• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    Method of in vitro diagnosis of alzheimer's disease based on the redox level of albumin in the cerebrospinal fluid. The present invention relates to an in vitro diagnostic method for alzheimer's disease (ad), comprising the steps of: a) determining in a cerebrospinal fluid (csf) sample the mercaptoalbumin (amf) content; and b) compare the determined content with the content of amf in csf of healthy subjects. If the amf content is lower than that of healthy subjects, it is indicative of ad. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2600386A1
    申请号:ES201631468
    申请日:2016-11-16
    公开日:2017-02-08
    发明作者:Ana Maria Ortiz Fernandez；Montserrat Costa Rierola；Salvador GRANCHA RAMON
    申请人:Grifols Worldwide Operations Ltd；
    IPC主号:
    专利说明:

    In vitro diagnostic method of Alzheimer's disease based on the redox level of albumin in the cerebrospinal fluid
    The present invention relates to the field of clinical diagnosis, and in particular refers to a method for in vitro diagnosis of Alzheimer's Disease (AD) based on the determination of the redox level of albumin in the cerebrospinal fluid (CSF), in particular the content of mercaptoalbumin (HMA), which is the reduced form of the albumin that Cys-34 cysteine has as a free thiol group.
    AD is a progressive neurodegenerative disease that is typically characterized by a loss of immediate memory and other mental abilities (such as higher cognitive abilities), as neurons die and different areas of the brain atrophy. The disease usually has an approximate average duration after the diagnosis of 10 years, although this duration may vary in direct proportion to the severity of the disease at the time of diagnosis.
    AD is the most common form of dementia, it is incurable and terminal, and it appears most frequently in people over 65 years of age, although it can also develop in rare cases from age 40.
    Usually, the initial symptom is the inability to acquire new memories, but is often confused with attitudes related to old age or stress. Given the suspicion of AD, the clinical diagnostic procedures available in the patient's life to date are based on guidelines and criteria established by the National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related disorders Association (NINCDS-ADRDA) (Mc Khann and others, 1984), basically based on clinical judgment according to the results of neuropsychological tests, reports of the patient's environment and general neurological evaluation. The neurological examination may also include an imaging study of the brain (neuroimaging).
    Currently, there is no definitive diagnosis method of AD, except for the histological analysis performed postmortem to the patient's brain.
    On the other hand, it is known that human albumin is a 66 kDa non-glycosylated protein. Quantitatively, it is the most important blood plasma protein and its concentration in normal plasma is between 35 and 50 g / L, constituting up to 60% of total plasma proteins (Peters TJ: All About Albumin; Biochemistry, Genetics and Medical Applications, Academic Press, San Diego, 1996). Similarly, in the CSF albumin is also the most abundant protein, constituting about 67% of total proteins with a concentration around 200 mg / L (Edward J. Thompson, 2005, The roster of CSF proteins, PROTEINS OF THE CEREBROSPINAL FLUID: Analysis and Interpretation in the Diagnosis and Treatment of Neurological Disease, 2nd Ed. London, UK: Elsevier Academic Press .: 13-31).
    The structure of human albumin consists of a 585 amino acid polypeptide and approximately 67% of alpha helices without beta sheets being present (Otagiri M., Chuang VT Pharmaceutically important pre-and posttranslational modifications of human serum albumin. Biol Pharm Bull 2009; 32: 527-534). Human albumin contains 6 methionine residues and 35 cysteine residues, the latter involved in the formation of 17 disulfide bonds. Cys-34 is the only free cysteine in the entire molecule. Human albumin presents


    specific antioxidant functions due to its ability to bind multiple ligands and radical capture properties, both closely related to its structure.
    Although there are many possibilities of albumin oxidation, Cys-34 is a site particularly sensitive to oxidation / reduction. Therefore, in general, it is legitimate to talk about the redox state of albumin in terms of Cys-34. By chromatographic separation of albumin, three fractions are obtained according to the redox state of Cys-34 (Peters, 1996 cited above):
    (i) the reduced form with the cysteine in the form of a free thiol group, called human mercaptoalbumin (HMA);
    (ii) the oxidized form with cysteine forming a disulfide bond with a small compound containing a thiol group, mainly cysteine or cysteinylglycine, but also with homocysteine and glutathione, called human non-mercaptoalbumin 1 (HNA1); Y
    (iii) the most oxidized form with cysteine as sulfonic or sulfonic acid, called human mercaptoalbumin 2 (HNA2).
    In a healthy healthy person, approximately 61-69% of total plasma albumin is in the form of HMA, 27-35% in the form of HNA1 and 3-5% in the form of HNA2 (Oettl K., and others: Oxidative damage of albumin in advanced liver disease, Biochim Biophys, Acta 2008; 1782: 469-473; Oettl K. and Marsche G. Redox State of Human Serum Albumin in Terms of Cysteine-34 in Health and Disease. Methods Enzymol. 2010; 474: 181-95; and Oettl K. et al. Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity; liver dysfunction and survival. J Hepatol, 2013, 59: 978-983). It is generally believed that the oxidation of HMA to HNA1 is reversible, while oxidation to HNA2 results in an irreversible process.
    Albumin can undergo various structural modifications, which causes its conformation to be modified and, therefore, its binding properties, as well as its redox state (Oettl, K. et al., 2010, cited above).
    The present invention is based on the surprising discovery that, in patients diagnosed with AD in life, the content of the reduced form of albumin (AMF) in the cerebrospinal fluid (CSF) is much lower compared to healthy control subjects. equivalent age range. This behavior was not observed for the content of AMF in the blood plasma, also comparing it with healthy subjects of equivalent age range control. In this way, it can also be said that in patients diagnosed with AD in life, the difference or quotient between the level of AMF in the CSF and in the plasma is increased compared to the same difference in healthy control subjects. of equivalent age range. Therefore, the two markers mentioned above, that is, the content of AMF in the CSF and the difference or quotient between the level of AMF in the CSF and plasma, are useful for the diagnosis of AD.
    As previously mentioned, the definitive diagnostic test for AD must be performed post-mortem, so the diagnosis in life is based on clinical judgment according to the results of neurological tests, reports of the patient's environment and general neurological evaluation. . Thus, the test of the present invention represents an objective, quantifiable, easily interpretable, reliable, reproducible diagnostic tool between different diagnostic centers, of relatively low cost and not influenced by cultural aspects, such as the educational level of the patient, such as It occurs with certain neuropsychological tests.


    As used herein, "healthy subject" and its plural, refer to subjects who do not suffer from AD.
    Therefore, the present invention, in a first aspect, relates to an in vitro diagnostic method of Alzheimer's disease (AD), which comprises the following steps: 5 a) determine in a cerebrospinal fluid (CSF) sample a patient's human mercaptoalbumin content (HMA); and b) compare the content determined in a) with the HMA content in CSF in healthy subjects.
    In a preferred embodiment, in step b) of the method of the present invention if the content of HMA 10 determined in step a) is less than that of healthy subjects, it is indicative of AD, more preferably, the patient is diagnosed with the EA.
    In a preferred embodiment, both the patient and the healthy subjects mentioned above are human beings, more preferably adult human beings.
    In another preferred embodiment, the content of HMA in CSF is measured by high performance liquid chromatography (HPLC) and fluorescence detection (FLD) using excitation and emission wavelengths 280 and 340 nm respectively, based on the methodology described by Oettl K., 2010 (supra). The quantification of HMA is carried out taking into account the height of the peak of interest obtained in the corresponding
    20 chromatogram
    The cut-off value, determined by calculating the ROC curve after adjusting the percentages of sensitivity (91%) and specificity (100%) to maximum values, below which the HMA content measured in stage a) is considered It is indicative of AD and / or that leads to the diagnosis of AD in the patient is,
    25 preferably 37% (w / v).
    In a second embodiment, the present invention relates to an in vitro diagnostic method of Alzheimer's disease (AD), which comprises the following steps: a) determining the content of mercaptoalbumin (AMF) in a cerebrospinal fluid (CSF) sample and 30 a sample of blood or plasma from a patient; b) determine a difference or ratio between the HMA content in the CSF sample and the HMA content in the blood or plasma sample determined in step a); and c) compare the difference or quotient determined in step b) with the corresponding difference or quotient in healthy subjects.
    In step b) of the method according to this second embodiment, it is contemplated that the determined difference is: the difference between the content of HMA in the CSF sample and the content of HMA in the blood or plasma sample determined in the stage a); or the difference between the content of HMA in the blood sample
    or plasma and the content of HMA in the CSF sample determined in step a). In one embodiment
    Preferably, in step b) the difference between the content of AMF in the CSF sample and the content of AMF in the blood or plasma sample determined in step a) is determined as a quotient (plasma AMF value / value of HMA in CSF).


    When in step b) the difference between the content of AMF in the CSF sample and the content of AMF in the blood or plasma sample determined in stage a), in a preferred embodiment, in stage c) of the method of the present invention if the difference determined in step b), such as, for example, the ratio of plasma HMA value / HMA value in CSF (plasma HMA / HMA CSF) is greater than in healthy subjects, is indicative of AD, more preferably, the patient is diagnosed with AD. In case the difference determined is another, the person skilled in the art will make the necessary adaptations to the method of the present invention (for example, in relation to the comparison with the corresponding value of the difference in healthy subjects).
    Additionally, and preferably, the blood or plasma sample is a plasma sample.
    In a preferred embodiment, both the patient and the healthy subjects mentioned above are human beings, more preferably adult human beings.
    In another preferred embodiment, the HMA content in CSF is measured by high performance liquid chromatography (HPLC) and fluorescence detection (FLD) using excitation and emission wavelengths 280 and 340 nm respectively, based on the described methodology. by Oettl K., 2010 (supra). The quantification of AMF is carried out taking into account the height of the peak of interest obtained in the corresponding chromatogram.
    The cut-off value, determined by calculating the ROC curve after adjusting the percentages of sensitivity and specificity to maximum values (100%), from which the difference determined in step b) is considered, such as, for example, The ratio of plasma HMA value / CSF HMA value (plasma HMA / CSF HCR) is indicative of AD and / or that leads to the diagnosis of AD in the patient is preferably 1.1.
    For a better understanding, the present invention is described in more detail below in reference to the attached figures, which are presented by way of example, and in reference to illustrative and non-limiting examples.
    Figure 1 shows the amount of AMF, by means of the height of the AMF peak (in percentage), obtained for plasma and CSF samples of controls (healthy subjects, as defined above) and of patients with AD . On the ordinate axis (“y” axis) the height of the AMF peak is shown (in percentage) and on the abscissa axis (“x” axis) the group is shown (on the left the healthy controls and on the right people with AD). Additionally, for each of the groups, the results obtained for the CSF samples are shown on the left and the results obtained for the plasma samples on the right.
    It is clear to one skilled in the art that if the content of AMF in CSF in patients presenting with AD is less than the content of AMF in CSF of healthy patients, the content of the two remaining albumin fractions according to the redox state of the Cys -34, that is, HNA1 and / or HNA2, will also be affected and may also serve as an indication of AD.


    EXAMPLE
    Example 1. Study of the diagnosis of Alzheimer's disease by measuring the content of HMA in CSF or the difference between said content and the content of HMA in plasma.
    5 Within the framework of a multicenter, randomized, blind, controlled study in 42 patients who were being treated with therapeutic albumin and who were diagnosed with mild to moderate AD, the present study was conducted to analyze the content of AMF in CSF and the difference between said content and plasma HMA content.
    10 For this, the content of AMF was measured in baseline samples (before the start of the clinical study) of the patients mentioned above, both in CSF (N = 34) and plasma (N = 37), in addition to CSF (N = 16) and plasma (N = 37) of healthy subjects. The samples mentioned above, in all cases were obtained by lumbar puncture in the case of CSF and by blood collection and subsequent separation of plasma, in the
    15 case of plasma samples, always following the standard medical procedures established for this purpose.
    The aforementioned CSF and plasma samples were aliquoted and frozen at a temperature equal to or less than -70 ° C immediately after extraction. Prior to HMA content analysis, the samples were
    20 thawed at room temperature and in the case of plasma samples, the concentration of albumin was determined by immunonephelometry or other equivalent method. The HMA content was measured directly in the CSF samples while the plasma samples were diluted to a concentration below 10 mg / ml in phosphate buffer pH 6.87. Next, the oxidized forms of albumin were analyzed by HPLC-FLD, as described above.
    25 The results obtained are summarized in Figure 1. As can be seen in this figure, patients with AD have a large decrease in the content of AMF in CSF compared to healthy subjects, while in plasma the decrease is slightly Minor. From the above, it is deduced not only the potential diagnosis of the content of AMF in CSF but also the difference between said content and
    30 plasma HMA content.
    The median HMA content obtained for patients with AS in CSF is 9.6%, while the median plasma content is 54.1%, the ratio of (plasma HMA / CSF HCR) being 5, 64. For healthy subjects, on the other hand, the median content of AMF in CSF is 77.4% and that of plasma is 65.6%.
    35 being the ratio (plasma HMA / CSF HMA) of 0.85.

    权利要求:
    Claims (10)
    [1]
    1. Method of in vitro diagnosis of Alzheimer's disease (AD), which includes the following stages:
    a) determine in a sample of cerebrospinal fluid (CSF) the content of mercaptoalbumin (AMF); Y5 b) compare the content determined in a) with the HMA content in CSF in healthy subjects.
    [2]
    2. In vitro diagnostic method according to claim 1, characterized in that in stage b) if the content of AMF determined in stage a) is lower than that of healthy subjects is indicative of AD.
    3. In vitro diagnostic method according to claim 2, characterized in that in stage b) if the content of AMF determined in stage a) is lower than in healthy subjects, the patient is diagnosed with AD.
    [4]
    4. In vitro diagnostic method according to any of the preceding claims, characterized in that the
    HMA content cut-off value below which is considered to be indicative of AD and / or that leads to diagnosis of AD is 37%.
    [5]
    5. In vitro diagnostic method according to any of the preceding claims, characterized in that the sample comes from a human being.
    In vitro diagnostic method according to claim 5, characterized in that said human being is an adult human being.
    [7]
    7. In vitro diagnostic method of Alzheimer's disease (AD), which comprises the following stages: a) determine the content of mercaptoalbumin (AMF) in a sample of cerebrospinal fluid (CSF) and 25 in a sample of blood or plasma of a patient; b) determine a difference or ratio between the HMA content in the CSF sample and the HMA content in the blood or plasma sample determined in step a); and c) compare the difference or quotient determined in step b) with the corresponding difference or
    Quotient in healthy subjects. 30
    [8]
    8. In vitro diagnostic method according to claim 7, characterized in that in step b) the difference between the content of AMF in the CSF sample and the content of AMF in the blood or plasma sample determined in the stage is determined a) as a ratio of the value of plasma HMA / HMA in CSF (plasma HMA / CSF HMA).
    [9]
    9. In vitro diagnostic method according to claim 7, characterized in that in step c) of the method of the present invention if the difference determined in stage b) is greater than that of healthy subjects, it is indicative of AD.
    10. In vitro diagnostic method according to claim 9, characterized in that in stage c) of the method of the present invention if the difference determined in stage b) is greater than that of healthy subjects the patient is diagnosed with AD .

    [11]
    11. In vitro diagnostic method according to any of claims 7 to 10, characterized in that the cut-off value of the quotient (plasma HMA / CSF HCR) above which is considered to be indicative of AD and / or that leads to diagnosis of AD is 1.1.
    12. In vitro diagnostic method according to any of claims 7 to 10, characterized in that the blood or plasma sample is a plasma sample.
    [13]
    13. In vitro diagnostic method according to any of claims 7 to 10, characterized in that the
    Sample comes from a human being. 10
    [14]
    14. In vitro diagnostic method according to claim 13, characterized in that said human being is an adult human being.

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