CN110082542B - Application of NF-L in detecting cerebrospinal fluid of neurosyphilis - Google Patents

Application of NF-L in detecting cerebrospinal fluid of neurosyphilis Download PDF

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CN110082542B
CN110082542B CN201910425993.XA CN201910425993A CN110082542B CN 110082542 B CN110082542 B CN 110082542B CN 201910425993 A CN201910425993 A CN 201910425993A CN 110082542 B CN110082542 B CN 110082542B
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伦文辉
许东梅
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Abstract

The invention relates to application of NF-L in detecting cerebrospinal fluid of nerve syphilis. Specifically, the invention provides a neurosyphilis detection kit, which comprises a detection reagent for detecting the NF-L level of cerebrospinal fluid. The invention also provides application of the first detection reagent for detecting the cerebrospinal fluid NF-L in preparing the neurosyphilis detection kit. The invention can be used for early diagnosis, typing and staging, curative effect evaluation and/or prognosis evaluation of the neurosyphilis, and has the advantages of high reliability, high sensitivity and the like.

Description

Application of NF-L in detecting cerebrospinal fluid of neurosyphilis
The application is a divisional application of Chinese invention patent application with the invention name of 'application of NF-L in neurological syphilis cerebrospinal fluid detection' and the application number of '201810254379.7'.
Technical Field
The invention relates to the technical field of biomedicine, in particular to application of NF-L in detecting cerebrospinal fluid of nerve syphilis.
Background
Intermediate Fibers (IFs) are one of 3 skeleton proteins constituting the nerve cell axonal complex network system, and have a fixing effect on cell nuclei, provide mechanical strength to cells, participate in cell connection, play a role in intracellular substance transport, participate in cell division activities, participate in information transfer activities, and the like. The intermediate fiber is a hollow fiber structure with a diameter of 10nm and is mainly classified into six types, such as neurofilament protein and the like. Neurofilament (NF) is only expressed in nerve cells and comprises three substructures of a Neurofilament Light chain (NF-L), a Neurofilament Medium chain (NF-M) and a Neurofilament Heavy chain (NF-H); the structure of the fiber is similar to other intermediate fibers, and comprises a head ammonia base region, a rod-shaped region of an alpha helix and a tail carboxyl base region. The neurofilament protein functions to stabilize the morphology of axons, maintain their diameter and maintain their stable conduction velocity, and plays a role in the processes of neuronal differentiation, axon growth and regeneration, etc.
NF-L is the first expressed substructure of the neurofilament protein and has a molecular weight of 68 kDa. NF-H is also one of the main components constituting the neurofilament protein, has a molecular weight of 205kDa, is the finally expressed neurofilament protein, and is directly related to the expansion of axon diameter and the increase of axon conduction velocity. Expression levels of NF-L and NF-H are reported to be independent of each other, which may be related to their different genomic locations.
The carboxy terminus of NF-H has 51 phosphorylated sites, varying in degree from proximal to distal. In neuronal soma or dendrites, NF-H is present essentially without phosphorylation, while in neuronal axons, it is present mostly in phosphorylated form, i.e. phosphorylated neurofibrillarin Heavy chain (pNF-H), which plays an important role in stabilizing axonal morphology and in the transduction of neural signals.
Syphilis is a systemic, infectious disease caused by the invasion of treponema pallidum into the human body. The treponema pallidum is a small and slender spiral microorganism, is propagated in a transverse division mode, and has a structure with axial fibers for maintaining the elasticity of the treponema pallidum, so that the treponema pallidum can flex and stretch, and the treponema pallidum can penetrate into host tissues. Treponema pallidum is not easy to survive outside human body and dies immediately after boiling, and general disinfectants such as dry soap water, alcohol and the like can kill the treponema pallidum easily, so that the treponema pallidum can not be cultured in vitro at present, can be stored for years at low temperature (-78 ℃), and can still keep the form activity and the toxicity of the treponema pallidum. The inability of treponema pallidum to be cultured in vitro limits the spread and invasion of treponema pallidum to a certain extent, but also causes great difficulty and invariance in the study of treponema pallidum and the study of syphilis diseases, so that the current diagnosis, treatment and prognosis study of syphilis is not greatly advanced.
The neurosyphilis is a chronic infectious disease caused by treponema pallidum invading the central nervous system, can cause the damage of the nervous system which is difficult to recover, and is the main cause of syphilis disability, so the neurosyphilis becomes a disease which seriously threatens the human health.
Neurosyphilis can occur in various stages of syphilis. The Neurosyphilis can be classified into Asymptomatic Neurosyphilis (asymptic Neurosyphilis), Meningeal Syphilis (meniral Syphilis, including syphilitic meningitis and syphilitic duralitis), Meningeal vascular Syphilis (meninogovasular Syphilis), parenchymal Neurosyphilis (paralytic dementia) and Tabes Dorsalis (Tabes Dorsalis)), and gummy Syphilis (see fig. 1).
Asymptomatic neurosyphilis refers to positive plasmacyesis examination of syphilis, abnormal cerebrospinal fluid exists, but symptoms and signs of an asymptomatic nervous system generally occur 12-18 months after infection and are the initial stage of the neurosyphilis, and asymptomatic neurosyphilis patients are easier to progress into symptomatic neurosyphilis than syphilis patients with normal cerebrospinal fluid, so that suspected patients should be subjected to cerebrospinal fluid examination, early treatment is discovered early in time, and progress of the asymptomatic neurosyphilis into the symptomatic neurosyphilis is avoided.
Meningeal syphilis, including syphilitic meningitis and syphilitic duralitis, occurs primarily within 12 months after syphilis infection, and may occur in 1.4% to 6% of syphilis patients, primarily because of the failure to adequately treat the early syphilis stage.
Meningovascular syphilis, including cerebrovascular syphilis and spinal meningovascular syphilis, typically occurs 5 to 12 years after syphilis infection, and 3.2% to 15% of syphilis patients progress to meningovascular syphilis before antibiotics have not been invented.
Substantial syphilis is a more advanced form of syphilis, including paralytic dementia and tuberculosis of the spinal cord. The mean incubation period for paralytic dementia is 15-20 years, and it has been reported that 5% of patients with syphilis progress to paralytic dementia, while untreated paralytic dementia die within 5 years.
The gum swelling type neurosyphilis is rare in the neurosyphilis and comprises encephaledema and spinal cord edema, clinical manifestations are different due to different incidence parts of the encephaledema, the encephaledema is mainly expressed by similar symptoms of brain tumors, such as progressive nervous system symptoms, epilepsy, high intracranial pressure and the like, and MRI can generate linear intensification similar to meningioma. While gum swelling of the spinal cord can lead to paralysis of the four limbs when it affects the cervical spine and paresis of the lower limbs when it affects the thoracic spine.
The clinical manifestations of the neurosyphilis are also complex and variable, the symptoms are not specific, almost all various symptoms and physical signs in neurology can appear, and similar clinical manifestations of neurology, ophthalmology, dermatology, psychiatric department and the like can appear, so that the misdiagnosis rate of the neurosyphilis is high and reaches 55.6%, for example, cerebral infarction of unknown reasons in young and strong years caused by the neurosyphilis, epilepsy, intellectual disability and the like appearing in young and strong years can be misdiagnosed, and therefore, correct diagnosis and timely treatment of the neurosyphilis are very important.
At present, no gold standard for diagnosing the neurosyphilis exists, and laboratory detection is helpful for diagnosing the neurosyphilis; however, no single test method is available for the diagnosis of neurosyphilis in all cases. Diagnosis of neurosyphilis relies on a combination of plasmacy tests, cerebrospinal fluid (CSF) examinations, neurological symptoms and signs. Further testing is required for patients presenting with clinical symptoms of neurosyphilis.
The plasmacyclinics test mainly comprises two types of tests, namely a non-treponema pallidum antigen plasma test and a treponema pallidum antigen plasma test. The non-treponema pallidum antigen Plasma test takes cardiolipin as an antigen to detect antibodies in Plasma which react with the cardiolipin, wherein the most widely applied at present is the Rapid Plasma reactive element annular card test (RPR, Rapid Plasma reading). The principle is that a mixture consisting of cardiolipin, lecithin and cholesterol is used as an antigen, special activated carbon particles are used for adsorption, and the result judgment is directly carried out by observing whether black aggregated particles appear on a white paperboard by naked eyes. The treponema pallidum antigen plasma test is directed to a specific component of treponema pallidum as an antigen and is therefore used for screening and definitive diagnosis of syphilis infection. Treponema pallidum gelatin agglutination Test (TPPA) coats delicate strain components of pathogenic TP on artificial carrier gelatin particles, detects corresponding syphilis antibody in plasma, and is the main treponema pallidum antigen plasma test at present because various non-specific reactions are eliminated in the reagent preparation process and the sensitivity and specificity are high.
Cerebrospinal fluid examinations primarily include CSF-RPR, CSF leukocyte counts, or protein levels. The principle of CSF-RPR is the same as that of plasma RPR, the specificity is similar to that of a cerebrospinal fluid Disease Research Laboratory (VDRL) test (CSF-VDRL), but the sensitivity is higher than that of CSF-VDRL, the CSF-RPR is a cerebrospinal fluid treponema nonspecific antibody test which is commonly used at present, and the CSF-RPR is generally positive, namely, the neurosyphus can be diagnosed. Important reference indicators for neurosyphilis also include cerebrospinal fluid cell count or protein level, and when CSF-RPR is negative, if clinical signs of neurosyphilis, positive plasmacytic tests, and cerebrospinal fluid cell count (generally CSF leukocyte count > 5/. mu.l is abnormal, and for patients with HIV infection, the cerebrospinal fluid cell count is high, and for improving diagnosis accuracy, the standard for abnormal cerebrospinal fluid cell count of such patients should be improved to leukocyte count > 20/. mu.l) and/or protein level is abnormal, the diagnosis as neurosyphilis can be considered.
A plurality of clinical researches prove that the rising degree of protein content in cerebrospinal fluid of a patient with the neurosyphilis is positively correlated with the severity of the disease and negatively correlated with the long-term prognosis; the positive oligoclonal zone (OCB) in the cerebrospinal fluid of the patient with the neurosyphilis, the rising of the content of tau protein in the cerebrospinal fluid, the rising of CXCL13 and the like all indicate that the immune response is generated in the central nervous system. But currently, there is no credible biological marker reflecting the degree of nerve injury of the neurosyphilis. Therefore, it is important to find an index for evaluating the degree of nerve damage and prognosis of patients with neurosyphilis.
It has been reported that many markers capable of reflecting central nervous system injury, such as amyloid beta precursor protein and amyloid beta, myelin basic protein, neuron-specific enolase, microtubule-associated protein tau, etc., have some changes in neurosyphilis, but all have problems such as poor specificity. Neurofilament proteins are presumed to be involved in a variety of neurological diseases, but their cellular molecular mechanisms are not clear. Through continuous research for years, the inventor finds that the cerebrospinal neurofilament light chain level of syphilis patients, particularly neurosyphilis patients, can fully reflect the progress of the neurosyphilis, so that the syphilis can be classified in stages, diagnosed in early stage, estimated in disease severity and evaluated in curative effect according to the cerebrospinal neurofilament light chain level.
The neurofilament protein exists only in nerve cells, and the nerve cells have strong specificity and strong enzymolysis resistance. NF-L is released into the cerebrospinal fluid after nerve cells are damaged. The inventor discovers that the NF-L level of the cerebrospinal fluid has great clinical significance by researching the NF-L level of the cerebrospinal fluid of a patient with the neurosyphilis, and explores related influence factors of the NF-L level. The inventor discovers through long-term clinical research that the level of NF-L in cerebrospinal fluid and the correlation between the NF-L and other factors can provide a reliable, effective and sensitive solution for early diagnosis, classification and staging, curative effect evaluation and/or prognosis evaluation of the neurosyphilis.
Disclosure of Invention
Therefore, in order to solve the above problems in the prior art, the present invention provides the following technical solutions:
1. a syphilis detection kit, wherein the kit comprises a detection reagent for detecting the level of a cerebrospinal neurofilament protein light chain.
2. The kit according to claim 1, wherein the detection reagent is an anti-neurilelin light chain antibody; preferably, the antibody is an antibody against a light chain of human neurofilament protein; it is also preferred that the antibody is a polyclonal antibody or a monoclonal antibody, most preferably a monoclonal antibody.
3. The kit according to technical scheme 1, wherein the kit further comprises a second detection reagent, and the second detection reagent is a detection reagent for one or more syphilis detection methods selected from the group consisting of VDRL detection, USR detection, TRUST detection, RPR detection, TPHA or TPPA detection, FTA-ABS detection, ELISA detection, blood NF-L detection, blood pNF-H detection, cerebrospinal fluid pNF-H detection; preferably, the second detection reagent is a detection reagent for a syphilis detection method selected from the group consisting of RPR detection, TPHA or TPPA detection, FTA-ABS detection, blood NF-L detection, blood pff-H detection, cerebrospinal fluid pff-H detection; more preferably, the second detection reagent is a detection reagent for FTA-ABS detection and/or TPPA detection.
4. The kit according to claim 1, wherein the kit further comprises an auxiliary reagent for assisting the antibody against the light chain of neurofilament to detect the light chain of cerebrospinal neurofilament by an ELISA detection method; preferably, the auxiliary reagent comprises a reagent selected from the group consisting of a neurofilament light chain antibody-coated microtiter plate, a neurofilament light chain antibody solution, a horseradish peroxidase conjugate solution, a neurofilament light chain protein standard sample, a dilution buffer, a washing solution, a substrate solution, and a stop solution.
5. The kit according to claim 1, wherein the second detection reagent further comprises a detection reagent for detecting an index selected from the group consisting of a blood NF-L level, a cerebrospinal fluid pNF-H level, a cerebrospinal fluid RPR titer, a blood RPR titer, a cerebrospinal fluid leukocyte, a cerebrospinal fluid protein, a pre-treatment and post-treatment blood NF-L difference, a pre-treatment and post-treatment cerebrospinal fluid NF-L difference, and a pre-treatment and post-treatment cerebrospinal fluid pNF-H difference.
6. The kit according to claim 1, wherein the kit further comprises a cerebrospinal fluid puncturing and extracting instrument and/or a cerebrospinal fluid cryopreservation tube.
7. The kit according to any one of claims 1 to 6, wherein the detection reagent is a detection reagent for qualitative or quantitative detection of cerebrospinal neurofilament light chain.
8. Use of a first detection reagent and optionally a second detection reagent for detecting cerebrospinal neurofilament light chain in the preparation of a kit according to any of claims 1 to 7.
9. The use according to claim 8, wherein:
the first detection reagent is used for carrying out quantitative detection or qualitative detection on the cerebrospinal neurofilament protein light chain;
more preferably, the detection reagent is an antibody against the light chain of neurofilament protein;
it is further preferred that the antibody is an antibody against a light chain of human neurofilament protein;
still more preferably, the antibody is a monoclonal antibody.
10. The use according to any one of claims 8 to 9, wherein the kit is used for early diagnosis, typing and staging, efficacy evaluation and/or prognosis evaluation of neurosyphilis.
The inventor firstly discovers that a certain correlation exists between the NF-L abnormality in blood and the development of the neurosyphilis and the occurrence of related symptoms through researching the NF-L level in the cerebrospinal fluid of the patient with the neurosyphilis, thereby having great clinical significance for the neurosyphilis. Because the difference between the NF-L of the group of patients with symptomatic neurosyphilis and the NF-L of the group of patients without symptomatic neurosyphilis has statistical significance, the difference indicates that the protein molecule level in the cerebrospinal fluid of different clinical typing or staged neurosyphilis patients is different, the protein molecule level in the cerebrospinal fluid of the patients is different, the immune reaction degree and the immune injury degree are also different, and therefore, the early diagnosis, the typing and staging, the curative effect evaluation and/or the prognosis evaluation of the neurosyphilis can be carried out according to the protein molecule level.
Drawings
FIG. 1 is a view showing the natural course of syphilis untreated.
FIG. 2 shows the results of NF-L analysis of cerebrospinal fluid (CSF) of various groups of patients. Wherein NS represents the symptomatic neurometavirus group (n ═ 20); ANS means asymptomatic neurosyphus group (n-46); s represents the recessive syphilis group (n ═ 18).
FIG. 3 shows the average cerebrospinal fluid NF-L levels for each group of patients. Wherein NS represents the symptomatic neurometavirus group (n ═ 20); ANS indicates asymptomatic neurosyphus group (n ═ 46, including 27 cerebrospinal fluid TRUST positive (+) patients and 19 cerebrospinal fluid TRUST negative (-) patients); s represents the recessive syphilis group (n ═ 18).
FIGS. 4 to 14 show the comparison of the NF-L level, the cerebroprotein level and the leukocyte level of cerebrospinal fluid before and after treatment of some of the individual patients with neurosyphilis, respectively.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. The described embodiments are, however, a subset of the embodiments of the invention and not all embodiments of the invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
As described above, the invention provides a neurosyphilis detection kit, which comprises a detection reagent for detecting the level of the cerebrospinal neurofilament protein light chain.
In some preferred embodiments, the detection reagent is a detection reagent for qualitative or quantitative detection of cerebrospinal fluid NF-L. More preferably, the detection reagent is used for quantitatively detecting the NF-L in cerebrospinal fluid.
In some preferred embodiments, the cerebrospinal fluid NF-L level is the cerebrospinal fluid NF-L protein level, more preferably, the detection agent is an anti-NF-L antibody, even more preferably, the antibody is an anti-human NF-L antibody, even more preferably, the antibody is a polyclonal antibody or a monoclonal antibody, and most preferably, a monoclonal antibody. The monoclonal antibody may be known, for example, from commercial reagents such as R & D Systems, Inc., GeneTex International Corporation, abcam, etc., or included in NF-L protease-linked diagnostic kits available from IBL, Germany, etc.
In some preferred embodiments, the kit further comprises an optional second detection reagent for detecting a second analyte selected from the group consisting of VDRL (venereal disease research laboratory), USR (unheated serum regaining), TRUST (toluidine red plasma non-heating assay), RPR (rapid plasma reaining), FTA-ABS (fluorescent antibody uptake), TPHA (trepma pallidum hemagglutination assay), TPPA (trepma pallidum particulate agglutination, trepma pallidum agglutination-ELISA, NF-NF, blood sample H-NF, and blood sample H-NF Detection of one or more syphilis in the group consisting of cerebrospinal fluid pNF-H detectionThe detection reagents for the method, these syphilis detection methods and the reagents used therefor are known. For example, VDRL assay, USR assay, TRUST assay, RPR assay, FTA-ABS assay, TPHA assay, TPPA assay and ELISA assay and reagents used therein can all be described in industry standards such as the syphilis diagnostic standard (WS 273-. The detection reagent for NF-L in blood or cerebrospinal fluid can be commercial kit
Figure BDA0002067509060000081
(Neurofament light) ELISA (Enzyme immunoassay for quantitative determination of Human Neurofament light (NF-L) protein in carbohydrate flow) (LBL International GME), the detection reagent for blood or cerebrospinal fluid pNF-H can be as described in the commercial kit Human Phosphorylated Neurofament H ELISA kit (BioVedor-laboratory I media I a.s.). More preferably, the second detection reagent is a detection reagent for a syphilis detection method selected from the group consisting of RPR detection, TPPA or TPHA detection, FTA-ABS detection, blood NF-L detection, blood pff-H detection, cerebrospinal fluid pff-H detection; it is further preferred that the second detection reagent is a detection reagent for FTA-ABS detection and/or TPPA detection. FTA-ABS and TPPA are specific indexes for diagnosing treponema pallidum infection, generally speaking, cerebrospinal fluid FTA-ABS negative can eliminate nerve syphilis, and the indexes can increase sensitivity and specificity for diagnosing nerve syphilis by combining with NF-L detection results.
In some preferred embodiments, the kit further comprises an auxiliary agent for aiding the detection of cerebrospinal fluid NF-L by ELISA detection using an anti-NF-L antibody. In some preferred embodiments, the auxiliary reagent comprises a reagent selected from the group consisting of NF-L antibody coated microtiter plates, NF-L antibody solutions, horseradish peroxidase conjugate solutions, NF-L protein standards, dilution buffers, wash solutions, substrate solutions, stop solutions.
In some preferred embodiments, the kit further comprises a cerebrospinal fluid puncture withdrawal instrument and/or a cerebrospinal fluid cryopreservation tube.
The invention also provides application of the first detection reagent and the optional second detection reagent for detecting the cerebrospinal fluid NF-L in preparing the neurosyphilis detection kit.
The first detection reagent can be a detection reagent for quantitatively or qualitatively detecting the NF-L in the cerebrospinal fluid, for example, the detection kit is a detection kit for qualitatively or quantitatively detecting the NF-L in the cerebrospinal fluid sample by an ELISA detection method. More preferably, the detection reagent is an anti-NF-L antibody, and even more preferably, the antibody can be an anti-human NF-L antibody; still more preferably, the antibody is a monoclonal antibody. The monoclonal antibody may be as described above.
The second detection reagent may be a detection reagent for detecting an index selected from the group consisting of a blood NF-L level, a cerebrospinal fluid pNF-H level, a cerebrospinal fluid RPR titer, a blood RPR titer, a cerebrospinal fluid leukocyte, a cerebrospinal fluid protein, a pre-treatment and post-treatment cerebrospinal fluid NF-L difference, and a pre-treatment and post-treatment cerebrospinal fluid pNF-H difference.
In some preferred embodiments, the kit is a kit for early diagnosis, typing staging, efficacy assessment and/or prognosis evaluation of neurosyphene.
When the neurosyphilis is diagnosed (including early diagnosis, typing and staging, curative effect evaluation and/or prognosis evaluation and the like), the neurosyphilis patients can be typed and staged (namely, the neurosyphilis is typed and/or staged) according to the NF-L level of cerebrospinal fluid; alternatively, the prognosis of a patient with neurosyphilis can be assessed by the difference in the prognosis of cerebrospinal fluid NF-L relative to the prognosis of the patient before (or referred to as before treatment). Thus, in some particular embodiments, the present invention provides a neurosyphene syphilis test kit comprising a test reagent for detecting the level of cerebrospinal fluid NF-L and for performing a typing staging or prognostic assessment of a patient suffering from neurosyphene syphilis. The invention also provides application of the detection reagent in preparing a kit for typing and staging (namely typing and/or staging) or prognosis evaluation of the patient with the neurosyphilis.
In diagnosing (including early diagnosis, staging, efficacy assessment and/or prognosis assessment, etc.) neurosyphilis, the cerebrospinal fluid NF-L level may be used for early diagnosis, staging, efficacy assessment and/or prognosis assessment of the neurosyphilis, either independently or in combination with one or more of the indices selected from the group consisting of cerebrospinal fluid NF-L level, cerebrospinal fluid pNF-H level, cerebrospinal fluid RPR titer, blood RPR titer, cerebrospinal fluid leukocytes, cerebrospinal fluid proteins, pre-and post-treatment cerebrospinal fluid NF-L difference, pre-and post-treatment cerebrospinal fluid pNF-H difference. Thus, in some embodiments, the present invention provides a neurosyphene syphilis test kit, comprising: a first detection reagent for detecting NF-L levels in cerebrospinal fluid; optionally a second detection reagent for detecting one or more indicators selected from the group consisting of cerebrospinal fluid NF-L level, cerebrospinal fluid pNF-H level, cerebrospinal fluid RPR titer, blood RPR titer, cerebrospinal fluid leukocytes, cerebrospinal fluid proteins, pre-treatment and post-treatment cerebrospinal fluid NF-L difference, pre-treatment and post-treatment cerebrospinal fluid pNF-H difference. The invention also provides application of the first detection reagent and/or the second detection reagent in preparation of a detection kit for early diagnosis, typing and staging, curative effect evaluation and/or prognosis evaluation of the neurosyphilis.
In the invention, the NF-L level of cerebrospinal fluid, the pNF-H level of cerebrospinal fluid, the RPR titer of blood, the leukocyte number of cerebrospinal fluid and the amount of cerebrospinal fluid are detected by known detection methods, and the NF-L difference value of cerebrospinal fluid before and after treatment, the NF-L difference value of cerebrospinal fluid before and after treatment and the pNF-H difference value of cerebrospinal fluid before and after treatment can be calculated by data measured by known methods. For example, NF-L, pNF-H can be measured by a commercial kit, and other indexes can be measured by a method specified by the national industry standard syphilis diagnostic standard (WS 273-.
Examples
1. General clinical data of patients
A total of 92 patients were enrolled in the study. According to WS 273 and 2007 diagnosis standards of syphilis, patients with symptomatic and asymptomatic syphilis and recessive syphilis are confirmed. Among them, 23 cases of symptomatic neurosyphilis group; group 51 asymptomatic neurosyphilis; the recessive syphilis control group comprises 18 cases.
Plasma TPPA of patients with symptomatic neurosyphotosis is all positive; plasma RPR titers were 1:1 in 1 patient, 2 in 1:4 patients, 2 in 1:8 patients, 3 in 1:16 patients, 4 in 1:32 patients, 4 in 1:64 patients, 2 in 1:128 patients, 5 in 1:256 patients. 23 positive cases of cerebrospinal fluid TPPA; cerebrospinal fluid RPR titer negative for 1, 6 in 1:1 patients, 3 in 1:2 patients, 5 in 1:4 patients, 3 in 1:8 patients, 4 in 1:16 patients, 1 in 1:32 patients. The median cerebrospinal fluid protein was 62.3mg/dl, with a maximum of 191.6mg/dl and a minimum of 30 mg/dl. The median number of cerebrospinal fluid leukocytes was 17X 106L, maximum 130X 106L, minimum value of 0X 106/L。
Plasma TPPA of asymptomatic neurosyphotosis patients is all positive; plasma RPR titers were 1:1 in 2 patients, 1:2 in 3 patients, 1:4 in 5 patients, 1:8 in 11 patients, 1:16 in 11 patients, 1:32 in 14 patients, 1:64 in 2 patients, 1:128 in 2 patients, 1:256 in 1 patient. Cerebrospinal fluid TPPA was positive in 44 cases and negative in 7 cases. Cerebrospinal fluid RPR titer negative 30 cases, 1:1 patient 9, 1:2 patient 9, 1:4 patient 2, 1:8 patient 1. The median cerebrospinal fluid protein was 29.6mg/dl, the maximum was 60.7mg/dl and the minimum was 7.2 mg/dl. The median number of cerebrospinal fluid leukocytes is 10X 106A maximum value of 216X 106L, minimum value of 1X 106/L。
The plasma TPPA of recessive syphilis patients is all positive; 3 patients with negative plasma RPR titers, 1:1 patient 1, 1:2 patient 3, 1:4 patient 3, 1:8 patient 2, 1:16 patient 3, 1:32 patient 1, 1:64 patient 1, 1:128 patient 1. 17 negative cases of cerebrospinal fluid TPPA and 1 positive case; cerebrospinal fluid RPR titers were all negative. The median of cerebrospinal fluid protein is 22.8mg/dl, the maximum value is 45.2mg/dl, and the minimum value is 8.6 mg/dl; the median number of white blood cells in cerebrospinal fluid is 3X 106L, maximum 5X 106L, minimum value of 0X 106/L。
2. Sample acquisition
According to the situation of patients entering the group, the lumbar puncture and the elbow venipuncture are reserved for taking cerebrospinal fluid and blood for routine examination, and cerebrospinal fluid and blood samples are reserved, and are stored in a refrigerator at-80 ℃ in a matching manner, and finally, the samples are uniformly detected, so that batch errors of sample detection are avoided.
Under the informed consent of the patients, 5ml of cerebrospinal fluid marker is collected by lumbar puncture, and 10ml of blood sample is collected by vein. Collecting cerebrospinal fluid by lumbar puncture, subpackaging with a freezing tube, and coding and marking; after collecting blood by venipuncture, placing the blood in a centrifuge with the temperature of 4 ℃, centrifuging the blood for 10 minutes at 3000 rpm, quickly separating supernatant clear plasma, placing the supernatant clear plasma in a freezing storage tube, and coding and marking. Storing cerebrospinal fluid and plasma samples in a refrigerator at-80 deg.C, and performing uniform detection.
3. Detection method
The detection methods employed in the examples are all known. Wherein the detection of the cerebrospinal fluid NF-L and the cerebrospinal fluid NF-L adopts
Figure BDA0002067509060000122
(Neuroxilent light) ELISA (Enzyme immunoassay for quantitative determination of human Neuroxilent light (NF-L) protein in temporal fluidic flow) (LBL International GME) was performed according to the instructions. Detection of plasma and cerebrospinal fluid pff-H was performed using a Human Phosphorylated neuroofamere H ELISA kit (biovector-laboratory i. Plasma RPR titer, cerebrospinal RPR titer, brain protein assay and detection of brain leukocytes were performed according to the method described in WS 273-.
4. Treatment regimens
The treatment method of symptomatic and asymptomatic neurosyphilis adopts a national standard treatment method, penicillin is 2400 ten thousand U/day, is divided into 400 ten thousand U/4 hours, and is intravenously dripped for continuous treatment for 14 days. Pre-treatment data is data detected using samples taken on day 0 prior to treatment; post-treatment data are the results of sample testing taken 180 days after treatment with the treatment regimen described above.
5. Results and analysis
Cerebrospinal fluid NF-L level and difference ratio of each group of patientsCompared with
The data for cerebrospinal fluid NF-L levels (Table 2) and comparative analysis (FIG. 2) results for each group of patients are as follows: the median of the cerebrospinal fluid NF-L of patients in the symptomatic neural syphilis group (NS), the asymptomatic neural syphilis group (ANS) and the recessive syphilis group (S) is 5806.25pg/ml, 217.59pg/ml and 266.32pg/ml respectively, wherein the level of the cerebrospinal fluid NF-L of the symptomatic neural syphilis group is higher than that of the asymptomatic neural syphilis group (P <0.001) and that of the recessive syphilis group (P <0.001), and the difference has statistical significance. The NF-L level of cerebrospinal fluid of patients in the asymptomatic neurosyphotoxin group and the recessive syphilis group is not different (P is 0.915). Thus, syphilis patients may be classified according to their cerebrospinal fluid NF-L levels, e.g. patients with symptomatic neurosyphilis may be distinguished from patients with asymptomatic neurosyphilis or occult syphilis.
TABLE 2 cerebrospinal fluid NF-L levels (n 92) in each group of patients
Figure BDA0002067509060000121
Figure BDA0002067509060000131
In addition, it can also be seen from fig. 3 that the level of NS group is much higher than that of ANS group and S group, which is consistent with the severity of different types of syphilis, e.g., nerve damage. In addition, the NF-L level of the cerebrospinal fluid is very high, even exceeds 8000pg/ml, so that the severity of syphilis can be quantitatively detected with high sensitivity according to the NF-L level of the cerebrospinal fluid.
Correlation analysis of NF-L in cerebrospinal fluid and various factors
The results of the correlation analysis of the cerebrospinal fluid NF-L of all patients are as follows: cerebrospinal fluid NF-L levels are correlated positively with the patient syphilis stage (r ═ 0.564, P <0.001), in addition to plasma NF-L levels (r ═ 0.257, P ═ 0.018), with plasma pfn-H levels (r ═ 0.352, P ═ 0.001), cerebrospinal fluid pfn-H levels (r ═ 0.764, P <0.001), age (r ═ 0.625, P <0.001), CSF proteins (r ═ 0.635, P <0.001), plasma RPR titers (r ═ 0.347, P ═ 0.001), RPR titers (r ═ 0.540, P < 0.001).
The results of the correlation analysis of each group of NS, ANS and S are as follows: the level of cerebrospinal fluid NF-L in NS group is positively correlated with blood pNF-H (r is 0.475, P is 0.034), cerebrospinal fluid pNF-H (r is 0.775, P is 0.001); the NF-L level of cerebrospinal fluid in ANS group is positively correlated with pNF-H (r is 0.541, P is 0.001) and cerebrospinal fluid protein (r is 0.287, P is 0.041); the NF-L level of cerebrospinal fluid in group S is positively correlated with the level of cerebrospinal protein (r is 0.666 and P is 0.003).
In addition, as can be seen from FIGS. 4 to 14, the detection result of NF-L in cerebrospinal fluid is substantially identical to the results of brain protein and brain leukocyte, but the severity of syphilis or the degree of damage caused by syphilis can be reflected more sensitively, and this is reflected in FIGS. 4 to 14, and is especially evident in FIGS. 7 and 12. For example, as can be seen in fig. 5, brain leukocytes clearly reflect signs of improvement following treatment, but brain proteins and cerebrospinal fluid NF-L clearly reflect positive therapeutic effects. For example, referring to fig. 10, the cerebroprotein results did not show positive efficacy, but the cerebrospinal fluid NF-L was able to respond with significant efficacy, which is in complete agreement with the syphilis symptom changes in this patient.
Cerebrospinal fluid NF-L prognostic assay
The prognosis is followed up for 25 persons, the group with symptom neurosyphilis is followed up for 15 persons, and the group without symptom neurosyphilis is followed up for 10 persons. The specific data are shown in Table 3.
(1) Comparison of Difference before and after NF-L treatment of cerebrospinal fluid
The median of the NF-L level of cerebrospinal fluid before treatment is 2141.76pg/ml, and the NF-L level of cerebrospinal fluid after treatment is 1057.37 pg/ml; the level of NF-L in cerebrospinal fluid decreased after treatment of neurosyphilis and was statistically significant (P0.006).
(2) Comparison of differences between cerebrospinal fluid NF-L before and after treatment of neurosyphilis group and asymptomatic neurosyphilis group
The median of the NF-L level change of cerebrospinal fluid of the group of the neurosyphilis is-2647.46 pg/ml, namely, the NF-L level change is reduced by 2647.46 pg/ml; the median of the change level of the NF-L level of the cerebrospinal fluid of the asymptomatic neurosyphilis group is 49.23pg/ml, namely the NF-L level is increased by 49.23 pg/ml; the comparison was statistically significant (P ═ 0.003).
Correlation analysis of NF-L and various factors of cerebrospinal fluid after treatment
The posttreatment cerebrospinal fluid NF-L level is associated with syphilis staging (r ═ 0.759, P <0.001), the treatment anterior cerebrospinal fluid NF-L level (r ═ 0.654, P ═ 0.001), the treatment anterior-posterior blood NF-L change level (r ═ 0.636, P ═ 0.001), the treatment posterior plasma pff-H level (r ═ 0.574, P ═ 0.005), the treatment anterior plasma pff-H level (r ═ 0.670, P ═ 0.001), the treatment anterior-posterior plasma pff-H change level (r ═ 0.670, P ═ 0.001), the treatment anterior cerebrospinal fluid NF-L level (r ═ 0.923, P <0.001), the treatment anterior-posterior cerebrospinal fluid NF-L change level (r ═ 0.548, P ═ 0.001), the treatment posterior cerebrospinal fluid pfrex-H level (r ═ 0.001, P ═ 0.694), the treatment anterior cerebrospinal fluid NF-L change level (r ═ 0.001, P ═ 0. 0.831, p ═ 0.003), cerebrospinal RPR (r ═ 0.495, P ═ 0.012), cerebroprotein (r ═ 0.631, P ═ 0.001) are relevant.
The level of NF-L changes in cerebrospinal fluid before and after treatment is related to syphilis staging (r ═ 0.611, P ═ 0.001), gender (r ═ 0.474, P ═ 0.017), pre-treatment blood NF-L level (r ═ 0.460, P ═ 0.031), pre-post cerebrospinal fluid NF-L level (r ═ 0.548, P ═ 0.005), pre-treatment cerebrospinal fluid NF-L level (r ═ 0.759, P <0.001), pre-treatment cerebrospinal fluid pNF-H level (r ═ 0.682, P <0.001), pre-treatment cerebrospinal fluid pNF-H level (r ═ 0.571, P ═ 0.003), RPR (r ═ 0.419, P ═ 0.037), cerebroprotein (r ═ 0.476, P ═ 0.016).
TABLE 3 horizontal change table before and after treatment of cerebrospinal fluid NF-L in the symptomatic and asymptomatic neurosyphenis groups.
Figure BDA0002067509060000141
Figure BDA0002067509060000151
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.

Claims (13)

1. The application of a first detection reagent for detecting a cerebrospinal neurofilament protein light chain in preparing a neurosyphilis detection kit, wherein the kit comprises:
(1) the first detection reagent; and
(2) a second detection reagent for one or more syphilis detection methods selected from the group consisting of VDRL detection, USR detection, TRUST detection, RPR detection, TPHA or TPPA detection, FTA-ABS detection, blood pNF-H detection, and cerebrospinal fluid pNF-H detection.
2. The use of claim 1, wherein the first detection reagent is an anti-neurturin light chain antibody.
3. The use of claim 2, wherein the antibody is an antibody against a light chain of human neurofilament protein.
4. The use according to claim 2, wherein the antibody is a polyclonal antibody or a monoclonal antibody.
5. The use of claim 2, wherein the antibody is a monoclonal antibody.
6. The use of claim 1, wherein the second detection reagent is a detection reagent for a syphilis detection method selected from the group consisting of RPR detection, TPHA or TPPA detection, FTA-ABS detection, blood pNF-H detection, cerebrospinal fluid pNF-H detection.
7. Use according to claim 6, wherein the second detection reagent is a detection reagent for FTA-ABS detection and/or TPPA detection.
8. The use of claim 1, wherein the kit further comprises an auxiliary reagent for detecting cerebrospinal fluid neurofilament light chain by ELISA detection using an antibody against the neurofilament light chain.
9. The use of claim 8, wherein the auxiliary reagent comprises a reagent selected from the group consisting of a neurofilament light chain antibody-coated microtiter plate, a neurofilament light chain antibody solution, a horseradish peroxidase conjugate solution, a neurofilament light chain protein standard sample, a dilution buffer, a washing solution, a substrate solution, and a stop solution.
10. The use of claim 1, wherein the second detection reagent further comprises a detection reagent for detecting an index selected from the group consisting of blood NF-L level, cerebrospinal fluid pff-H level, cerebrospinal fluid RPR titer, blood RPR titer, cerebrospinal fluid leukocytes, cerebrospinal fluid proteins, pre-and post-treatment blood NF-L difference, pre-and post-treatment cerebrospinal fluid pff-H difference.
11. The use of claim 1, wherein the kit further comprises a cerebrospinal fluid puncture withdrawal apparatus and/or a cerebrospinal fluid cryopreservation tube.
12. The use of any one of claims 1 to 11, wherein the first detection reagent is a detection reagent for qualitative or quantitative detection of cerebrospinal neurofilament light chain.
13. The use according to claim 1, wherein the kit is for distinguishing between symptomatic and asymptomatic neurosyphilis, for determining the severity of neurosyphilis and/or for determining the prognostic effect of neurosyphilis.
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