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WO2021009074A1 - Nouveaux marqueurs utilisés en tant que prédicteurs précoces de la maladie d'alzheimer - Google Patents

Nouveaux marqueurs utilisés en tant que prédicteurs précoces de la maladie d'alzheimer Download PDF

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WO2021009074A1
WO2021009074A1 PCT/EP2020/069648 EP2020069648W WO2021009074A1 WO 2021009074 A1 WO2021009074 A1 WO 2021009074A1 EP 2020069648 W EP2020069648 W EP 2020069648W WO 2021009074 A1 WO2021009074 A1 WO 2021009074A1
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test subject
cerebral
accumulation
gfap
subject
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Charlotte Teunissen
Hugo Vanderstichele
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ADX Neurosciences NV
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ADX Neurosciences NV
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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
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4709—Amyloid plaque core protein
    • 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
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer

Definitions

  • the present invention generally relates to brain neuroscience field and relates to a new marker for evaluating cerebral beta-amyloid (Ab) accumulation in the brain and methods for analysis thereof.
  • the invention introduces a marker to be used in pre-symptomatic diagnosis, in clinical trial enrichment settings, and evaluation of drug efficacy of therapeutic and prophylactic drugs in Alzheimer's disease.
  • AD Alzheimer's disease
  • amyloid plaques which are extracellular deposits consisting mainly of aggregated beta-amyloid (Ab) peptide
  • neurofibrillary tangles which are deposits consisting predominantly of hyperphosphorylated tau (pTau) protein.
  • the underlying disease pathology precedes the onset of cognitive symptoms by many years (Jack et al, 2018).
  • AD Cerbrospinal fluid
  • PET positron emission tomography
  • CSF cerebrospinal fluid
  • AD affects 10% of people over the age of 65 and is expected to affect >100 million by 2050 (Association As, 2017; Brookmeyer et al., 2007).
  • PET is effective for detecting Ab accumulation, it requires high examination cost and long time for executing the examination, and thus is not a diagnostic method that allows for a majority of elderly people to easily undergo the examination. Consequently, there is a great need for more cost-effective and minimally invasive methods that can detect early Ab accumulation in a routine setting and detect early-onset of neurodegeneration.
  • NfL blood neurofilament light
  • MCI mild cognitive impairment
  • AD dementia Alzheimer's disease
  • GFAP glial fibrillary acidic protein
  • astrogliosis the principal intermediate filament cytoskeletal protein of astrocytes
  • Increased GFAP expression was shown in areas surrounding Ab plaques as well as with increasing severity of tauopathy in AD brain (Hondius et al., 2016). While GFAP plasma immunoassays are available, this biomarker is understudied in AD (Bogoslovsky et al., 2017).
  • WO2011149947 and AU2017200029 encompasses a method for determining Ab turnover in blood and uses hereto a labeled amino acid that is administered to a patient prior to collecting a blood sample from the patient. The turn over of Ab is measured by determining the amount of labeled Ab and unlabeled Ab.
  • W02011070174 describes a method that introduces a change in ionic strength and in the molecular interactions within a sample leading to the release of Ab40 and Ab42 bound to plasma proteins and other components. This allows for the estimation of the total level of Ab in plasma.
  • W02014081851 relates to methods for modeling the in vivo kinetics and metabolism of amyloid-b (Ab) isoforms.
  • methods for determining one or more kinetic parameters of Ab42 and at least one other Ab peptide are described. Determination whether a subject has amyloid pathology is based on a difference between the two kinetic parameters.
  • WO2012140296 describes a highly specific antibody that recognizes Ab17 in a specific manner without showing any substantial cross-reactivity towards other Ab species such as Ab15, Ab16, Ab38, Ab40 or Ab42.
  • W02015111430 describes an improved method for measuring APP cleavage peptides (also referred to as Ab-like peptides) in blood using a antibody-immobilized carrier to capture APP cleavage peptides, dissociating the APP cleavage peptides from the carrier and detecting them using matrix-assisted laser desorption/ionization mass spectrometry.
  • the method measures APP cleavage peptides is particularly suitable for small blood samples or in samples where the peptides are present in trace amount in the blood sample.
  • WO2015178398 discloses marker panels and methods for determining a cerebral Ab accumulation status based on measuring a combination on measuring a combination of ratio's of Ab-like peptides
  • WO2017047529 discloses marker panels and methods for determining a cerebral Ab accumulation status based on measuring a combination of a ratio of Ab peptides (Ab39/ Ab42 or (Ab40/ Ab42), and the ratio of Ab petide and Ab-like peptide (ARR669-711/Ab42).
  • GFAP biomarker is understudied in AD.
  • One patent in connection to GFAP measurement in plasma includes W02005029087 which describes the use of serum or plasma GFAP as a diagnostic marker for intracerebral hemorrhage.
  • the invention especially relates to methods for the very early assessment of intracerebral hemorrhage. Plasma GFAP level is measured using Elecsys technology.
  • Simoa is another one of these techniques, and has the advantage to be translatable to daily clinical practice due to automation of procedure with high throughput, and to be easily transferrable to and implementable in all neurochemical laboratories.
  • studies showed that plasma amyloid levels decrease over the Alzheimer's continuum (Janelidze et al., 2016; Verberk et al., 2018; Vergallo et al., 2019; Shi et al., 2019 ) and with reasonable accuracy amyloid abnormal and normal individuals can be discriminated (Janelidze et al., 2016), even at the pre-symptomatic phase (Verberk et al., Shi et al., 2019).
  • the present invention generally concerns an improved marker for determining a cerebral Ab accumulation state in a living body-derived sample from a test subject.
  • the invention as set out in the claims shows for the first time that the combination of Ab42/Ab40 ratio and GFAP measurement in blood or plasma samples improves the accuracy for detecting abnormal Ab accumulation, even before any clinical symptoms of cognitive function decline can be observed in the test subject.
  • the invention provides in a first aspect a marker for determining a cerebral Ab accumulation state in a living body-derived sample from a test subject, the marker comprising a combination of the analytes Ab42/Ab40 ratio and GFAP.
  • the invention also provides a syndrome diagnosis marker for determining cognitive impairment in a test subject, the marker comprising a combination of the analytes Ab42/Ab40 ratio and GFAP.
  • analytic method for determining a cerebral Ab accumulation state in a test subject comprising:
  • said analytic method is characterized in that the cerebral Ab accumulation state is determined in the test subject before said test subject shows any clinical symptoms of cognitive function decline, or wherein the test subject is at the very early stages of a neurodegenerative disease showing clinical symptoms of subjective cognitive decline (SCD) or mild cognitive decline (MCI).
  • the cerebral Ab accumulation state is determined in the test subject before said test subject shows any clinical symptoms of cognitive function decline, or wherein the test subject is at the very early stages of a neurodegenerative disease showing clinical symptoms of subjective cognitive decline (SCD).
  • the cerebral Ab accumulation state is determined in the test subject before said test subject shows any clinical symptoms of cognitive function decline.
  • the marker and method optionally incorporate additional analytes besides Ab42/Ab40 ratio and GFAP.
  • the marker and methods of the present invention are particularly beneficial for patients with neurodegenerative disease or patients susceptive of neurodegenerative disease, such as, for example, for patients with early-onset of AD, even before any clinical symptoms can be observed, or for patients with AD.
  • the marker and methods are particularly advantageous in a clinical trial enrichment setting of who would be referred to a specialized center for a PET scan and who should not. It also finds its use in predicting progression of symptoms, in predicting risk of development of dementia, and in therapeutic effectiveness monitoring.
  • Figure 1A to 1C show boxplots of plasma biomarker levels stratified for amyloid PET status.
  • Figure 1A to 1C X-axis from left to right: Normal amyloid PET, Abnormal amyloid PET.
  • Figure 1A Y-axis Plasma Ab42/Ab40 ratio;
  • Figure IB Y-axis Plasma GFAP in pg/mL.
  • Figure 1C Y-axis Plasma NfL in pg/mL.
  • Figure ID to IF show boxplots of plasma biomarker levels stratified for syndrome diagnosis.
  • X-axis from left to right SCD, MCI, AD.
  • Figure ID Y-axis Plasma Ab42/Ab40 ratio.
  • Figure IE Y-axis Plasma GFAP in pg/mL.
  • Figure IF Y-axis Plasma NfL in pg/mL.
  • the p-values were calculated using univariate analysis of variance adjusted for age and gender and in case of more than two groups bonferroni-corrections for multiple comparisons was applied.
  • Figure 2A to 2C show boxplots of plasma biomarker levels for amyloid PET status-stratified syndrome diagnosis.
  • Figure 2A to 2C X-axis from left to right: Amyloid normal SCD; Amyloid abnormal SCD; Amyloid normal MCI; Amyloid abnormal MCI; Amyloid abnormal AD.
  • Figure 2A Y-axis Plasma Ab42/Ab40 ratio;
  • Figure 2B Y-axis Plasma GFAP in pg/mL.;
  • Figure 2C Y-axis Plasma NfL in pg/mL.
  • the p-values were calculated using univariate analysis of variance adjusted for age and gender with post-hoc bonferroni- correction.
  • levels were natural log transformed for normal distribution of the data prior to age and gender adjusted group comparisons.
  • Figure 3 shows ROCs for prediction of an abnormal amyloid PET scan by the plasma biomarkers or a combined model in the total study population in Figure 3A; and in the non-demented population only in Figure 3B.
  • X-axis Specificity
  • Y-axis Sensitivity.
  • Individual biomarkers plasma GFAP (— line), Abeta 1-42/1-40 ratio (-o- line) and NfL (-+- line) are plotted and the best-fitting model best predicting an abnormal amyloid PET status is plotted
  • X-axis CSF markers from left to right: Ab42, tTau, pTau, pTau/ Ab42 ratio;
  • Y-axis plasma markers from bottom to top: GFAP, NfL, Abb42/ Abb40 ratio.
  • the present invention provides a marker for determining a cerebral Ab accumulation state in a living body-derived sample from a test subject, the marker comprising a combination of the analytes Ab42/Ab40 ratio and GFAP.
  • Ab is used as an abbreviation of beta-amyloid.
  • Ab is a cleavage product of APP, through sequential proteolytic processing by b- and y-secretases The y-secretase, which cuts at the C- terminal end of the Ab peptide, cleaves within the transmembrane region of APP to generate a number of Ab isoforms of 36-43 amino acid residues in length.
  • Three major forms of Ab detected in the CSF are Ab40, Ab38, and Ab42 (respectively 40, 38 and 42 in length) with other minor abundance forms 15, 16, 17, 34, 37, and 39 amino acids in length.
  • Abc, Ab1-c ⁇ q ⁇ 3c and Abetal-x are synonymously used herein and designate beta-amyloid peptide with 1-x amino acid residues in length.
  • Glial fibrillary acidic protein is a 55 kDa cytosolic protein that is a major structural component of astroglial filaments and is the major intermediate filament protein in astrocytes.
  • GFAP Glial fibrillary acidic protein
  • the marker for determining a cerebral Ab accumulation state in a living body-derived sample from a test subject comprises, in addition to Ab40/Ab42 ratio and GFAP, one or more additional analytes, such as one or more known CSF biomarkers of AD pathology, brain atrophy and brain metabolism.
  • the one or more additional analytes are preferably chosen from the group consisting of NfL, APOE s4 carriership and tTau. tTau measured in plasma is referred to as plasma tau.
  • body-derived sample or test sample refers to a sample of bodily fluid obtained for the purpose of diagnosis, prognosis, or evaluation of a test subject of interest, such as a patient.
  • Living body-derived samples or test samples include blood, serum, plasma, cerebrospinal fluid, urine, saliva and body secreting fluid.
  • Preferred test samples are blood, serum and plasma, with plasma representing the most preferred sample.
  • Serum is the liquid fraction of whole blood that is collected after the blood is allowed to clot and removal of the clot.
  • Plasma is produced when whole blood is treated with an anticoagulant, such as e.g. EDTA, and cells are removed.
  • the test subject is a human being.
  • the test subject does not show any clinical symptoms of cognitive function decline or the test subject is at the very early stages of a neurodegenerative disease showing only clinical symptoms of subjective cognitive decline (SCD) or mild cognitive decline (MCI).
  • the test subject is a non- demented individual having a cerebral abnormal amyloid status.
  • the test subject does not show any clinical symptoms of cognitive decline or has clinical symptoms of subjective cognitive decline (SCD) or mild cognitive decline (MCI).
  • the test subject does not show any clinical symptoms of cognitive function decline or has clinical symptoms of SCD only.
  • the test subject does not show any clinical symptoms of cognitive function decline.
  • the subject is at the very early stages of a neurodegenerative disease; preferably AD.
  • neurodegenerative disease refers to a disease that is associated with an altered, preferably decreasing degree of neuronal viability and/or activity.
  • Non-limiting examples of neurodegenerative disease include, but are not limited to Alzheimer's disease, Parkinson's disease, Huntington disease, Lewy body dementia and Prion diseases, and their corresponding stages with baseline syndrome diagnosis.
  • the term "marker” as used herein, refers to any kind of molecule that is, directly or indirectly, for example by itself or through precursors, derivatives or products thereof, or interactions with other molecules, organelles, cells, tissues or the like, associated with and, preferably, indicative of a certain physiological state of test subject.
  • the physiological state of the test subject is a disease involving neuronal damages.
  • the physiological state of the test subject is at the very early stage of disease, preferably before any clinical symptoms of cognitive function decline are observed, such that it is a potential indicator of SCD or MCI and eventual progression to dementia.
  • the marker as used herein, is composed of one or more analytes, the analyte most frequently being a single kind of biomolecule.
  • the analyte is a protein or peptide that is differentially expressed in a disease or a diseased test subject compared to the healthy test subject, and the disease can be diagnosed by way of analysis of the protein level present in a body-derived or test samples obtained from the test subject.
  • the analyte is an allele-carrier that is differentially present in a disease or a diseased test subject compared to the healthy test subject.
  • the marker is a combination of analytes, and may include the ratio of one analyte level to another analyte level.
  • the marker comprises a combination of the analytes Ab42/Ab40 ratio and GFAP.
  • the marker consists of a combination of the analytes Ab42/Ab40 ratio and GFAP, and one or more further analytes.
  • the marker consists of a combination of the analytes Ab42/Ab40 ratio, GFAP and NfL. As shown in the example section, this marker setting turns out to accurately identify an abnormal cerebral amyloid status.
  • the marker for determining a cerebral Ab accumulation state in a test subject consists of a combination of the analytes Ab42/Ab40 ratio, GFAP and APOE s4 carriership. This marker setting turns out to accurately identify an abnormal amyloid status.
  • APOE polymorphisms have been associated with changes in brain function.
  • APOE encodes apolipoprotein E.
  • APOE e4 increases the lifetime risk of AD by twofold to fourfold (Nussbaum et al, 2015; Nussbaum and Ellis, 2003).
  • AROE-eA codes for the apolipoprotein-e4 (apoE4), which compared to other isoforms, is less effective in maintaining cerebral lipid homeostasis and in breaking down Ab peptide, thus facilitating the formation of extracellular insoluble oligomers.
  • APOE s4 carriership can be determined using techniques for genotyping, PCR, sequencing,..., or commercial kits developed for that purpose (e.g. EUROArray APOE Direct).
  • the marker for determining a cerebral Ab accumulation state in the patient is highly associated with performance on various cognitive tests.
  • Tests to measure cognitive impairment include Mini-Mental State Examination (MMSE) covering global cognition, but also various tests in major cognitive domain such as domain of attention, memory, executive functioning, etc...
  • MMSE Mini-Mental State Examination
  • the marker as defined in the present invention can be used for syndrome diagnosis and/or differential diagnosis and/or early detection of vascular problems.
  • the marker may be helpful in the differentiation of different psychological problems (depression, schizophrenie, bipolar disorder,...)
  • the invention provides a syndrome diagnosis marker for determining cognitive impairment in a test subject, the marker comprising a combination of the analytes Ab42/Ab40 ratio and GFAP.
  • the marker for syndrome diagnosis comprises, in addition to Ab40/Ab42 ratio and GFAP, one or more additional analytes, such as one or more known CSF biomarkers of AD pathology, brain atrophy and brain metabolism.
  • the syndrome diagnosis marker for determining cognitive impairment in test subject comprises a combination of the analytes Ab42/Ab40 ratio and GFAP and NfL.
  • such marker will be tested in a living body- derived sample from a test subject.
  • the marker for syndrome diagnosis is evaluated in a test subject before the test subject shows any clinical symptoms of cognitive function decline, or wherein the test subject is at the very early stages of a neurodegenerative disease showing clinical symptoms of SCD or MCI.
  • the invention relates to a marker according to any of the described embodiments used in a method for determining a cerebral Ab accumulation state in a living body-derived sample wherein a decreased Ab42/Ab40 ratio and increased GFAP identifies/predicts neural damage due to an abnormal amyloid status.
  • the marker as described finds its application in an analytic method for determining a cerebral Ab accumulation state in a living body-derived sample.
  • the present invention relates to an analytic method for determining a cerebral Ab accumulation state in a test subject, the method comprising:
  • a living body-derived sample derived from the test subject o subjecting a living body-derived sample derived from the test subject to a measuring step of a marker, said marker comprising the combination of the analytes Ab42, Ab40 and GFAP, to obtain measurement levels of Ab42, Ab40 and GFAP;
  • o a calculation step of calculating the ratio of Ab42 level to Ab40 level: Ab42/ Ab40; and o an evaluation step of determining that an amount of cerebral Ab accumulation of the test subject is larger than an amount of cerebral Ab accumulation of a subject having normal cognitive function who is negative for cerebral Ab accumulation when the ratio Ab42/ Ab40 of the test subject is lower than the standard levels which is the ratio Ab42/ Ab40 of the subject having normal cognitive function and being negative for Ab accumulation, and the GFAP level of the test object is higher than the standard level which is the GFAP level of the subject having normal cognitive function and being negative for cerebral Ab accumulation.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decline or wherein the test subject is at the very early stages of a neurodegenerative disease showing SCD or MCI.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decliner or wherein the test subject is at the very early stages of a neurodegenerative disease showing SCD.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decline.
  • the example section shows that plasma GFAP combined with plasma Ab42/Ab40 ratio demonstrate clinical and screening diagnostic capabilities of an Area under ROC curve greater than 0,85.
  • the marker of the method comprises one or more analytes additional to Ab42, Ab40 and GFAP.
  • the measuring step applied in the present invention measures the levels of each of the analytes Ab42, Ab40 and GFAP, and optionally one or more analytes, in a qualitative or analytical manner using a immmuno-assay (IA).
  • Sandwich lA's to that purpose are well known in the art, the most common one being an enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • ELISA enzyme-linked immunosorbent assay
  • ELISA's rely on specific antibodies to bind the target antigen (peptide or protein), and a detection system to indicate the presence and quantity of antigen binding.
  • Different biochemical techniques may be used for detecting the binding of the de antibody and the analyte molecule in an ELISA set-up, nonlimiting examples of ELISA's using different biochemical techniques include colorimetric lAs, fluorescent lAs, chemiluminescence lAs, etc...
  • the measuring step applied in the present invention measures the levels of each of the analytes Ab42, Ab40 and GFAP using a fully-automated immunoassay.
  • the fully- automated immunoassay reaches a sensitivity at femtomolar.
  • the measuring step applied in the present invention measures the levels of each of the analytes Ab42, Ab40 and GFAP using a chemiluminescence ELISA.
  • the measuring step applied in the present invention measures the levels of each of the analytes Ab42, Ab40 and GFAP using Elecsys technology.
  • the measuring step applied in the methods of the present invention measures the levels of each of the analytes Ab42, Ab40, GFAP and optionally NfL using a digital ELISA.
  • the measuring step applied in the methods of the present invention measures the levels of each of the analytes Ab42, Ab40, GFAP and optionally NfL using Simoa technology. Simoa technology has been described and is known in the art (Rissin et al., 2010; Wilson et al., 2016).
  • the analytical method of detecting a cerebral Ab accumulation state may be carried out in as singleplex or multiplex.
  • singleplex set up single protein molecules are counted.
  • a "multiplex" experiment is defined herein as one which allows detection of susceptibility to, or the incidence of a cerebral Ab accumulation state by analysis of the Ab42, Ab40 and GFAP level linked to susceptibility to, or the incidence of, neural damage using a single sample. Multiplexing provides technical advantages because neural damage may be accurately diagnosed from a single sample by identifying the level of all analytes present in the marker.
  • a single sample may be divided into several samples, each of which is used in an individual experiment to detect the level of at least one but not all of the panel of analytes whose analyte level is linked to the susceptibility to, or the incidence of, cerebral Ab accumulation. Therefore, a single sample or portion of a sample may provide the analyte level for analyte which is then used collectively in order to diagnose susceptibility to, or the incidence of, cerebral Ab accumulation.
  • the levels of each of the analytes Ab42, Ab40, GFAP and/or one or more other analytes are measured using digital ELISA technology, preferably Simoa technology or other high-sensitive immuno-assay technology, such as Erenna, to be able to measure with reasonable accuracy in these low analyte concentrations.
  • measurement of the Ab42 and Ab40 analyte on the one hand, and measurement of GAFP and/or NfL analyte on the other hand are done in different freeze-thaw cycles.
  • measurement in the measuring step occurs in sequential order within the same run.
  • the obtained Ab42 measure is normalized by using the Ab40 measure in the body-derived sample. This is done in the calculation step of calculating the ratio of Ab42 level to Ab40 level: Ab42/ Ab40.
  • the marker for use in the method of the invention employs a marker comprising a combination of the analytes Ab42/Ab40 ratio, GFAP and NfL, or, alternatively the analytes Ab42/Ab40 ratio, GFAP and APOE s4 carriership.
  • the analytic method for determining a cerebral Ab accumulation state of a test subject comprises:
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decline or wherein the test subject is at the very early stages of a neurodegenerative disease showing SCD or MCI.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decliner or wherein the test subject is at the very early stages of a neurodegenerative disease showing SCD.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decline.
  • the present invention relates to an analytic method for determining a cerebral Ab accumulation state of a test subject, the method comprising:
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decline or wherein the test subject is at the very early stages of a neurodegenerative disease showing SCD or MCI.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decliner or wherein the test subject is at the very early stages of a neurodegenerative disease showing SCD.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decline.
  • the present invention relates to an analytic method for determining a cerebral Ab accumulation state of a test subject, the method comprising:
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decline or wherein the test subject is at the very early stages of a neurodegenerative disease showing SCD or MCI.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decliner or wherein the test subject is at the very early stages of a neurodegenerative disease showing SCD.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decline.
  • the present invention relates to a method for early AD syndrome diagnosis of a test subject, the method comprising performing the analytic method as for determining a cerebral Ab accumulation state of a test subject on a living body-derived sample derived from the test subject to determine that an amount of cerebral Ab accumulation of the test subject is larger than an amount of cerebral Ab accumulation of a subject having normal cognitive function who is negative for cerebral Ab accumulation, and based thereon, diagnose that the test subject is at early stage of neurodegenerative disease when cerebral Ab accumulation of the test subject is larger than an amount of cerebral Ab accumulation of a subject having normal cognitive function and being negative for cerebral Ab accumulation.
  • the diagnosis of early stage of neurodegenerative disease is preferably a diagnosis of early stage of AD, preferably at the stage wherein no clinical symptoms of cognitive function decline are observed or wherein only subjective or mild cognitive decline is observed. More preferably the early stage of neurodegenerative disease is at the stage of clinical symptoms showing subjective cognitive decline (SCD) or mild cognitive decline (MCI).
  • SCD subjective cognitive decline
  • MCI mild cognitive decline
  • the present invention relates to a method for identifying a test subject as having or being at risk of development of dementia, the method comprising:
  • test subject has or is at risk of development of dementia if the cerebral Ab accumulation of the test subject is larger than an amount of cerebral Ab accumulation of a subject having normal cognitive function and being negative for cerebral Ab accumulation.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decline or wherein the test subject is at the very early stages of a neurodegenerative disease showing SCD or MCI.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decliner or wherein the test subject is at the very early stages of a neurodegenerative disease showing SCD.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decline.
  • the methods as described are conducted once or a plurality of times over time allowing predicting susceptibility to, or the incidence of, future progression of cerebral Ab accumulation, or predicting potential risk of developing dementia. Susceptibility to, or the incidence of developing dementia will be higher if higher cerebral Ab accumulation over time is determined.
  • the markers and methods for determining a cerebral Ab accumulation state of a test subject also find their application in triage settings. From a cost-effective and time-wise point of view, patient stratification for selecting a patient based on its larger cerebral Ab accumulation state for further examination such as PET or invasive techniques is particularly suitable. Patient stratification also helps in selecting the drug's potential patient to participate in a clinical trial. As disclosed, the markers and methods of the present invention allow for sensitive cerebral Ab accumulation measurement in test subjects at early-stage AD. Test subjects having larger cerebral Ab accumulation state compared to normals may benefit from further examination and/or early enrollment in clinical trials. Further, the methods as presented here can be applied before and after a therapeutic intervention, such as drug administration, and the cerebral Ab accumulation state before and after such medical intervention will determine efficacy of the medical intervention.
  • the present invention relates to a method for test subject stratification, the method comprising performing the analytic method according to any of the embodiments of the present invention for determining a cerebral Ab accumulation state of a test subject on a living body- derived sample derived from the test subject to determine that an amount of cerebral Ab accumulation of the test subject is larger than an amount of cerebral Ab accumulation of a subject having normal cognitive function who is negative for cerebral Ab accumulation, and based thereon, indicate the test subject as being suitable for
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decline or wherein the test subject is at the very early stages of a neurodegenerative disease showing SCD or MCI.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decliner or wherein the test subject is at the very early stages of a neurodegenerative disease showing SCD.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decline.
  • the present invention relates to a method for test subject stratification, the method comprising performing the analytic method for determining a cerebral Ab accumulation state of a test subject on a living body-derived sample derived from the test subject to determine that an amount of cerebral Ab accumulation of the test subject is larger than an amount of cerebral Ab accumulation of a subject having normal cognitive function who is negative for cerebral Ab accumulation, and based thereon, indicate the test subject as being suitable for
  • cerebral Ab accumulation of the test subject is larger than an amount of cerebral Ab accumulation of a subject having normal cognitive function.
  • the present invention relates to a method for determining efficacy of a therapeutic intervention, the method comprising performing before and after a therapeutic intervention the analytic method according to any of the embodiments of the present invention for determining a cerebral Ab accumulation state of a test subject on a living body-derived sample derived from the test subject to determine that an amount of cerebral Ab accumulation of the test subject is larger than an amount of cerebral Ab accumulation of a subject having normal cognitive function who is negative for cerebral Ab accumulation, and based thereon, determine efficacy of the therapeutic intervention.
  • the therapeutic intervention in the test subject is efficient if cerebral Ab accumulation of the test object before therapeutic intervention is higher than after therapeutic intervention.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decline or wherein the test subject is at the very early stages of a neurodegenerative disease showing SCD or MCI.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decliner or wherein the test subject is at the very early stages of a neurodegenerative disease showing SCD.
  • said analytic method is typically characterized in that the cerebral Ab accumulation state is determined in the test subject before the test subject shows any clinical symptoms of cognitive function decline.
  • the marker comprises the combination of the analytes Ab42/ Ab40 ratio, and GFAP.
  • the marker comprises one or more additional analytes; preferably said one or more additional analytes are selected from NfL and APOE s4 carriership.
  • the measurement levels of NfL can be obtained, whether or not in combination with evaluation of APOE s4 carriership.
  • the present invention provides the use of Ab42, Ab40, and GFAP as a marker for determining a cerebral Ab accumulation state of a test subject wherein said test subject does not show any clinical symptom of cognitive decline or wherein the test subject is at the very early stages of a neurogenerative disease showing clinical symptoms of subjective cognitive decline (SCD) or mild cognitive decline (MCI).
  • SCD subjective cognitive decline
  • MCI mild cognitive decline
  • said use is characterized in that a reduced ratio Ab42/ Ab40 of the test subject compared to the standard levels of the ratio Ab42/ Ab40 in a subject having normal cognitive function and being negative for cerebral Ab accumulation and an increased GFAP level in the test subject compared to the GFAP level of a subject having normal cognitive function and being negative for cerebral Ab accumulation are indicative for cerebral Ab accumulation in the test subject.
  • the cerebral Ab accumulation in the subject having normal cognitive function and being negative for cerebral Ab accumulation, can be measured using conventional methods, such for example PET imaging. Even further, the marker panel of the present invention shows that they are even more sensitive than the conventional methods for determination of cerebral Ab accumulation.
  • the present invention provides the use of b42, Ab40, and GFAP as a marker for identifying a test subject as having or being at risk of development of dementia, wherein said test subject does not show any clinical symptom of cognitive decline or wherein the test subject is at the very early stages of a neurogenerative disease showing clinical symptoms of subjective cognitive decline (SCD) or mild cognitive decline (MCI).
  • SCD subjective cognitive decline
  • MCI mild cognitive decline
  • said use is characterized in that a reduced ratio Ab42/ Ab40 of the test subject compared to the standard levels of the ratio Ab42/ Ab40 in a subject having normal cognitive function and being negative for cerebral Ab accumulation and an increased GFAP level in the test subject compared to the GFAP level of a subject having normal cognitive function and being negative for cerebral Ab accumulation are indicative for cerebral Ab accumulation in the test subject and wherein said increased cerebral Ab accumulation in the test subject has or is at increased risk of development of dementia if the cerebral Ab accumulation of the test subject is larger than an amount of cerebral Ab accumulation of a subject having normal cognitive function and being negative for cerebral Ab accumulation.
  • the present invention provides the use of b42, Ab40, and GFAP as a marker for test subject stratification wherein said test subject does not show any clinical symptom of cognitive function decline or wherein the test subject is at the very early stages of a neurodegenerative disease showing clinical symptoms of subject cognitive function decline (SCD) or mild cognitive decline (MCI).
  • SCD subject cognitive function decline
  • MCI mild cognitive decline
  • said use is characterized in that a reduced ratio Ab42/ Ab40 of the test subject compared to the standard levels of the ratio Ab42/ Ab40 in a subject having normal cognitive function and being negative for cerebral Ab accumulation and an increased GFAP level in the test subject compared to the GFAP level of a subject having normal cognitive function and being negative for cerebral Ab accumulation are indicative for cerebral Ab accumulation in the test subject and wherein said increased cerebral Ab accumulation indicates that the test subject is being suitable for further examination and/or being suitable for treatment with a therapeutic product acting against cerebral Ab accumulation.
  • the present invention provides the use of b42, Ab40, and GFAP as a marker for determining the efficacy of a therapeutic intervention against cerebral Ab accumulation in a test subject wherein said test subject does not show any clinical symptoms of cognitive function decline or wherein the test subject is at the very early stages of a neurodegenerative disease showing clinical symptoms of subjective cognitive decline (SCD) or mild cognitive decline (MCI).
  • SCD subjective cognitive decline
  • MCI mild cognitive decline
  • said use is characterized in that a reduced ratio Ab42/ Ab40 of the test subject compared to the standard levels of the ratio Ab42/ Ab40 in a subject having normal cognitive function and being negative for cerebral Ab accumulation and an increased GFAP level in the test subject compared to the GFAP level of a subject having normal cognitive function and being negative for cerebral Ab accumulation are indicative for cerebral Ab accumulation in the test subject and wherein said increased cerebral Ab accumulation indicates that the test subject is being suitable to undergo the therapeutic intervention against the cerebral Ab accumulation.
  • one or more additional analytes can be analyzed.
  • said one or more additional analytes are chosen from the group consisting of NfL and APOE s4 carriership.
  • an increased level of NfL in the test subject is additionally indicative for cerebral Ab accumulation.
  • the levels of each of the analytes Ab42, Ab40, GFAP, and, optionally NfL are determined using a digital ELISA.
  • the levels of each of the analytes Ab42, Ab40, GFAP, and, optionally NfL are determined in a living body- derived sample of the test subject; preferably a living body-derived sample selected from a blood, plasma or serum sample. Even further, the living body-derived sample is obtained from the test subject at the very early stages of a neurodegenerative disease; preferably Alzheimer's disease.
  • kits for use in a method for determining a cerebral Ab accumulation state of a test subject, or, in a method for early AD syndrome diagnosis, comprising:
  • Plasma analyses EDTA plasma was sampled through venipuncture, centrifuged within one hour at 1800 x g for 10 minutes, and stored at -80 °C in aliquots of 500mI in polypropylene tubes in the Amsterdam UMC, VUmc Biobank. Prior to analysis, samples were shortly thawed at room temperature using a cold-air fan, centrifuged at 10.000 x g and subsequently kept on ice. All samples were measured in duplicates onboard of the automated Simoa FID-1 analyzer by trained personnel. Research prototype blood amyloid beta (Amyblood) Simoa assays were developed that specifically detect Abetal-42 and Abetal-40.
  • the automated two-step analytical Simoa procedure of the Amyblood singleplex assays were as follows. In step one for 120 minutes, 25pL of 250K helper beads (Quanterix) and 250K paramagnetic carboxylated beads that were activated with 0.1 mg/mL EDC and coated with 0.2 mg/mL of either monoclonal antibody 21F12 or 2G3 (ADx Neurosciences, Belgium) were incubated with 100pL of 4-fold (for Abetal-42) or 10-fold (for Abetal-40) pre-diluted plasma EDTA in PBS-based buffer with 0.1% casein, 0.1% Tween20, 200pg/mL FIBR-1 (Scantibodies Laboratory Inc., United States) and 20 pL of 0.1 pg/mL of 8x sNFIS-LC-biotinylated detector 3D6 monocolonal antibody (ADx Neurosciences).
  • step one for 120 minutes 25pL of 250K helper beads (Quanterix) and 250K paramagnetic carb
  • step two After a wash cycle, in step two a 5 minute 15 second incubation followed with 50 pM streptavidin-conjugated b-galactosidase (Quanterix). After a next wash, 25pL Resorufin b-D-galactopyranoside (Quanterix) was added and beads were pulled onto the imaging disc, followed by time-lapsed fluorescent imaging.
  • the standard curves were constructed in a range from 0 to 20 pg/mL using Abetal-40 and Abetal-42 recombinant peptides (ADx neurosciences). For Amyblood analysis, samples were randomly divided over seven independent runs in which Abetal-40 and Abtal-42 measurement occurred in sequential order within the same run.
  • APOE e4 carriers had one or two APOE e4 copies, whereas non-carriers only had APOE e2 or APOE e3 alleles.
  • TMTA, TMT B and stroop scores were natural log transformed for normality of data, and subsequently inverted so that for all neuropsychological tests a lower score means worse performance. Missing TMT B values were imputed by multiplying an individual's TMT A score by the average TMT B to TMT A ratio. All neuropsychological test scores were transformed into Z-scores for comparability of effect sizes. The number of missing baseline neuropsychological test performance ranged from 87% to 98%
  • Baseline demographics were performed using Chi square tests, T-tests or non- parametric equivalents as appropriate for two groups, and univariate analyses of variance for more than two groups.
  • CSF and plasma biomarker levels were additionally compared using univariate analysis of variance with adjustment for possible covariates age and gender.
  • Cross-sectional relationships between cognitive performance (dependent variables; Z-transformed neuropsychological test scores) and plasma biomarkers (independent variables; Z-transformed plasma markers) were assessed using linear regression analysis (all separate models). The analysis was performed adjusted for age, gender and education (model 1) and with an additional correction for diagnosis (model 2).
  • P-values were corrected for multiple testing using the 10% false discovery rate (10%FDR) procedure (Olsson et al., 2016).
  • Receiver operating characteristic (ROC) curves of plasma markers predicting an abnormal amyloid PET scan were constructed and youden's cut-offs were calculated as the maximum sum of sensitivity and specificity.
  • a best fitting logistic regression model that optimally predicts an abnormal amyloid PET status was determined using the backward elimination regression procedure based on Wald's p statistics. Variables included in this model were age, gender, diagnosis, APOE e4 carriership and all plasma markers. Predicted values of the optimal panel were plotted as ROC curve and Youden's cut-off was established. Wald's elimination regression procedure with subsequent ROC analysis was repeated for the non-demented group only (i.e. SCD + MCI). Global associations between plasma biomarker levels and CSF biomarker levels were assessed using Pearson's correlation analysis, both for total group and after stratification for syndrome diagnosis SCD, MCI or AD.
  • SCD subjective cognitive decline
  • MCI mild cognitive impairment
  • AD Alzheimer's dementia
  • MMSE mini mental state examination
  • CSF cerebrospinal fluid
  • Abeta amyloid beta
  • tTau total tau
  • pTaul81 tau phosphorylated at threonine 181
  • GFAP Glial fibrillary acidic protein
  • NfL Neurofilament light.
  • * upon re-analysis adjusted for age and gender, p-value remained p ⁇ 0.001.
  • MMSE Mann Whitney U test: p ⁇ 0.001
  • Plasma Abetal-42/1-40 ratio was found associated to baseline test performance on the MMSE (global cognition), and to various tests in the domains of attention, memory and executive functioning (all: p ⁇ 0.05FDR) but not language.
  • Plasma GFAP levels were related to performance on all tests covering global cognition and all major cognitive domains (all: p ⁇ 0.05FDR).
  • Plasma NfL levels were related to performance on MMSE and to most tests covering all major cognitive domains.
  • Plasma biomarkers and neuropsychological test performance were associated with performance on various cognitive tests (table 4). More specifically, when adjusting for age, gender and education, baseline plasma Abetal-42/1-40 ratio associated with baseline test performance on the MMSE (global cognition), and to various tests in the domains of attention, memory and executive functioning (all: p ⁇ 0.05 FDR ) but not language. Plasma GFAP levels related to a larger number of tests, i.e. all tests covering global cognition and all major cognitive domains (all: p ⁇ 0.05 FDR ). Plasma NfL levels were related to performance on MMSE and to several tests covering all major cognitive domains. After additionally adjusting for diagnosis, none of the plasma markers were significantly related to baseline performance on any of the neuropsychological tests (data not shown).
  • Plasma Abeta 1-42/1-40 ratio 0.15 ⁇ 0.03 0.17 ⁇ 0.03 0.14 ⁇ 0.03 ⁇ 0.001 * Plasma Abetal-42, pg/mL 24 ⁇ 6 27 ⁇ 6 23 ⁇ 6 ⁇ 0.001 * Plasma Abetal-40, pg/mL 160 ⁇ 29 165 ⁇ 30 157 ⁇ 28 0.053 f Plasma GFAP, pg/mL 146 ⁇ 78 96 ⁇ 53 168 ⁇ 77 ⁇ 0.001 * Plasma NfL, pg/mL 14 ⁇ 9 11 ⁇ 6 15 ⁇ 10 ⁇ 0.001 *
  • AVLT immediate recall -0.12 (-0.25-0.01) 0.07 (-0.03-0.17) -0.28 (-0.41 - -0.16) 0.03 (-0.08-0.13) -0.30 (-0.43 - -0.18) -0.02 (-0.13-0.09) AVLT delayed recall -0.15 (-0.28 - -0.02) 0.04 (-0.06-0.14) -0.29 (-0.42 - -0.17) 0.02 (-0.09-0.13) -0.25 (-0.38 - -0.12) 0.05 (-0.06-0.16) AVLT recognition -0.15 (-0.28 - -0.02) 0.00 (-0.11-0.12) -0.24 (-0.37- -0.11) 0.02 (-0.10-0.15) -0.20 (-0.33 - -0.06) 0.05 (-0.07-0.18) AT A -0.19 (-0.32 - -0.06) -0.04 (-0.15-0.07) -0.28 (-0.42
  • Plasma NfL 71 % (64 - 79%) 1 1.5 pg/mL 73% 64%
  • AUC with 95% confidence interval was calculated using receiver operator curve analysis. Youden's cut-off is specified as the cut-off at the maximum sum of sensitivity and specificity. Model includes the predicted values of the combined plasma Abetal-42/1-40 ratio, plasma GFAP, APOE e4 carriership and age panel, for which values were predicted using logistic regression analysis.
  • Abeta amyloid beta
  • GFAP Glial fibrillary acidic protein
  • NfL Neurofilament light
  • AUC Area Under the Curve
  • 95%CI 95% confidence interval.
  • Plasma levels Abetal-40, NfL and GFAP, and CSF levels Abetal-42, tTau and pTaul81 and the CSF pTau/Abetal-42 ratio were natural log transformed prior to analysis.
  • pTaul81 tau phosphorylated at threonine 181. *p ⁇ 0.05, **P ⁇ 0.01.
  • Alzheimer's disease Alzheimers Dement. 2007;3(3):186-191.
  • Plasma amyloid beta 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease. Alzheimers Dement. 2019 May 18.

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Abstract

La présente invention concerne d'une manière générale le domaine des neurosciences cérébrales et concerne un nouveau marqueur pour évaluer l'accumulation de bêta-amyloïde (Aβ) cérébrale dans le cerveau et des procédés d'analyse de celle-ci. En particulier, l'invention concerne un marqueur à utiliser dans un diagnostic pré-symptomatique, dans des configurations d'enrichissement d'essai clinique, et l'évaluation de l'efficacité médicamenteuse de médicaments thérapeutiques et prophylactiques dans la maladie d'Alzheimer.
PCT/EP2020/069648 2019-07-12 2020-07-10 Nouveaux marqueurs utilisés en tant que prédicteurs précoces de la maladie d'alzheimer Ceased WO2021009074A1 (fr)

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WO2023068173A1 (fr) * 2021-10-18 2023-04-27 エーザイ・アール・アンド・ディー・マネジメント株式会社 BIOMARQUEUR POUR ÉVALUER L'ACCUMULATION D'AMYLOÏDE-β INTRACÉRÉBRALE
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WO2022197651A1 (fr) * 2021-03-16 2022-09-22 Neurovision Imaging, Inc. Procédés à base de biofluide pour diagnostiquer des états associés à la maladie d'alzheimer
WO2023068173A1 (fr) * 2021-10-18 2023-04-27 エーザイ・アール・アンド・ディー・マネジメント株式会社 BIOMARQUEUR POUR ÉVALUER L'ACCUMULATION D'AMYLOÏDE-β INTRACÉRÉBRALE
CN120089387A (zh) * 2025-05-07 2025-06-03 脑玺(苏州)智能科技有限公司 超早期认知下降状态的识别方法、装置及电子设备

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