggest that this is the case in the mouse, but it remains to be determined whether this applies to larger mammals, especially humans. Arachnoid villi in rodents are few in number, small and simple in structure (Kida et al., 1993) compared with arachnoid villi and granulations in humans (Upton and Weller, 1985). It will be interesting to see whether applying the techniques used in this paper can resolve the question of how much CSF drains into the blood through arachnoid villi and granulations in humans, and under what circumstances.
Using intraventricular and cisternal infusions, the authors found that CSF outflow into lymphatic vessels was significantly slower in aged than in young mice. Evidence that this also occurs in humans comes from a study by Mony de Leon et al. (de Leon et al., 2017), who showed by PET that CSF clearance is reduced in Alzheimer's.
The relevance of CSF drainage to Alzheimer's disease, however, still needs to be determined. As shown in experimental studies by Helen Cserr et al in the 1980s (Szentistvanyi et al., 1984) and extended more recently by Carare et al. (Carare et al., 2008, 2013; Weller et al., 2015), interstitial fluid and solutes, including Aβ, drain from the brain parenchyma along narrow, 100–150nm-wide basement membranes in the walls of cerebral arteries and capillaries. This pathway constitutes the major lymphatic drainage pathway from the brain parenchyma.
Failure of the intramural periarterial drainage (IPAD) pathway with age is associated with cerebral amyloid angiopathy (CAA) and Alzheimer's disease. The extremely small size of the IPAD pathways means that they are difficult to resolve with current imaging techniques. We hope that applying similar pegylated and small-molecule NIR tracer techniques used in the present study might further resolve the dynamics of IPAD. Clinical demonstration of IPAD in human patients would greatly assist in monitoring impairment of Aβ elimination from the brain in the elderly, thereby improving the diagnosis and management of CAA and Alzheimer's disease.
References:
Kida S, Pantazis A, Weller RO.
CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance.
Neuropathol Appl Neurobiol. 1993 Dec;19(6):480-8.
PubMed.
Upton ML, Weller RO.
The morphology of cerebrospinal fluid drainage pathways in human arachnoid granulations.
J Neurosurg. 1985 Dec;63(6):867-75.
PubMed.
de Leon MJ, Li Y, Okamura N, Tsui WH, Saint-Louis LA, Glodzik L, Osorio RS, Fortea J, Butler T, Pirraglia E, Fossati S, Kim HJ, Carare RO, Nedergaard M, Benveniste H, Rusinek H.
Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET.
J Nucl Med. 2017 Sep;58(9):1471-1476. Epub 2017 Mar 16
PubMed.
Szentistványi I, Patlak CS, Ellis RA, Cserr HF.
Drainage of interstitial fluid from different regions of rat brain.
Am J Physiol. 1984 Jun;246(6 Pt 2):F835-44.
PubMed.
Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JA, Perry VH, Weller RO.
Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology.
Neuropathol Appl Neurobiol. 2008 Apr;34(2):131-44. Epub 2008 Jan 16
PubMed.
Carare RO, Hawkes CA, Jeffrey M, Kalaria RN, Weller RO.
Cerebral amyloid angiopathy, Prion angiopathy, CADASIL and the spectrum of Protein Elimination-Failure Angiopathies (PEFA) in neurodegenerative disease with a focus on therapy.
Neuropathol Appl Neurobiol. 2013 Mar 13;
PubMed.
Weller RO, Hawkes CA, Carare RO, Hardy J.
Does the difference between PART and Alzheimer's disease lie in the age-related changes in cerebral arteries that trigger the accumulation of Aβ and propagation of tau?.
Acta Neuropathol. 2015 May;129(5):763-6. Epub 2015 Mar 27
PubMed.
Comments
University of Palermo
University of Palermo
In this paper, Ma et al. report that the outflow of cerebrospinal fluid in mice is predominantly through lymphatic vessels, and is reduced with aging. They hypothesize that the lymphatic system may represent a target for age-associated neurological conditions.
The presence of lymphatics in human dura mater was first described by Mascagni in 1787 in his famous book “Vasorum lymphaticorum corporis humani historia et ichonographia.” Since then, his observations, in human subjects, were confirmed by a number of authors who studied connections between subarachnoid space and cervical lymph nodes (Schwalbe 1869; Key and Retzius, 1875; Zwillinger, 1912; Weed, 1914). In 1953, Lecco reported that, during a histological examination of the dura mater of 30 humans, lymphatic structures were found in only four of them. He concluded that lymphatics probably develop in the dura mater of humans for some unknown functional reason and independent of age. In 1964, Földi et al. reported that in human meninges, vessels with the characteristic morphology of lymphatics appeared only in the dura, particularly in regions close to the jugular foramen. In 2015, Aspelund et al. reported that in mice, dural lymphatics were more abundant in the basal than in the apical region.
Currently, we lack:
We want to stress that the present report of Ma et al. did not confute the dogma that lymphatics are absent from in the central nervous system. In fact, dura mater is not, from both an anatomical and embryological point of view, a component of the neuraxis but one of its covers, along with the other meningeal layers.
Moreover, the blood–brain barrier prevents the formation of transudate (interstitial fluid) in the nervous tissue, thus preventing any change in the volume of these structures that would interfere with the functioning of neurons. Since transudate does not form, it is not necessary to have any lymphatic vessel here, as we already reported (Bucchieri et al., 2015).
References:
Schwalbe G. Der Arachnoidealraum, ein Lymphraum und sein Zusammenhang mit dem Perichorioidealraum. Z med Wiss 7, 465- (1869).
Key A, Retzius G. Studien in der Anatomie des Nervensystems und des Bindegewebes. Samson und Wallin, 1875
Zwillinger H. Die Lymphbahnen des oberen Nasalschnittes und deren Beziehungen zu den perimeningealen Lymphraumen. Arch Laryngol und Rhinol 26, 66-78 (1912).
Weed LH. Studies on Cerebro-Spinal Fluid. No. IV : The dual Source of Cerebro-Spinal Fluid. J Med Res. 1914 Sep;31(1):93-118.11. PubMed.
LECCO V. [Probable modification of the lymphatic fissures of the walls of the venous sinuses of the dura mater]. Arch Ital Otol Rinol Laringol. 1953 May-Jun;64(3):287-96. PubMed.
Földi M, Gellért A, Kozma M, Poberai M, Zoltán OT, Csanda E. New contributions to the anatomical connections of the brain and the lymphatic system. Acta Anat (Basel). 1966;64(4):498-505. PubMed.
Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015 Jun 29;212(7):991-9. Epub 2015 Jun 15 PubMed.
Bucchieri F, Farina F, Zummo G, Cappello F. Lymphatic vessels of the dura mater: a new discovery?. J Anat. 2015 Nov;227(5):702-3. Epub 2015 Sep 18 PubMed.
View all comments by Francesco CappelloUniversity of Southampton School of Medicine
University of Southampton School of Medicine
This is a detailed study of CSF drainage. Its novel techniques include pegylated and small-molecule near-infrared (NIR) tracers and lymphatic-specific reporter mice, combined with stereo microscopy and quantitative measurements of tracers in venous blood. From their studies in mice, the authors suggest that the major route for CSF drainage is by perineural pathways, including the olfactory nerves. They found no drainage of tracer along lymphatics in the dura and detected no drainage of CSF directly into venous blood through arachnoid villi. Furthermore, the authors detected reduced clearance of CSF in aged mice, which may have relevance for Alzheimer's disease.
The elegant techniques are a step forward in resolving some of the problems associated with the dynamics of CSF drainage. The authors confirmed many findings from previous studies, and the imaging and quantitation of tracers in venous blood improve our understanding of the physiology of CSF drainage that complements the anatomical studies.
One primary hypothesis tested was that CSF does not flow directly into the venous blood via arachnoid villi. The authors’ results suggest that this is the case in the mouse, but it remains to be determined whether this applies to larger mammals, especially humans. Arachnoid villi in rodents are few in number, small and simple in structure (Kida et al., 1993) compared with arachnoid villi and granulations in humans (Upton and Weller, 1985). It will be interesting to see whether applying the techniques used in this paper can resolve the question of how much CSF drains into the blood through arachnoid villi and granulations in humans, and under what circumstances.
Using intraventricular and cisternal infusions, the authors found that CSF outflow into lymphatic vessels was significantly slower in aged than in young mice. Evidence that this also occurs in humans comes from a study by Mony de Leon et al. (de Leon et al., 2017), who showed by PET that CSF clearance is reduced in Alzheimer's.
The relevance of CSF drainage to Alzheimer's disease, however, still needs to be determined. As shown in experimental studies by Helen Cserr et al in the 1980s (Szentistvanyi et al., 1984) and extended more recently by Carare et al. (Carare et al., 2008, 2013; Weller et al., 2015), interstitial fluid and solutes, including Aβ, drain from the brain parenchyma along narrow, 100–150nm-wide basement membranes in the walls of cerebral arteries and capillaries. This pathway constitutes the major lymphatic drainage pathway from the brain parenchyma.
Failure of the intramural periarterial drainage (IPAD) pathway with age is associated with cerebral amyloid angiopathy (CAA) and Alzheimer's disease. The extremely small size of the IPAD pathways means that they are difficult to resolve with current imaging techniques. We hope that applying similar pegylated and small-molecule NIR tracer techniques used in the present study might further resolve the dynamics of IPAD. Clinical demonstration of IPAD in human patients would greatly assist in monitoring impairment of Aβ elimination from the brain in the elderly, thereby improving the diagnosis and management of CAA and Alzheimer's disease.
References:
Kida S, Pantazis A, Weller RO. CSF drains directly from the subarachnoid space into nasal lymphatics in the rat. Anatomy, histology and immunological significance. Neuropathol Appl Neurobiol. 1993 Dec;19(6):480-8. PubMed.
Upton ML, Weller RO. The morphology of cerebrospinal fluid drainage pathways in human arachnoid granulations. J Neurosurg. 1985 Dec;63(6):867-75. PubMed.
de Leon MJ, Li Y, Okamura N, Tsui WH, Saint-Louis LA, Glodzik L, Osorio RS, Fortea J, Butler T, Pirraglia E, Fossati S, Kim HJ, Carare RO, Nedergaard M, Benveniste H, Rusinek H. Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET. J Nucl Med. 2017 Sep;58(9):1471-1476. Epub 2017 Mar 16 PubMed.
Szentistványi I, Patlak CS, Ellis RA, Cserr HF. Drainage of interstitial fluid from different regions of rat brain. Am J Physiol. 1984 Jun;246(6 Pt 2):F835-44. PubMed.
Carare RO, Bernardes-Silva M, Newman TA, Page AM, Nicoll JA, Perry VH, Weller RO. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol. 2008 Apr;34(2):131-44. Epub 2008 Jan 16 PubMed.
Carare RO, Hawkes CA, Jeffrey M, Kalaria RN, Weller RO. Cerebral amyloid angiopathy, Prion angiopathy, CADASIL and the spectrum of Protein Elimination-Failure Angiopathies (PEFA) in neurodegenerative disease with a focus on therapy. Neuropathol Appl Neurobiol. 2013 Mar 13; PubMed.
Weller RO, Hawkes CA, Carare RO, Hardy J. Does the difference between PART and Alzheimer's disease lie in the age-related changes in cerebral arteries that trigger the accumulation of Aβ and propagation of tau?. Acta Neuropathol. 2015 May;129(5):763-6. Epub 2015 Mar 27 PubMed.
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