CN118112253A - Application of plasma neurofilament light chain protein in preparation or screening of products related to excessive daytime sleepiness of parkinsonism - Google Patents
Application of plasma neurofilament light chain protein in preparation or screening of products related to excessive daytime sleepiness of parkinsonism Download PDFInfo
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- CN118112253A CN118112253A CN202410150151.9A CN202410150151A CN118112253A CN 118112253 A CN118112253 A CN 118112253A CN 202410150151 A CN202410150151 A CN 202410150151A CN 118112253 A CN118112253 A CN 118112253A
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- 206010041349 Somnolence Diseases 0.000 title claims abstract description 55
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 title claims abstract description 48
- 101000979333 Homo sapiens Neurofilament light polypeptide Proteins 0.000 title claims abstract description 26
- 102100023057 Neurofilament light polypeptide Human genes 0.000 title claims abstract description 20
- 238000012216 screening Methods 0.000 title claims abstract description 11
- 208000027089 Parkinsonian disease Diseases 0.000 title abstract description 13
- 206010034010 Parkinsonism Diseases 0.000 title abstract description 13
- 229940079593 drug Drugs 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 5
- 208000018737 Parkinson disease Diseases 0.000 claims description 29
- 239000000126 substance Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- 238000003745 diagnosis Methods 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229940121649 protein inhibitor Drugs 0.000 claims description 2
- 239000012268 protein inhibitor Substances 0.000 claims description 2
- 238000001514 detection method Methods 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 239000000090 biomarker Substances 0.000 abstract description 23
- 230000007774 longterm Effects 0.000 abstract description 4
- 108010064539 amyloid beta-protein (1-42) Proteins 0.000 abstract description 3
- 210000004369 blood Anatomy 0.000 abstract description 3
- 239000008280 blood Substances 0.000 abstract description 3
- 210000005259 peripheral blood Anatomy 0.000 abstract description 2
- 239000011886 peripheral blood Substances 0.000 abstract description 2
- 238000007619 statistical method Methods 0.000 abstract description 2
- 101800000263 Acidic protein Proteins 0.000 abstract 1
- 206010018341 Gliosis Diseases 0.000 abstract 1
- 230000007387 gliosis Effects 0.000 abstract 1
- 210000002381 plasma Anatomy 0.000 description 28
- 208000032140 Sleepiness Diseases 0.000 description 7
- 230000037321 sleepiness Effects 0.000 description 6
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 4
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- 102100039289 Glial fibrillary acidic protein Human genes 0.000 description 3
- 241001112258 Moca Species 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000009593 lumbar puncture Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
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- 206010002869 Anxiety symptoms Diseases 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
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- 206010050515 Hyposmia Diseases 0.000 description 1
- 238000000585 Mann–Whitney U test Methods 0.000 description 1
- 206010061533 Myotonia Diseases 0.000 description 1
- 206010071390 Resting tremor Diseases 0.000 description 1
- 238000012352 Spearman correlation analysis Methods 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
- G01N2800/2835—Movement disorders, e.g. Parkinson, Huntington, Tourette
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Abstract
The invention provides an application of plasma neurofilament light chain protein in preparation or screening of products related to excessive daytime sleepiness of parkinsonism, and belongs to the technical field of biological medicines. The invention collects peripheral blood of parkinsonism patients of large samples, detects the baseline plasma neurofilament light chain protein, gliosis acidic protein, p-tau181, abeta 40 and Abeta 42 levels of all participants, evaluates whether the patients have excessive daytime sleepiness and the severity thereof, carries out follow-up on the patients once per year, carries out continuous follow-up for 3 years, evaluates the excessive daytime sleepiness of the patients again and measures the plasma biomarker levels of the patients during the follow-up, finally carries out statistical analysis by using a generalized estimation equation and a linear mixed model, and shows that the plasma NfL levels have obvious correlation with the excessive daytime sleepiness in long-term follow-up, and the plasma NfL levels can be used as the blood biomarker of the excessive daytime sleepiness of parkinsonism patients.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of plasma neurofilament light chain protein in preparation or screening of products related to excessive daytime sleepiness of parkinsonism.
Background
Parkinson's disease is one of the most common neurodegenerative diseases, and the main clinical manifestations include motor symptoms such as bradykinesia, resting tremor, myotonia, etc., and non-motor symptoms such as constipation, hyposmia, anxiety depression, cognitive decline, sleep disorder, etc. Excessive daytime sleepiness is one of the common non-motor symptoms of parkinson's disease patients, which can seriously affect the quality of life of the patient, increasing the risk of accidents. The pathogenesis of excessive daytime sleepiness in parkinson's disease is currently unknown and lacks effective biomarkers, so it is urgent and important to find easily accessible hematological biomarkers.
In recent years, more and more research has been devoted to the search for potential biomarkers that can predict early days of excessive sleepiness in parkinson's disease patients. Among them, pathological proteins related to Alzheimer's disease, including cerebrospinal fluid phosphorylated tau protein (p-tau 181), cerebrospinal fluid amyloid beta (Abeta 42) have been demonstrated to have the potential to predict excessive daytime sleepiness in Parkinson's disease. However, lumbar puncture is an invasive examination, resulting in difficult cerebrospinal fluid access. Therefore, there is a need to find a blood biomarker that can replace invasive examinations such as lumbar puncture and can rapidly and effectively predict excessive daytime sleepiness of parkinson's patients.
Disclosure of Invention
Aiming at the technical problems, the invention provides application of the plasma neurofilament light chain protein in preparation or screening of products related to excessive daytime sleepiness of the parkinsonism for the first time. The invention collects peripheral blood of parkinsonian patients with large samples, uses a hypersensitive single molecule array (simoa) technology to detect the baseline plasma neurofilament light chain protein (neurofilament LIGHT CHAIN, nfL), glial fiber acid protein (glial fibrillary acidic protein, GFAP), p-tau181, abeta 40 and Abeta 42 levels of all participants, and uses an Epworth somnolence assessment scale (Epworth SLEEPINESS SCALE, ESS) to evaluate whether the patients have excessive daytime sleepiness and the severity thereof (ESS is more than or equal to 10 and is the excessive daytime sleepiness). Patients were followed once a year for 3 years. The ESS scale was again used at the follow-up to evaluate the patient's daytime excessive sleepiness and to measure the patient's plasma biomarker levels. Statistical analysis using a generalized estimation equation and a linear mixed model showed that plasma NfL levels had a significant correlation with daytime excessive sleepiness during long-term follow-up, i.e., plasma NfL levels could be used as a hematological biomarker of excessive daytime sleepiness in parkinson's patients.
In order to achieve the above purpose, the invention adopts the following technical scheme:
One of the purposes of the invention is to provide the application of the plasma neurofilament light chain protein in the preparation and/or screening of products for preventing, detecting, diagnosing and/or treating excessive daytime sleepiness of the parkinsonism.
Further, the product for detecting excessive daytime sleepiness of the parkinsonism is an agent which can detect the expression level of the neurofilament light chain protein in blood plasma.
Furthermore, the diagnosis product for excessive daytime sleepiness of the Parkinson's disease is a kit, and the kit contains a reagent capable of detecting the expression level of the neurofilament light chain protein in blood plasma.
Further, the diagnosis product for excessive daytime sleepiness of the Parkinson's disease is a chip, and the chip contains an agent capable of detecting the expression level of the neurofilament light chain protein in blood plasma.
Further, the product for treating excessive daytime sleepiness of the parkinsonism is a pharmaceutical composition, and the pharmaceutical composition comprises a neurofilament light chain protein inhibitor, wherein the inhibitor can reduce the expression level of the neurofilament light chain protein.
Furthermore, the pharmaceutical composition also comprises other medicines compatible with the inhibitor and pharmaceutically acceptable auxiliary materials.
It is another object of the present invention to provide a method for screening a candidate substance for treating excessive daytime sleepiness in parkinson's disease, which comprises treating a system expressing or containing a neurofilament light chain protein gene with a substance to be screened and detecting the expression of the neurofilament light chain protein gene in the system; wherein, if the substance to be screened can reduce the expression level of the neurofilament light chain protein gene, the substance is indicated to be a candidate substance for treating excessive daytime sleepiness of the Parkinson disease.
The invention also aims to provide application of the method in screening excessive daytime sleepiness candidate substances for treating parkinsonism.
Compared with the prior art, the invention has the following beneficial effects:
Previous studies have found that cerebrospinal fluid p-tau181 and aβ42 have the potential to predict excessive daytime sleepiness in parkinson's disease. However, lumbar puncture is an invasive examination, resulting in difficult cerebrospinal fluid access. In contrast, the present invention found that plasma NfL levels had a significant correlation with excessive daytime sleepiness, i.e., plasma NfL levels were useful as a hematological biomarker of excessive daytime sleepiness in parkinson's disease patients. The invention successfully searches for another brand new blood biomarker for rapidly and effectively predicting excessive daytime sleepiness of the parkinsonism patient for the first time, which has great significance in the aspects of expanding the excessive daytime sleepiness biomarker of the parkinsonism and reducing the injury to the patient.
Drawings
FIG. 1 is a graph showing the evaluation results of the daytime sleepiness associated index in a patient with Parkinson's disease in example 1 of the present invention;
FIG. 2 is a comparison of baseline plasma biomarkers for patients with Parkinson's disease with and without excessive daytime sleepiness in example 1 of the invention, wherein (A) the comparison of baseline plasma biomarkers for patients with Parkinson's disease with and without excessive daytime sleepiness was tested for significance using the Mann-Whitney U test; (B) Correlation of plasma biomarkers with ESS scores in parkinson's disease patients, significance was tested using Spearman correlation analysis;
FIG. 3 shows the variation of the index during follow-up in example 1 of the present invention;
FIG. 4 is a plot of the ESS score during follow-up in example 1 of the present invention;
FIG. 5 is a correlation of plasma biomarkers during long term follow-up with the occurrence of excessive daytime sleepiness in patients with Parkinson's disease in example 1 of the invention;
FIG. 6 is a correlation of plasma biomarkers with ESS scores of patients with Parkinson's disease during long-term follow-up in example 1 of the invention.
Detailed Description
The following examples are illustrative of the invention and are not intended to limit the scope of the invention. Modifications and substitutions to methods, procedures, or conditions of the present invention without departing from the spirit and nature of the invention are intended to be within the scope of the present invention. The reagents, instruments, etc. used in the following examples are commercially available, and the methods used in the examples are consistent with the methods conventionally used unless otherwise specified.
The technical scheme of the invention is further elaborated in the following in conjunction with examples.
Example 1
1) Baseline was included in 159 patients with parkinson's disease, and clinical characteristics such as sex, age, height, weight, etc. of the patients, course of disease, medication, etc. were collected, and the patients were evaluated for excessive daytime sleepiness (if ESS was greater than or equal to 10 points, excessive daytime sleepiness was observed) using the Epworth sleepiness assessment scale (Epworth SLEEPINESS SCALE, ESS). Patient motor symptoms were assessed using UPDRS-III. The quality of sleep of the patients was assessed using the Parkinson' S DISEASE SLEEP SCALE nd version, pdss-2. Patients were evaluated for depression and anxiety symptoms using the hamilton depression scale (Hamilton depression RATING SCALE, HDRS,24 entry version) and the hamilton anxiety scale (Hamilton anxiety RATING SCALE, HARS). Patient cognitive function was assessed using the montreal cognitive assessment scale (Montreal cognitive assessment, moCA). The evaluation results are shown in fig. 1. The patient's plasma NfL, GFAP, p-tau181, aβ40 and aβ42 levels were then tested using simoa techniques and the test results are shown in figure 2.
Fig. 2 shows: at baseline, the plasma NfL levels were higher in patients with excessive daytime sleepiness compared to those without excessive daytime sleepiness, and plasma NfL levels correlated positively with ESS scores (fig. 2).
2) Patients with included parkinson's disease were given annual follow-up, once a year for 3 years (3 years follow-up time for clinical index), again assessed for ESS score at follow-up, to determine if patients developed excessive daytime sleepiness, and again assessed for motor symptoms, depression and anxiety symptoms, cognitive function, and plasma NfL, GFAP, p-tau181, aβ40 and aβ42 levels. Wherein the index changes during the follow-up period are shown in fig. 3, and the ESS score changes during the follow-up period are shown in fig. 4.
3) The generalized estimation equation and the linear mixed model are used for analyzing the correlation between the hematology index and the excessive daytime sleepiness, and the specific operation is as follows:
In a 2 year follow-up (2 years follow-up time for hematology index), the correlation of plasma biomarkers with clinical features and EDS presence was studied using a Generalized Estimation Equation (GEE) model that allows for the correlation of repeated measurements on the same patient. In this model, EDS exists as a dependent variable. We have built two types of models: i) Uncorrected model: each biomarker (the levels of p-tau181, a-beta 40 and a-beta 42, the ratio of a-beta 42/a-beta 40 and p-tau 181/a-beta 42 in plasma) was repeatedly measured as an independent repeat variable. ii) correction model: each biomarker was analyzed to control gender, age, disease duration, BMI, LEDD, DA, moCA, UPDRS-II and UPDRS-III scores, and follow-up time, respectively.
The relationship between plasma biomarkers and clinical features and ESS scores during 2 years of follow-up was studied using a linear mixed effect model, taking into account the correlation between repeat measurements and different follow-up times. We performed two types of models: i) Unadjusted model: the time-varying ESS score was taken as a dependent variable for each model, repeated measurements of each biomarker as a fixed effect, and intercept as a random effect. ii) adjusting the model: each biomarker was analyzed to control gender, age, disease duration, BMI, LEDD, DA, moCA, UPDRS-II and UPDRS-III scores, and follow-up time, respectively.
The results of the follow-up analysis are shown in fig. 5 and 6.
The corrected generalized estimated equation model shows that higher plasma NfL levels (OR 1.047[1.002-1.094], p=0.042) during follow-up have a significant correlation with the occurrence of EDS. The corrected linear mixed effect model showed that higher plasma NfL levels (β0.097[0.012-0.183], p=0.026) correlated with higher ESS scores during follow-up (fig. 5-6). I.e., plasma NfL levels, can be used as a hematological biomarker of excessive daytime sleepiness in parkinson's disease patients.
The above embodiments are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solutions of the present invention should fall within the protection scope defined by the claims of the present invention without departing from the design spirit of the present invention.
Claims (8)
1. The use of plasma neurofilament light chain protein in the preparation and/or screening of products for the prevention, detection, diagnosis and/or treatment of excessive daytime sleepiness in parkinson's disease.
2. The use according to claim 1, wherein said product for detecting excessive daytime sleepiness in parkinson's disease is an agent capable of detecting the expression level of neurofilament light chain protein in plasma.
3. The use according to claim 1, wherein said diagnosis of excessive daytime sleepiness in parkinson's disease is a kit comprising reagents capable of detecting the expression level of neurofilament light chain protein in plasma.
4. The use according to claim 1, wherein said diagnosis of excessive daytime sleepiness in parkinson's disease is a chip containing reagents capable of detecting the expression level of neurofilament light chain protein in plasma.
5. The use according to claim 1, wherein said product for the treatment of excessive daytime sleepiness in parkinson's disease is a pharmaceutical composition comprising a neurofilament light chain protein inhibitor, said inhibitor reducing the expression level of neurofilament light chain protein.
6. The use according to claim 5, wherein the pharmaceutical composition further comprises other drugs compatible with the inhibitor and pharmaceutically acceptable excipients.
7. A method for screening a candidate substance for treating excessive daytime sleepiness in parkinson's disease, which comprises treating a system expressing or containing a neurofilament light chain protein gene with a substance to be screened and detecting the expression of the neurofilament light chain protein gene in the system; wherein, if the substance to be screened can reduce the expression level of the neurofilament light chain protein gene, the substance is indicated to be a candidate substance for treating excessive daytime sleepiness of the Parkinson disease.
8. Use of the method of claim 7 for the screening of candidate substances for excessive daytime sleepiness in the treatment of parkinson's disease.
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| CN202410150151.9A CN118112253A (en) | 2024-02-02 | 2024-02-02 | Application of plasma neurofilament light chain protein in preparation or screening of products related to excessive daytime sleepiness of parkinsonism |
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