Auxiliary diagnosis system and device for neurodegenerative diseases and storage medium

Abstract

The invention relates to an auxiliary diagnosis system and device for neurodegenerative diseases and a storage medium. Based on a single molecule immunoassay technology, the relevance between the ratio of a P-tau217 concentration value and an A beta 42 concentration value and the neurodegenerative disease is deeply analyzed, a reference interval is designed, and an efficient screening tool is further developed; and high-specificity, high-sensitivity and high-accuracy auxiliary screening of neurodegenerative diseases such as Alzheimer's disease, subcortical ischemic vascular dementia and frontotemporal dementia is realized.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to auxiliary diagnostic systems, devices and storage media for neurodegenerative diseases. Background Technology

[0002] Neurodegenerative diseases are a class of diseases caused by the gradual loss or even death of neuronal structure or function in the brain and spinal cord. These include Alzheimer's disease (AD), frontotemporal dementia (FTD), and subcortical ischemic vascular dementia (SIVD). The pathological development of Alzheimer's disease is divided into three stages: preclinical AD, mild cognitive impairment (MCI) of AD, and dementia of AD. The pathogenesis of neurodegenerative diseases is not yet fully understood. Currently, the screening and assessment methods for neurodegenerative diseases mainly include three approaches: clinical assessment, imaging examination, and laboratory examination. Clinical assessment, as a routine examination, has shortcomings such as strong subjectivity and low standardization. Moreover, it requires relatively professional and systematic training and a long period of development for a clinician to have systematic and standardized cognitive assessment capabilities. Imaging assessment, such as magnetic resonance imaging (MR) or computed tomography (CT), is mostly nonspecific, and there may be no obvious signs of atrophy or involvement in the early stages.

[0003] In the current healthcare system, cognitive screening based on scale assessments remains a crucial strategy for early identification due to its significant cost advantages. However, existing screening systems have the following shortcomings: First, the lack of qualified and experienced clinicians in primary healthcare settings may lead to significant inter-operator variability, affecting the reliability of assessment results; second, due to heterogeneity in education levels, systematic assessment scales imported from abroad may not be suitable for effective assessment in the Chinese population, and there is a lack of locally validated community screening tools; third, scale-based screening has limitations in sensitivity thresholds, making it difficult to effectively identify individuals with positive biomarkers in the preclinical stage.

[0004] In summary, the pathological causes of neurodegenerative diseases are complex, and the molecular mechanisms are unclear. Clinical detection methods mainly include clinical assessment, imaging examinations, and laboratory tests. However, definitive diagnosis often relies on cumbersome auxiliary screening methods, which not only have poor patient compliance but are also expensive, time-consuming, and involve complicated procedures. Therefore, there is an urgent need for an auxiliary diagnostic protocol for neurodegenerative diseases that is highly compliant, economical, sensitive, accurate, and easy to perform. Summary of the Invention

[0005] In response to the shortcomings of existing technologies and practical needs, this invention provides an auxiliary diagnostic system, device, and storage medium for neurodegenerative diseases, aiming to achieve high specificity, sensitivity, and accuracy in assisting the screening of neurodegenerative diseases.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] In a first aspect, the present invention provides an auxiliary diagnostic system for neurodegenerative diseases, the auxiliary diagnostic system comprising a sample data acquisition module, a data calculation module, and an auxiliary diagnostic module;

[0008] The data acquisition module is used to acquire the concentrations of p-tau217 and Aβ42 in the biological sample of the target object; the data calculation module is used to calculate the ratio of p-tau217 to Aβ42 concentrations of the target object, p-tau217 / Aβ42; the auxiliary diagnosis module is used to make auxiliary judgments based on p-tau217 / Aβ42 and output the results.

[0009] Preferably, the neurodegenerative disease includes at least one of Alzheimer's disease, subcortical ischemic vascular dementia, or frontotemporal dementia.

[0010] In this invention, based on single-molecule immunoassay technology, in-depth analysis of samples from multiple centers revealed significant differences in P-tau217 / Aβ42 among healthy individuals, patients with AD-related MCI and AD patients, frontotemporal dementia (FTD), and subcortical ischemic vascular dementia (SIVD). Plasma P-tau217 / Aβ42 was significantly higher in patients with AD-related MCI and AD-related dementia than in healthy individuals, FTD patients, and SIVD patients. This further validates its applicability to assist in the screening of neurodegenerative cognitive impairment with high specificity, sensitivity, and accuracy.

[0011] Preferably, in the auxiliary diagnostic module: when p-tau217 / Aβ42≤0.018, the target object is determined to be a negative neurodegenerative disease, and the output result is negative.

[0012] Preferably, in the auxiliary diagnostic module: when 0.018 < p-tau217 / Aβ42 ≤ 0.052, the target object is determined to be positive for frontotemporal dementia or subcortical ischemic vascular dementia, and the output result is positive for frontotemporal dementia or subcortical ischemic vascular dementia; preferably, when 0.018 < p-tau217 / Aβ42 ≤ 0.023, the output result is positive for frontotemporal dementia, and when 0.023 < p-tau217 / Aβ42 ≤ 0.052, the output result is positive for subcortical ischemic vascular dementia.

[0013] Preferably, in the auxiliary diagnostic module: when p-tau217 / Aβ42 > 0.052, the target object is determined to be positive for Alzheimer's disease or subcortical ischemic vascular dementia; when 0.052 < p-tau217 / Aβ42 ≤ 0.093, the output result is positive for subcortical ischemic vascular dementia; when p-tau217 / Aβ42 > 0.093, the output result is positive for Alzheimer's disease.

[0014] In this invention, a targeted auxiliary diagnostic module is designed to not only effectively distinguish between healthy individuals and patients, but also to efficiently differentiate between Alzheimer's disease patients, frontotemporal dementia patients, and subcortical ischemic vascular dementia patients. The established diagnostic cutoff value achieved a diagnostic accuracy and sensitivity of 93.9% and 96.0% for patients with free temporal dementia (FTD), Alzheimer's disease (AD), and Alzheimer's disease-related microvascular disease (MCD), respectively. The established diagnostic cutoff value achieved a diagnostic accuracy and sensitivity of 75.4% and 77.3% for patients with semi-infantile vascular disease (SIVD), Alzheimer's disease (AD), and Alzheimer's disease-related MCD, respectively.

[0015] Preferably, the biological sample includes bodily fluid samples such as blood and / or cerebrospinal fluid.

[0016] In this invention, screening based on p-tau217 / Aβ42 can serve as an initial screening assessment, thereby helping to further screen suspected individuals who require further PET or cerebrospinal fluid testing. If plasma p-tau217 / Aβ42 is positive, it is recommended to use PET or cerebrospinal fluid analysis for subsequent diagnostic evaluation, combined with a comprehensive analysis of medical history, family history, and neurological scales. If plasma p-tau217 / Aβ42 is inconsistent with the clinical manifestations of MCI and AD, further investigations may be considered to identify other causes.

[0017] Preferably, the detection method for biological samples includes the detection method of the ultra-automated single-molecule immunoassay platform.

[0018] This invention is developed based on single-molecule immunoassay technology, which can accurately capture extremely low concentrations of biomarkers in the blood. It has ultra-high sensitivity and high specificity, low detection bottleneck, short detection cycle, and low price, making it suitable for clinical and community screening.

[0019] Secondly, the present invention provides a method for tracing the source of samples for neurodegenerative diseases, the method comprising:

[0020] The concentrations of p-tau217 and Aβ42 in the sample were detected, and the sample was identified using the auxiliary diagnostic system for neurodegenerative diseases described in the first aspect.

[0021] Preferably, the neurodegenerative disease includes at least one of Alzheimer's disease, subcortical ischemic vascular dementia, or frontotemporal dementia.

[0022] In this invention, the auxiliary diagnostic system can also be used for non-disease diagnosis purposes, such as identifying different sample types, tracing the source of samples for neurodegenerative diseases, and facilitating the statistical analysis, storage, and retrospective analysis of different related samples.

[0023] Thirdly, the present invention provides an electronic device comprising a memory, a processor, and a computer program stored in the memory and executable on the processor, wherein the processor, when executing the computer program, performs the functions of an auxiliary diagnostic system for neurodegenerative diseases as described in the first aspect.

[0024] Fourthly, the present invention provides a computer-readable storage medium storing a computer program that, when executed by a processor, performs the functions of an auxiliary diagnostic system for neurodegenerative diseases as described in the first aspect.

[0025] Compared with the prior art, the present invention has at least the following beneficial effects:

[0026] This invention, based on single-molecule detection technology, discovered significant differences in P-tau217 / Aβ42 levels among healthy individuals, patients with AD-related MCI, AD patients, SIVD patients, and FTD patients. Based on P-tau217 / Aβ42, an auxiliary diagnostic system was further developed, achieving a diagnostic accuracy of 97.3%, sensitivity of 96.0%, and specificity of 98.1% for healthy individuals, AD, and AD-related MCI. The established diagnostic cutoff value achieved diagnostic accuracy, sensitivity, and specificity of 64.4%, 69.2%, and 62.7% for normal samples and FTD patients, respectively, and 83.1%, 92.5%, and 77.3% for normal samples and SIVD patients, respectively. The established diagnostic cutoff values ​​achieved diagnostic accuracy, sensitivity, and specificity of 93.9%, 96.0%, and 89.7% for patients with FTD, AD, and AD-related MCI, respectively. For patients with SIVD, AD, and AD-related MCI, the diagnostic accuracy, sensitivity, and specificity reached 75.4%, 77.3%, and 73.1%, respectively. Furthermore, the single-molecule immunoassay platform can accurately capture extremely low concentrations of biomarkers in the blood, exhibiting ultra-high sensitivity and specificity, low detection bottleneck, and short detection cycle, making it suitable for assisting community screening. Attached Figure Description

[0027] Figure 1 Box plot of P-tau217 / Aβ42 group distribution;

[0028] Figure 2 Scatter plots for diagnosing healthy individuals, AD and AD-related MCI patients, FTD patients, and SIVD patients using the P-tau217 / Aβ42 reference interval;

[0029] Figure 3 ROC curves for normal samples, FTD patients, and SIVD patients diagnosed based on P-tau217 / Aβ42;

[0030] Figure 4 ROC curves for diagnosing different neurodegenerative cognitive impairments based on P-tau217 / Aβ42. Detailed Implementation

[0031] The technical solution of the present invention will be further described below with reference to the accompanying drawings and specific embodiments. However, the following examples are merely simplified examples of the present invention and do not represent or limit the scope of protection of the present invention. The scope of protection of the present invention is determined by the claims.

[0032] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased from legitimate channels.

[0033] Example 1

[0034] This embodiment analyzes the levels of P-tau217 / Aβ42 in healthy individuals, individuals with AD-related MCI (mild cognitive impairment) and AD (AD-related dementia), individuals with frontotemporal dementia (FTD), and individuals with subcortical ischemic vascular dementia (SIVD).

[0035] Peripheral blood samples were collected from 150 healthy individuals across multiple centers nationwide, along with samples from 81 patients with AD-related MCI (mild cognitive impairment) and AD (AD-related dementia) (collectively referred to as Alzheimer's disease), 40 patients with frontotemporal dementia (FTD), and 68 patients with subcortical ischemic vascular dementia (SIVD). The levels of phosphorylated Tau217 protein (P-tau217) and β-amyloid protein (Aβ) 42 were detected using the ultra-automated single-molecule immunoassay platform. The specific detection process included:

[0036] Samples are pretreated, instrument analysis parameters are set, and detection program is selected. The pretreated sample is transferred to the instrument's testing area, and the working solution is placed inside. The instrument automatically completes the detection process according to the selected program, automatically calling the standard curve to calculate the sample results. After the experiment, the results are exported.

[0037] After removing outliers, the distribution of P-tau217 / Aβ42 in 110 healthy individuals, 75 patients with AD-related MCI and AD, 39 patients with FTD, and 67 patients with SIVD is as follows: Figure 1 As shown, P-tau217 / Aβ42 varies among different patients, indicating its potential for auxiliary diagnostic use.

[0038] Example 2

[0039] This embodiment designs an auxiliary diagnostic reference interval.

[0040] This embodiment, based on the sample data from Embodiment 1, further designs an auxiliary diagnostic reference interval, such as... Figure 2 As shown, a P-tau217 / Aβ42 ratio > 0.018 can screen for individuals with frontotemporal dementia (FTD) and subcortical ischemic vascular dementia (SIVD), while a P-tau217 / Aβ42 ratio > 0.052 can screen for AD-related MCI (mild cognitive impairment) and AD.

[0041] Example 3

[0042] This embodiment verifies the diagnostic efficacy of the diagnostic interval in Embodiment 2.

[0043] Based on the diagnostic intervals in Example 2, predictions were made for 110 healthy human samples, 75 AD-related MCI patient samples and AD patient samples, 39 FTD patient samples, and 67 SIVD patient samples, and the prediction accuracy, sensitivity, and specificity were calculated.

[0044] The calculation formulas for each diagnostic indicator are as follows:

[0045]

[0046]

[0047]

[0048] Wherein, Accuracy represents accuracy, Sensitivity represents sensitivity, Specificity represents specificity, TP represents the number of true positives, TN represents the number of true negatives, FP represents the number of false positives, and FN represents the number of false negatives.

[0049] The diagnostic accuracy of P-tau217 / Aβ42 for patients with AD-related MCI, AD samples, and healthy individuals was 97.3%, sensitivity was 96.0%, and specificity was 98.1%; for patients with FTD, the diagnostic accuracy was 75.2% and sensitivity was 10.3%; and for patients with SIVD, the diagnostic accuracy and sensitivity were 78.5% and 46.2%, respectively.

[0050] Example 4

[0051] This embodiment designs the cutoff values ​​for diagnosing different individuals with neurodegenerative cognitive impairment and normal samples.

[0052] Based on the sample data from Example 1, this embodiment designed cutoff values ​​for diagnosing different neurodegenerative cognitive impairment (SDI) populations and normal samples. The cutoff value for P-tau217 / Aβ42 in diagnosing normal samples and FTD patients was established as 0.018, and the cutoff value in diagnosing normal samples and SIVD patients was 0.023. Figure 3 Using P-tau217 / Aβ42 > 0.018, patients with FTD can be screened from normal samples and FTD patients, with a diagnostic sensitivity of 69.2%, specificity of 62.7%, and AUC of 0.678. Using P-tau217 / Aβ42 > 0.023, patients with SIVD can be screened from normal samples and SIVD patients, with a diagnostic sensitivity of 92.5%, specificity of 77.3%, and AUC of 0.927.

[0053] Example 5

[0054] This embodiment designs cutoff values ​​for diagnosing different neurodegenerative cognitive impairment populations.

[0055] Based on the sample data from Example 1, this embodiment further designed cutoff values ​​for diagnosing different neurodegenerative cognitive impairment populations. The cutoff value for P-tau217 / Aβ42 in diagnosing AD-related MCI patients, AD patients, and FTD patients was established to be 0.052, and the cutoff value for diagnosing AD-related MCI patients, AD patients, and SIVD patients was 0.093. Figure 4 With a P-tau217 / Aβ42 ratio > 0.052, patients with AD-related MCI and AD can be screened from FTD patients, AD-related MCI patients, and AD patients, with a diagnostic accuracy of 93.9%, sensitivity of 96.0%, specificity of 89.7%, and AUC of 0.965. With a P-tau217 / Aβ42 ratio > 0.093, patients with SIVD, AD-related MCI, and AD can be screened from SIVD patients, AD-related MCI patients, and AD patients, with a diagnostic accuracy of 75.4%, sensitivity of 77.3%, specificity of 73.1%, and AUC of 0.797.

[0056] Example 6

[0057] This embodiment provides an auxiliary diagnostic system for neurodegenerative diseases. The auxiliary diagnostic system includes a sample data acquisition module, a data calculation module, and an auxiliary diagnostic module. The data acquisition module is used to acquire the concentrations of p-tau217 and Aβ42 in a biological sample of a target object. The data calculation module is used to calculate the ratio of p-tau217 to Aβ42 concentrations in the target object, p-tau217 / Aβ42. The auxiliary diagnostic module is used to make auxiliary judgments based on the p-tau217 / Aβ42 ratio and output the results. The auxiliary diagnostic module can make judgments based on the cutoff values ​​designed in embodiments 4-5.

[0058] Example 7

[0059] This embodiment provides an electronic device, which includes a memory, a processor, and a computer program stored in the memory and executable on the processor. When the processor executes the computer program, it implements the functions of the auxiliary diagnostic system as described in Embodiment 6.

[0060] Those skilled in the art will understand that the device of the present invention can be obtained using various forms of hardware, software, firmware, dedicated processors, or combinations thereof.

[0061] Example 8

[0062] This embodiment provides a computer-readable storage medium storing a computer program. The computer program has program code, which, when run in a corresponding processor, controller, computing device, or terminal, implements the functions of the auxiliary diagnostic system as described in Embodiment 6.

[0063] In summary, this invention, based on single-molecule detection technology, revealed significant differences in P-tau217 / Aβ42 levels among healthy individuals, patients with AD-related MCI, AD patients, SIVD patients, and FTD patients. Further development of an auxiliary diagnostic system based on P-tau217 / Aβ42 achieved a diagnostic accuracy of 97.3%, a sensitivity of 96.0%, and a specificity of 98.1% for healthy individuals, AD, and AD-related MCI. However, its diagnostic performance was poor for FTD and SIVD patients, with an accuracy of 75.2% and a sensitivity of 10.3% for FTD patients, and 78.5% and 46.2% for SIVD patients, respectively. The diagnostic cutoff value achieved 64.4%, 69.2%, and 62.7% accuracy, sensitivity, and specificity for normal samples and patients with Freezing Toxic Disease (FTD), respectively. For SIVD patients, the accuracy, sensitivity, and specificity reached 83.1%, 92.5%, and 77.3%, respectively. For FTD patients, Alzheimer's disease (AD) and AD-related MCI patients, the diagnostic cutoff value achieved 93.9%, 96.0%, and 89.7% accuracy, respectively. For SIVD patients, AD and AD-related MCI patients, the accuracy, sensitivity, and specificity reached 75.4%, 77.3%, and 73.1%, respectively. Furthermore, the single-molecule immunoassay platform can accurately capture extremely low concentrations of biomarkers in the blood, exhibiting ultra-high sensitivity and specificity, low detection bottleneck, and short detection cycle, making it suitable for assisting community screening.

[0064] The applicant declares that the above description is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention fall within the protection and disclosure scope of the present invention.

Claims

1. An auxiliary diagnostic system for neurodegenerative diseases, characterized in that, The auxiliary diagnostic system includes a sample data acquisition module, a data calculation module, and an auxiliary diagnostic module. The data acquisition module is used to acquire the concentrations of p-tau217 and Aβ42 in the biological sample of the target object; The data calculation module is used to calculate the ratio of p-tau217 to Aβ42 concentrations of the target object, p-tau217 / Aβ42. The auxiliary diagnostic module is used to make auxiliary judgments based on p-tau217 / Aβ42 and output the results.

2. The auxiliary diagnostic system for neurodegenerative diseases according to claim 1, characterized in that, The neurodegenerative diseases include at least one of Alzheimer's disease, subcortical ischemic vascular dementia, or frontotemporal dementia.

3. The auxiliary diagnostic system for neurodegenerative diseases according to claim 1, characterized in that, In the auxiliary diagnostic module: when p-tau217 / Aβ42≤0.018, the target object is judged to be a negative neurodegenerative disease, and the output result is negative.

4. The auxiliary diagnostic system for neurodegenerative diseases according to claim 1, characterized in that, In the auxiliary diagnostic module: when 0.018 < p-tau217 / Aβ42 ≤ 0.052, the target object is judged to be positive for frontotemporal dementia or subcortical ischemic vascular dementia, and the output result is positive for frontotemporal dementia or subcortical ischemic vascular dementia.

5. The auxiliary diagnostic system for neurodegenerative diseases according to claim 1, characterized in that, In the auxiliary diagnostic module: when p-tau217 / Aβ42 > 0.052, the target object is judged to be positive for Alzheimer's disease or subcortical ischemic vascular dementia; when 0.052 < p-tau217 / Aβ42 ≤ 0.093, the output result is positive for subcortical ischemic vascular dementia; when p-tau217 / Aβ42 > 0.093, the output result is positive for Alzheimer's disease.

6. The auxiliary diagnostic system for neurodegenerative diseases according to any one of claims 1-5, characterized in that, The biological samples include blood and / or cerebrospinal fluid.

7. A method for tracing the source of samples in neurodegenerative diseases, characterized in that, The method includes: The concentrations of p-tau217 and Aβ42 in the sample are detected, and the sample is identified using the auxiliary diagnostic system for neurodegenerative diseases according to any one of claims 1-6.

8. The method for tracing the source of samples for neurodegenerative diseases according to claim 7, characterized in that, The neurodegenerative diseases include at least one of Alzheimer's disease, subcortical ischemic vascular dementia, or frontotemporal dementia.

9. An electronic device comprising a memory, a processor, and a computer program stored in the memory and executable on the processor, characterized in that, When the processor executes the computer program, it implements the functions of the auxiliary diagnostic system for neurodegenerative diseases as described in any one of claims 1-6.

10. A computer-readable storage medium storing a computer program, characterized in that, When the computer program is executed by the processor, it implements the functions of the auxiliary diagnostic system for neurodegenerative diseases as described in any one of claims 1-6.

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