Search Results (20)

Dura mater plays a critical role in neurofluid homeostasis, yet comparative data on capillary network density and organization between cranial and spinal regions remain limited. This study addresses this gap by systematically analyzing capillary architecture and aquaporin (AQP) expression in porcine cranial (parietal, falx) and spinal dura mater. Immunofluorescence labeling and confocal microscopy were used to assess capillary density, spatial distribution, and AQP1/AQP4 expression patterns across over 1000 capillaries in these regions. Cranial dura exhibited a 3–4 times higher capillary density compared to spinal dura, with capillaries predominantly localized to meningeal–dural border cell interfaces in cranial regions and a more dispersed distribution in spinal dura. Both AQP1 and AQP4 were detected as discrete clusters within capillary walls, with higher expression in cranial compared to spinal dura. Lymphatic vessels (PDPN-positive) were also observed adjacent to capillaries, supporting a dual-system model for fluid and waste exchange. These findings highlight the dura’s region-specific vascular specialization, with cranial regions favoring dense, structured capillary networks suited for active fluid exchange. This work establishes a foundation for investigating capillary-driven fluid dynamics in pathological states like subdural hematomas or hydrocephalus. Full article

The Gliomas account for 81% of all malignant central nervous system tumors and are classified by WHO into four grades of malignancy. Glioblastoma multiforme (GBM), the most common grade IV glioma, exhibits an extremely aggressive phenotype and a dismal five-year survival rate of only 6%, underscoring the urgent need for novel therapeutic approaches. Immunotherapy has emerged as a promising strategy, and photodynamic therapy (PDT) in particular has attracted attention for its dual cytotoxic and immunostimulatory effects. In GBM models, PDT induces immunogenic cell death characterized by the release of damage-associated molecular patterns (DAMPs), which promote antigen presentation and activate T cell responses. Additionally, PDT transiently increases blood–brain barrier permeability, facilitating immune cell infiltration into the tumor microenvironment, and enhances clearance of waste products via stimulation of meningeal lymphatic vessels. Importantly, PDT can reprogram or inactivate immunosuppressive tumor-associated macrophages, thereby counteracting the pro-tumoral microenvironment. Despite these encouraging findings, further preclinical and clinical studies are required to elucidate PDT’s underlying immunological mechanisms fully and to optimize treatment regimens that maximize its efficacy as part of integrated immunotherapeutic strategies against GBM. Full article

Background: The brain’s vascular system has recently been shown to provide an important efflux pathway for cerebral waste clearance (CWC). However, little is known about the influence of aging or diabetes on the CWC. The aim of the current study is to investigate the vasculature contribution to CWC under aging and diabetic conditions. Methods: Male Wistar rats under aging and diabetic conditions were evaluated using dynamic intra-cisterna superparamagnetic iron oxide-enhanced susceptibility-weighted imaging (SPIO-SWI). Theoretical analysis of the expected signal intensity using SPIO-SWI was compared with the corresponding dynamic in vivo images. Quantitative susceptibility mapping (QSM) was used to evaluate the iron-based tracer concentration in the venous system. Results: Our data demonstrated that the theoretical analysis predicted the dynamic changes in the signal intensity after SPIO infusion. The distinct hyperintense signals due to the lower concentration of the SPIO over time in cerebrospinal fluid (CSF) and meningeal lymphatic (ML) vessels likely represented the CWC through various efflux pathways, including cerebral vascular and ML vessels. The QSM analysis further revealed reduced CWC from the vasculature in both the aged and diabetic groups compared to the younger group. Conclusions: Our results demonstrated that SPIO-SWI can quantitatively evaluate the CWC efflux contributions from cerebral vascular vessels under aging or diabetic conditions. Full article

The brain, the most important component of the central nervous system (CNS), is protected by multiple intricate barriers that strictly regulate the entry of proteins and cells. Thus, the brain is often described as an organ with immune privilege. Within the brain parenchyma, microglia are thought to be the primary resident immune cells, with no other immune-related cells present under normal conditions. On the other hand, recent studies in the meningeal border regions have revealed the presence of meningeal-specific lymphatic vessels and channels that connect to the skull bone marrow. Importantly, resident macrophage populations specific to these boundary regions, known as CNS-associated macrophages (CAMs) or border-associated macrophages (BAMs), have been identified. In contrast to the brain parenchyma, the meninges contain many immune-related structures and cells, making them an important immune interface at the CNS border. CAMs serve a dual function, triggering immune responses under pathological conditions and supporting the maintenance of brain homeostasis. This review focuses on the immune architecture of the meninges and the roles of CAMs in humans and mice, summarizing and discussing recent advances in this field. Full article

The glymphatic system, an analog of the peripheral lymphatic system in the brain, and the meningeal lymphatic system are critical to central nervous system health. The glymphatic system functions to distribute cerebrospinal fluid and important compounds throughout the brain and to remove metabolic waste. The flow of cerebrospinal fluid through this system is affected by changes in cerebral blood flow, intracranial pressure, and vascular tone. Cetaceans experience profound cardiorespiratory alterations while diving that can directly affect cerebrospinal fluid and blood flow and, thus, glymphatic function. Our goal was to investigate glymphatic and lymphatic system structures, including perivascular spaces, aquaporin-4 water channels, meningeal lymphatic, and dural venous sinus vessels in the common dolphin (Delphinus delphis), using immunofluorescent labeling, histochemical staining, and postmortem computed tomography (CT) angiography. We highlight perivascular spaces and aquaporin-4 water channels surrounding blood vessels in the parenchyma and demonstrate evidence of meningeal lymphatic vessels and associated dural venous sinuses. These results demonstrate that common dolphins possess the key anatomical structures required for functional glymphatic and meningeal lymphatic systems. Future studies can build upon these anatomical discoveries to study the function and role of these systems in brain health in this species. Full article

A primary purpose of sleep for humans is to remove toxins and metabolic wastes from the brain (e.g., Aβ, tau, lactate) that would otherwise build up and compromise brain functionality. There are currently no drugs or devices that have been clinically shown in humans to enhance brain toxin removal, either during sleep or wakefulness. This perspective article focuses on a recently (re)discovered major route of toxin drainage from the human brain through meningeal lymphatic vessels (mLVs) and the primary enhancer of their flow—the cytokine Vascular Endothelial Growth Factor (VEGF). The purpose of this perspective article is to present pre-clinical and clinical evidence relevant to a new bioengineered technology (Transcranial Radiofrequency Treatment; TRFT) that appears to enhance mLV flow to increase brain toxin cleansing in humans during wakefulness. In being both safe and non-invasive, TRFT is administered in-home, presently through a device called “MemorEM”. Two months of daily TRFT during wakefulness increased the typically low plasma/brain levels of VEGF in Alzheimer’s Disease (AD) subjects, which was associated with increased Aβ and tau toxin removal from their brains during wakefulness—ostensibly through VEGF-increased mLV flow. Even irrespective of baseline VEGF levels, brain toxin cleansing was increased by TRFT in AD subjects, who also experienced a notable reversal of their cognitive impairment after TRFT. Additional clinical studies are nonetheless required to firmly establish TRFT’s brain cleansing abilities during wakefulness. In performing a major duty of sleep, TRFT during wakefulness is proposed as a viable intervention to counter the decline in nighttime brain toxin cleansing that occurs with aging and in multiple brain diseases, most notably Alzheimer’s Disease. The implications of TRFT for insomnia and for sleep deprivation are also discussed, as is the potential for TRFT to extend healthy human longevity. Full article

Background: Cranial Rhythmic Impulse (CRI) or Primary Respiratory Mechanism (PRM), movement felt on the scalp or the rest of the body, respectively, is a fundamental concept used by osteopaths in their practice for their diagnosis and treatment. However, the physiological basis of this phenomenon remains unclear. Sutherland, the founder of cranial osteopathy, proposed in 1939 that PRM was due to the movement of the cranial bones pulled by the meninges, themselves pushed by the fluctuation of cerebrospinal fluid and the motility of the central nervous system. Since then, Sutherland’s theory has become dogma, despite scientific progress refuting it, and few osteopaths have attempted to find better explanations. Objective: This systematic review of Medline, Science Direct and the Cochrane Library indexed electronic databases explores current knowledge of the physiological mechanisms underlying the Primary Respiratory Movement (PRM) or Cranial Rhythmic Impulse (CRI). Methods: We entered the following identified keywords: “osteopathy in the cranial field”; “cranial rhythmic impulse”; and “primary respiratory mechanism”. We identified 193 studies, evaluated 115, and identified 28 articles that fulfilled our criteria. We classified the studies in terms of methodological rigor, types of studies and tools used. No study had three good-level items, and only five studies had two good-level items corresponding to the type of study and tools used. The protocol of the review has been registered on PROSPERO-CRD42023488497. Results: Out of the 28 articles, 20 referenced at least one of Sutherland’s hypotheses, often quoting the model to critique or challenge it, while 25 of them refer to other hypotheses and/or mechanisms underlying PRM/CRI: 11 concern vasomotion in blood vessels (7) and lymphatic vessels (6), 20 THM waves, 14 heart rate variability, 9 ventilation rate, 2 the extra-cellular matrix and 1 oxidative metabolism. Conclusions: Although Sutherland’s theory remains prevalent in general beliefs, in scientific literature, THM waves driven by autonomous system activity have gained prominence, emerging as the leading hypothesis. The results from this systematic review confirm the need for a paradigm shift for the CRI/PRM in osteopathy, and for more rigorous evaluation and communication on a model in step with evolving scientific data. Full article

The COVID-19 pandemic, caused by infection with the SARS-CoV-2 virus, is associated with cognitive impairment and Alzheimer’s disease (AD) progression. Once it enters the brain, the SARS-CoV-2 virus stimulates accumulation of amyloids in the brain that are highly toxic to neural cells. These amyloids may trigger neurological symptoms in COVID-19. The meningeal lymphatic vessels (MLVs) play an important role in removal of toxins and mediate viral drainage from the brain. MLVs are considered a promising target to prevent COVID-19-exacerbated dementia. However, there are limited methods for augmentation of MLV function. This review highlights new discoveries in the field of COVID-19-mediated amyloid accumulation in the brain associated with the neurological symptoms and the development of promising strategies to stimulate clearance of amyloids from the brain through lymphatic and other pathways. These strategies are based on innovative methods of treating brain dysfunction induced by COVID-19 infection, including the use of photobiomodulation, plasmalogens, and medicinal herbs, which offer hope for addressing the challenges posed by the SARS-CoV-2 virus. Full article

The lymphatic system is a channel for fluid transport and cell migration, but it has always been controversial in promoting and suppressing cancer. VEGFC/VEGFR3 signaling has long been recognized as a major molecular driver of lymphangiogenesis. However, many studies have shown that the neural network of lymphatic signaling is complex. Lymphatic vessels have been found to play an essential role in the immune regulation of tumor metastasis and cardiac repair. This review describes the effects of lipid metabolism, extracellular vesicles, and flow shear forces on lymphangiogenesis. Moreover, the pro-tumor immune tolerance function of lymphatic vessels is discussed, and the tasks of meningeal lymphatic vessels and cardiac lymphatic vessels in diseases are further discussed. Finally, the value of conversion therapy targeting the lymphatic system is introduced from the perspective of immunotherapy and pro-lymphatic biomaterials for lymphangiogenesis. Full article

Emerging evidence suggests that an important function of the sleeping brain is the removal of wastes and toxins from the central nervous system (CNS) due to the activation of the brain waste removal system (BWRS). The meningeal lymphatic vessels (MLVs) are an important part of the BWRS. A decrease in MLV function is associated with Alzheimer’s and Parkinson’s diseases, intracranial hemorrhages, brain tumors and trauma. Since the BWRS is activated during sleep, a new idea is now being actively discussed in the scientific community: night stimulation of the BWRS might be an innovative and promising strategy for neurorehabilitation medicine. This review highlights new trends in photobiomodulation of the BWRS/MLVs during deep sleep as a breakthrough technology for the effective removal of wastes and unnecessary compounds from the brain in order to increase the neuroprotection of the CNS as well as to prevent or delay various brain diseases. Full article

The lack of a conventional lymphatic system that permeates throughout the entire human brain has encouraged the identification and study of alternative clearance routes within the cerebrum. In 2012, the concept of the glymphatic system, a perivascular network that fluidically connects the cerebrospinal fluid to the lymphatic vessels within the meninges via the interstitium, emerged. Although its exact mode of action has not yet been fully characterized, the key underlying processes that govern solute transport and waste clearance have been identified. This review briefly describes the perivascular glial-dependent clearance system and elucidates its fundamental role in neurodegenerative diseases. The current knowledge of the glymphatic system is based almost exclusively on animal-based measurements, but these face certain limitations inherent to in vivo experiments. Recent advances in organ-on-a-chip technology are discussed to demonstrate the technology’s ability to provide alternative human-based in vitro research models. Herein, the specific focus is on how current microfluidic-based in vitro models of the neurovascular system and neurodegenerative diseases might be employed to (i) gain a deeper understanding of the role and function of the glymphatic system and (ii) to identify new opportunities for pharmacological intervention. Full article

The blood–brain barrier (BBB) limits the delivery of majority of cancer drugs and thereby complicates brain tumor treatment. The nasal-brain-lymphatic system is discussed as a pathway for brain drug delivery overcoming the BBB. However, in most cases, this method is not sufficient to achieve a therapeutic effect due to brain drug delivery in a short distance. Therefore, it is necessary to develop technologies to overcome the obstacles facing nose-to-brain delivery of promising pharmaceuticals. In this study, we clearly demonstrate intranasal delivery of liposomes to the mouse brain reaching glioblastoma (GBM). In the experiments with ablation of the meningeal lymphatic network, we report an important role of meningeal pathway for intranasal delivery of liposomes to the brain. Our data revealed that GBM is characterized by a dramatic reduction of intranasal delivery of liposomes to the brain that was significantly improved by near-infrared (1267 nm) photostimulation of the lymphatic vessels in the area of the cribriform plate and the meninges. These results open new perspectives for non-invasive improvement of efficiency of intranasal delivery of cancer drugs to the brain tissues using nanocarriers and near-infrared laser-based therapeutic devices, which are commercially available and widely used in clinical practice. Full article

Photodynamic therapy (PDT) is a promising add-on therapy to the current standard of care for patients with glioblastoma (GBM). The traditional explanation of the anti-cancer PDT effects involves the PDT-induced generation of a singlet oxygen in the GBM cells, which causes tumor cell death and microvasculature collapse. Recently, new vascular mechanisms of PDT associated with opening of the blood–brain barrier (OBBB) and the activation of functions of the meningeal lymphatic vessels have been discovered. In this review, we highlight the emerging trends and future promises of immunotherapy for brain tumors and discuss PDT-OBBB as a new niche and an important informative platform for the development of innovative pharmacological strategies for the modulation of brain tumor immunity and the improvement of immunotherapy for GBM. Full article

There is a growing prevalence of vascular cognitive impairment (VCI) worldwide, and most research has suggested that cerebral small vessel disease (CSVD) is the main contributor to VCI. Several potential physiopathologic mechanisms have been proven to be involved in the process of CSVD, such as blood-brain barrier damage, small vessels stiffening, venous collagenosis, cerebral blood flow reduction, white matter rarefaction, chronic ischaemia, neuroinflammation, myelin damage, and subsequent neurodegeneration. However, there still is a limited overall understanding of the sequence and the relative importance of these mechanisms. The glymphatic system (GS) and meningeal lymphatic vessels (mLVs) are the analogs of the lymphatic system in the central nervous system (CNS). As such, these systems play critical roles in regulating cerebrospinal fluid (CSF) and interstitial fluid (ISF) transport, waste clearance, and, potentially, neuroinflammation. Accumulating evidence has suggested that the glymphatic and meningeal lymphatic vessels played vital roles in animal models of CSVD and patients with CSVD. Given the complexity of CSVD, it was significant to understand the underlying interaction between glymphatic and meningeal lymphatic transport with CSVD. Here, we provide a novel framework based on new advances in main four aspects, including vascular risk factors, potential mechanisms, clinical subtypes, and cognition, which aims to explain how the glymphatic system and meningeal lymphatic vessels contribute to the progression of CSVD and proposes a comprehensive insight into the novel therapeutic strategy of CSVD. Full article