Meningeal Lymphatics in Central Nervous System Diseases.

Since its recent discovery, the meningeal lymphatic system has reshaped our understanding of central nervous system (CNS) fluid exchange, waste clearance, immune cell trafficking, and immune privilege. Meningeal lymphatics have also been demonstrated to functionally modify the outcome of neurological disorders and their responses to treatment, including brain tumors, inflammatory diseases such as multiple sclerosis, CNS injuries, and neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. In this review, we discuss recent evidence of the contribution of meningeal lymphatics to neurological diseases, as well as the available experimental methods for manipulating meningeal lymphatics in these conditions. Finally, we also provide a discussion of the pressing questions and challenges in utilizing meningeal lymphatics as a prime target for CNS therapeutic intervention and possibly drug delivery for brain disorders.

Regulation of CNS pathology by Serpina3n/SERPINA3: The knowns and the puzzles.

Neuroinflammation, blood-brain barrier (BBB) dysfunction, neuron and glia injury/death and myelin damage are common central nervous system (CNS) pathologies observed in various neurological diseases and injuries. Serine protease inhibitor (Serpin) clade A member 3n (Serpina3n), and its human orthologue SERPINA3, is an acute-phase inflammatory glycoprotein secreted primarily by the liver into the bloodstream in response to systemic inflammation. Clinically, SERPINA3 is dysregulated in brain cells, cerebrospinal fluid and plasma in various neurological conditions. Although it has been widely accepted that Serpina3n/SERPINA3 is a reliable biomarker of reactive astrocytes in diseased CNS, recent data have challenged this well-cited concept, suggesting instead that oligodendrocytes and neurons are the primary sources of Serpina3n/SERPINA3. The debate continues regarding whether Serpina3n/SERPINA3 induction represents a pathogenic or a protective mechanism. Here, we propose possible interpretations for previously controversial data and present perspectives regarding the potential role of Serpina3n/SERPINA3 in CNS pathologies, including demyelinating disorders where oligodendrocytes are the primary targets. We hypothesise that the 'good' or 'bad' aspects of Serpina3n/SERPINA3 depend on its cellular sources, its subcellular distribution (or mis-localisation) and/or disease/injury types. Furthermore, circulating Serpina3n/SERPINA3 may cross the BBB to impact CNS pathologies. Cell-specific genetic tools are critically important to tease out the potential roles of cell type-dependent Serpina3n in CNS diseases/injuries.

The Role of Beta2-Microglobulin in Central Nervous System Disease.

Central nervous system (CNS) disorders represent the leading cause of disability and the second leading cause of death worldwide, and impose a substantial economic burden on society. In recent years, emerging evidence has found that beta2 -microglobulin (B2M), a subunit of major histocompatibility complex class I (MHC-I) molecules, plays a crucial role in the development and progression in certain CNS diseases. On the one hand, intracellular B2M was abnormally upregulated in brain tumors and regulated tumor microenvironments and progression. On the other hand, soluble B2M was also elevated and involved in pathological stages in CNS diseases. Targeted B2M therapy has shown promising outcomes in specific CNS diseases. In this review, we provide a comprehensive summary and discussion of recent advances in understanding the pathological processes involving B2M in CNS diseases (e.g., Alzheimer's disease, aging, stroke, HIV-related dementia, glioma, and primary central nervous system lymphoma).

Morphogenetic Designs, and Disease Models in Central Nervous System Organoids.

Since the emergence of the first cerebral organoid (CO) in 2013, advancements have transformed central nervous system (CNS) research. Initial efforts focused on studying the morphogenesis of COs and creating reproducible models. Numerous methodologies have been proposed, enabling the design of the brain organoid to represent specific regions and spinal cord structures. CNS organoids now facilitate the study of a wide range of CNS diseases, from infections to tumors, which were previously difficult to investigate. We summarize the major advancements in CNS organoids, concerning morphogenetic designs and disease models. We examine the development of fabrication procedures and how these advancements have enabled the generation of region-specific brain organoids and spinal cord models. We highlight the application of these organoids in studying various CNS diseases, demonstrating the versatility and potential of organoid models in advancing our understanding of complex conditions. We discuss the current challenges in the field, including issues related to reproducibility, scalability, and the accurate recapitulation of the in vivo environment. We provide an outlook on prospective studies and future directions. This review aims to provide a comprehensive overview of the state-of-the-art CNS organoid research, highlighting key developments, current challenges, and prospects in the field.

The Glycocalyx: The Importance of Sugar Coating the Blood-Brain Barrier.

The endothelial glycocalyx (GCX), located on the luminal surface of vascular endothelial cells, is composed of glycoproteins, proteoglycans, and glycosaminoglycans. It plays a pivotal role in maintaining blood-brain barrier (BBB) integrity and vascular health within the central nervous system (CNS), influencing critical processes such as blood flow regulation, inflammation modulation, and vascular permeability. While the GCX is ubiquitously expressed on the surface of every cell in the body, the GCX at the BBB is highly specialized, with a distinct composition of glycans, physical structure, and surface charge when compared to GCX elsewhere in the body. There is evidence that the GCX at the BBB is disrupted and partially shed in many diseases that impact the CNS. Despite this, the GCX has yet to be a major focus of therapeutic targeting for CNS diseases. This review examines diverse model systems used in cerebrovascular GCX-related research, emphasizing the importance of selecting appropriate models to ensure clinical relevance and translational potential. This review aims to highlight the importance of the GCX in disease and how targeting the GCX at the BBB specifically may be an effective approach for brain specific targeting for therapeutics.

The role of T-lymphocytes in central nervous system diseases.

The central nervous system (CNS) has been considered an immunologically privileged site. In the past few decades, research on inflammation in CNS diseases has mostly focused on microglia, innate immune cells that respond rapidly to injury and infection to maintain CNS homeostasis. Discoveries of lymphatic vessels within the dura mater and peripheral immune cells in the meningeal layer indicate that the peripheral immune system can monitor and intervene in the CNS. This review summarizes recent advances in the involvement of T lymphocytes in multiple CNS diseases, including brain injury, neurodegenerative diseases, and psychiatric disorders. It emphasizes that a deep understanding of the pathogenesis of CNS diseases requires intimate knowledge of T lymphocytes. Aiming to promote a better understanding of the relationship between the immune system and CNS and facilitate the development of therapeutic strategies targeting T lymphocytes in neurological diseases.

Progressive Encephalomyelopathy in an Older Man: A Case Report From the National Multiple Sclerosis Society Case Conference Proceedings.

We present a case of subacute onset progressive encephalomyelopathy in a 77-year-old man with symmetric lateral column signal abnormalities on spinal MRI. We discuss the differential and presumptive final diagnosis along with a review of the postulated disease immunopathogenesis.

The Role of Glia Telomere Dysfunction in the Pathogenesis of Central Nervous System Diseases.

Maintaining the telomere length is decisive for the viability and homeostasis process of all the cells of an organism, including human glial cells. Telomere shortening of microglial cells has been widely associated with the onset and progression of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Additionally, traumatic brain injury appears to have a positive correlation with the telomere-shortening process of microglia, and telomere length can be used as a non-invasive biomarker for the clinical management of these patients. Moreover, telomere involvement through telomerase reactivation and homologous recombination also known as the alternative lengthening of telomeres (ALT) has been described in gliomagenesis pathways, and particular focus has been given in the translational significance of these mechanisms in gliomas diagnosis and prognostic classification. Finally, glia telomere shortening is implicated in some psychiatric diseases. Given that telomere dysfunction of glial cells is involved in the central nervous system (CNS) disease pathogenesis, it represents a promising drug target that could lead to the incorporation of new tools in the medicinal arsenal for the management of so far incurable conditions.

Emerging Role of ABC Transporters in Glia Cells in Health and Diseases of the Central Nervous System.

ATP-binding cassette (ABC) transporters play a crucial role for the efflux of a wide range of substrates across different cellular membranes. In the central nervous system (CNS), ABC transporters have recently gathered significant attention due to their pivotal involvement in brain physiology and neurodegenerative disorders, such as Alzheimer's disease (AD). Glial cells are fundamental for normal CNS function and engage with several ABC transporters in different ways. Here, we specifically highlight ABC transporters involved in the maintenance of brain homeostasis and their implications in its metabolic regulation. We also show new aspects related to ABC transporter function found in less recognized diseases, such as Huntington's disease (HD) and experimental autoimmune encephalomyelitis (EAE), as a model for multiple sclerosis (MS). Understanding both their impact on the physiological regulation of the CNS and their roles in brain diseases holds promise for uncovering new therapeutic options. Further investigations and preclinical studies are warranted to elucidate the complex interplay between glial ABC transporters and physiological brain functions, potentially leading to effective therapeutic interventions also for rare CNS disorders.

The role of annexins in central nervous system development and disease.

Annexins, a group of Ca2+-dependent phospholipid-binding proteins, exert diverse roles in neuronal development, normal central nervous system (CNS) functioning, neurological disorders, and CNS tumors. This paper reviews the roles of individual annexins (A1-A13) in these contexts. Annexins possess unique structural and functional features, such as Ca2+-dependent binding to phospholipids, participating in membrane organization, and modulating cell signaling. They are implicated in various CNS processes, including endocytosis, exocytosis, and stabilization of plasma membranes. Annexins exhibit dynamic roles in neuronal development, influencing differentiation, proliferation, and synaptic formation in CNS tissues. Notably, annexins such as ANXA1 and ANXA2 play roles in apoptosis and blood-brain barrier (BBB) integrity. Neurological disorders, including Alzheimer's disease, multiple sclerosis, and depression, involve annexin dysregulation, influencing neuroinflammation, blood-brain barrier integrity, and stress responses. Moreover, annexins contribute to the pathogenesis of CNS tumors, either promoting or suppressing tumor growth, angiogenesis, and invasion. Annexin expression patterns vary across different CNS tumor types, providing potential prognostic markers and therapeutic targets. This review underscores the multifaceted roles of annexins in the CNS, highlighting their importance in normal functioning, disease progression, and potential therapeutic interventions.

Retrospective Analysis of Pathological Diagnosis of Central Nervous System Diseases in Tibet / 中国医学科学院学报

Objective To analyze the disease spectrum and clinicopathological characteristics of central nervous system(CNS)diseases diagnosed based on pathological findings in Tibet. Methods We collected the data of all the cases with CNS lesions in Tibet Autonomous Region People's Hospital from January 2013 to December 2020.The clinicopathological features were analyzed via light microscopy,immunohistochemical staining,and special staining. Results A total of 383 CNS cases confirmed by pathological diagnosis were enrolled in this study,with a male-to-female ratio of 188∶195 and an average age of(40.03±17.39)years(0-74 years).Among them,127(33.2%)cases had non-neoplastic diseases,with a male-to-female ratio of 82∶45 and an average age of(31.99±19.29)years;256(66.8%)cases had neoplastic diseases,with a male-to-female ratio of 106∶150 and an average age of(44.01±14.87)years.The main non-neoplastic diseases were nervous system infectious diseases,cerebral vascular diseases,meningocele,cerebral cyst,and brain trauma.Among the infectious diseases,brain abscess,granulomatous inflammation,cysticercosis,and hydatidosis were common.The main neoplastic diseases included meningioma,pituitary adenoma,neuroepithelial tumor,schwannoma,metastatic tumor,and hemangioblastoma.The meningioma cases consisted of 95.4%(103/108)cases of grade Ⅰ,3.7%(4/108)cases of grade Ⅱ,and only 1(1/108,0.9%)case of grade Ⅲ.Among the neuroepithelial tumor cases,the top three were glioblastoma,grade Ⅲ diffuse glioma,and ependymoma. Conclusions There are diverse CNS diseases confirmed by pathological diagnosis in Tibet,among which non-neoplastic diseases account for 1/3 of all the cases.Infectious and vascular diseases are the most common non-neoplastic diseases in Tibet,and tuberculosis and parasitic infections are relatively common.The types and proportion of brain tumors in Tibet are different from those in other regions of China,and meningioma is the most common in Tibet,with higher proportion than neuroepithelial tumor.

An overview of the physiological and pathological role of mast cells in the central nervous system

Neurological disorders present a major group of diseases with the global prevalence of 6.3%. They are responsible for 12% global mortality. Mast cells are one of the most abundantly present cell of the immune system in the connective tissue and the central nervous system is not an exception. In this article is presented a review of studies on mast cells regarding their physiological role in cental nervous system. We also disscuss their role in several conditions like: multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's disease, neuropsychiatric disorders, cerebrovascular disorders and central nervous system trauma, epilepsy, seizures and tumors. Finally, we evaluate whether they can be used as a targed for pharmaceutical treatment (AU)

Síndrome CLIPPERS. A propósito de un caso / CLIPPERS syndrome: A case report

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Nueva mutación en el gen ALDH3A2 en un niño con síndrome de Sjögren-Larsson / A new mutation in the ALDH3A2 gene in a boy with Sjögren-Larsson syndrome

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Neurosarcoidosis presenting with isolated intracranial mass lesion and communicating hydrocephalus / Neurosarcoidosis con lesión de tipo masa intracraneal aislada e hidrocefalia comunicante

Isolated neurosarcoidosis is a very rare disease, which makes up 5-15% of sarcoidosis cases. Hydrocephalus is a rare clinical feature with a prevalence of 6% among these patients. Considering neurosarcoidosis in the differential diagnosis of a unique parenquimal mass lesion could help in the early identification of this disease. We report the case of a 27-year-old African man who developed with a sole intracranial mass lesion mimicking radiologically a glioma, which finally came out as an isolated neurosarcoidosis. There is a difficulty in diagnosis when isolated neurosarcoidosis appears. In addition, the low prevalence of the disease entails a not standardized medical treatment. Natural outcome is poor even when hydrocephalus is resolved. Multimodal treatments including complete pharmacological treatment do not seem to assure a better outcome in these patients until date

La neurosarcoidosis cerebral aislada es una enfermedad muy rara, que representa entre el 5-15% de los casos de sarcoidosis. La hidrocefalia es una característica clínica poco frecuente, con una prevalencia del 6% entre estos pacientes. Considerar la neurosarcoidosis en el diagnóstico diferencial de una lesión de tipo masa parenquimatosa única puede ayudar en la identificación temprana de esta enfermedad. Presentamos el caso de un varón africano de 27 años de edad, que presenta una lesión de tipo masa única intracraneal que simulaba radiológicamente un glioma, y que finalmente se reveló como una neurosarcoidosis aislada. Es difícil establecer un diagnóstico cuando aparece una neurosarcoidosis cerebral aislada. Además, la baja prevalencia de la enfermedad conlleva un tratamiento médico no estandarizado. El pronóstico natural es malo, incluso cuando se resuelve la hidrocefalia. Hasta la fecha, los tratamientos multimodales, incluido el tratamiento farmacológico completo, no parecen asegurar un mejor resultado en estos pacientes

Hipoglucèmia / No disponible

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Incontinentia pigmenti

Incontinentia pigmenti is a rare genodermatosis in which the skin involvement occurs in all patients. Additionally, other ectodermal tissues may be affected, such as the central nervous system, eyes, hair, nails and teeth. The disease has a X-linked dominant inheritance pattern and is usually lethal to male fetuses. The dermatological findings occur in four successive phases, following the lines of Blaschko: First phase - vesicles on an erythematous base; second phase - verrucous hyperkeratotic lesions; third phase - hyperchromic spots and fourth phase - hypochromic atrophic lesions.

La 18F-FDG PET/TC ayuda a desenmascarar a la gran imitadora: un caso de neurosarcoidosis con implicación aislada en la médula espinal / 18F-FDG PET/CT helps in unmasking the great mimicker: a case of neurosarcoidosis with isolated involvement of the spinal cord

Durante 4 semanas, un paciente varón de 36 años, sin historial clínico de relevancia, presentó entumecimiento en las extremidades inferiores, inestabilidad al andar, retención de orina y estreñimiento. La RM de la médula espinal mostró edema difuso en la médula dorsal cervicotorácica, así como imágenes de lesiones intramedulares sólidas indicativas de metástasis. Se realizó una 18F-FDG PET/TC para identificar la malignidad primaria de los focos hipermetabólicos dentro de la médula cervicotorácica, así como la leve linfoadenopatía hiliar bilateral hipermetabólica y los nódulos pulmonares hipermetabólicos indicativos de sarcoidosis frente a metástasis. El diagnóstico de sarcoidosis fue respaldado al identificarse un granuloma no caseificante en la biopsia del nódulo pulmonar. El paciente respondió bien al tratamiento con esteroides y los síntomas desaparecieron en 3 semanas

A 36 year-old male with no significant past medical history presented with lower extremity numbness, gait instability, and urinary and bowel retention of 4 weeks onset. Spine MRI revealed diffuse oedema of cervicothoracic spinal cord with several solid enhancing intramedullary lesions, suggestive of metastases. The 18F-FDG PET/CT performed to identify the primary malignancy demonstrated mild hypermetabolic foci within the cervicothoracic cord, as well as a mildly hypermetabolic bilateral hilar lymphadenopathy and a mildly hypermetabolic pulmonary nodule, suggestive of sarcoidosis versus metastasis. The diagnosis of sarcoidosis was supported by identifying non-caseating granuloma in the biopsy of the pulmonary nodule. The patient responded well to steroid-therapy, with the symptoms being resolved within 3 weeks

Péptido relacionado con el gen de la calcitonina: un neuropéptido clave en la migraña / Calcitonin gene-related peptide: a key player neuropeptide in migraine

El péptido relacionado con el gen de la calcitonina (CGRP) es un neuropéptido multifuncional producido por el empalme alternativo del gen de la calcitonina. El CGRP está ampliamente distribuido en el sistema nervioso, particularmente en estructuras anatómicas posiblemente implicadas en la fisiopatología de la migraña, incluyendo el sistema trigeminovascular. En las últimas dos décadas, el conjunto de datos de estudios clínicos y de ciencias básicas ha establecido el papel fundamental del CGRP en migraña. El CGRP aumenta la sensibilidad a los estímulos sensoriales en múltiples niveles, tanto en el sistema nervioso periférico como en el central. En el cerebro, la amplia distribución del CGRP y de sus receptores indica varios sitios posibles en los cuales este péptido actúa como neuromodulador. En la actualidad, el CGRP ha surgido como un objetivo terapéutico para nuevos tratamientos en la migraña. El objetivo de la revisión es exponer la evidencia detrás del papel del CGRP en la migraña y el estado actual de las nuevas alternativas terapéuticas basadas en el CGRP (AU)

Calcitonin gene-related peptide (CGRP) is a multifunctional neuropeptide produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP is widely distributed in the nervous system, particularly at anatomical areas thought to be involved with migraine pathophysiology, including the trigeminovascular nociceptive system. Over the past two decades, a convergence of basic and clinical evidence has established the CGRP as a key player in migraine. CGRP enhances sensitivity to sensory input at multiple levels in both the periphery and central nervous system. Within the brain, the wide distribution of CGRP and CGRP receptors provides numerous possible targets for CGRP to act as a neuromodulator. Now, CGRP has emerged as a promising therapeutic target for a number of novel treatments for migraine. This review discusses the evidence behind the role of CGRP in migraine and the state of CGRP-based mechanism treatment development (AU)

Pemetrexed for primary central nervous system lymphoma in the elderly

Objective. The aim of this study was to evaluate the efficacy and safety of a consecutive series of elderly patients with primary central nervous system lymphoma (PCNSL) treated with single-agent pemetrexed without radiotherapy or intrathecal chemotherapy. Methods. Twelve histologically confirmed newly diagnosed PCNSL patients older than 65 years were studied between 2008 and 2013. An induction chemotherapy was initially given (pemetrexed 600 mg/m2 on day 1, every 3 weeks). Patients achieving a complete, partial response or stable disease proceeded to a maintenance phase (up to 6 cycles). Patients with progressive/recurrent disease (PD) were treated with whole brain radiotherapy on an individual basis. Results. Four patients presented complete response, six patients showed partial response and two patients presented progressive disease. The median progression-free survival (PFS) was 9.0 months [95 % confidence interval (CI) 2.0-45.3] and the median overall survival was 19.5 months (95 % CI 5.0-45.3). Adverse events included leukocytopenia, anemia, fatigue, rash and vomiting. No neurotoxicity or treatment-related death was observed. The estimated 1-year and 2-year survival rate was 66.7 and 41.7 %, respectively. Conclusions. Our efficacy results demonstrate that the single-agent pemetrexed was feasible, active and well tolerated in elderly patients with PCNSL. Furthermore, this single-agent regimen results in higher response rates and less toxicity comparable with other chemotherapy or radiotherapy regimens. Prospectively, controlled studies are warranted to confirm such results (AU)

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