Deep Cervical Nodes Research Articles

Cystic cervical metastasis: A diagnostic dilemma

Metastasis of head neck squamous cell carcinoma to regional deep cervical nodes is a common and usually are bony hard, solid. But sometimes they may present as a cystic mass which makes it a diagnostic challenge, in absence of evident primary, for the treating doctor. Previously they have been labeled as cancers of branchial cleft cysts which have undergone malignant degeneration. With the advancement in understanding of tumor pathophysiology most researchers now have concluded that these are tumors from tissue of waldeyer’s ring which have the potential of producing cystic cervical metastasis. : A 57-year-old male presented to our department with a right side slow growing neck swelling for 2 years. The rest of ear, nose, throat examination was normal. The fine needle aspiration cytology revealed clear fluid. The diagnosis of branchial cleft cyst was made and patient counselled for surgery for benign lesion. After a period of one month the patient presented with change in voice, difficulty in swallowing and another swelling on left side of the neck. FNAC from the left side swelling revealed metastatic squamous cell carcinoma and PET-CT revealed a tongue base growth. Patient underwent an excision of growth from tongue base and neck dissection on both sides. Even for cystic neck swelling in an adult over 40 years of age, the possibility of malignancy should be kept, until proven otherwise.

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

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.

Clinicopathological Study on TB Lymphadenopathy Case

Background: Tuberculosis in the form of pulmonary and extrapulmonary TB is common in developing countries like Bangladesh. Among extrapulmonary TB, lymphnode TB is still common in our setting. So, the objectives of the present study were to evaluate theclinicopathological findings among the lymphnode TB cases in our context.
 Materials and methods: This observational study was done from January 2017 to December 2019 among 300 lymphnode TB cases in a tertiary care hospital during a three-year study period. Patients were selected after obtaining informed written consent and clinical evaluation. Then enlarged lymphnodes were evaluated by FNAC or histopathology. If lymphnode TB features were found then the patients were included in our study.Other findings like metastasis, lymphoma or pyogenic lymphadenitis were excluded from this study. After collection, data was recorded and analyzed by Microsoft Excel.
 Results: Among 300 cases of TB lymphadenitis subjects were commonly within the age groups 11-20 years (Male 63 and female 51) and 21-30 years(male 45 and female 42) with amale: female ratioof 1.22:1. Regarding different clinical signs and symptoms,low grade fever was found in 21(7%) cases, local lymphnode pain and tenderness was found in 67 (22%) and 63(21%) of subjects. Discharging sinuses was present in 33(11%) patients, 35(12%) had history of weight loss, 39 (13%) had anorexia and 42(14%) had history of night sweats. Regarding locationof different lymph node areas, 125(41.67%) patients had deep cervical nodes, 65(21.67%) had supraclavicular lymph nodes, 60(20%) had lymph nodes in the posterior triangle 33 (11%) in jugulo-omohyoid and 17 (5.66%) in submandibular area. Among all cases, 83% cases showed bilateral and 17% showed unilateral involvement.Regarding nature of lymph nodes, firm, matted multiple lymphnodes were found in 130(43%) cases, single discrete nodes were found in 70(23.33%) cases, others were found as suppurative noded with single and multiple sinuses. Cytopathological and histopathological findings revealed caseating granuloma with epithelioid cell with Langerhans type giant cell was found in 220(73%) cases, caseating granuloma with epithelioid cell was found in 47(16%) epithelioid cell was found in 20(7%) cases and epitheliod cells with smear positive AFB was found in 13(4%) cases.
 Conclusion: TB lymphadenitis is still a common form of extrapulmonary tuberculosis and it has variable clinical and pathological presentations.
 Chatt Maa Shi Hosp Med Coll J; Vol.20 (1); January 2021; Page 77-80

Hypercalcemia in Disseminated Coccidioidomycosis

Abstract Introduction: Hypercalcemia is associated with various granulomatous diseases, most commonly sarcoidosis and tuberculosis, less frequently fungal disease. We present a rare case of hypercalcemia associated with disseminated coccidioidomycosis. Clinical Case: A 44-year-old man with ESRD s/p DDRT on immunosuppression presented with fever and cough. His physical exam was significant for tender scattered cutaneous nodules. His labs revealed non-PTH mediated hypercalcemia: calcium 12 mg/dL (normal 8.5–10.1 mg/dL), albumin 2.2 g/dL (normal 3.6–5.1 g/dL) and PTH 41 pg/mL (normal 14–72 pg/mL). Further hypercalcemia work-up was unremarkable: PTHrP 16 pg/mL (normal 14–27 pg/mL); 25-hydroxyvitamin D 33 ng/mL (normal 30–100 ng/mL); 1,25-hydroxyvitamin D 62 pg/mL (normal 20–79 pg/mL); serum electrophoresis was indeterminate; and immunofixation did not detect monoclonal proteins. His highest calcium level was 12.8 mg/dL with albumin 1.9 g/dL. He underwent additional tests that explained his presentation: sputum culture grew Coccidioides immitis; CT scan showed miliary pulmonary nodules, and bilateral deep cervical and mediastinal lymph node enlargement; lumbar puncture revealed elevated protein and cell counts; and a biopsy of a nodule on his thigh revealed Coccidioides immitis. He was treated with amphotericin for disseminated coccidioidomycosis with pulmonary, cutaneous and possible CSF involvement. He received IV fluids, furosemide and pamidronate for treatment of hypercalcemia. Based on his presentation, evaluation and complete resolution without recurrence of hypercalcemia after treatment of disseminated coccidioidomycosis, the most likely cause of hypercalcemia was disseminated coccidioidomycosis. Hypercalcemia is associated with various granulomatous diseases. It is a rare complication of disseminated coccidioidomycosis that is important to recognize as Coccidioides is endemic in the United States. The pathology of the disease is pyogenic granuloma. In contrast to sarcoidosis, our case and previous case studies of hypercalcemia in coccidioidomycosis did not show an elevation of 1,25 dihydroxyvitamin D. Various potential inducers have been implicated including PTHrP, lipopolysaccharide, prostaglandin E, interleukin 1 and transforming growth factor β. It has been demonstrated that granulomas produce PTHrP; however, not all patients with granulomas develop hypercalcemia. One theory is that hypercalcemia may be a sequelae in cases with a greater number and extent of lesions making PTHrP as seen in disseminated disease. Conclusion: Hypercalcemia is a rare complication of disseminated coccidioidomycosis that is important to recognize as coccidioidomycosis is endemic in the United States. The mechanism of hypercalcemia is poorly understood; in contrast to other granulomatous disease, it appears to be unrelated to 1,25-hydroxyvitamin D.

39607 Mapping the Draining Lymph Nodes in Central Nervous System Malignancies

ABSTRACT IMPACT: We seek to determine which lymph nodes drain the human brain. OBJECTIVES/GOALS: Lymphatic vessels train lymphatic fluid from the central nervous system (CNS), but the specific lymph nodes that these vessels drain to remains unknown in humans. We intend on using technetium tilmanocept (TcTM)to map the draining lymph nodes of the CNSin humans. METHODS/STUDY POPULATION: Patients having a tumor resected are eligible for the trial. All patients will have TcTM injected intracranially after tumor resection. Six patients will be enrolled in Cohort 1 to define the time course of drainage to the lymph nodes. Patients in Cohort 1 will be imaged with planar LS within 7 hours of injection and the following day. Either 12 or 24 patients will be enrolled into Cohort 2 to localize the draining lymph nodes with SPECT-CT. The optimal imaging timepoint from Cohort 1 will be used for Cohort 2. Patients in Cohort 2 will be stratified depending on if their tumor is in the frontal, parietal, occipital, or temporal lobe. RESULTS/ANTICIPATED RESULTS: We anticipate that we will detect TcTMin the deep cervical lymph nodes after injection into the brain. It is unclear exactly which lymph nodes the tracer will go to. We hypothesize that the results among patients will be similar, but interindividual variation is a possibility. Furthermore, patients with disease in different lobes of the brain may have different lymph drainage patterns. DISCUSSION/SIGNIFICANCE OF FINDINGS: We seek to answer a fundamental question of human anatomy: what lymph nodes drain the human brain? Additionally, knowing which nodes drain the human brain could shape future research of immunotherapy in patients with brain cancer or autoimmune disease such as multiple sclerosis.

Normal head and neck lymph nodes in the paediatric population

To determine the normal range of head and neck lymph nodes in a paediatric population. A retrospective review was undertaken of 200 brain magnetic resonance imaging (MRI) examinations in patients aged between 5 months to 16 years. Exclusion criteria included possible causes for lymphadenopathy. Studies were reported previously as normal. Eight regions were assessed for the presence of nodes, short and long axis of the largest node measured, and the ratio was calculated. Most commonly identifiable nodes were the deep cervical, submandibular, and posterior cervical in 100%, 99.5%, and 92.5% of studies. In the long axis, the three largest were the submandibular, deep, and posterior cervical with mean values of 19.7, 18.1, and 15.4 mm, respectively. For the S/L ratio, the three with the most oval shape were the pre-auricular, occipital, and submental with ratios of 0.64, 0.63, and 0.6, respectively. A positive correlation between the occipital and deep cervical lymph node groups with age was found to be stronger than the rest of localisations. This study characterises the normal distribution, size, and shape of head and neck lymph nodes in a healthy paediatric population, demonstrating that rounder and larger lymph nodes may be a normal finding, depending on their location and patient age.

Impaired meningeal lymphatic drainage in patients with idiopathic Parkinson's disease.

Animal studies implicate meningeal lymphatic dysfunction in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (PD). However, there is no direct evidence in humans to support this role1-5. In this study, we used dynamic contrast-enhanced magnetic resonance imaging to assess meningeal lymphatic flow in cognitively normal controls and patients with idiopathic PD (iPD) or atypical Parkinsonian (AP) disorders. We found that patients with iPD exhibited significantly reduced flow through the meningeal lymphatic vessels (mLVs) along the superior sagittal sinus and sigmoid sinus, as well as a notable delay in deep cervical lymph node perfusion, compared to patients with AP. There was no significant difference in the size (cross-sectional area) of mLVs in patients with iPD or AP versus controls. In mice injected with α-synuclein (α-syn) preformed fibrils, we showed that the emergence of α-syn pathology was followed by delayed meningeal lymphatic drainage, loss of tight junctions among meningeal lymphatic endothelial cells and increased inflammation of the meninges. Finally, blocking flow through the mLVs in mice treated with α-syn preformed fibrils increased α-syn pathology and exacerbated motor and memory deficits. These results suggest that meningeal lymphatic drainage dysfunction aggravates α-syn pathology and contributes to the progression of PD.

Anti-PD-(L)1 immunotherapy for brain metastases in non-small cell lung cancer: Mechanisms, advances, and challenges.

The brain is one of the most common metastatic sites in non-small cell lung cancer (NSCLC), which is associated with an extremely poor prognosis. Despite the availability of several therapeutic options, the treatment efficacy remains unsatisfactory for NSCLC brain metastases. Anti-programmed cell death-1 (PD-1) and its ligand (PD-L1) monoclonal antibodies have reshaped therapeutic strategies in advanced NSCLC. Preliminary evidence has shown that anti-PD-(L)1 monotherapy is also effective in NSCLC patients with brain metastases. However, the traditional view asserted that these therapeutic antibodies were incapable of crossing the blood-brain barrier (BBB) with large molecular size, thus most patients with brain metastases were excluded from most studies on anti-PD-(L)1 immunotherapy. Therefore, the efficacy and its mechanisms of action of anti-PD-(L)1 immunotherapy against brain metastases in NSCLC have not been clarified. In this review, we will survey the underlying mechanisms and current clinical advances of anti-PD-(L)1 immunotherapy in the treatment of brain metastases in NSCLC. The trafficking of activated cytotoxic T cells that are mainly derived from the primary tumor and deep cervical lymph nodes is critical for the intracranial response to anti-PD-(L)1 immunotherapy, which is driven by interferon-γ (IFN-γ). Additionally, promising combined strategies with the rationale in the treatment of brain metastases will be presented to provide future directions for clinical study design. Several significant challenges in the preclinical and clinical studies of brain metastases, as well as potential solutions, will also be discussed.

Cerebral Vessels: An Overview of Anatomy, Physiology, and Role in the Drainage of Fluids and Solutes.

The cerebral vasculature is made up of highly specialized structures that assure constant brain perfusion necessary to meet the very high demand for oxygen and glucose by neurons and glial cells. A dense, redundant network of arteries is spread over the entire pial surface from which penetrating arteries dive into the cortex to reach the neurovascular units. Besides providing blood to the brain parenchyma, cerebral arteries are key in the drainage of interstitial fluid (ISF) and solutes such as amyloid-beta. This occurs along the basement membranes surrounding vascular smooth muscle cells, toward leptomeningeal arteries and deep cervical lymph nodes. The dense microvasculature is made up of fine capillaries. Capillary walls contain pericytes that have contractile properties and are lined by a highly specialized blood–brain barrier that regulates the entry of solutes and ions and maintains the integrity of the composition of ISF. They are also important for the production of ISF. Capillaries drain into venules that course centrifugally toward the cortex to reach cortical veins and empty into dural venous sinuses. The walls of the venous sinuses are also home to meningeal lymphatic vessels that support the drainage of cerebrospinal fluid, although such pathways are still poorly understood. Damage to macro- and microvasculature will compromise cerebral perfusion, hamper the highly synchronized movement of neurofluids, and affect the drainage of waste products leading to neuronal and glial degeneration. This review will present vascular anatomy, their role in fluid dynamics, and a summary of how their dysfunction can lead to neurodegeneration.

A potential defense mechanism against amyloid deposition in cerebellum

Amyloid-β (Aβ) is the major component of senile plaques in Alzheimer’s disease (AD) brains. Senile plaques are generally observed in cerebral cortex (CTX) rather than cerebellum (CBL) in AD patients. However, it is not clear why CBL has less Aβ deposition than CTX. It is very important to elucidate the mechanism of suppressing Aβ deposition in CBL, because it contributes to understanding of not only AD pathogenesis but also prevention and cure of AD. In this study, we explored to figure out the potential mechanism of reducing Aβ deposition in CBL. We observed higher age-dependent elevation of Aβ level in CTX rather than CBL of human APP knock-in AD model mice, although we detected no significant differences in the levels of interstitial fluid Aβ in these brain tissues. These data imply that less Aβ deposition in CBL is due to enhanced Aβ clearance rather than altered Aβ production in CBL. To gain insights into Aβ clearance in CBL, we injected fluorescence-labeled Aβ in brain tissues. Importantly diffusion area of fluorescent Aβ in CBL was roughly six-times larger than that in CTX within 2 h of injection. In addition, injected Aβ area in CBL decreased sharply after 24 h and CBL-injected Aβ was robustly detected in deep cervical lymph nodes (DcLNs). In contrast, diffusion area of fluorescent Aβ in CTX was consistent up to 72 h and CTX-injected Aβ was faintly detected in DcLNs. Our data suggest that enhanced Aβ drainage in association with meningeal lymphatic system is responsible for less Aβ deposition in CBL.

Anatomical Features of the Deep Cervical Lymphatic System and Intrajugular Lymphatic Vessels in Humans.

Background: Studies in rodents have re-kindled interest in the study of lymphatics in the central nervous system. Animal studies have demonstrated that there is a connection between the subarachnoid space and deep cervical lymph nodes (DCLNs) through dural lymphatic vessels located in the skull base and the parasagittal area. Objective: To describe the connection of the DCLNs and lymphatic tributaries with the intracranial space through the jugular foramen, and to address the anatomical features and variations of the DCLNs and associated lymphatic channels in the neck. Methods: Twelve formalin-fixed human head and neck specimens were studied. Samples from the dura of the wall of the jugular foramen were obtained from two fresh human cadavers during rapid autopsy. The samples were immunostained with podoplanin and CD45 to highlight lymphatic channels and immune cells, respectively. Results: The mean number of nodes for DCLNs was 6.91 ± 0.58 on both sides. The mean node length was 10.1 ± 5.13 mm, the mean width was 7.03 ± 1.9 mm, and the mean thickness was 4 ± 1.04 mm. Immunohistochemical staining from rapid autopsy samples demonstrated that lymphatic vessels pass from the intracranial compartment into the neck through the meninges at the jugular foramen, through tributaries that can be called intrajugular lymphatic vessels. Conclusions: The anatomical features of the DCLNs and their connections with intracranial lymphatic structures through the jugular foramen represent an important possible route for the spread of cancers to and from the central nervous system; therefore, it is essential to have an in-depth understanding of the anatomy of these lymphatic structures and their variations.

Metastasis to ipsilateral medial retropharyngeal and deep cervical lymph nodes in 22 dogs with thyroid carcinoma.

To determine the rate of nodal metastasis to the medial retropharyngeal (MRP) and deep cervical lymph nodes in dogs surgically treated for thyroid carcinoma. Retrospective study. Twenty-two client-owned dogs. Medical records between July 2015 and October 2019 at the Universities of Missouri and Florida were reviewed. Dogs that underwent thyroidectomy with concurrent elective MRP lymphadenectomy ± deep cervical lymphadenectomy were included. Tumor site, preoperative staging, and histopathological findings were recorded. Twenty-two dogs with 26 total thyroid carcinomas were included. Primary tumors were lateralized in 19 dogs, bilateral in two dogs, and bilateral and midline ectopic in one dog. All dogs underwent ipsilateral MRP resection, including bilateral resection in dogs with bilateral tumors. Three contralateral MRP lymph nodes were excised from dogs with unilateral carcinomas. Four deep cervical lymph nodes and one superficial cervical lymph node were excised. Metastases were identified in 14 lymph nodes in 10 of 22 (45%) dogs. All four excised deep cervical lymph nodes and one contralateral MRP lymph node were identified as metastatic. Size of deposit could be classified in 13 of 14 metastatic lymph nodes. Macrometastasis was detected in seven lymph nodes, micrometastasis was detected in one node, and isolated tumor cells were detected in five lymph nodes. Regional metastasis was common within the lymph nodes sampled in this population of dogs with thyroid carcinoma. These results provide evidence to justify further exploration of a larger population to verify the rate of regional metastasis and determine the prognostic impact of nodal metastasis.

Effects of experimental cervical spinal cord injury on peripheral adaptive immunity.

Adaptive immunity is critical for controlling infections, which are a leading cause of morbidity and mortality in patients with spinal cord injury (SCI). In rats and mice, compromised peripheral adaptive immune responses, as shown by splenic atrophy and lowered frequencies of peripheral lymphocytes, were shown to result from high-level thoracic SCI. However, whether cervical SCI, which is the most common level of SCI in humans, impairs adaptive immunity remains largely unknown. In the present study, we induced cervical SCI in rats at the C7/T1 level by clip compression and looked at changes in peripheral adaptive immunity at 2-, 10- and 20-weeks post-injury. Specifically, we quantified changes in the frequencies of T- and B- lymphocytes in the blood and the mandibular and deep cervical lymph nodes, which drain the cervical spinal cord. We also assessed changes in serum IgG and IgM immunoglobulin levels, as well as spleen size. We found a significant decline in circulating T- and B- cell frequencies at 10 weeks post-SCI, which returned to normal at 20 weeks after injury. We found no effect of cervical SCI on T- and B- cell frequencies in the draining lymph nodes. Moreover, cervical SCI had no effect on net spleen size, although injured rats had a higher spleen/body weight ratio than sham controls at all time points of the study. Lastly, IgG and IgM immunoglobulin declined at 2 weeks, followed by a significant increase in IgM levels at 10 weeks of injury. These data indicate that cervical SCI causes a significant imbalance in circulating lymphocytes and immunoglobulin levels at 2 and 10 weeks. As we discuss in this article, these findings are largely in line with clinical observations, and we anticipate that this study will fuel more research on the effect of adaptive immunity on SCI recovery.

Improvement of glymphatic\u2013lymphatic drainage of beta-amyloid by focused ultrasound in Alzheimer\u2019s disease model

Drainage of parenchymal waste through the lymphatic system maintains brain homeostasis. Age-related changes of glymphatic–lymphatic clearance lead to the accumulation beta-amyloid (Aβ) in dementia models. In this study, focused ultrasound treatment in combination with microbubbles (FUS-MB) improved Aβ drainage in early dementia model mice, 5XFAD. FUS-MB enhanced solute Aβ clearance from brain, but not plaques, to cerebrospinal fluid (CSF) space and then deep cervical lymph node (dCLN). dCLN ligation exaggerated memory impairment and progress of plaque formation and also the beneficial effects of FUS-MB upon Aβ removal through CSF-lymphatic routes. In this ligation model, FUS-MB improved memory despite accumulation of Aβ in CSF. In conclusion, FUS-MB enhances glymphatic–lymphatic clearance of Aβ mainly by increasing brain-to-CSF Aβ drainage. We suggest that FUS-MB can delay dementia progress in early period and benefits of FUS-MB depend on the effect of Aβ disposal through CSF-lymphatics.

In vivo T1 mapping for quantifying glymphatic system transport and cervical lymph node drainage

Dynamic contrast-enhanced magnetic resonance imaging (MRI) for tracking glymphatic system transport with paramagnetic contrast such as gadoteric acid (Gd-DOTA) administration into cerebrospinal fluid (CSF) requires pre-contrast data for proper quantification. Here we introduce an alternative approach for glymphatic system quantification in the mouse brain via T1 mapping which also captures drainage of Gd-DOTA to the cervical lymph nodes. The Gd-DOTA injection into CSF was performed on the bench after which the mice underwent T1 mapping using a 3D spoiled gradient echo sequence on a 9.4 T MRI. In Ketamine/Xylazine (KX) anesthetized mice, glymphatic transport and drainage of Gd-DOTA to submandibular and deep cervical lymph nodes was demonstrated as 25–50% T1 reductions in comparison to control mice receiving CSF saline. To further validate the T1 mapping approach we also verified increased glymphatic transport of Gd-DOTA transport in mice anesthetized with KX in comparison with ISO. The novel T1 mapping method allows for quantification of glymphatic transport as well as drainage to the deep and superficial cervical lymph nodes. The ability to measure glymphatic transport and cervical lymph node drainage in the same animal longitudinally is advantageous and time efficient and the coupling between the two systems can be studied and translated to human studies.

Photostimulation of Extravasation of Beta-Amyloid through the Model of Blood-Brain Barrier

Alzheimer’s disease (AD) is an incurable pathology associated with progressive decline in memory and cognition. Phototherapy might be a new promising and alternative strategy for the effective treatment of AD, and has been actively discussed over two decades. However, the mechanisms of therapeutic photostimulation (PS) effects on subjects with AD remain poorly understood. The goal of this study was to determine the mechanisms of therapeutic PS effects in beta-amyloid (Aβ)-injected mice. The neurological severity score and the new object recognition tests demonstrate that PS 9 J/cm2 attenuates the memory and neurological deficit in mice with AD. The immunohistochemical assay revealed a decrease in the level of Aβ in the brain and an increase of Aβ in the deep cervical lymph nodes obtained from mice with AD after PS. Using the in vitro model of the blood-brain barrier (BBB), we show a PS-mediated decrease in transendothelial resistance and in the expression of tight junction proteins as well an increase in the BBB permeability to Aβ. These findings suggest that a PS-mediated BBB opening and the activation of the lymphatic clearance of Aβ from the brain might be a crucial mechanism underlying therapeutic effects of PS in mice with AD. These pioneering data open new strategies in the development of non-pharmacological methods for therapy of AD and contribute to a better understanding of the PS effects on the central nervous system.

Glymphatic System Visualized by Chemical-Exchange-Saturation-Transfer Magnetic Resonance Imaging

Dysfunction of the glymphatic system may play a significant role in the development of neurodegenerative diseases. However, in vivo imaging of the glymphatic system is challenging. In this study, we describe an unconventional MRI method for imaging the glymphatic system based on chemical exchange saturation transfer, which we tested in an in vivo porcine model of impaired glymphatic function. The blood, lymph, and cerebrospinal fluid (CSF) from one pig were used for testing the MRI effect in vitro at 7 Tesla (T). Unilateral deep cervical lymph node ligation models were then performed in 20 adult male Sprague-Dawley rats. The brains were scanned in vivo dynamically after surgery using the new MRI method. Behavioral tests were performed after each scanning session and the results were tested for correlations with the MRI signal intensity. Finally, the pathological assessment was conducted in the same brain slices. The special MRI effect in the lymph was evident at about 1.0 ppm in water and was distinguishable from those of blood and CSF. In the model group, the intensity of this MRI signal was significantly higher in the ipsilateral than in the contralateral hippocampus. The correlation between the signal abnormality and the behavioral score was significant (Pearson's, R2 = 0.9154, p < 0.005). We conclude that the novel MRI method can visualize the glymphatic system in vivo.

Role of meningeal lymphatic vessels in the T cell response against Toxoplasma gondii

Abstract Toxoplasma gondii is an intracellular protozoan parasite that causes persistent infection in the central nervous system (CNS). Studies have demonstrated that continuous T cell recruitment to the brain is necessary for parasite control. However, the mechanisms by which T cell responses against T. gondii are maintained remain poorly understood. Recently, it was discovered that the meninges harbor a previously unappreciated lymphatic network that drains CNS protein and immune cells. We hypothesized that the meningeal lymphatic network is necessary for maintaining host-protective T cell responses against T. gondii. To test this hypothesis, we performed surgical ligation of the lymphatic vessels that carry cerebrospinal fluid via meningeal lymphatic vessels to the cervical lymph nodes. Following blockade of meningeal lymphatic outflow, we observed a decrease in the number and frequency of antigen-specific T cells in the deep cervical lymph nodes, supporting a role for meningeal lymphatic drainage in maintaining T cell responses against the parasite. We have also observed extensive lymphangiogenesis in the meninges during infection. Lymphangiogenesis has not previously been reported in response to CNS infection but could influence antigen or immune cell outflow from the CNS. Together, our results demonstrate that the meningeal lymphatic network dynamically responds to CNS infection with T. gondii and contributes to T cell responses against the parasite.

Subdural haematomas drain into the extracranial lymphatic system through the meningeal lymphatic vessels

Subdural haematomas (SDHs) are characterized by rapidly or gradually accumulated haematomas between the arachnoid and dura mater. The mechanism of haematoma clearance has not been clearly elucidated until now. The meningeal lymphatic vessel (mLV) drainage pathway is a novel system that takes part in the clearance of waste products in the central nervous system (CNS). This study aimed to explore the roles of the mLV drainage pathway in SDH clearance and its impacting factors. We injected FITC-500D, A488-fibrinogen and autologous blood into the subdural space of mice/rats and found that these substances drained into deep cervical lymph nodes (dCLNs). FITC-500D was also observed in the lymphatic vessels (LYVE+) of the meninges and the dCLNs in mice. The SDH clearance rate in SDH rats that received deep cervical lymph vessel (dCLV) ligation surgery was significantly lower than that in the control group, as evaluated by haemoglobin quantification and MRI scanning. The drainage rate of mLVs was significantly slower after the SDH model was established, and the expression of lymphangiogenesis-related proteins, including LYVE1, FOXC2 and VEGF-C, in meninges was downregulated. In summary, our findings proved that SDH was absorbed through the mLV drainage pathway and that haematomas could inhibit the function of mLVs.

Identification of Lyve-1 positive macrophages as resident cells in meninges of rats.

Meningeal immunity along with its associated lymphatic vasculatures is widely discussed recently. Lymphatic vessels in meninges drain interstitial fluid into the deep-cervical lymph nodes. The vessels are composed of cells that express the cardinal marker for lymphatic endothelium-the lymphatic vessel hyaluronan receptor-1 (Lyve-1). However, studies also show the presence of nonendothelial Lyve-1 expressing cells in certain tissues. Therefore, we were curious if nonendothelial Lyve-1+ cells are also present in dura mater of meninges. We show that Lyve-1+ endothelial cells are distributed adjacent to the blood vessels in the brain dura mater of rats. We did not observe any lymphatic vessels in spinal dura mater. Interestingly, we also observed isolated population of nonlymphatic Lyve-1+ cells in both brain and spinal dura mater. Morphologically, the Lyve-1+ cells were extensively pleomorphic, sometimes elongated or round. Surprisingly, the thoracolumbal meningeal Lyve-1+ cells were predominantly round in morphology. Using endothelial specific marker VEGFR3 and macrophage markers CD68 and CD169, we observed that the isolated Lyve-1+ cells lacked endothelial cell signature, but were either CD68+ or CD169+ macrophages. Moreover, we observed that the Lyve-1+ cells colocalized with collagen fibers in the meninges, and some of Lyve-1+ cells had intracellular collagen. The study for the first time demonstrates the presence of Lyve-1 positive macrophages in the lymphatic and nonlymphatic regions in the meninges of rats.