Diagnostic markers for progressive supranuclear palsy

Abstract

To provide a biomarker which is useful for diagnosis of a progress property supranuclear paralysis.SOLUTION: There is provided a biomarker in cerebrospinal fluid, which is a peptide fragment of chromogranin B which is expressed as a peak of an m / z value of 6255 in mass analysis of the cerebrospinal fluid sample, and which has a negative correlation with a progress property supranuclear paralysis. There is also provided, a biomarker in cerebrospinal fluid sample, which is formed of a peptide fragment of chromogranin B which is expressed as a peak of an m / z value of 6255 in the mass analysis of the cerebrospinal fluid sample, and a chromogranin B protein, and which is quantitated as a ratio of an amount of the peptide fragment and an amount of the chromogranin B protein in the cerebrospinal fluid sample. There is provided a biomarker which is the chromogranin B protein in the cerebrospinal fluid which has a positive correlation with the progress property supranuclear paralysis.SELECTED DRAWING: Figure 4

Description

[Technical Field]

[0001] The present disclosure relates to biomarkers that can be used in the diagnosis of progressive supranuclear palsy. [Background technology]

[0002] Progressive supranuclear palsy (PSP) is a type of Parkinson's syndrome (PS), which also includes corticobasal degeneration (CBD), multiple system atrophy (MSA), and Parkinson's disease (PD).

[0003] PSP is a progressive neurodegenerative disease of unknown cause, and no fully effective treatment has yet been found. Pathologically, PSP is characterized by the formation of abnormally phosphorylated tau aggregates in the brain, and although this is thought to be involved in the pathology, the full picture has not yet been elucidated.

[0004] According to epidemiological studies in Japan, the prevalence of PSP is estimated to be approximately 20 per 100,000 people. However, an analysis of forensic autopsies confirmed PSP pathology in 4.6% of autopsied brains from people aged 60 or older, suggesting that the number of PSP cases is potentially much higher.

[0005] PSP is typically characterized by gait disturbance accompanied by a tendency to fall and impaired vertical eye movement. However, no clear biomarkers are known for PSP, and clinical diagnosis is made based on clinical symptoms and imaging findings, with a definitive diagnosis ultimately being made by pathological diagnosis of the brain at autopsy.

[0006] Advances in clinical research have revealed that PSP can have a wide variety of clinical manifestations, including not only Richardson's syndrome, which exhibits a typical clinical picture, but also subtypes characterized by prominent tremors and muscle rigidity similar to PD, subtypes characterized by prominent cerebellar symptoms like MSA, subtypes characterized by prominent speech disorders and freezing of gait, and subtypes characterized by clinical manifestations similar to CBD. As such, PSP exhibits a wide variety of clinical manifestations, making it difficult to differentiate and diagnose from other PS diseases, especially in the early stages of the disease. Currently, the only way to assess disease progression or treatment efficacy is by assessing the scale of clinical signs (Non-Patent Documents 1-5). While disease-modifying therapies using anti-tau antibodies are being developed, the difficulty of diagnosis is thought to be one of the factors that hinder the execution of clinical trials. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Litvan et al., Neurology, 1996, 47(1):1-9. [Non-patent document 2] Williams et al., Brain, 2005, 128:1247-1258 [Non-patent document 3] Williams et al., Movement Disorders, 2007, 22(15):2235-2241 [Non-patent document 4] Kanazawa et al., Mov. Disord., 2009, 24(9):1312-8. [Non-patent document 5] Golbe and Ohman-Strickland, Brain, 2007, 130:1552-1565 Summary of the Invention [Problem to be solved by the invention]

[0008] Therefore, there is a strong need for new diagnostic tools to assess or determine whether a subject has PSP, and in particular for biomarkers that correlate with the presence of PSP. [Means for solving the problem]

[0009] In a search for biomarkers characteristic of PSP patients, the present inventors identified chromogranin B (abbreviated as "CHGB") as a substance that exhibits PSP-specific changes in patient cerebrospinal fluid. The peptide bCHGB_6255, which appears to be a specific degradation product of chromogranin B protein and has a mass-to-charge ratio of 6255 in the MS spectrum, was found to have lower levels (i.e., peak intensity or amount) in cerebrospinal fluid samples from PSP patients than in cerebrospinal fluid samples from non-PSP individuals, such as PD patients and healthy controls, and thus can be used as a biomarker for PSP. Meanwhile, the cerebrospinal fluid level of CHGB protein itself was found to be specifically elevated in PSP patients. Furthermore, it was found that determining the ratio of CHGB protein to bCHGB_6255 provides a biomarker with significantly greater utility for diagnosing PSP or distinguishing PSP from other parkinsonian disorders, such as PD.

[0010] The present disclosure includes at least the following embodiments. [1] A biomarker in cerebrospinal fluid for assessing the possibility of progressive supranuclear palsy. It is a peptide fragment of chromogranin B that is expressed as a peak with an m / z value of 6255 in mass spectrometry of a cerebrospinal fluid sample and shows a negative correlation with progressive supranuclear palsy. [2] A biomarker for assessing the possibility of progressive supranuclear palsy, comprising a peptide fragment of chromogranin B, which is expressed as a peak with an m / z value of 6255 in mass spectrometry of a cerebrospinal fluid sample, and chromogranin B protein, and which (i) is quantified as the ratio of the amount of the peptide fragment to the amount of chromogranin B protein in the cerebrospinal fluid sample, and shows a positive correlation with progressive supranuclear palsy, or (ii) is quantified as the ratio of the amount of the peptide fragment to the amount of chromogranin B protein in the cerebrospinal fluid sample, and shows a negative correlation with progressive supranuclear palsy. [3] A biomarker for assessing the possibility of progressive supranuclear palsy, the biomarker being chromogranin B protein in cerebrospinal fluid, which positively correlates with progressive supranuclear palsy. [4] A method for collecting data to assess the possibility that a subject is suffering from progressive supranuclear palsy, the method comprising quantifying a peptide fragment of chromogranin B, which is represented by a peak with an m / z value of 6255 in mass spectrometry, using a cerebrospinal fluid sample derived from the subject, and collecting quantitative data of the peptide fragment as data showing a negative correlation with progressive supranuclear palsy. [5] 1. A method of collecting data to assess the likelihood that a subject has progressive supranuclear palsy, comprising: Quantifying a peptide fragment of chromogranin B, which is expressed as a peak with an m / z value of 6255 by mass spectrometry, using a cerebrospinal fluid sample derived from the subject; (i) the ratio of the amount of chromogranin B protein to the amount of the peptide fragment in the cerebrospinal fluid sample; or (ii) the ratio of the amount of the peptide fragment to the amount of chromogranin B protein in the cerebrospinal fluid sample. and quantifying the ratio of (i) above, wherein the ratio of (i) above is collected as data that shows a positive correlation with progressive supranuclear palsy, or the ratio of (ii) above is collected as data that shows a negative correlation with progressive supranuclear palsy. [6] 1. A method for collecting data to assess the possibility that a subject is suffering from progressive supranuclear palsy, the method comprising quantifying the concentration of chromogranin B protein in cerebrospinal fluid derived from the subject, wherein the quantitative data of the protein is collected as data that shows a positive correlation with progressive supranuclear palsy. [Effects of the Invention]

[0011] Embodiments of the present disclosure enable the collection of biochemical data useful for the diagnosis of PSP from patient-derived samples. Biomarkers according to embodiments of the present disclosure may provide new tools that can be used in place of or in addition to existing tools in the diagnosis of PSP, and may contribute to improving the diagnosis and treatment of PSP by providing objective indicators for the evaluation or assessment of disease progression or treatment efficacy. [Brief explanation of the drawings]

[0012] [Figure 1] Figure 1 shows the SELDI-TOF MS analysis of cerebrospinal fluid samples from individuals with progressive supranuclear palsy (PSP), Parkinson's disease (PD), and a healthy control (CTL), including the region of the peak at m / z 6255 (indicated by the square bracket). MS spectra from two individuals from each group are shown. [Figure 2] Figure 2 shows the results of an ELISA experiment examining the amount of chromogranin B protein in cerebrospinal fluid samples from patients with progressive supranuclear palsy (PSP), Parkinson's disease (PD), corticobasal syndrome (CBS), and healthy controls (CTL). [Figure 3] FIG. 3 shows a receiver operating characteristic (ROC) analysis based on chromogranin B protein abundance values ​​in cerebrospinal fluid samples in a population including multiple PSP individuals and non-PSP individuals, respectively. [Figure 4] Figure 4 shows a comparison of the [chromogranin B protein amount] / [bCHGB_6255 amount] ratio in cerebrospinal fluid samples from healthy controls (CTL), Parkinson's disease patients (PD), and progressive supranuclear palsy (PSP) individuals. DETAILED DESCRIPTION OF THE INVENTION

[0013] In one aspect, the present disclosure provides a biomarker for assessing the likelihood of progressive supranuclear palsy. The biomarker is a cerebrospinal fluid biomarker that is a peptide fragment of chromogranin B that shows a negative correlation with progressive supranuclear palsy and is expressed as a peak with an m / z value of 6255 in mass spectrometry of a cerebrospinal fluid sample. In the present disclosure, this peptide fragment is referred to as bCHGB_6255.

[0014] Liquid chromatography-tandem mass spectrometry (LC-MS / MS) analysis revealed that bCHGB_6255 is a fragment containing amino acid residues 500-530 (SEQ ID NO: 2) of the 657 amino acid sequence of mature chromogranin B protein (SEQ ID NO: 1). The amino acid sequence of the full-length chromogranin B protein, prior to removal of the putative 20-amino acid signal peptide, can be found in GenBank under accession number AAH00375.1.

[0015] In the present disclosure, the term "negatively correlated with progressive supranuclear palsy" means that the quantity (level) of the target substance is lower on average in a group of individuals affected with progressive supranuclear palsy compared to a group of non-affected individuals. Therefore, the lower the level of a biomarker negatively correlated with progressive supranuclear palsy, the more likely the individual is to be diagnosed with progressive supranuclear palsy. Conversely, the term "positively correlated with progressive supranuclear palsy" means that the quantity (level) of the target substance is higher on average in a group of individuals affected with progressive supranuclear palsy compared to a group of non-affected individuals. Therefore, the higher the level of a biomarker positively correlated with progressive supranuclear palsy, the more likely the individual is to be diagnosed with progressive supranuclear palsy.

[0016] It has been found that bCHGB_6255 in cerebrospinal fluid is a biomarker that shows a negative correlation with progressive supranuclear palsy.That is, the lower the level of this chromogranin B-derived peptide in a cerebrospinal fluid sample, the more likely the subject from which the sample is derived is to suffer from progressive supranuclear palsy.Based on this correlation, the present disclosure provides the use of bCHGB_6255 as a biomarker for assessing, determining, or diagnosing the possibility of progressive supranuclear palsy.

[0017] Methods for collecting cerebrospinal fluid samples are well known to those skilled in the art. Typically, cerebrospinal fluid is collected by lumbar puncture. It has previously been reported that various peptide fragments derived from granin family proteins, such as chromogranin B, are present in cerebrospinal fluid, and that these peptide fragments are not necessarily random degradation products, and that at least some of them may have specific biological activities (Bartolomucci et al., Endocr. Rev., 2011, 32(6): 755-797). However, it was completely unknown that bCHGB_6255, among the peptide fragments of chromogranin B, could be a biomarker for progressive supranuclear palsy. It is also possible that bCHGB_6255 is not a degradation product of the full-length CHGB protein but is translated independently of the full-length CHGB protein.

[0018] Specific examples of mass spectrometry techniques that can detect and quantify bCHGB_6255 in cerebrospinal fluid samples include, but are not limited to, surface-enhanced laser desorption / ionization time-of-flight mass spectrometry (SELDI-TOF MS). Those skilled in the art can appropriately select and combine specific mass spectrometry techniques suitable for detecting and quantifying peptides in biological fluid samples such as cerebrospinal fluid.

[0019] For example, the relative or absolute amount of bCHGB_6255 in cerebrospinal fluid can be measured by subjecting cerebrospinal fluid samples of the same weight or volume to mass spectrometry under the same conditions and comparing the intensities of ion peaks between samples, by looking at the difference in relative intensity with other peaks in the mass spectrum, or by looking at the difference in relative intensity with a known amount of a standard substance included in the mass spectrometry.

[0020] It is also possible to produce an antibody specific to the bCHGB_6255 sequence. An embodiment is also contemplated in which a "peptide fragment of chromogranin B expressed as a peak with an m / z value of 6255 in mass spectrometry" is detected and quantified, for example, by immunoblotting using the antibody and a cerebrospinal fluid sample.

[0021] In exemplary embodiments of each aspect of the present disclosure, the level of bCHGB_6255 is measured in a cerebrospinal fluid sample (test sample) derived from a subject (i.e., collected from the subject), and the measured level is compared with a reference level. If the measured level is lower than the reference level, it is determined that the subject is likely to be suffering from progressive supranuclear palsy. The reference level here may be based on the level of bCHGB_6255 measured in a cerebrospinal fluid sample (preferably under the same conditions as the subject-derived sample) from an individual (preferably multiple individuals) not suffering from progressive supranuclear palsy.

[0022] In the present disclosure, an individual not afflicted with progressive supranuclear palsy can be, for example, a healthy individual and / or an individual not afflicted with progressive supranuclear palsy, for example, an individual afflicted with another parkinsonian disease but not afflicted with progressive supranuclear palsy.

[0023] The "reference level" in the present disclosure may be a cutoff value obtained by ROC (Receiver Operating Characteristic) curve analysis of values ​​measured in cerebrospinal fluid samples from multiple individuals. ROC curve analysis and determination of cutoff values ​​are well known to those skilled in the art. Most typically, sensitivity (i.e., true positive rate) is plotted on the upward vertical axis, and (1-specificity) (i.e., false positive rate) is plotted on the horizontal axis extending from the bottom of the vertical axis to the right. The cutoff value is the point with the shortest distance to the point in the upper left corner of the graph (the ideal point where sensitivity = 1 and specificity = 1), or the point where the Youden Index (sensitivity + specificity - 1) is maximized.

[0024] However, it should be understood that, in general, the threshold level of a biomarker can be made looser or stricter depending on the purpose of each individual test (for example, whether the purpose is initial screening to broadly select a group of patient candidates, or whether the purpose is diagnosing each individual patient, etc.), and that the reference levels in the present disclosure can also be determined in advance by a person skilled in the art based on their ordinary skills for each individual application, and can be varied as appropriate.

[0025] In one embodiment, the reference level is based on the level of bCHGB_6255 measured in a cerebrospinal fluid sample collected from the same subject at an earlier time point (preferably under the same conditions as the test sample), and if the measured level is lower than the reference level, it is determined that the likelihood of the subject having progressive supranuclear palsy has increased or that the progressive supranuclear palsy has worsened compared to that earlier time point.

[0026] In one embodiment, the level of bCHGB_6255 is measured in a cerebrospinal fluid sample (test sample) from a subject, and the lower the measured level, the more likely the subject is to suffer from progressive supranuclear palsy, or the more severe the subject's progressive supranuclear palsy is assessed to be.

[0027] According to another aspect of the present disclosure, a biomarker for assessing the possibility of progressive supranuclear palsy is a cerebrospinal fluid biomarker consisting of a peptide fragment of chromogranin B (bCHGB_6255), which is expressed as a peak with an m / z value of 6255 in mass spectrometry of a cerebrospinal fluid sample, and chromogranin B protein. This composite biomarker is quantified as (i) the ratio of the amount of chromogranin B protein to the amount of bCHGB_6255 in the cerebrospinal fluid sample, or (ii) the ratio of the amount of bCHGB_6255 to the amount of chromogranin B protein in the cerebrospinal fluid sample. This composite biomarker is a significantly superior biomarker compared to a biomarker consisting of bCHGB_6255 alone, and enables the diagnosis of progressive supranuclear palsy with significantly higher confidence.

[0028] The ratio (i) above is expressed as [amount of chromogranin B protein in the cerebrospinal fluid sample] / [amount of bCHGB_6255 in the cerebrospinal fluid sample], and is a biomarker that positively correlates with progressive supranuclear palsy. That is, the higher this ratio in the cerebrospinal fluid sample, the more likely the subject from which the sample was derived is to suffer from progressive supranuclear palsy. The ratio (ii) above is expressed as [amount of bCHGB_6255 in the CSF sample] / [amount of chromogranin B protein in the CSF sample], and is a biomarker that negatively correlates with progressive supranuclear palsy. That is, the lower this ratio in the CSF sample, the more likely the subject from which the sample was derived is to suffer from progressive supranuclear palsy. Based on such correlations, the present disclosure provides the use of bCHGB_6255 and chromogranin B as biomarkers for assessing, determining the likelihood of, or diagnosing progressive supranuclear palsy.

[0029] The amount of chromogranin B protein refers to the total amount of chromogranin B protein including the full-length amino acid sequence of mature chromogranin B protein. Examples of methods that can measure the amount of chromogranin B protein in a cerebrospinal fluid sample include, but are not limited to, enzyme-linked immunosorbent assay (ELISA) and immunoblotting using specific antibodies.

[0030] In an exemplary embodiment, the ratio of (i) or (ii) is measured in a cerebrospinal fluid sample (test sample) from a subject, and the measured level is compared with a reference level.If the measured level of the ratio of (i) is higher than the reference level, or if the measured level of the ratio of (ii) is lower than the reference level, it is determined that the subject is likely to suffer from progressive supranuclear palsy.The reference level here can be based on the ratio measured in the cerebrospinal fluid sample of an individual (preferably a plurality of individuals) who does not suffer from progressive supranuclear palsy (preferably under the same conditions as the sample from the subject).The reference level can also be the cutoff value obtained by ROC curve analysis of the ratio measured in the cerebrospinal fluid sample from a plurality of individuals.

[0031] In one embodiment, the reference level is based on a ratio measured in a cerebrospinal fluid sample collected from the same subject at an earlier time point (preferably under the same conditions as the test sample), and if the measured level of the ratio (i) is higher than the reference level, or if the measured level of the ratio (ii) is lower than the reference level, it is determined that the subject is more likely to be affected by progressive supranuclear palsy or that their progressive supranuclear palsy has worsened compared to that earlier time point.

[0032] In one embodiment, the ratio of (i) or (ii) is measured in a cerebrospinal fluid sample (test sample) derived from a subject, and the higher the measured level of the ratio of (i) or the lower the measured level of the ratio of (ii), the higher the possibility that the subject is suffering from progressive supranuclear palsy, or the more severe the subject's progressive supranuclear palsy is assessed to be.

[0033] Chromogranin B protein itself in a cerebrospinal fluid sample can also be a biomarker for assessing the likelihood of progressive supranuclear palsy. Chromogranin B protein shows a positive correlation with progressive supranuclear palsy. That is, according to one aspect of the present disclosure, a biomarker for assessing the likelihood of progressive supranuclear palsy is chromogranin B protein in cerebrospinal fluid. In one embodiment, if the chromogranin B protein concentration in cerebrospinal fluid is higher than a reference value of 70 ng / mL or higher, it is determined that the subject is likely to be suffering from progressive supranuclear palsy. In another embodiment, if the chromogranin B protein concentration in cerebrospinal fluid is higher than a reference value of 75 ng / mL or higher, 80 ng / mL or higher, 90 ng / mL or higher, 100 ng / mL or higher, 110 ng / mL or higher, or 120 ng / mL or higher, it is determined that the subject is likely to be suffering from progressive supranuclear palsy.

[0034] The discovery of biomarkers has established a new method for collecting data useful for diagnosing progressive supranuclear palsy. Therefore, in another aspect, the present disclosure provides a method for collecting data to assess, determine, or diagnose the likelihood that a subject has progressive supranuclear palsy. The method includes quantifying a peptide fragment of chromogranin B (bCHGB_6255), which is expressed as a peak with an m / z value of 6255 in mass spectrometry, using a cerebrospinal fluid sample from the subject. Quantitative data on this peptide fragment is collected as data showing a negative correlation with progressive supranuclear palsy. Previously, it was completely unknown that quantifying a peptide fragment of chromogranin B, let alone measuring the amount of any specific molecule in a biological sample, would be useful for diagnosing progressive supranuclear palsy.

[0035] In yet another related aspect, a method for collecting data to assess, determine, or diagnose a subject's likelihood of suffering from progressive supranuclear palsy includes quantifying a peptide fragment of chromogranin B (bCHGB_6255), which is expressed as a peak with an m / z value of 6255 by mass spectrometry, in a cerebrospinal fluid sample from the subject, and further includes quantifying (i) the ratio of the amount of chromogranin B protein to the amount of bCHGB_6255 in the cerebrospinal fluid sample, or (ii) the ratio of the amount of bCHGB_6255 to the amount of chromogranin B protein in the cerebrospinal fluid sample. In this method, the ratio (i) is collected as data that positively correlates with progressive supranuclear palsy, or the ratio (ii) is collected as data that negatively correlates with progressive supranuclear palsy. As described above, the amount of chromogranin B protein can be quantified by methods known to those skilled in the art, such as ELISA or immunoblotting.

[0036] In another aspect, the present disclosure provides a method for collecting data to assess, determine, or diagnose a subject's likelihood of suffering from progressive supranuclear palsy, the method comprising quantifying chromogranin B protein concentration in cerebrospinal fluid from the subject, the quantitative data being collected as data that positively correlates with progressive supranuclear palsy. [Example]

[0037] Specific embodiments will be described in detail below with reference to examples, but these are merely examples and the invention of the present disclosure is not limited to these examples.

[0038] Example 1: First Exploratory Study In a study to discover and identify biomarkers for PSP, cerebrospinal fluid (CSF) samples collected from eight PSP patients (mean age 72.6 years) and eight healthy control individuals (mean age 72.1 years) were analyzed under identical conditions by SELDI-TOF MS.

[0039] In this and other examples, PSP patients were diagnosed based on the criteria described in Non-Patent Documents 1 to 4. CBS (corticobasal syndrome) patients were diagnosed based on the criteria described in Mathew et al., J. Neurol. Neurosurg. Psychiatry, 2012, 83(4):405-10. PD patients were diagnosed based on the criteria described in Postuma et al., Mov. Disord., 2015, 30(12):1591-601. Control individuals (groups) are referred to as CTL. All mass spectrometry analyses were performed at the Takamatsu Laboratory of Protenova Co., Ltd.

[0040] Of 219 peaks analyzed on the MS spectrum, 24 peaks were detected as candidates for substances that may be differentially expressed between the PSP group and the CTL group.

[0041] Example 2: Second exploratory study CSF samples collected from six PSP patients (mean age 74.5 years), six PD patients (mean age 74.5 years), and six healthy control individuals (mean age 74.3 years), a separate cohort from Example 1, were analyzed by SELDI-TOF MS. One of the 24 candidate substances identified in Example 1 was selected as the most promising reproducible candidate. This candidate substance was expressed as an m / z value of 6255, and its amount was reduced in CSF from PSP patients (Figure 1). This candidate substance satisfied the following criteria: the peak intensity in the MS spectrum was significantly different between the PSP and PD groups, and between the PSP and CTL groups (i.e., decreased in the PSP group), but not between the PD and CTL groups.

[0042] This candidate substance was concentrated and purified by repeated fractionation using an anion column and subsequent separation using reverse-phase HPLC, and finally analyzed by LC-MS / MS. As a result, this substance was identified as a peptide fragment derived from chromogranin B protein. This peptide fragment is designated bCHGB_6255. Chromogranin B protein itself is designated CHGB. More specifically, bCHGB_6255 was identified as a fragment containing amino acids 500 to 530 (SEQ ID NO: 2) of the CHGB protein (657 amino acids in total as shown in SEQ ID NO: 1).

[0043] Example 3: Validation study of CHGB CSF samples collected from 53 PSP patients (mean age 73.6 years), 24 PD patients (mean age 73.0 years), 15 CBS patients (mean age 73.5 years), and 20 CTLs (mean age 69.2 years), which were different cohorts from those used in Examples 1 and 2, were analyzed by enzyme-linked immunosorbent assay (ELISA) using anti-CHGB antibodies that can detect full-length CHGB protein.

[0044] The ELISA results shown in Figure 2 revealed that the mean CSF CHGB levels (total CHGB protein levels) were 76.8 ng / mL in PSP patients, 61.5 ng / mL in PD patients, 61.2 ng / mL in CBS patients, and 59.0 ng / mL in CTL patients. CHGB levels in PSP patients were significantly higher than those in PD, CBS, and CTL patients (p < 0.05). Interestingly, although the peptide fragment bCHGB_6255 of CHGB protein was decreased in PSP patients, the level of CHGB protein itself tended to be higher in PSP patients. Receiver operating characteristic (ROC) analysis of CHGB yielded an area under the curve (AUC) of 0.671, a sensitivity of 62.3%, and a specificity of 66.1% (Figure 3). The positive predictive value (PPV) was 57.9% and the negative predictive value (NPV) was 62.7%.

[0045] The relative value (CHGB / bCHGB_6255 ratio) calculated by dividing the amount of CHGB protein detected in CSF by the amount of bCHGB_6255 was found to be highly correlated with PSP, making it a biomarker that can reliably distinguish PSP from both PD and CTL (Figure 4).

[0046] [Conclusion] We have demonstrated that cerebrospinal fluid (CSF) chromogranin B may be a useful diagnostic marker for progressive supranuclear palsy (PSP). Specifically, a peptide fragment of chromogranin B (bCHGB_6255), which appears as an m / z value of 6255 when detected by mass spectrometry, was found to be specifically decreased in the CSF of patients with PSP. Meanwhile, the CSF chromogranin B protein concentration tended to be elevated in patients with PSP. A biomarker expressed as the ratio of CSF bCHGB_6255 levels to chromogranin B protein levels was found to show a significantly higher correlation with PSP. These new findings provide a novel and powerful diagnostic tool for PSP, a condition that has previously lacked a diagnostic tool. This biomarker may contribute to improved diagnosis, treatment, and understanding of the disease mechanism.

Claims

1. A biomarker for assessing the possibility of progressive supranuclear palsy, comprising a peptide fragment of chromogranin B, which is expressed as a peak with an m / z value of 6255 in mass spectrometry of a cerebrospinal fluid sample, and chromogranin B protein, and which (i) is quantified as the ratio of the amount of the peptide fragment to the amount of chromogranin B protein in the cerebrospinal fluid sample, and shows a positive correlation with progressive supranuclear palsy, or (ii) is quantified as the ratio of the amount of the peptide fragment to the amount of chromogranin B protein in the cerebrospinal fluid sample, and shows a negative correlation with progressive supranuclear palsy.

2. 1. A method of collecting data to assess the likelihood that a subject has progressive supranuclear palsy, comprising: Quantifying a peptide fragment of chromogranin B, which is expressed as a peak with an m / z value of 6255 by mass spectrometry, using a cerebrospinal fluid sample derived from the subject; (i) the ratio of the amount of chromogranin B protein to the amount of the peptide fragment in the cerebrospinal fluid sample; or (ii) the ratio of the amount of the peptide fragment to the amount of chromogranin B protein in the cerebrospinal fluid sample. and quantifying the ratio of (i) above, wherein the ratio of (i) above is collected as data that shows a positive correlation with progressive supranuclear palsy, or the ratio of (ii) above is collected as data that shows a negative correlation with progressive supranuclear palsy.

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