scholarly journals Cerebrospinal Fluid Biomarkers in Childhood Leukemias

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 438
Author(s):  
Chrysanthy Ikonomidou

Involvement of the central nervous system (CNS) in childhood leukemias remains a major cause of treatment failures. Analysis of the cerebrospinal fluid constitutes the most important diagnostic pillar in the detection of CNS leukemia and relies primarily on cytological and flow-cytometry studies. With increasing survival rates, it has become clear that treatments for pediatric leukemias pose a toll on the developing brain, as they may cause acute toxicities and persistent neurocognitive deficits. Preclinical research has demonstrated that established and newer therapies can injure and even destroy neuronal and glial cells in the brain. Both passive and active cell death forms can result from DNA damage, oxidative stress, cytokine release, and acceleration of cell aging. In addition, chemotherapy agents may impair neurogenesis as well as the function, formation, and plasticity of synapses. Clinical studies show that neurocognitive toxicity of chemotherapy is greatest in younger children. This raises concerns that, in addition to injury, chemotherapy may also disrupt crucial developmental events resulting in impairment of the formation and efficiency of neuronal networks. This review presents an overview of studies demonstrating that cerebrospinal fluid biomarkers can be utilized in tracing both CNS disease and neurotoxicity of administered treatments in childhood leukemias.

Author(s):  
Eduardo E. Benarroch ◽  
Jeremy K. Cutsforth-Gregory ◽  
Kelly D. Flemming

The meninges, ventricular system, subarachnoid space, and cerebrospinal fluid (CSF) constitute a functionally unique system that has an important role in maintaining a stable environment within which the central nervous system can function. The membranes that constitute the meninges serve as supportive and protective structures for neural tissue. The CSF itself provides a cushioning effect during rapid movement of the head and mechanical buoyancy to the brain. In addition to providing a pathway for the removal of brain metabolites, it functions as a chemical reservoir that protects the local environment of the brain from changes that may occur in the blood, thus ensuring the brain’s continued undisturbed performance. The CSF system is present at the supratentorial, posterior fossa, and spinal levels. Because of this extensive anatomical distribution and function, pathologic alterations of the CSF system can occur in many neurologic disorders.


Author(s):  
Peggy Mason

The central nervous system develops from a proliferating tube of cells and retains a tubular organization in the adult spinal cord and brain, including the forebrain. Failure of the neural tube to close at the front is lethal, whereas failure to close the tube at the back end produces spina bifida, a serious neural tube defect. Swellings in the neural tube develop into the hindbrain, midbrain, diencephalon, and telencephalon. The diencephalon sends an outpouching out of the cranium to form the retina, providing an accessible window onto the brain. The dorsal telencephalon forms the cerebral cortex, which in humans is enormously expanded by growth in every direction. Running through the embryonic neural tube is an internal lumen that becomes the cerebrospinal fluid–containing ventricular system. The effects of damage to the spinal cord and forebrain are compared with respect to impact on self and potential for improvement.


1980 ◽  
Vol 239 (1) ◽  
pp. H108-H113 ◽  
Author(s):  
J. R. Haywood ◽  
G. D. Fink ◽  
J. Buggy ◽  
M. I. Phillips ◽  
M. J. Brody

The area postrema has been shown to have a major role in mediating the pressor effects of peripheral angiotensin in the dog, cat, and rabbit. The purpose of this study was to ascertain the function of the medullary circumventricular structure in the conscious rat. The pressor potency of angiotensin administered into the vertebral and carotid arteries was compared with intra-aortic infusions of angiotensin. Although no difference in pressor activity of angiotensin could be detected between intraaortic and intravertebral administration, greater sensitivity was observed during intracarotid infusion. No difference in the course of one-kidney renal hypertension was observed between sham-lesioned rats and animals with an area postrema lesion. In addition, lesioned and sham-lesioned animals showed equivalent responses to graded doses of angiotensin administered either intravenously or into the lateral ventricle. It was concluded that in the rat the area postrema plays no role in mediating the central nervous system actions of angiotensin whether the peptide reaches the brain via the blood or the cerebrospinal fluid.


1917 ◽  
Vol 25 (6) ◽  
pp. 789-806 ◽  
Author(s):  
John A. Kolmer ◽  
Claude P. Brown ◽  
Anna M. Freese

Four different varieties of easily cultivated microorganisms have been cultured from the cerebrospinal fluid and tissues of cases of acute anterior poliomyelitis; namely, a streptococcus, a diplococcus, diphtheroids, and Gram-negative bacilli. It is not contended that they were all inherent in the tissues; a part were doubtless extraneous. The streptococci and diplococd may be considered as the most significant of the bacteria cultivated and are distinguishable from each other by biological tests. The streptococci grew both aerobically and anaerobically; under anaerobic conditions growth was slow, the cocci became small and round, and were more easily decolorized with alcohol in the Gram stain. They were not found in the anaerobic cultures of 106 cerebrospinal fluids; they were found in one of twenty anaerobic blood cultures and frequently in the cerebrum, cerebellum, pons and medulla, cord, tonsils, lungs, liver, kidneys, spleen, pancreas, thymus gland, suprarenal glands, and mesenteric glands of fatal cases. The diplococci are Gram-positive and, transplanted to solid media, yield luxuriant growths and a staphylococcus grouping. They grew aerobically and anaerobically, but more slowly under the latter condition, and the cocci became smaller and more rounded. Diplococci were found in the anaerobic cultures of 48 of 106 cerebrospinal fluids; also in the cerebrum, cerebellum) pons and medulla, cord, tonsils, lungs, liver, kidneys, spleen, pancreas, and mesenteric glands of fatal cases. The filtrates of emulsions of tissues containing streptococci and diplococci passed through fine Kitasato and Pasteur-Chamberland filters were sterile unless large amounts of filtrates were collected. The amount of filtrate collected and cultured is therefore of considerable importance in filtration experiments. The small forms of streptococci and diplococci in old anaerobic cultures are filterable with these filters, while young aerobic cultures containing large forms are not, unless large amounts of culture are filtered. Intracranial, intravenous, and intraperitoneal injection of these easily cultivated streptococci, diplococci, diphtheroids, and Gramnegative bacilli failed to produce paralysis in rabbits or monkeys. With two exceptions all the cultures were transplants from the original anaerobic ascites-broth-kidney cultures of cerebrospinal fluid and various tissues. Arthritis and meningitis were produced by the streptococci, but there were neither clinical iior histological evidences of true poliomyelitis. Occasional bacteriological studies since 1898 have shown that easily cultivated micrococci and bacilli may be present in the cerebrospinal fluid and tissues of the central nervous system of persons suffering with acute anterior poliomyelitis. The majority of bacteriologists have found the cerebrospinal fluid, blood, and nervous organs sterile. Opinions have varied in regard to the significance of the organisms and the micrococci in particular, but the consensus of opinion has been to the effect that they are secondary invaders and unable of themselves to produce poliomyelitis in the lower animals. After allowing for contaminations due to technical errors in securing specimens, the total number of observations indicates that easily cultivated micrococci occur sometimes in the brain and cord of persons suffering from epidemic poliomyelitis. Our studies have shown that they may be found not only in these locations, but also in the spleen, kidneys, suprarenal glands, and other organs. It is not known that they exert an influence in this disease, although they may possibly give rise to the production of antibodies) assuming their entrance not to be wholly agonal,as the cultures of streptococci are frequently of sufficient virulence to produce meningitis in rabbits and monkeys. Our experiments are in accord with those of other investigators who found that these microorganisms do not produce poliomyelitis in the lower animals, and are therefore in sharp contrast with the recent reports which would attribute an etiologic relationship of streptococi and allied organisms to that disease. At present this wide divergence of result cannot be accounted for, but it does not seem that it is possible for it to reside in any condition of the cultures employed by us as they were obtained from undoubted cases of epidemic poliomyelitis and inoculated in early generations. As regards these easily cultivatable microorganisms, we agree at present with those who regard them as secondary and probably terminal invaders rather than the actual etiologic agent of the disease.


2020 ◽  
Vol 6 (43) ◽  
pp. eaaz9360 ◽  
Author(s):  
Lenora Higginbotham ◽  
Lingyan Ping ◽  
Eric B. Dammer ◽  
Duc M. Duong ◽  
Maotian Zhou ◽  
...  

Alzheimer’s disease (AD) lacks protein biomarkers reflective of its diverse underlying pathophysiology, hindering diagnostic and therapeutic advancements. Here, we used integrative proteomics to identify cerebrospinal fluid (CSF) biomarkers representing a wide spectrum of AD pathophysiology. Multiplex mass spectrometry identified ~3500 and ~12,000 proteins in AD CSF and brain, respectively. Network analysis of the brain proteome resolved 44 biologically diverse modules, 15 of which overlapped with the CSF proteome. CSF AD markers in these overlapping modules were collapsed into five protein panels representing distinct pathophysiological processes. Synaptic and metabolic panels were decreased in AD brain but increased in CSF, while glial-enriched myelination and immunity panels were increased in brain and CSF. The consistency and disease specificity of panel changes were confirmed in >500 additional CSF samples. These panels also identified biological subpopulations within asymptomatic AD. Overall, these results are a promising step toward a network-based biomarker tool for AD clinical applications.


2016 ◽  
Vol 90 (20) ◽  
pp. 9285-9292 ◽  
Author(s):  
Akiko Takenaka ◽  
Hiroki Sato ◽  
Fusako Ikeda ◽  
Misako Yoneda ◽  
Chieko Kai

ABSTRACTIn the current study, we generated recombinant chimeric canine distemper viruses (CDVs) by replacing the hemagglutinin (H) and/or phosphoprotein (P) gene in an avirulent strain expressing enhanced green fluorescent protein (EGFP) with those of a mouse-adapted neurovirulent strain. Anin vitroexperimental infection indicated that the chimeric CDVs possessing the H gene derived from the mouse-adapted CDV acquired infectivity for neural cells. These cells lack the CDV receptors that have been identified to date (SLAM and nectin-4), indicating that the H protein defines infectivity in various cell lines. The recombinant viruses were administered intracerebrally to 1-week-old mice. Fatal neurological signs of disease were observed only with a recombinant CDV that possessed both the H and P genes of the mouse-adapted strain, similar to the parental mouse-adapted strain, suggesting that both genes are important to drive virulence of CDV in mice. Using this recombinant CDV, we traced the intracerebral propagation of CDV by detecting EGFP. Widespread infection was observed in the cerebral hemispheres and brainstems of the infected mice. In addition, EGFP fluorescence in the brain slices demonstrated a sequential infectious progression in the central nervous system: CDV primarily infected the neuroependymal cells lining the ventricular wall and the neurons of the hippocampus and cortex adjacent to the ventricle, and it then progressed to an extensive infection of the brain surface, followed by the parenchyma and cortex. In the hippocampal formation, CDV spread in a unidirectional retrograde pattern along neuronal processes in the hippocampal formation from the CA1 region to the CA3 region and the dentate gyrus. Our mouse model demonstrated that the main target cells of CDV are neurons in the acute phase and that the virus spreads via neuronal transmission pathways in the hippocampal formation.IMPORTANCECDV is the etiological agent of distemper in dogs and other carnivores, and in many respects, the pathogenesis of CDV infection in animals resembles that of measles virus infection in humans. We successfully generated a recombinant CDV containing the H and P genes from a mouse-adapted neurovirulent strain and expressing EGFP. The recombinant CDV exhibited severe neurovirulence with high mortality, comparable to the parental mouse-adapted strain. The mouse-infectious model could become a useful tool for analyzing CDV infection of the central nervous system subsequent to passing through the blood-cerebrospinal fluid barrier and infectious progression in the target cells in acute disease.


1930 ◽  
Vol 51 (6) ◽  
pp. 889-902 ◽  
Author(s):  
Jules Freund

1. Antibodies can be extracted from the brain and spinal cord of rabbits actively or passively immunized with typhoid bacilli. 2. The titers of the antibodies in the extracts of brain and cord depend upon the titer of the blood serum. In actively immunized rabbits the following numerical relationships exist between the titers of the serum and of these organ extracts: The ratio of the titer of the serum is to the titers of extract of brain and of the spinal cord about as 100 is to 0.8; the titer of the serum is to the titer of the cerebrospinal fluid as 100 is to 0.3. In passively immunized rabbits the titer of the serum is to the titer of brain and spinal-cord extract as 100 is to 0.7. 3. The antibodies recovered from the brain are not due to the presence of blood in it for perfusion of the brain does not reduce its antibody content appreciably. 4. Antibodies penetrate into the spinal fluid from the blood even in the absence of inflammation of the meninges. When the penetration is completed the following numerical relationship exists between the titer of the serum and that of the cerebrospinal fluid: 100 to 0.25. 5. The penetration into the cerebrospinal fluid of antibodies injected intravenously proceeds at a slow rate, being completed only several hours after the immune serum has been injected. The penetration of antibodies into the tissue of the brain occurs at a very rapid rate. It is completed within 15 minutes. 6. It is very unlikely that when the immune serum is injected intravenously the antibodies reach the brain tissue by way of the cerebrospinal fluid, for (1) the antibody titer of the cerebrospinal fluid is lower than that of the brain extract, and (2) antibodies penetrate faster into the tissue of the brain than into the cerebrospinal fluid.


1998 ◽  
Vol 35 (5) ◽  
pp. 409-411 ◽  
Author(s):  
Y. Noda ◽  
Y. Uchinuno ◽  
H. Shirakawa ◽  
S. Nagasue ◽  
N. Nagano ◽  
...  

A bovine fetus aborted at 187 days of gestation was serologically and immunohistopathologically examined. Serum and cerebrospinal fluid samples had high titers of virus-neutralizing antibody for Aino virus. A severe necrotizing encephalopathy was noted. Aino virus antigen was demonstrated in neuroglial cells within the brain lesion. The destruction of developing neuronal cells appeared to be a significant feature of the pathogenesis of lesions due to Aino virus infection in the central nervous system.


Pharmacology ◽  
2017 ◽  
Vol 101 (1-2) ◽  
pp. 29-34 ◽  
Author(s):  
Ali Sigaroudi ◽  
Martina Kinzig ◽  
Oliver Wahl ◽  
Christoph Stelzer ◽  
Michael Schroeter ◽  
...  

Background: Bisoprolol and metoprolol are moderately lipophilic, beta(1)-selective betablockers reported to cause adverse effects in the central nervous system (CNS), such as sleep disturbance, suggesting that both drugs may reach relevant concentrations in the brain. CNS beta(2)-receptor blockade has been suspected to be related to such effects. The higher molecular size of bisoprolol (325 Dalton) and the higher beta(1)-selectivity compared to metoprolol (267 Dalton) would suggest a lower rate of CNS effects. Methods: To address the pharmacokinetic background of this assumption, we quantified to which extent these beta(1)-blockers are able to enter the cerebrospinal fluid (CSF) in 9 (bisoprolol group) and 10 (metoprolol group) neurological patients who had received one of the drugs orally for therapeutic purposes prior to lumbar puncture. We quantified their total concentrations by liquid chromatography/tandem mass spectrometry in paired serum and CSF samples. Results: Median (interquartile range) in CSF reached 55% (47-64%) of total serum concentrations for bisoprolol and 43% (27-81%) for metoprolol, corresponding to 78% (67-92%) and 48% (30-91%) of respective unbound serum concentrations. Conclusion: The extent of penetration of bisoprolol and metoprolol into the CSF is similar and compatible with the assumption that both drugs may exert direct effects in the CNS.


Author(s):  
Joshua H. Smith ◽  
Jose Jaime García

The cerebrospinal fluid present in the central nervous system plays an important role in the physiological activities and protection of the brain. Disruptions of CSF flow lead to different forms of a disease known as hydrocephalus, characterized by a significant increment of the ventricular space. In acute hydrocephalus the Sylvius aqueduct is blocked and ventricular pressure is greatly increased.


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