Dynamics of Evans blue clearance from cerebrospinal fluid into meningeal lymphatic vessels and deep cervical lymph nodes

AbstractThe lack of draining lymphatic vessels in the central nervous system (CNS) contributes to the so-called “CNS immune privilege.” However, despite such a unique anatomic feature, dendritic cells (DCs) are able to migrate from the CNS to cervical lymph nodes through a yet unknown pathway. In this report, labeled bone marrow-derived myeloid DCs were injected stereotaxically into the cerebrospinal fluid (CSF) or brain parenchyma of normal rats. We found that DCs injected within brain parenchyma migrate little from their site of injection and do not reach cervical lymph nodes. In contrast, intra-CSF-injected DCs either reach cervical lymph nodes or, for a minority of them, infiltrate the subventricular zone, where neural stem cells reside. Surprisingly, DCs that reach cervical lymph nodes preferentially target B-cell follicles rather than T-cell-rich areas. This report sheds a new light on the specific role exerted by CSF-infiltrating DCs in the control of CNS-targeted immune responses. (Blood. 2006; 107:806-812)

Download Full-text

Neural glymphatic system: Clinical implications and potential importance of melatonin

Melatonin Research ◽

10.32794/mr112500111 ◽

2021 ◽

Vol 4 (4) ◽

pp. 551-565

Author(s):

Ryan D Bitar ◽

Jorge L Torres-Garza ◽

Russel J Reiter ◽

William T Phillips

Keyword(s):

Lymph Nodes ◽

Subarachnoid Space ◽

Slow Wave Sleep ◽

Lymphatic Vessels ◽

Amyloid Β ◽

Secretory Product ◽

Cervical Lymph Nodes ◽

Waste Products ◽

Glymphatic System ◽

The Brain

The central nervous system was thought to lack a lymphatic drainage until the recent discovery of the neural glymphatic system. This highly specialized waste disposal network includes classical lymphatic vessels in the dura that absorb fluid and metabolic by-products and debris from the underlying cerebrospinal fluid (CSF) in the subarachnoid space. The subarachnoid space is continuous with the Virchow-Robin peri-arterial and peri-vascular spaces which surround the arteries and veins that penetrate into the neural tissue, respectively. The dural lymphatic vessels exit the cranial vault via an anterior and a posterior route and eventually drain into the deep cervical lymph nodes. Aided by the presence of aquaporin 4 on the perivascular endfeet of astrocytes, nutrients and other molecules enter the brain from peri-arterial spaces and form interstitial fluid (ISF) that baths neurons and glia before being released into peri-venous spaces. Melatonin, a pineal-derived secretory product which is in much higher concentration in the CSF than in the blood, is believed to follow this route and to clear waste products such as amyloid-β from the interstitial space. The clearance of amyloid-β reportedly occurs especially during slow wave sleep which happens concurrently with highest CSF levels of melatonin. Experimentally, exogenously-administered melatonin defers amyloid-β buildup in the brain of animals and causes its accumulation in the cervical lymph nodes. Clinically, with increased age CSF melatonin levels decrease markedly, co-incident with neurodegeneration and dementia. Collectively, these findings suggest a potential association between the loss of melatonin, decreased glymphatic drainage and neurocognitive decline in the elderly.

Download Full-text

An Experimental Model of Human Leukemic Meningitis in the Nude Rat

Blood ◽

10.1182/blood.v90.1.298 ◽

1997 ◽

Vol 90 (1) ◽

pp. 298-305 ◽

Cited By ~ 7

Author(s):

Tara A. Barone ◽

Robert J. Plunkett ◽

Philip Hohmann ◽

Agnieszka Lis ◽

Norman Glenister ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Lymph Nodes ◽

Lymphoblastic Leukemia ◽

Human Condition ◽

Leukemic Cells ◽

Leukemia Cell Line ◽

Cervical Lymph Nodes ◽

Nude Rat ◽

Leukemic Meningitis ◽

Meningeal Leukemia

Abstract An experimental animal model of meningeal leukemia was developed in the nude rat, rnu/rnu, using the human-derived acute lymphoblastic leukemia cell line HPB-ALL. Anesthetized rats were placed in a modified stereotaxic frame and then injected intrathecally, at the level of the cisterna magna, with human leukemic cells. Cerebrospinal fluid and tissue samples from brain, spinal cord, heart, liver, kidney, spleen, bone marrow, and cervical lymph nodes were subjected to histopathologic examination and molecular genetic screening by clonotype primer-directed polymerase chain reaction (CPD-PCR). Ninety-three percent of animals (n = 14) developed signs of meningeal irritation leading to death 30 to 63 days postinjection (median, 36.0 days, mean, 38.7); death occurred between 30 and 39 days in 77% of all animals. Leukemic cells progressively infiltrated the pericerebellar and pericerebral subarachnoid space and infiltrated the Virchow-Robin (perivascular) space. The infiltrating meningeal leukemia closely resembled the pathologic presentation in the human condition. By CPD-PCR, leukemic cells were first detected in cerebrospinal fluid (CSF ) on day 4 postinjection, were variably present over the ensuing 17 days, and were consistently detected after day 21. At terminal stages, CPD-PCR tissue surveys showed leukemic DNA in all brains and spinal cords and rarely in cervical lymph nodes, but leukemic DNA was not detected in any other tissue screened. Leukemic meningitis was reliably produced with a predictable survival time. Intrathecal administration of leukemic cells was an efficient means of transmitting leukemic meningitis and it compartmentalized the disease to the central nervous system (CNS), eliminating potential complications of systemic illness. The use of human-derived cell lines may render this model more relevant to the development of future therapeutic strategies to treat leukemia and lymphoma that invade the CNS.

Download Full-text

Altered Cerebrospinal Fluid Clearance and Increased Intracranial Pressure in Rats 18 h After Experimental Cortical Ischaemia

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.712779 ◽

2021 ◽

Vol 14 ◽

Author(s):

Steven W. Bothwell ◽

Daniel Omileke ◽

Rebecca J. Hood ◽

Debbie-Gai Pepperall ◽

Sara Azarpeykan ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Intracranial Pressure ◽

Lymph Nodes ◽

Subarachnoid Space ◽

Ex Vivo ◽

Bimodal Distribution ◽

Cervical Lymph Nodes ◽

Post Stroke ◽

Spinal Subarachnoid Space

Oedema-independent intracranial pressure (ICP) rise peaks 20–22-h post-stroke in rats and may explain early neurological deterioration. Cerebrospinal fluid (CSF) volume changes may be involved. Cranial CSF clearance primarily occurs via the cervical lymphatics and movement into the spinal portion of the cranio-spinal compartment. We explored whether impaired CSF clearance at these sites could explain ICP rise after stroke. We recorded ICP at baseline and 18-h post-stroke, when we expect changes contributing to peak ICP to be present. CSF clearance was assessed in rats receiving photothrombotic stroke or sham surgery by intraventricular tracer infusion. Tracer concentration was quantified in the deep cervical lymph nodes ex vivo and tracer transit to the spinal subarachnoid space was imaged in vivo. ICP rose significantly from baseline to 18-h post-stroke in stroke vs. sham rats [median = 5 mmHg, interquartile range (IQR) = 0.1–9.43, n = 12, vs. −0.3 mmHg, IQR = −1.9–1.7, n = 10], p = 0.03. There was a bimodal distribution of rats with and without ICP rise. Tracer in the deep cervical lymph nodes was significantly lower in stroke with ICP rise (0 μg/mL, IQR = 0–0.11) and without ICP rise (0 μg/mL, IQR = 0–4.47) compared with sham rats (4.17 μg/mL, IQR = 0.74–8.51), p = 0.02. ICP rise was inversely correlated with faster CSF transit to the spinal subarachnoid space (R = −0.59, p = 0.006, Spearman’s correlation). These data suggest that reduced cranial clearance of CSF via cervical lymphatics may contribute to post-stroke ICP rise, partially compensated via increased spinal CSF outflow.

Download Full-text

The cerebrospinal fluid and the cervical lymph nodes

The Anatomical Record ◽

10.1002/ar.1090560405 ◽

1933 ◽

Vol 56 (4) ◽

pp. 359-363 ◽

Cited By ~ 18

Author(s):

O. A. Mortensen ◽

W. E. Sullivan

Keyword(s):

Cerebrospinal Fluid ◽

Lymph Nodes ◽

Cervical Lymph Nodes

Download Full-text

Drainage of interstitial fluid from different regions of rat brain

AJP Renal Physiology ◽

10.1152/ajprenal.1984.246.6.f835 ◽

1984 ◽

Vol 246 (6) ◽

pp. F835-F844 ◽

Cited By ~ 41

Author(s):

I. Szentistvanyi ◽

C. S. Patlak ◽

R. A. Ellis ◽

H. F. Cserr

Keyword(s):

Cerebrospinal Fluid ◽

Horseradish Peroxidase ◽

Lymph Nodes ◽

Caudate Nucleus ◽

Evans Blue ◽

Subarachnoid Space ◽

Interstitial Fluid ◽

Internal Capsule ◽

Olfactory Nerve ◽

Flow Through

Studies were carried out in anesthetized rats comparing dynamics and pathways of interstitial fluid (ISF) drainage from different regions of brain. Rates of drainage from brain and flow into cerebrospinal fluid (CSF) were estimated from the efflux from brain and influx into CSF of radioiodinated albumin (RISA) following microinjection into caudate nucleus, internal capsule, or midbrain: pathways of flow through the subarachnoid space and into lymph were traced from the distribution of horseradish peroxidase and/or Evans blue-labeled albumin after injection into brain. ISF drainage rates (mul X g brain-1 X min-1) estimated for the three injection sites were 0.18, 0.19, and 0.29, respectively. Flow of ISF into bulk CSF sampled from the cisterna magna accounted for 60-75% of efflux from midbrain but only 10-15% of efflux from caudate nucleus or internal capsule. RISA was concentrated in the subarachnoid space, relative to bulk CSF, in sleeves of adventitial tissue surrounding pericerebral arteries, possibly accounting for the low recovery of isotope from bulk CSF. From the subarachnoid space, some fluid drained via olfactory nerve sheaths to retropharyngeal lymph nodes.

Download Full-text

Role of cervical lymph nodes in the systemic humoral immune response to human serum albumin microinfused into rat cerebrospinal fluid

Journal of Neuroimmunology ◽

10.1016/0165-5728(89)90136-7 ◽

1989 ◽

Vol 25 (2-3) ◽

pp. 185-193 ◽

Cited By ~ 134

Author(s):

Christine Harling-Berg ◽

Paul M. Knopf ◽

Jennifer Merriam ◽

Helen F. Cserr

Keyword(s):

Immune Response ◽

Cerebrospinal Fluid ◽

Human Serum Albumin ◽

Serum Albumin ◽

Lymph Nodes ◽

Human Serum ◽

Humoral Immune Response ◽

Cervical Lymph Nodes ◽

Humoral Immune

Download Full-text

Primary effusion lymphoma involving cerebrospinal fluid, deep cervical lymph nodes and adenoids. Report of a case supporting the lymphatic connection between brain and lymph nodes

Neuropathology ◽

10.1111/neup.12353 ◽

2016 ◽

Vol 37 (3) ◽

pp. 249-258

Author(s):

Carlos Santonja ◽

Camino Medina-Puente ◽

Cristina Serrano del Castillo ◽

Alfonso Cabello Úbeda ◽

Socorro María Rodríguez-Pinilla

Keyword(s):

Cerebrospinal Fluid ◽

Lymph Nodes ◽

Primary Effusion Lymphoma ◽

Cervical Lymph Nodes

Download Full-text

Cerebrospinal Fluid Dendritic Cells Infiltrate the Brain Parenchyma and Target the Cervical Lymph Nodes under Neuroinflammatory Conditions

PLoS ONE ◽

10.1371/journal.pone.0003321 ◽

2008 ◽

Vol 3 (10) ◽

pp. e3321 ◽

Cited By ~ 56

Author(s):

Eric Hatterer ◽

Monique Touret ◽

Marie-Françoise Belin ◽

Jérôme Honnorat ◽

Serge Nataf

Keyword(s):

Cerebrospinal Fluid ◽

Dendritic Cells ◽

Lymph Nodes ◽

Brain Parenchyma ◽

Cervical Lymph Nodes ◽

The Brain

Download Full-text

Non-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes

Nature Communications ◽

10.1038/s41467-021-27887-0 ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Mehmet Sait Albayram ◽

Garrett Smith ◽

Fatih Tufan ◽

Ibrahim Sacit Tuna ◽

Mehmet Bostancıklıoğlu ◽

...

Keyword(s):

Lymph Nodes ◽

Human Brain ◽

Animal Studies ◽

Cranial Nerves ◽

Lymphatic Vessels ◽

Cervical Lymph Nodes ◽

Age Related ◽

Fluid Attenuated Inversion Recovery ◽

Protein Rich ◽

Lymphatic Fluid

AbstractMeningeal lymphatic vessels have been described in animal studies, but limited comparable data is available in human studies. Here we show dural lymphatic structures along the dural venous sinuses in dorsal regions and along cranial nerves in the ventral regions in the human brain. 3D T2-Fluid Attenuated Inversion Recovery magnetic resonance imaging relies on internal signals of protein rich lymphatic fluid rather than contrast media and is used in the present study to visualize the major human dural lymphatic structures. Moreover we detect direct connections between lymphatic fluid channels along the cranial nerves and vascular structures and the cervical lymph nodes. We also identify age-related cervical lymph node atrophy and thickening of lymphatics channels in both dorsal and ventral regions, findings which reflect the reduced lymphatic output of the aged brain.

Download Full-text