Both Berezuk et al. and Suzuki et al. focus on the often-neglected role of the Virchow-Robin spaces that control the rate of bulk flow of brain interstitial fluid (ISF), including clearance of potentially toxic substances from brain. Therefore, changes in the volume of these periarterial spaces, as shown by Berezuk et al., in patients with cerebrovascular disorder during sleep, and altered influx of water into the brains of Alzheimer’s disease (AD) patients compared to controls, as shown by Suzuzki et al., are both extremely interesting. The papers illustrate the dynamic physiological changes in the volume of the Virchow-Robin spaces during sleep and disease-driven changes in AD, which both can influence the rate of ISF-CSF solute exchanges and fluid-mediated clearance of solutes from brain.
The broader question remains, however, exactly how changes in the Virchow-Robin space volume contribute to clearance of solutes from brain, and how the size of these perivascular spaces relates to changes in the cerebral vascular system and blood vessels including small vessel disease, loss of blood-brain barrier (BBB) integrity, and transport function, all of which can affect ISF-CSF dynamics. For example, during sleep in the mouse model, it has been shown that accelerated ISF-to-CSF bulk flow rate is responsible for an approximately 40 percent of the increase in total Aβ clearance from the brain, whereas approximately 60 percent increase in Aβ clearance during sleep is regulated by accelerated transvascular Aβ transport (Xie et al., 2013) via transport across the BBB (Deane et al., 2004), as recently reviewed in greater detail (Tarasoff-Conway et al., 2015). However, how these two transport phenomena relate to each other is not currently known. More work is also needed to establish, for example, the consequences of interrupted ISF-CSF flow drainage along the Virchow-Robin spaces when blocked by blood-derived products coming into the brain across the disrupted BBB and/or by proteinaceous products generated in brain, as both processes likely occur simultaneously in many neurodegenerative diseases, including Alzheimer’s.
References:
Berezuk C, Ramirez J, Gao F, Scott CJ, Huroy M, Swartz RH, Murray BJ, Black SE, Boulos MI.
Virchow-Robin Spaces: Correlations with Polysomnography-Derived Sleep Parameters.
Sleep. 2015 Jun 1;38(6):853-8.
PubMed.
Suzuki Y, Nakamura Y, Yamada K, Igarashi H, Kasuga K, Yokoyama Y, Ikeuchi T, Nishizawa M, Kwee IL, Nakada T.
Reduced CSF Water Influx in Alzheimer's Disease Supporting the β-Amyloid Clearance Hypothesis.
PLoS One. 2015;10(5):e0123708. Epub 2015 May 6
PubMed.
Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M.
Sleep drives metabolite clearance from the adult brain.
Science. 2013 Oct 18;342(6156):373-7.
PubMed.
Deane R, Wu Z, Zlokovic BV.
RAGE (yin) versus LRP (yang) balance regulates alzheimer amyloid beta-peptide clearance through transport across the blood-brain barrier.
Stroke. 2004 Nov;35(11 Suppl 1):2628-31.
PubMed.
Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, Axel L, Rusinek H, Nicholson C, Zlokovic BV, Frangione B, Blennow K, Ménard J, Zetterberg H, Wisniewski T, de Leon MJ.
Clearance systems in the brain-implications for Alzheimer disease.
Nat Rev Neurol. 2015 Aug;11(8):457-70. Epub 2015 Jul 21
PubMed.
Using PET imaging, Suzuki et al. demonstrate that clearance of Aβ from the brain parenchyma into the cerebrospinal fluid is reduced in aged individuals and in those with Alzheimer’s disease (Suzuki et al., 2015). We have demonstrated that clearance of Aβ from the parenchyma occurs along the basement membranes of capillaries and arteries toward the subarachnoid space (Carare et al., 2008; Keable et al., 2016). It is still unclear how much Aβ is released into the subarachnoid space and how much reaches the cervical lymph nodes, although earlier physiological studies estimate that only 10 percent of interstitial fluid reaches the CSF (Carare et al., 2008; Keable et al., 2016; Szentistvanyi et al., 1996). With the accumulation of Aβ in the walls of arteries, the clearance of interstitial fluid along those walls decreases, and thus less Aβ reaches the CSF (Hawkes et al., 2011). Aging also impairs the convective influx of CSF into the parenchyma (Kress et al., 2014). The study by Suzuki et al. provides further evidence that impairment of the different mechanisms for the exchanges between interstitial fluid and cerebrospinal fluid require careful experimental investigation, since the molecular mechanisms may be translated into therapies for Alzheimer’s disease patients.
Impairment of perivascular drainage along the basement membranes of capillaries and arteries results in the accumulation of Aβ in the walls of cortical capillaries and arteries as cerebral amyloid angiopathy, a common finding in Alzheimer’s disease (Iadecola and Zhang, 1996). It is likely that blocking the perivascular drainage pathways in the cortex results in the dilatation of perivascular spaces in the underlying white matter (Weller et al., 2015). The study by Berezuk, Ramirez, and colleagues demonstrates the relationship between sleep and dilated perivascular spaces in a cohort of people of a mean age of 60 years old (Berezuk et al., 2015). The dimensions of the perivascular spaces in the white matter and basal ganglia were correlated to the efficiency of sleep and to the time spent awake after the first sleep and before final awakening. Poor sleep correlated with enlarged perivascular spaces and difficulty in staying asleep correlated especially with the dilated perivascular spaces in the basal ganglia. The anatomical structure of the arteries in the basal ganglia is different from that of the arteries in the cortex, because arteries in the basal ganglia possess a double layer of leptomeninges around them, allowing excess fluid to accumulate between the two (Alcolado et al., 1988; Pollock et al., 1997). Our current observations (manuscript under preparation) demonstrate that arteries in the white matter are also surrounded by a double layer of leptomeninges, in contrast to arteries in the cortex that only have one layer of leptomeninges tightly adjacent to the rest of the wall of the artery.
Sleep is associated with the release of multiple neurotransmitters, including acetylcholine that actively maintains the tone of arteries (Iadecola and Zhang, 1996), contributing to efficient perivascular clearance (Sauvet et al., 2014). Berezuk et al. provide substantial evidence that lack of sleep affects perivascular clearance from the brain parenchyma, probably due to an imbalance in the neurotransmitters that regulate the tone of arteries, resulting in dilatation of perivascular spaces in areas where the anatomical structure of arteries permits the accumulation of excess fluid. This opens the avenue for further experimental studies to clarify the exact mechanisms underlying the dynamics of sleep, neurotransmitters and effects on impaired perivascular clearance.
References:
Alcolado R, Weller RO, Parrish EP, Garrod D.
The cranial arachnoid and pia mater in man: anatomical and ultrastructural observations.
Neuropathol Appl Neurobiol. 1988 Jan-Feb;14(1):1-17.
PubMed.
Berezuk C, Ramirez J, Gao F, Scott CJ, Huroy M, Swartz RH, Murray BJ, Black SE, Boulos MI.
Virchow-Robin Spaces: Correlations with Polysomnography-Derived Sleep Parameters.
Sleep. 2015 Jun 1;38(6):853-8.
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.
Hawkes CA, Härtig W, Kacza J, Schliebs R, Weller RO, Nicoll JA, Carare RO.
Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy.
Acta Neuropathol. 2011 Apr;121(4):431-43. Epub 2011 Jan 23
PubMed.
Iadecola C, Zhang F.
Permissive and obligatory roles of NO in cerebrovascular responses to hypercapnia and acetylcholine.
Am J Physiol. 1996 Oct;271(4 Pt 2):R990-1001.
PubMed.
Keable A, Fenna K, Yuen HM, Johnston DA, Smyth NR, Smith C, Al-Shahi Salman R, Samarasekera N, Nicoll JA, Attems J, Kalaria RN, Weller RO, Carare RO.
Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy.
Biochim Biophys Acta. 2016 May;1862(5):1037-46. Epub 2015 Aug 29
PubMed.
Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D, Xie L, Kang H, Xu Q, Liew JA, Plog BA, Ding F, Deane R, Nedergaard M.
Impairment of paravascular clearance pathways in the aging brain.
Ann Neurol. 2014 Dec;76(6):845-61. Epub 2014 Sep 26
PubMed.
Pollock H, Hutchings M, Weller RO, Zhang ET.
Perivascular spaces in the basal ganglia of the human brain: their relationship to lacunes.
J Anat. 1997 Oct;191 ( Pt 3):337-46.
PubMed.
Sauvet F, Florence G, Van Beers P, Drogou C, Lagrume C, Chaumes C, Ciret S, Leftheriotis G, Chennaoui M.
Total sleep deprivation alters endothelial function in rats: a nonsympathetic mechanism.
Sleep. 2014 Mar 1;37(3):465-73.
PubMed.
Suzuki Y, Nakamura Y, Yamada K, Igarashi H, Kasuga K, Yokoyama Y, Ikeuchi T, Nishizawa M, Kwee IL, Nakada T.
Reduced CSF Water Influx in Alzheimer's Disease Supporting the β-Amyloid Clearance Hypothesis.
PLoS One. 2015;10(5):e0123708. Epub 2015 May 6
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.
Weller RO, Hawkes CA, Kalaria RN, Werring DJ, Carare RO.
White matter changes in dementia: role of impaired drainage of interstitial fluid.
Brain Pathol. 2015 Jan;25(1):63-78.
PubMed.
Comments
University of Southern California
Both Berezuk et al. and Suzuki et al. focus on the often-neglected role of the Virchow-Robin spaces that control the rate of bulk flow of brain interstitial fluid (ISF), including clearance of potentially toxic substances from brain. Therefore, changes in the volume of these periarterial spaces, as shown by Berezuk et al., in patients with cerebrovascular disorder during sleep, and altered influx of water into the brains of Alzheimer’s disease (AD) patients compared to controls, as shown by Suzuzki et al., are both extremely interesting. The papers illustrate the dynamic physiological changes in the volume of the Virchow-Robin spaces during sleep and disease-driven changes in AD, which both can influence the rate of ISF-CSF solute exchanges and fluid-mediated clearance of solutes from brain.
The broader question remains, however, exactly how changes in the Virchow-Robin space volume contribute to clearance of solutes from brain, and how the size of these perivascular spaces relates to changes in the cerebral vascular system and blood vessels including small vessel disease, loss of blood-brain barrier (BBB) integrity, and transport function, all of which can affect ISF-CSF dynamics. For example, during sleep in the mouse model, it has been shown that accelerated ISF-to-CSF bulk flow rate is responsible for an approximately 40 percent of the increase in total Aβ clearance from the brain, whereas approximately 60 percent increase in Aβ clearance during sleep is regulated by accelerated transvascular Aβ transport (Xie et al., 2013) via transport across the BBB (Deane et al., 2004), as recently reviewed in greater detail (Tarasoff-Conway et al., 2015). However, how these two transport phenomena relate to each other is not currently known. More work is also needed to establish, for example, the consequences of interrupted ISF-CSF flow drainage along the Virchow-Robin spaces when blocked by blood-derived products coming into the brain across the disrupted BBB and/or by proteinaceous products generated in brain, as both processes likely occur simultaneously in many neurodegenerative diseases, including Alzheimer’s.
References:
Berezuk C, Ramirez J, Gao F, Scott CJ, Huroy M, Swartz RH, Murray BJ, Black SE, Boulos MI. Virchow-Robin Spaces: Correlations with Polysomnography-Derived Sleep Parameters. Sleep. 2015 Jun 1;38(6):853-8. PubMed.
Suzuki Y, Nakamura Y, Yamada K, Igarashi H, Kasuga K, Yokoyama Y, Ikeuchi T, Nishizawa M, Kwee IL, Nakada T. Reduced CSF Water Influx in Alzheimer's Disease Supporting the β-Amyloid Clearance Hypothesis. PLoS One. 2015;10(5):e0123708. Epub 2015 May 6 PubMed.
Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18;342(6156):373-7. PubMed.
Deane R, Wu Z, Zlokovic BV. RAGE (yin) versus LRP (yang) balance regulates alzheimer amyloid beta-peptide clearance through transport across the blood-brain barrier. Stroke. 2004 Nov;35(11 Suppl 1):2628-31. PubMed.
Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, Axel L, Rusinek H, Nicholson C, Zlokovic BV, Frangione B, Blennow K, Ménard J, Zetterberg H, Wisniewski T, de Leon MJ. Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol. 2015 Aug;11(8):457-70. Epub 2015 Jul 21 PubMed.
View all comments by Berislav ZlokovicUniversity of Southampton School of Medicine
University of Southampton School of Medicine
Using PET imaging, Suzuki et al. demonstrate that clearance of Aβ from the brain parenchyma into the cerebrospinal fluid is reduced in aged individuals and in those with Alzheimer’s disease (Suzuki et al., 2015). We have demonstrated that clearance of Aβ from the parenchyma occurs along the basement membranes of capillaries and arteries toward the subarachnoid space (Carare et al., 2008; Keable et al., 2016). It is still unclear how much Aβ is released into the subarachnoid space and how much reaches the cervical lymph nodes, although earlier physiological studies estimate that only 10 percent of interstitial fluid reaches the CSF (Carare et al., 2008; Keable et al., 2016; Szentistvanyi et al., 1996). With the accumulation of Aβ in the walls of arteries, the clearance of interstitial fluid along those walls decreases, and thus less Aβ reaches the CSF (Hawkes et al., 2011). Aging also impairs the convective influx of CSF into the parenchyma (Kress et al., 2014). The study by Suzuki et al. provides further evidence that impairment of the different mechanisms for the exchanges between interstitial fluid and cerebrospinal fluid require careful experimental investigation, since the molecular mechanisms may be translated into therapies for Alzheimer’s disease patients.
Impairment of perivascular drainage along the basement membranes of capillaries and arteries results in the accumulation of Aβ in the walls of cortical capillaries and arteries as cerebral amyloid angiopathy, a common finding in Alzheimer’s disease (Iadecola and Zhang, 1996). It is likely that blocking the perivascular drainage pathways in the cortex results in the dilatation of perivascular spaces in the underlying white matter (Weller et al., 2015). The study by Berezuk, Ramirez, and colleagues demonstrates the relationship between sleep and dilated perivascular spaces in a cohort of people of a mean age of 60 years old (Berezuk et al., 2015). The dimensions of the perivascular spaces in the white matter and basal ganglia were correlated to the efficiency of sleep and to the time spent awake after the first sleep and before final awakening. Poor sleep correlated with enlarged perivascular spaces and difficulty in staying asleep correlated especially with the dilated perivascular spaces in the basal ganglia. The anatomical structure of the arteries in the basal ganglia is different from that of the arteries in the cortex, because arteries in the basal ganglia possess a double layer of leptomeninges around them, allowing excess fluid to accumulate between the two (Alcolado et al., 1988; Pollock et al., 1997). Our current observations (manuscript under preparation) demonstrate that arteries in the white matter are also surrounded by a double layer of leptomeninges, in contrast to arteries in the cortex that only have one layer of leptomeninges tightly adjacent to the rest of the wall of the artery.
Sleep is associated with the release of multiple neurotransmitters, including acetylcholine that actively maintains the tone of arteries (Iadecola and Zhang, 1996), contributing to efficient perivascular clearance (Sauvet et al., 2014). Berezuk et al. provide substantial evidence that lack of sleep affects perivascular clearance from the brain parenchyma, probably due to an imbalance in the neurotransmitters that regulate the tone of arteries, resulting in dilatation of perivascular spaces in areas where the anatomical structure of arteries permits the accumulation of excess fluid. This opens the avenue for further experimental studies to clarify the exact mechanisms underlying the dynamics of sleep, neurotransmitters and effects on impaired perivascular clearance.
References:
Alcolado R, Weller RO, Parrish EP, Garrod D. The cranial arachnoid and pia mater in man: anatomical and ultrastructural observations. Neuropathol Appl Neurobiol. 1988 Jan-Feb;14(1):1-17. PubMed.
Berezuk C, Ramirez J, Gao F, Scott CJ, Huroy M, Swartz RH, Murray BJ, Black SE, Boulos MI. Virchow-Robin Spaces: Correlations with Polysomnography-Derived Sleep Parameters. Sleep. 2015 Jun 1;38(6):853-8. 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.
Hawkes CA, Härtig W, Kacza J, Schliebs R, Weller RO, Nicoll JA, Carare RO. Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol. 2011 Apr;121(4):431-43. Epub 2011 Jan 23 PubMed.
Iadecola C, Zhang F. Permissive and obligatory roles of NO in cerebrovascular responses to hypercapnia and acetylcholine. Am J Physiol. 1996 Oct;271(4 Pt 2):R990-1001. PubMed.
Keable A, Fenna K, Yuen HM, Johnston DA, Smyth NR, Smith C, Al-Shahi Salman R, Samarasekera N, Nicoll JA, Attems J, Kalaria RN, Weller RO, Carare RO. Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy. Biochim Biophys Acta. 2016 May;1862(5):1037-46. Epub 2015 Aug 29 PubMed.
Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D, Xie L, Kang H, Xu Q, Liew JA, Plog BA, Ding F, Deane R, Nedergaard M. Impairment of paravascular clearance pathways in the aging brain. Ann Neurol. 2014 Dec;76(6):845-61. Epub 2014 Sep 26 PubMed.
Pollock H, Hutchings M, Weller RO, Zhang ET. Perivascular spaces in the basal ganglia of the human brain: their relationship to lacunes. J Anat. 1997 Oct;191 ( Pt 3):337-46. PubMed.
Sauvet F, Florence G, Van Beers P, Drogou C, Lagrume C, Chaumes C, Ciret S, Leftheriotis G, Chennaoui M. Total sleep deprivation alters endothelial function in rats: a nonsympathetic mechanism. Sleep. 2014 Mar 1;37(3):465-73. PubMed.
Suzuki Y, Nakamura Y, Yamada K, Igarashi H, Kasuga K, Yokoyama Y, Ikeuchi T, Nishizawa M, Kwee IL, Nakada T. Reduced CSF Water Influx in Alzheimer's Disease Supporting the β-Amyloid Clearance Hypothesis. PLoS One. 2015;10(5):e0123708. Epub 2015 May 6 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.
Weller RO, Hawkes CA, Kalaria RN, Werring DJ, Carare RO. White matter changes in dementia: role of impaired drainage of interstitial fluid. Brain Pathol. 2015 Jan;25(1):63-78. PubMed.
View all comments by Roy WellerMake a Comment
To make a comment you must login or register.