JP2023005573A - Diagnosis marker for progress property supranuclear paralysis - Google Patents

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

Application for application of Article 30, Paragraph 2 of the Patent Act (1) Announced on August 17, 2020 in the abstract collection of the 61st Annual Meeting of the Japanese Society of Neurology. (2) Announced at MDS Virtual Congress 2020 on September 11, 2020.

The present disclosure relates to biomarkers that can be used to diagnose progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) leads to corticobasal degeneration (CBD), multiple system atrophy (MSA), and Parkinson's disease (PD). It is one of the "Parkinson's syndrome (PS)" including.

PSP is a progressive neurodegenerative disease of unknown etiology, and a sufficiently effective treatment has not yet been found. Pathologically, PSP is characterized by the formation of aggregates of abnormally phosphorylated tau in the brain, and although it is presumed that this is involved in the pathology, the full picture has not yet been elucidated.

According to epidemiological studies in Japan, the prevalence of PSP is estimated at about 20 per 100,000 people. On the other hand, analysis of forensic autopsy cases confirmed PSP pathology in 4.6% of autopsy brains aged 60 years or older, suggesting that there are potentially many more PSP cases.

Typical PSP is characterized by gait disturbance with susceptibility to falls and impaired vertical eye movements. However, no definite biomarker is known for PSP, and clinical diagnosis is made based on clinical symptoms and imaging findings, etc., and finally a definitive diagnosis is made by pathological diagnosis of the autopsy brain.

With the development of clinical research, in addition to Richardson's syndrome presenting a typical clinical picture, there is a subtype with conspicuous tremor and muscle stiffness similar to PD, a subtype with cerebellar symptoms in the foreground such as MSA, and language. It has been clarified that there may be various clinical manifestations of PSP, such as a subtype with conspicuous disturbances and frozen legs, and a subtype with a clinical picture similar to CBD. As described above, PSP has a wide variety of clinical symptoms, and it is often difficult to distinguish and diagnose it from other PS diseases, especially in the early stages of the disease. At present, there is no means other than making judgments based on the symptom scale (Non-Patent Documents 1 to 5). The development of disease-modifying therapies using anti-tau antibodies is also underway, but this difficulty in diagnosis is thought to be one of the factors that make clinical trials difficult.

Litvan et al., Neurology, 1996, 47(1):1-9. Williams et al., Brain, 2005, 128:1247-1258 Williams et al., Movement Disorders, 2007, 22(15):2235-2241 Kanazawa et al., Mov. Disord., 2009, 24(9):1312-8. Golbe and Ohman-Strickland, Brain, 2007, 130:1552-1565

Therefore, there is a strong demand for establishment of a new diagnostic means for evaluating or judging the possibility that a subject is suffering from PSP. In particular, there is a need for biomarkers that correlate with the presence of PSP.

In studies to search for biomarkers characteristic of PSP patients, the present inventors have found that chromogranin B (abbreviated as "CHGB") is a substance that exhibits changes specific to PSP in the patient's cerebrospinal fluid. ) were identified. The peptide bCHGB_6255, which appears to be a specific degradation product of this chromogranin B protein and is located at a mass-to-charge ratio of 6255 in the MS spectrum, has levels (i.e., peak intensity or amount) in cerebrospinal fluid samples from PSP patients that are higher than those in PD patients and healthy controls. It was found to be lower than the levels in cerebrospinal fluid samples from non-PSP individuals, such as ours, and that it can be used as a biomarker for PSP. On the other hand, the cerebrospinal fluid level of CHGB protein itself was found to be specifically elevated in PSP patients. We also found that determining the ratio of CHGB protein to bCHGB_6255 provides a significantly more useful biomarker for diagnosing PSP or distinguishing PSP from other Parkinsonian diseases such as PD. was done.

The present disclosure includes at least the following embodiments.
[1]
A biomarker for assessing the likelihood of having progressive supranuclear palsy, the peptide fragment of chromogranin B presenting as a peak with an m/z value of 6255 in mass spectrometry of a cerebrospinal fluid sample and progressive A cerebrospinal fluid biomarker negatively correlated with supranuclear palsy.
[2]
A peptide fragment of chromogranin B, represented as a peak with an m/z value of 6255 in mass spectrometry of a cerebrospinal fluid sample, and chromogranin B, a biomarker for assessing the likelihood of having progressive supranuclear palsy (i) positively correlated with progressive supranuclear palsy, quantified as the ratio of the amount of chromogranin B protein to the amount of said peptide fragment in a cerebrospinal fluid sample, or (ii) the cerebrospinal fluid. A cerebrospinal fluid biomarker quantified as the ratio of the amount of said peptide fragment to the amount of chromogranin B protein in a fluid sample and negatively correlated with progressive supranuclear palsy.
[3]
A biomarker for assessing the likelihood of having progressive supranuclear palsy, the biomarker being chromogranin B protein in cerebrospinal fluid that positively correlates with progressive supranuclear palsy.
[4]
A method of collecting data for assessing the likelihood that a subject is suffering from progressive supranuclear palsy, comprising: using a cerebrospinal fluid sample from said subject, mass spectrometric analysis of m/z 6255 A method comprising quantifying peptide fragments of chromogranin B expressed as peak values, wherein the quantitative data of said peptide fragments are collected as data negatively correlated with progressive supranuclear palsy.
[5]
A method of collecting data for assessing the likelihood that a subject is suffering from progressive supranuclear palsy, comprising:
quantifying a peptide fragment of chromogranin B represented by a peak with an m/z value of 6255 in 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 said peptide fragment in said cerebrospinal fluid sample, or
(ii) quantifying the ratio of the amount of said peptide fragment to the amount of chromogranin B protein in said cerebrospinal fluid sample, wherein said ratio of (i) is positively correlated with progressive supranuclear palsy. A method, collected as data, or wherein the ratio of (ii) is negatively correlated with progressive supranuclear palsy.
[6]
1. A method of collecting data for assessing the likelihood that a subject is suffering from progressive supranuclear palsy, comprising quantifying chromogranin B protein concentration in cerebrospinal fluid from said subject, A method, wherein quantitative data for said protein are collected as data positively correlated with progressive supranuclear palsy.

Embodiments of the present disclosure allow biochemical data to be collected from patient-derived samples that are useful for the diagnosis of PSP. Biomarkers according to embodiments of the present disclosure represent a new tool that is useful in place of or in addition to existing tools in diagnosing PSP, and provide an objective index for assessment or determination of disease progression or treatment efficacy. By providing it, we can contribute to the improvement of diagnosis and treatment of PSP.

Figure 1 shows m/z The portion containing the area of the peak with value 6255 (shown in square brackets) is shown. The MS spectra of two individuals per group are illustrated. FIG. 2 depicts chromogranin B protein levels in cerebrospinal fluid samples from progressive supranuclear palsy patients (PSP), Parkinson's disease patients (PD), corticobasal ganglia syndrome patients (CBS), and healthy controls (CTL). Results of quantitation ELISA experiments are shown. FIG. 3 shows a receiver operating characteristic (ROC) analysis based on chromogranin B protein abundance values in cerebrospinal fluid samples in populations containing multiple PSP and non-PSP individuals, respectively. FIG. 4 shows [chromogranin B protein amount]/[bCHGB_6255 amount] in cerebrospinal fluid samples from healthy control (CTL), Parkinson's disease (PD), and progressive supranuclear palsy (PSP) individuals. A ratio comparison is shown.

In one aspect, the present disclosure provides biomarkers for assessing the likelihood of suffering from progressive supranuclear palsy. This biomarker is a peptide fragment of chromogranin B that is negatively correlated with progressive supranuclear palsy and is represented as a peak with an m/z value of 6255 in mass spectrometry of cerebrospinal fluid samples. is a biomarker. This peptide fragment is referred to as bCHGB_6255 in this disclosure.

As identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), bCHGB_6255 is located at amino acid residues 500-530 (SEQ ID NO: 1) of the full-length 657 amino acids (SEQ ID NO: 1) of the mature chromogranin B protein. 2). The amino acid sequence of the full-length chromogranin B protein, before the 20 amino acid putative signal peptide is removed, can be found, for example, under GenBank accession number AAH00375.1.

In the present disclosure, the term "negatively correlates with progressive supranuclear palsy" means that the amount (level) of the object is means lower on average. Therefore, the lower the level of a biomarker that is negatively correlated with progressive supranuclear palsy, the more likely it is that the individual is suffering from progressive supranuclear palsy. Conversely, the term "positively correlated with progressive supranuclear palsy" means that the quantity value (level) of the object is means higher than average. Therefore, the higher the level of a biomarker positively correlated with progressive supranuclear palsy, the more likely it is that the individual is suffering from progressive supranuclear palsy.

bCHGB_6255 in cerebrospinal fluid was found to be a biomarker negatively correlated 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 whom the sample was derived is suffering from progressive supranuclear palsy. Based on such correlations, the present disclosure provides the use of bCHGB_6255 as a biomarker for assessing, determining the likelihood of, or diagnosing progressive supranuclear palsy.

Methods for collecting cerebrospinal fluid samples are well known to those skilled in the art. Typically, cerebrospinal fluid is obtained by lumbar puncture. The existence of various peptide fragments derived from granin family proteins, such as chromogranin B, in cerebrospinal fluid, and that these peptide fragments are not necessarily random degradation products, and that at least some of them are specific (Bartolomucci et al., Endocr. Rev., 2011, 32(6): 755-797). However, it was completely unknown that among the peptide fragments of chromogranin B, bCHGB_6255 could be a biomarker for progressive supranuclear palsy. It is not excluded that bCHGB_6255 is translated independently of the full-length CHGB protein rather than a digest of the full-length CHGB protein.

A specific example of mass spectrometry that can detect and quantify bCHGB_6255 in cerebrospinal fluid samples is surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). -flight mass spectrometry), but not necessarily limited to this. Those skilled in the art can appropriately select or combine specific mass spectrometry techniques suitable for detection and quantification of peptides in biological fluid samples such as cerebrospinal fluid.

For example, subjecting cerebrospinal fluid samples of the same weight or volume to mass spectrometry under the same conditions and comparing the intensity of ion peaks between samples, looking at differences in relative intensity with other peaks in the mass spectrum, Relative or absolute amounts of bCHGB_6255 in cerebrospinal fluid can be determined, such as by looking at the difference in relative intensity with a known amount of reference material included in mass spectrometry.

It is also possible to generate antibodies specific to the bCHGB_6255 sequence. Embodiments are also contemplated in which the "peptide fragment of chromogranin B represented by mass spectrometry as a peak with an m/z value of 6255" is detected and quantified, e.g., by immunoblotting using the antibody and a cerebrospinal fluid sample. be.

In an exemplary embodiment of aspects of the present disclosure, the level of bCHGB_6255 in a cerebrospinal fluid sample (test sample) from a subject (i.e., taken from the subject) is measured, and the measured level is compared to a reference level. be. If the measured level is lower than the reference level, it is determined that the subject is likely suffering from progressive supranuclear palsy. The reference level here is bCHGB_6255 measured in cerebrospinal fluid samples of individuals (preferably multiple individuals) not suffering from progressive supranuclear palsy (preferably under the same conditions as the above subject-derived samples). can be based on the level of

In the present disclosure, an individual not suffering from progressive supranuclear palsy is e.g. a healthy individual and/or an individual not suffering from progressive supranuclear palsy, e.g. , but not suffering from progressive supranuclear palsy.

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

However, in general, the biomarker threshold level is determined according to the purpose of the individual test (for example, whether it is for the purpose of initial screening to select a broad group of patient candidates, or for the purpose of diagnosing individual patients, etc.). The reference levels in this disclosure can also be predetermined based on the ordinary skill of a person skilled in the art in a particular application and can be varied accordingly. should be understood.

In one embodiment, the reference level is based on the level of bCHGB_6255 measured in a cerebrospinal fluid sample taken from the same subject at a previous time point (preferably under the same conditions as the test sample); is below the reference level, it is determined that the patient is more likely to have progressive supranuclear palsy or has worsened progressive supranuclear palsy compared to that previous time point.

In one embodiment, the level of bCHGB_6255 is measured in a sample of cerebrospinal fluid from a subject (the test sample), and the lower the measured level, the more likely the subject is suffering from progressive supranuclear palsy. High or the subject's progressive supranuclear palsy is assessed as more severe.

According to another aspect of the present disclosure, the biomarker for assessing the likelihood of suffering from progressive supranuclear palsy is chromogranin B, represented as a peak with an m/z value of 6255 in mass spectrometry of cerebrospinal fluid samples. A cerebrospinal fluid biomarker consisting of a peptide fragment (bCHGB_6255) 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 a cerebrospinal fluid sample, or (ii) the ratio of the amount of bCHGB_6255 to the amount of chromogranin B protein in a cerebrospinal fluid sample. be done. This composite biomarker is significantly superior to biomarkers consisting of bCHGB_6255 alone, allowing for significantly more reliable diagnosis of progressive supranuclear palsy affliction.

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

The amount of chromogranin B protein means the total amount of chromogranin B protein with full length amino acid sequence of mature chromogranin B protein. Examples of methods by which the amount of chromogranin B protein can be measured in a cerebrospinal fluid sample include, but are not limited to, enzyme-linked immunosorbent assay (ELISA) using specific antibodies and immunoblotting.

In one exemplary embodiment, the ratio of (i) or (ii) is measured in a sample of cerebrospinal fluid from a subject (test sample), and the measured level is compared to a reference level. If the measured level of the ratio in (i) is higher than the reference level, or if the measured level of the ratio in (ii) is lower than the reference level, then the subject may be suffering from progressive supranuclear palsy. is determined to be high. The reference level here is the ratio measured in cerebrospinal fluid samples of individuals (preferably a plurality of individuals) not suffering from progressive supranuclear palsy (preferably under the same conditions as the subject-derived samples) can be based on The reference level may be a cutoff value obtained by ROC curve analysis for ratios measured in cerebrospinal fluid samples from multiple individuals.

In one embodiment, the reference level is based on a ratio measured in a cerebrospinal fluid sample taken from the same subject at a previous time point (preferably under the same conditions as the test sample), and (i) If the measured level of the ratio is higher than the reference level, or if the measured level of the ratio in (ii) is lower than the reference level, the patient is likely to have progressive supranuclear palsy compared to the previous time point. determined to be more sexually active or progressive supranuclear palsy worse.

In one embodiment, the ratio of (i) or the ratio of (ii) is measured in a sample of cerebrospinal fluid from a subject (test sample), and the higher the measured level of the ratio of (i), or (ii) ) ratio, the more likely the subject is suffering from progressive supranuclear palsy, or the more severe the subject's progressive supranuclear palsy is assessed. .

Chromogranin B protein in cerebrospinal fluid samples may itself also be a biomarker for assessing the potential for progressive supranuclear palsy. Chromogranin B protein is positively correlated with progressive supranuclear palsy. Thus, according to one aspect of the present disclosure, a biomarker for assessing the likelihood of having progressive supranuclear palsy is chromogranin B protein in cerebrospinal fluid. In one embodiment, the subject is likely to have progressive supranuclear palsy if the chromogranin B protein concentration in the cerebrospinal fluid is higher than a reference value of 70 ng/mL or greater. be. In another embodiment, the chromogranin B protein concentration in the cerebrospinal fluid is 75 ng/mL or greater, 80 ng/mL or greater, 90 ng/mL or greater, 100 ng/mL or greater, 110 ng/mL or greater, or 120 ng It is determined that the subject is likely to be suffering from progressive supranuclear palsy if it is higher than the reference value of ≧/mL.

It can be said that the discovery of biomarkers has established a new method of collecting useful data for the diagnosis of progressive supranuclear palsy. Accordingly, in another aspect, the present disclosure provides a method of collecting data to assess, determine, or diagnose the likelihood that a subject is suffering from progressive supranuclear palsy. The method involves quantifying a peptide fragment of chromogranin B (bCHGB_6255), represented as a peak with an m/z value of 6255 by mass spectrometry, using a cerebrospinal fluid sample from a subject. Quantitative data for this peptide fragment are collected as data negatively correlated with progressive supranuclear palsy. Conventionally, it was not known at all that quantification of peptide fragments of chromogranin B and measurement of the amount of some specific molecule in a biological sample would be useful for the diagnosis of progressive supranuclear palsy. rice field.

In yet another related aspect, a method of collecting data for assessing, determining the likelihood of, or diagnosing that a subject is suffering from progressive supranuclear palsy comprises: using the sample to quantify a peptide fragment of chromogranin B (bCHGB_6255) represented by a peak with an m/z value of 6255 in mass spectrometry, and further comprising: (i) the amount of bCHGB_6255 in the cerebrospinal fluid sample; Further comprising quantifying the ratio of the amount of chromogranin B protein or (ii) the ratio of the amount of bCHGB_6255 to the amount of chromogranin B protein in said cerebrospinal fluid sample. In this method, either (i) the ratio is collected as data showing a positive correlation with progressive supranuclear palsy, or (ii) the data showing a negative correlation with progressive supranuclear palsy. collected as As described above, the amount of chromogranin B protein can be quantified by methods known to those skilled in the art, such as ELISA and immunoblotting.

In another aspect, the present disclosure provides a method of collecting data to assess, determine, or diagnose the likelihood that a subject is suffering from progressive supranuclear palsy, comprising: A method is provided comprising quantifying chromogranin B protein concentration in spinal fluid. Quantitative data for this protein are collected as data positively correlated with progressive supranuclear palsy.

Hereinafter, specific embodiments will be described in detail by showing examples, but these are examples and the invention of the present disclosure is not limited to these examples.

[Example 1: First exploratory study]
In a study to explore and identify biomarkers for PSP, cerebrospinal fluid (CSF) was collected from each of eight PSP patients (mean age 72.6 years) and eight healthy controls (mean age 72.1 years). fluid) samples were analyzed under the same conditions by the SELDI-TOF MS method.

In this and other examples, PSP patients are those diagnosed based on the criteria described in Non-Patent Documents 1-4. CBS (Corticobasal Ganglia Syndrome) patients are those diagnosed based on the criteria described in Mathew et al., J. Neurol. Neurosurg. Psychiatry, 2012, 83(4):405-10. PD patients are those diagnosed based on the criteria described in Postuma et al., Mov. Disord., 2015, 30(12):1591-601. Control individuals (groups) are designated as CTL. All mass spectrometric analyzes were carried out at the contractor, Protenova Co., Ltd. Takamatsu Laboratory.

Among 219 peaks analyzed on the MS spectrum, 24 peaks were detected as candidate substances that could show differential expression between the PSP and CTL groups.

[Example 2: Second exploratory study]
Separate cohorts from Example 1, 6 PSP patients (mean age 74.5 years), 6 PD patients (mean age 74.5 years), and 6 healthy controls (mean age 74.3 years), respectively. The collected CSF samples were analyzed by SELDI-TOF MS. One of the 24 candidate substances found in Example 1 was selected as the most reproducible candidate. This candidate appears as an m/z value of 6255, and its abundance was reduced in CSF from PSP patients (Fig. 1). This candidate substance has a significant difference in peak intensity between the PSP group and the PD group, and between the PSP group and the CTL group (that is, a decrease in the PSP group) in the MS spectrum, and The condition of no significant difference from the CTL group was met.

This candidate substance was concentrated and purified by repeating anion column fractionation and reversed-phase HPLC separation, and finally analyzed by LC-MS/MS. As a result, this substance was identified as corresponding to a peptide fragment derived from the chromogranin B protein. This peptide fragment is called bCHGB_6255. The chromogranin B protein itself is denoted CHGB. More specifically, bCHGB_6255 was identified as a fragment containing amino acids 500-530 (SEQ ID NO:2) of the CHGB protein (full length 657 amino acids shown in SEQ ID NO:1).

[Example 3: CHGB verification study]
53 PSP patients (average age 73.6 years), 24 PD patients (average age 73.0 years), 15 CBS patients (average age 73.5 years), and 20 patients, which are different cohorts from Examples 1 and 2 CSF samples collected from each CTL (mean age 69.2 years) were analyzed by enzyme-linked immunosorbent assay (ELISA) using an anti-CHGB antibody that can detect full-length CHGB protein.

According to the ELISA results shown in Figure 2, the average CHGB level in CSF (CHGB total protein level) was 76.8 ng/mL in the PSP patient group, 61.5 ng/mL in the PD patient group, and 61.2 ng/mL in the CBS patient group. , and 59.0 ng/mL in the CTL group. CHGB levels in the PSP patient group were significantly higher than those in the PD, CBS, and CTL groups (p < 0.05). In other words, bCHGB_6255, a peptide fragment of the CHGB protein, was decreased in the PSP patient group, whereas, interestingly, the level of the CHGB protein itself tended to be higher in the PSP patient group. 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% (Fig. 3). The positive predictive value (PPV) was 57.9% and the negative predictive value (NPV) was 62.7%.

The relative value of the amount of CHGB protein detected in CSF divided by the amount of bCHGB_6255 (CHGB/bCHGB_6255 ratio) was highly correlated with PSP and discriminated PSP from both PD and CTL with high confidence. It became a biomarker that can be used (Fig. 4).

[Conclusion]
It has become clear that chromogranin B in cerebrospinal fluid can be useful as a diagnostic marker for progressive supranuclear palsy. Specifically, a peptide fragment of chromogranin B (bCHGB_6255), which appears as an m/z value of 6255 when detected by mass spectrometry, was specifically reduced in the cerebrospinal fluid of a group of patients with progressive supranuclear palsy. It was found to On the other hand, the concentration of chromogranin B protein in cerebrospinal fluid tended to increase in the progressive supranuclear palsy group. A biomarker, expressed as the ratio of bCHGB_6255 levels and chromogranin B protein abundance in cerebrospinal fluid, was found to be significantly more correlated with progressive supranuclear palsy. These new findings provide biomarkers that are new and powerful diagnostic tools for progressive supranuclear palsy, which until now lacked diagnostic tools. It can contribute to treatment and improvement of disease mechanism elucidation.

Claims (6)

A biomarker for assessing the likelihood of having progressive supranuclear palsy, the peptide fragment of chromogranin B presenting as a peak with an m/z value of 6255 in mass spectrometry of a cerebrospinal fluid sample and progressive A cerebrospinal fluid biomarker negatively correlated with supranuclear palsy. A peptide fragment of chromogranin B, represented as a peak with an m/z value of 6255 in mass spectrometry of a cerebrospinal fluid sample, and chromogranin B, a biomarker for assessing the likelihood of having progressive supranuclear palsy (i) positively correlated with progressive supranuclear palsy, quantified as the ratio of the amount of chromogranin B protein to the amount of said peptide fragment in a cerebrospinal fluid sample, or (ii) the cerebrospinal fluid. A cerebrospinal fluid biomarker quantified as the ratio of the amount of said peptide fragment to the amount of chromogranin B protein in a fluid sample and negatively correlated with progressive supranuclear palsy. A biomarker for assessing the likelihood of having progressive supranuclear palsy, the biomarker being chromogranin B protein in cerebrospinal fluid that positively correlates with progressive supranuclear palsy. A method of collecting data for assessing the likelihood that a subject is suffering from progressive supranuclear palsy, comprising: using a cerebrospinal fluid sample from said subject, mass spectrometric analysis of m/z 6255 A method comprising quantifying peptide fragments of chromogranin B expressed as peak values, wherein the quantitative data of said peptide fragments are collected as data negatively correlated with progressive supranuclear palsy. A method of collecting data for assessing the likelihood that a subject is suffering from progressive supranuclear palsy, comprising:
quantifying a peptide fragment of chromogranin B represented by a peak with an m/z value of 6255 in 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 said peptide fragment in said cerebrospinal fluid sample, or
(ii) quantifying the ratio of the amount of said peptide fragment to the amount of chromogranin B protein in said cerebrospinal fluid sample, wherein said ratio of (i) is positively correlated with progressive supranuclear palsy. A method, collected as data, or wherein the ratio of (ii) is negatively correlated with progressive supranuclear palsy. 1. A method of collecting data for assessing the likelihood that a subject is suffering from progressive supranuclear palsy, comprising quantifying chromogranin B protein concentration in cerebrospinal fluid from said subject, A method, wherein quantitative data for said protein are collected as data positively correlated with progressive supranuclear palsy.

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