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WO2018137028A1 - Procédés, compositions et kits d'évaluation d'une inflammation cérébrale dans la dépression et de conditions associées - Google Patents

Procédés, compositions et kits d'évaluation d'une inflammation cérébrale dans la dépression et de conditions associées Download PDF

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WO2018137028A1
WO2018137028A1 PCT/CA2018/050081 CA2018050081W WO2018137028A1 WO 2018137028 A1 WO2018137028 A1 WO 2018137028A1 CA 2018050081 W CA2018050081 W CA 2018050081W WO 2018137028 A1 WO2018137028 A1 WO 2018137028A1
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depression
subject
microglial activation
level
treatment
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Jeffrey H. MEYER
Elaine SETIAWAN
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Centre for Addiction and Mental Health
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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
    • G01N33/88—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving prostaglandins or their receptors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/16—Devices for psychotechnics; Testing reaction times ; Devices for evaluating the psychological state
    • A61B5/165—Evaluating the state of mind, e.g. depression, anxiety
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7271—Specific aspects of physiological measurement analysis
    • A61B5/7275—Determining trends in physiological measurement data; Predicting development of a medical condition based on physiological measurements, e.g. determining a risk factor
    • 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
    • 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
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/30—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indices; for individual health risk assessment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry
    • G01N2800/304—Mood disorders, e.g. bipolar, depression

Definitions

  • the present invention relates to the state of brain inflammation in depressed subjects, and in particular the state of microglial activation in the brain of depressed subjects.
  • MDD major depressive disorder
  • MDE major depressive episodes
  • MDD is highly impactful, often lifelong with recurrent episodes, and greatly increases the risk of suicide (1 ' 4"6) .
  • MDD has several molecular subtypes (7"14) and there is increasing evidence that inflammation plays a role in MDD. Investigations frequently report greater plasma levels of the cytokines IL-6 and T F-a, and to some extent C-reactive protein during MDD, indicating that excessive autoimmune activity occurs in at least a subset of MDD (15"44) .
  • cytokine inducing agents such as vaccinations, and lipopolysaccharide administration
  • IFN-a chronic interferon
  • administration of cytokine inducing agents can increase symptoms of depression (47 ' 48) .
  • Traumatic brain injury, which induces brain inflammation (49"52) is frequently associated with depressed mood (53) .
  • Lifetime rates of MDE in systemic lupus erythematosis and multiple sclerosis, illnesses with brain inflammation are about 50%, suggesting a link between inflammation and mood symptoms (54"59) .
  • MDD often transitions from infrequent solitary MDE with good inter-episode recovery towards increasingly persistent disease, with greater proportions of time spent in the midst of a MDE (2a ' 3a) a phenomenology strongly suggestive of neuropathological progression.
  • neuroprogression which may be defined as progressive damage of the brain with greater duration of illness, is firmly established at a neuropathological level in neuropsychiatric illnesses like Parkinson's disease and Alzheimer's disease, it is not well established in MDD, with few investigations demonstrating greater levels of pathology with longer duration of illness.
  • Pathologies posited in the literature as potential components of neuroprogression in MDD include loss of astroglia and resultant reduced glutamate uptake > loss of somatostatin positive interneurons, (5a) decreased neurogenesis' ⁇ persistence of elevated MAO-A level, (7a) hippocampal volume loss (8a) , and chronic microglial activation, (9a ' 10a) however, only hippocampal volume loss has been demonstrated, primarily through cross sectional studies, to exhibit greater magnitude of effect with greater duration of MDD, (8a ' lla) with mean reductions of 4% overall.
  • Microglial activation an important aspect of neuroinflammation, occurs when microglia with small cell bodies and longer thinner dendrites, morphologically oriented towards detecting molecular patterns associated with damage or inflammation, shift from this monitoring role into an activated state in which their cell bodies enlarge and dendrites either become thicker or are removed entirely if the cell becomes amoeboid.
  • microglia may produce cytokines, complement proteins, reactive oxygen species, and proteinases. The production of cytokines may have autocrine effects to recruit more activated microglia whereas the latter three processes may lead to cascades of neuronal damage and further inflammation.
  • neuronal damage as sequelae of reactive oxygen species and proteinases may also induce activation of microglia through microglial detection of damage associated molecular patterns with upregulation of tolllike receptors such as TLR3 and TLR4 receptors, the latter which was found in a sample of dorsolateral prefrontal cortex of MDD subjects.
  • TLR3 and TLR4 receptors tolllike receptors
  • positron emission tomography may be applied to measure translocator protein (TSPO) binding in vivo.
  • TSPO is an 18 kDa protein located on outer mitochondrial membranes in microglia and increased expression of TSPO occurs when microglia are activated during neuroinflammation (66) .
  • a new generation of positron emission tomography radiotracers were developed with superior quantification of TSPO binding and among these, [ 18 F]FEPPA has excellent properties including high, selective affinity for TSPO (67) , increased binding during induced neuroinflammation (68) and a high ratio of specific binding relative to free and non-specific binding (69) .
  • the first neuroimaging study applied [ U C] PBR28 PET to investigate TSPO levels in MDD, which was negative (70) .
  • This earlier study assessed whether TSPO levels were elevated in a sample of 10 MDD subjects (scanned once) under a variety of states (treated, untreated, symptomatic, partially symptomatic) hence, this study cannot be considered definitive for determining whether TSPO binding is elevated in MDE.
  • TSPO VT an index of translocator protein (TSPO) level, a marker of microglial activation
  • TSPO translocator protein
  • TSPO VT translocator protein total distribution volume
  • active disease is intended to mean the presence of a depressogenic brain change that is masked by use of an antidepressant which creates resiliency against the depressogenic brain change but does not reverse the depressogenic brain change itself.
  • an antidepressant which creates resiliency against the depressogenic brain change but does not reverse the depressogenic brain change itself.
  • Approximately 50% of MDE cases are associated with recurrence over 2 to 3 years but this rate of recurrence is lowered when ongoing antidepressant treatment is administered (71) .
  • active disease is present, this would predict recurrence unless antidepressant treatment is continued.
  • a problem in the clinical field is that many clinical trials of antidepressants do not yield significant results.
  • a method of assessing a level of brain inflammation in a subject comprising:
  • the level of microglial activation is a measure of brain inflammation.
  • a method of assessing the chronological advancement of depression, including neuroprogression, in a depressed subject comprising:
  • an increase in the level of microglial activation at the second time point compared to the first time point is indicative of the chronological advancement, including neuroprogression, of depression in the subject.
  • the subject has major depressive disorder (MDD), major depressive episode(s), melancholia or atypical depression, psychotic depression, antenatal and postnatal depression, bipolar disorder, cyclothymic disorder, persistent depressive disorder (dysthymia), seasonal affective disorder or a mood state that is characterized by one or more symptoms of depression.
  • MDD major depressive disorder
  • major depressive episode(s) melancholia or atypical depression
  • psychotic depression antenatal and postnatal depression
  • bipolar disorder cyclothymic disorder
  • cyclothymic disorder cyclothymic disorder
  • persistent depressive disorder dysthymia
  • seasonal affective disorder or a mood state that is characterized by one or more symptoms of depression.
  • the subject has major depressive disorder.
  • the subject is undergoing treatment for depression, is undergoing treatment for depression but is treatment- resistant or treatment-refractory, or is not undergoing treatment for depression.
  • the subject may be diagnosed as having depression or the subject may be undiagnosed.
  • the subject is undiagnosed but exhibits one or more signs or symptoms of depression or MDD.
  • microglial activation is measured by a blood test, positron emission tomography (PET) scan, or both.
  • the blood test comprises:
  • PGE2 blood prostaglandin E2
  • PPD2 blood prostaglandin D2
  • a decrease in blood [PGE2], blood [PGD2], or both, in the blood sample compared to a healthy control is predictive or indicative of a treated depressed subject or a treated depressed subject that is treatment-resistant or treatment-refractory.
  • the blood [PGE2] in the sample is below 1500pg/ml, or more preferably below 1400pg/ml, or still more preferably below 1300pg/ml, or still more preferably below 1200pg/ml, or still more preferably below HOOpg/ml, or still more preferably below 1050pg/ml, or still more preferably below lOOOpg/ml, or still more preferably below 950pg/ml, or still more preferably below 900pg/ml, or still more preferably below 850pg/ml, or still more preferably below 800pg/ml, or still more preferably below 750pg/ml, or still more preferably below 700pg/ml, or still more preferably below 650pg/ml, or still more preferably below 600pg/ml, or still more preferably below 550pg/ml, or most preferably below 500pg/ml.
  • the PET scan measures translocator protein (TSPO) binding.
  • TSPO translocator protein
  • the PET scan measures translocator protein total distribution volume.
  • the PET scan is performed on grey matter regions of the brain.
  • PGE2 blood prostaglandin E2
  • PPD2 blood prostaglandin D2
  • a decrease in blood [PGE2], blood [PGD2], or both, in the blood sample compared to a healthy control is predictive of a treated depressed subject or a treated depressed subject that is treatment-resistant or treatment-refractory.
  • kits for assessing a level of brain inflammation in a depressed subject comprising:
  • one or more diagnostic agents for quantifying PGE2, PGD2, or both in a blood sample of the depressed subject and
  • one or more components, diluents or buffers for use with the above-identified diagnostic agents are one or more components, diluents or buffers for use with the above-identified diagnostic agents.
  • a method of preventing or inhibiting the chronological advancement of depression, including neuroprogression, in a subject comprising:
  • the treatment for depression is maintained, or
  • the treatment for depression is modified
  • a method of preventing or inhibiting the chronological advancement of depression, including neuroprogression, in a subject comprising:
  • the treatment for depression is maintained, or
  • the treatment for depression is modified.
  • modifying the treatment for depression may comprise, for example, but not limited to, modifying a dose, or adding or removing the administration, of one or more medications in the treatment.
  • the method further comprises counseling and/or monitoring the subject.
  • the method further comprises:
  • the additional measurements may be taken over time until the subject exhibits no further increase in the level of brain inflammation as determined via measurement of microglial activation, or the measurements may be taken to monitor the subject periodically for changes to microglial activation.
  • a method of determining a level of microglial activation in a subject and optionally treating the subject comprising: quantifying a duration of untreated depression by subtracting the age at which treatment for depression began from the age of onset of depression and adding any treatment-free period, wherein a longer duration of untreated depression is indicative of an increased level of microglial activation.
  • the any treatment- free period is over 1 month or greater, 2 months or greater, 3 months or greater, 4 months or greater, 5 months or greater, 6 months or greater, 9 months or greater, or 1 year or greater.
  • the method further comprises treating the subject.
  • the method further comprises determining a second level of microglial activation by performing a blood test, PET scan, or both.
  • the blood test comprises:
  • PGE2 blood prostaglandin E2
  • PPD2 blood prostaglandin D2
  • a decrease in blood [PGE2], blood [PGD2], or both, in the blood sample compared to a healthy control is predictive of a treated depressed subject or a treated depressed subj ect that may be treatment-resistant or treatment-refractory.
  • the PET scan measures translocator protein (TSPO) binding.
  • TSPO translocator protein
  • the PET scan measures translocator protein total distribution volume.
  • the PET scan is performed on grey matter regions of the brain.
  • a method of determining a length of untreated depression in a depressed subject comprising: measuring a level of microglial activation in the brain of the subject,
  • FIG. Prostaglandin E2 in Healthy Controls, Untreated and Treated Major Depressive Episodes.
  • PGE2 serum prostaglandin E2
  • N-MDE untreated major depressive episodes
  • T-MDE treated major depressive episodes
  • This graph illustrates that serum prostaglandin E2 (PGE2) level is lower in treated major depressive episodes (T-MDE) as compared to untreated major depressive episodes (NT-MDE) or as compared to healthy controls (HC). It is also lower in treated major depressive episodes (T-MDE) as compared to untreated major depressive episodes (NT-MDE).
  • PGE2 serum prostaglandin E2
  • T-MDE treated major depressive episodes
  • T-MDE treated major depressive episodes
  • T-MDE treated major depressive episodes
  • T-MDE treated major depressive episodes
  • T-MDE treated major depressive episodes
  • Units of PGE2 are pg/ml. The minimum detection range for PGD2 in serum was 23.5pg/ml.
  • the TSPO VT is an index of translocator protein density, a marker of brain inflammation.
  • PGE2 and PGF2a refer to prostaglandin E2 and prostaglandin F2alpha. In treated major depressive episodes not currently responsive to treatment, the PGE2/ PGF2a ratio is predictive of TSPO VT in the PFC (the PFC is a large region of brain tissue that may be representative of other brain regions).
  • TSPO VT was scaled in those with a single nucleotide polymorphism that reduces binding of this and other second generation PET radiotracers to TSPO (72 ' 73) so as to remove the effect of this nuisance variable (those with one copy of the allele are scaled up by a factor of 1.4 and homozygotes for the allele, which are rare are not measurable with the technique).
  • TSPO VT is elevated in the PFC, it is often elevated in other brain regions.
  • the relationship of serum PGE2/PGF2a to the PFC TSPO V T is similar to TSPO VT values in other brain regions.
  • TSPO VT was associated with an increase of 0 15, 0 18, and 0 17 TSPO VT per year of untreated MDD in the respective regions.
  • All second generation TSPO radioligands such as [ 18 F]FEPPA, show differential binding according to the single nucleotide polymorphism rs6971 of the TSPO gene resulting in high affinity binders (HAB) and mixed affinity binders (MAB). MABs have been multiplied by 1 -4 in this figure to adjust for the genotype difference.
  • TSPO V T and duration of MDD exposure were 0 17, 0 19, and 0 20, respectively for the prefrontal cortex, anterior cingulate cortex, and insula whereas the slopes of the linear relationship between TSPO V T and duration of antidepressant exposure were - 0 13, -0 16, and -0 ⁇ 13, respectively.
  • TSPO VT presented is adjusted by genotype such that the TSPO V T of mixed affinity binders of the rs6971 polymorphism, which influences binding of second generation PET radioligand for TSPO, were multiplied by 1 4.
  • a correction to reduce variance in TSPO V T was applied to adjust values to correspond to an antidepressant exposure of 2 years: The difference between the duration of antidepressant exposure and 2 years multiplied by the slope of the linear predictor of the effect of antidepressant exposure on TSPO V T was applied as a correction factor.
  • a correction to reduce variance in TSPO VT was applied to adjust values to correspond to a duration of MDD of 18 years. The difference between the duration of MDD and 18 years multiplied by the slope of the linear predictor of the effect of duration of MDD on TSPO VT was applied as a correction factor.
  • MDD Compared to Short Duration of Untreated MDD and Healthy Controls.
  • TSPO radioligands such as [ 18 F]FEPPA, show differential binding according to the single nucleotide polymorphism rs6971 of the TSPO gene resulting in high affinity binders (HAB) and mixed affinity binders (MAB). Red bars indicate means in each group.
  • HAB high affinity binders
  • MAB mixed affinity binders
  • a method of assessing a level of brain inflammation in a subject comprising measuring a level of microglial activation in the brain of the subject, wherein the level of microglial activation is a measure of brain inflammation.
  • a method of assessing chronological advancement of depression, including neuroprogression, in a subject a method of assessing chronological advancement of depression, including neuroprogression, in a subject.
  • Chronological advancement of depression refers to the progressive worsening of depression symptoms over time, characterized by infrequent depressive episodes with good inter-episode recovery towards increasingly persistent depression, with greater proportions of time spent in the midst of a depressive episode.
  • Neuroprogression is likely to be a significant component of the chronological advancement of depression.
  • microglial activation in the brain is implicated in neuroprogression. As is shown herein, there is a relationship between increasing duration of untreated depression and related illness and a greater level of microglial activation.
  • This method comprises measuring a level of microglial activation in a brain of the subject at a first time point; and measuring the level of microglial activation in the brain of the subject at a second time point, wherein an increase in the level of microglial activation at the second time point compared to the first time point is indicative of the chronological advancement of depression, including neuroprogression, in the subject.
  • depression is meant to encompass any type of depression, ranging from mild to severe depression, any disorder that includes one or more symptoms of depression, or any mood state that is characterized by one or more symptoms of depression. In a particular embodiment, which is not meant to be limiting in any manner, the disorder is MDD.
  • Symptoms of depression may include, as presented in the Diagnostic and
  • a subject that has depression or is suspected of having depression may exhibit one or more of the symptoms listed above.
  • Depression may be associated with a variety of disorders including, but not limited to major depressive disorder (MDD), major depressive episode (MDE), MDE secondary to MDD, melancholia and atypical depression, psychotic depression, antenatal and postnatal depression, bipolar disorder, cyclothymic disorder, persistent depressive disorder (dysthymia), or seasonal affective disorder.
  • Depression is also meant to encompass a mood state that is characterized by one or more symptoms of depression. Depression may be clinically diagnosed, by use of DSM- IV or V, Hamilton Depression Rating Scale or another psychiatric rating scale, or may not be clinically diagnosed but suspected.
  • the depression is MDD.
  • MDD may vary from minor to severe, and is typically diagnosed by a qualified medical practitioner as a person having 5 or more of the above symptoms for a period of more than 2 weeks.
  • the subject may be currently undergoing treatment for depression before practicing any of the methods as described herein.
  • the subject is currently undergoing treatment for depression but is treatment- resistant or treatment-refractory.
  • the subject is not undergoing treatment for depression, or has not been diagnosed by a medical practitioner.
  • the subject is suspected of having depression or a depressive disorder, for example, but not limited to MDD.
  • treatment may comprise the administration of any medication that is meant to stop, slow or decrease the severity of symptoms of depression, improve the symptoms of depression, modulate inflammation, or modulate microglial activity.
  • Medications may include any active agent, therapeutic, or the like.
  • medication for depression includes antidepressants.
  • antidepressants include, without limitation, serotonin and norepinephrine reuptake inhibitors (S RIs), for example, but not limited to desvenlafaxine (PristiqTM, KhedezlaTM), duloxetine (CymbaltaTM), levomilnacipran (FetzimaTM), venlafaxine (Effexor XRTM), and milnacipran (SavellaTM); selective serotonin reuptake inhibitors (SSRIs), for example, but not limited to sertraline (ZoloftTM), fluoxetine (ProzacTM, SarafemTM), citalopram (CelexaTM), escitalopram (LexaproTM), paroxetine (PaxilTM, PexevaTM, BrisdelleTM), fluvoxamine (LuvoxTM), and vilazodone (ViibrydTM); monoamine
  • medication for depression includes antiinflammatory agents, inflammation modulators, and microglial function modulators.
  • Representative agents include, without limitation, prostaglandin synthesis inhibitors, for example, but not limited to nonsteroidal anti-inflammatory drugs (NSAIDs) such as COX-1 and COX-2 inhibitors (cyclooxygenase-1 or -2 inhibitors), for example, but not limited to acetylsalicylic acid (AspirinTM), ibuprofen (AdvilTM, MotrinTM), naproxen (AleveTM, AnaproxTM, NaprelanTM, NaprosynTM), celecoxib (CelebrexTM), diclofenac (CambiaTM, CataflamTM, VoltarenTM, ZipsorTM, ZorvolexTM), diflunisal (DolobidTM), etodolac (LodineTM), indomethacin (IndocinTM), ketoprofen (OrudisTM), ketorolac (To)
  • NSAIDs nonsteroidal
  • any other active agent, therapeutic, or the like is contemplated in the treatment of depression.
  • a subject undergoing treatment for depression but that is treatment-resistant or treatment-refractory is defined as responding inadequately, poorly, negligibly or not at all to the treatment.
  • microglial activation is measured by a blood test, positron emission tomography (PET) scan, or both.
  • PET positron emission tomography
  • microglial activation is measured by a blood test.
  • One embodiment of the blood test comprises measuring one or more of blood prostaglandin E2 (PGE2) concentration ([PGE2]) and blood prostaglandin D2 (PGD2) concentration ([PGD2]) in a blood sample obtained from the subject.
  • PGE2 blood prostaglandin E2
  • PPD2 blood prostaglandin D2
  • Other blood components may also be identified or measured.
  • [PGE2] and [PGD2] may be measured with diagnostic agents alone or via one or more suitable quantitative methods known in the art.
  • the diagnostic agents may include anti-PGE2 or anti-PGD2 antibodies or fragments thereof which retain binding, anti-PGE2 or anti-PGD2 antibodies in conjunction with labeled antibody conjugates or secondary antibodies, antibody derivatives in conjunction with labeled antibody derivative conjugates or secondary antibodies, or any other labeled agent that is known to bind to PGE2 or PGD2.
  • the diagnostic agents bound to PGE2 and PGD2 may be therefore quantified with any technique known in the art, for example, but not limited to, immunoassay (for example, but not limited to enzyme-linked immunosorbent assay (ELISA)), radioimmunoassay, mass spectrometry, high-performance liquid chromatography (HPLC), gas chromatography- mass spectrometry, or other chromatographic or non-chromatographic procedures.
  • immunoassay for example, but not limited to enzyme-linked immunosorbent assay (ELISA)
  • ELISA enzyme-linked immunosorbent assay
  • radioimmunoassay radioimmunoassay
  • mass spectrometry mass spectrometry
  • HPLC high-performance liquid chromatography
  • gas chromatography- mass spectrometry or other chromatographic or non-chromatographic procedures.
  • PGE2 in serum can be measured using an ELISA kit involving a monoclonal anti-PGE2 antibody and horseradish peroxidase labelled PGE2 (rndsystems.com; Bio-Techne), Minneapolis, Minnesota, Prostaglandin E2 Assay, "Parameter" KGE004B, SKGE004B, PKGE004B).
  • PGD2 in serum can be measured using an ELISA kit involving a sandwich enzyme immunoassay technique (My Biosource.com, Southern California, San Diego, Human Prostaglandin D2 ELISA Kit, MBS700128).
  • the blood [PGE2] in the sample is preferably below 1500pg/ml, or more preferably below 1400pg/ml, or still more preferably below 1300pg/ml, or still more preferably below 1200pg/ml, or still more preferably below HOOpg/ml, or still more preferably below 1050pg/ml, or still more preferably below lOOOpg/ml, or still more preferably below 950pg/ml, or still more preferably below 900pg/ml, or still more preferably below 850pg/ml, or still more preferably below 800pg/ml, or still more preferably below 750pg/ml, or still more preferably below 700pg/ml, or still more preferably below 650pg/ml, or still more preferably below 600pg/ml, or still more preferably below 1500pg/ml, or more preferably below 1400pg/ml, or still more preferably below 1300pg/ml
  • microglial activation is quantified by a PET scan that measures translocator protein (TSPO) binding.
  • TSPO translocator protein
  • Increased expression of TSPO occurs when microglia are activated during neuroinflammation and with greater duration of untreated depression.
  • the PET scan measures translocator protein total distribution volume (TSPO VT), an index of TSPO density.
  • the PET scan may be performed on one or more grey matter regions of the brain, for example, the prefrontal cortex, anterior cingulate cortex, or insula.
  • Specific areas include, without limitation, the medial prefrontal cortex, ventrolateral prefrontal cortex, dorsolateral prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, insula, temporal cortex, parietal cortex, occipital cortex, hippocampus, thalamus, dorsal putamen, dorsal caudate, ventral striatum or any combination thereof.
  • PET radiotracer that has high, selective affinity for TSPO is
  • the present invention also provides a method of assessing a level of brain inflammation in a depressed subject, the method comprising measuring one or more of blood prostaglandin E2 (PGE2) concentration ([PGE2]) and blood prostaglandin D2 (PGD2) concentration ([PGD2]) in a blood sample obtained from the subject.
  • PGE2 blood prostaglandin E2
  • PPD2 blood prostaglandin D2
  • a decrease in blood [PGE2], blood [PGD2], or both, in the blood sample compared to a healthy control is indicative of a depressed subject.
  • the methods described above and throughout may be useful in the clinical staging of depression.
  • the staging concept is practical as it can differentiate early, milder depression from progressed, chronic depression and enable the selection of different treatment approaches depending on the subject's stage of depression.
  • the present invention also provides for a kit for assessing a level of brain inflammation in a subject.
  • the kit comprises one or more diagnostic agents for quantifying PGE2, PGD2, or a combination thereof, in a blood sample of the subject and one or more components, diluents or buffers, for practicing a suitable quantitative method for determining the amount or concentration of the prostaglandin markers representative for microglial inflammation.
  • Possible diagnostic agents are described above and throughout.
  • a method of preventing or inhibiting the chronological advancement of depression, including neuroprogression, in a subject comprising measuring microglial activation in a brain of the subject at a first time period, treating the subject for depression, and measuring microglial activation in the brain of the subject at a second time point, wherein:
  • the treatment for depression is maintained, or
  • the treatment for depression is modified.
  • the step of treating may be performed prior to or in between the steps of measuring microglial activation
  • the level of microglial activation may be an indication that the treatment for depression is preventing or inhibiting the chronological advancement of depression, including neuroprogression.
  • the level of microglial activation at the second time point is greater than the first measurement, then it is contemplated that the treatment be modified to reduce or halt the increase microglial activation, which is reflective of the chronological advancement of the disease.
  • the measurement at the second time point may be performed at any time after the first measurement at the first time point, for example, without limitation, 1 month, 6 months, 1 year, 5 years, 10 years, or at any time in between.
  • the time between measurements be sufficient so as to allow the new dosage regimens to take effect or normalize in the subject.
  • this is two weeks, 4 weeks, 1 month or any other suitable time period.
  • treating the subject comprises administering medication as described above and throughout.
  • modifying a treatment for depression may comprise modifying the dose, or adding or removing the administration, of one or more medications in the treatment. Modifying the dose also may involve increasing the dose of the medication, for example if it is believed that the effect of a medication is unsuitable for a desired therapeutic effect, or decreasing the dose of a medication, for example if adverse side effects are being observed. Adding or removing medications may permit the selection of a more effective combination of medications for attenuating depression symptoms or treating disorders such as MDD. For example, the subject may be currently being administered one but may benefit more from a combination of medications, for example, but not limited to two, three or more medications.
  • the method comprises counseling and/or monitoring the subject.
  • Counseling may be an important part of treatment and can aid in coping with feelings, solving problems and changing behavior patterns that may contribute to depression symptoms.
  • Counseling may include, but without wishing to be limiting, behavioral therapy, cognitive therapy, cognitive-behavioral therapy, interpersonal therapy, and solution-focused therapy and may be offered by a psychiatrist, psychologist, social worker, counselor or other therapist.
  • Monitoring may include, without limitation, follow-up meetings to monitor symptoms, or institutionalization should such measures be deemed necessary by a qualified medical practitioner.
  • Monitoring may be performed by evaluating the subj ect's self-rated scales, such as the Patient Health Questionnaire (PHQ-9), Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR), or Beck's Depression Inventory (BDI), and tracking depressive symptoms, suicidality, treatment adherence and side effects from treatment. It can be determined if the current medications are still effective or if they are becoming less effective, requiring modification to the treatment.
  • PHQ-9 Patient Health Questionnaire
  • QIDS-SR Quick Inventory of Depressive Symptomatology - Self Report
  • BDI Beck's Depression Inventory
  • a method of determining a level of microglial activation in a subject and optionally treating the subject comprising quantifying a duration of untreated depression by subtracting the age at which treatment for depression began from the age of onset of depression and adding any treatment-free period. A longer duration of untreated depression is indicative of an increased level of microglial activation.
  • duration of untreated depression refers to a period of time that the subj ect is not undergoing treatment and is considered treatment-free.
  • the age at which treatment for depression began includes the age at which the subject began a regular medication treatment regime, which can include the daily, bi-daily, or weekly intake of one or more antidepressants, antiinflammatory agents, inflammation modulators, or microglial function modulators.
  • the regular medication treatment regime includes the occasional forgetfulness to take one or more doses of the one or more medication, for example, one, two, three or more doses of the one or more medication in a one-, two-, or more, week time frame.
  • the treatment regime may be prescribed by a professional.
  • Age of onset includes the age at which the subject became depressed, ranging from mild to severe depression, for example, ranging from a mood disorder having one or more symptoms of depression to having major depressive disorder or the like.
  • the depression may have been clinically diagnosed, or may not have been clinically diagnosed wherein the onset would be when the first symptoms of depression appeared.
  • the any treatment-free period is 1 month or greater, 2 months or greater, 3 months or greater, 4 months or greater, 5 months or greater, 6 months or greater, 9 months or greater, or 1 year or greater.
  • the method may further comprise treating the subject, as described throughout.
  • the method further comprises determining a second level of microglial activation by performing a blood test, PET scan, or both.
  • the blood test comprises measuring one or more of [PGE2] and blood [PGD2] in a blood sample obtained from the subject, wherein a decrease in blood [PGE2], blood [PGD2], or both, compared to a healthy control is predictive of a treated depressed subject or a treated depressed subject that is treatment-resistant or treatment-refractory.
  • the PET scan comprises measuring translocator protein (TSPO) binding.
  • TSPO translocator protein
  • the PET scan measures translocator protein total distribution volume.
  • the PET scan is performed on grey matter regions of the brain.
  • the present invention further provides for a method of determining a length of untreated depression in a depressed subject, the method comprising measuring a level of microglial activation in the brain of the subject. Every 14-18% increase in the level of microglial activation compared to a healthy subject is indicative of 10 years of untreated depression.
  • Group 1 Healthy
  • Inclusion criteria are: (i) age 18-65; (ii) good physical health; (iii) non- cigarette smoking; (iv) negative urine pregnancy test at screening and scan days (for women); (v) negative urine screen for drugs of abuse.
  • Exclusion criteria (i) past or current diagnosis of axis I or axis II disorder as determined by the SCID I and SCID II for DSM IV (74) ; (ii) history of psychotropic medication use; (iii) history of neurological illness or autoimmune disorder.
  • Group 2 Current major depressive episode (MDE) secondary to MDD receiving antidepressant treatment : Inclusion criteria are: (i) Age 18 to 65; (ii) good physical health with no active medical conditions; (iii) non-cigarette smoking; (iv) no past or current substance abuse or dependence with present substance abuse additionally ruled out with a negative drug screen; (v) negative urine pregnancy test at screening and scan days (for women); (vi) primary diagnosis of current major depressive episode (MDE) and major depressive disorder (MDD) verified by SCID for DSM IV (74) ; (vii) score greater than 19 on the 17 item HDRS at screening; (viii) Non-response to a clinical trial of at least one antidepressant given at appropriate clinical dose; (ix) presently taking an antidepressant at a standard clinical dose.
  • MDE Current major depressive episode
  • MDD major depressive disorder
  • Inclusion criteria are: (i) DSM-IV diagnosis of current major depressive episode (MDE) and major depressive disorder (MDD) verified by SCID for DSM IV (74) , and a psychiatric consultation (ii) early onset type MDD with first MDE prior to age 40 (iii) antidepressant free for at least six weeks (iv) score greater than 17 on the 17 item HDRS (75) at screening.
  • Other exclusion criteria included concurrent active axis 1 disorder s (74) , including current alcohol or substance dependence, MDE with psychotic symptoms, bipolar I or bipolar II disorder, and borderline or antisocial personality disorder.
  • PGE2 in serum was also measured using an ELISA kit involving a monoclonal anti-PGE2 antibody and horseradish peroxidase labelled PGE2 (rndsystems.com; Bio-Techne), Minneapolis, Minnesota, Prostaglandin E2 Assay, "Parameter” KGE004B, SKGE004B, PKGE004B).
  • PGD2 in serum was measured using an ELISA kit involving a sandwich enzyme immunoassay technique (My Biosource.com, Southern California, San Diego, Human Prostaglandin D2 ELISA Kit, MBS700128).
  • the detection range for PGD2 in serum with this latter kit is 23.5pg/ml to 1500pg/ml.
  • MDE subjects hereafter termed MDE subjects
  • 30 healthy participants completed the study.
  • HDRS Health Rating Scale
  • MDE subjects that were medication-free reported not having taken anti-depressant medications for at least six weeks prior to the PET scan day and had a negative urine screen.
  • MDE subjects taking medication reported receiving a stable dose of medication for at least four weeks prior to the PET scan day.
  • Other exclusion criteria included concurrent alcohol or substance dependence, MDE with psychotic symptoms, bipolar disorder (type I or II), and borderline or antisocial personality disorder. All were free of acute medical illnesses for the previous two weeks and none had history of neurological illness, autoimmune disorder, severe hepatic or renal disease, gastrointestinal disease, ischemic heart disease, cerebrovascular disorder, or congestive heart failure.
  • the scan duration was 125 minutes following the injection of [ 18 F]FEPPA.
  • Regions of interest were generated using the in-house software, ROMI, as previously described. 10a ' 16a Time activity curves were used to measure TSPO VT using a two- tissue compartment model, which is an optimal model to quantitate TSPO VT with [ 18 F]FEPPA PET.
  • MRI 2-dimensional axial proton density magnetic resonance imaging
  • Signa 3-T MRI scanner section thickness, 2 mm; repetition time, 6000 ms; echo time, 8 ms; flip angle, 90°; number of excitations, 1; acquisition matrix, 256 x 192; and field of view, 16 5 mm).
  • DNA Extraction and Polymorphism Genotyping The binding affinity of the second generation of radiotracers for TSPO, including [ 18 F]FEPPA, is known to be affected by a co-dominantly expressed single nucleotide polymorphism (rs6971, C ⁇ T) in exon 4 of the TSPO gene. 24a High affinity binders (HAB, Alal47/Alal47) and mixed affinity binders (MAB, Alal47/Thrl47) account for 90% to 95% of the population in North America. The polymorphism rs6971 was genotyped as described previously.
  • HAB High affinity binders
  • MAB mixed affinity binders
  • TSPO VT data were analyzed by multivariate analysis of covariance (MANCOVA) with TSPO Vrin PFC, ACC, and INS as the dependent variables and years of untreated MDE and genotype as independent predictor variables.
  • MANCOVA multivariate analysis of covariance
  • a second MANCOVA model for the same dependent variables applied a different set of predictor variables which included duration of MDE, years of antidepressant exposure, and genotype. For both models an additional stepwise approach was taken to additionally assess the effect of age as an independent variable.
  • TSPO VT was assessed within every brain region applying analyses of variance with group and genotype as the predictor variables.
  • Microglial activation refers to a change in morphology in microglial cells such that their cell bodies enlarge, their dendrites thicken and/or they change into a shape like an amoeba. Without wishing to be limited by theory, during microglial activation, microglia might alter how they secrete cytokines and prostaglandins and that this could also be influenced by antidepressant treatment.
  • Figure 1 shows that PGE2 levels in serum are reduced during MDE, and further reduced during antidepressant treated MDE.
  • Figure 2 shows further that serum PGE2 levels are reduced and that serum PGD2 levels are further reduced. PGD2 levels are demonstrated as often being reduced because they were often below the level of detectability with the PGD2 assay.
  • the results herein suggest it is possible to differentiate some subjects with MDE, and subjects with MDE receiving antidepressant treatment from healthy controls by measuring PGE2, PGD2, or combinations of both in blood.
  • serum PGE2 levels below 1500pg/ml, 1400pg/ml, 1300pg/ml, 1200pg/ml, l lOOpg/ml, 1050pg/ml, lOOOpg/ml, 950pg/ml, 900pg/ml, 850pg/ml, 800pg/ml, 750pg/ml, 700pg/ml are more likely to occur in untreated MDE as compared to healthy subjects and serum PGE2 levels below 1500pg/ml, 1400pg/ml, 1300pg/ml, 1200pg/ml, l lOOpg/ml, 1050pg/ml, lOOOpg/ml, 950pg/
  • serum PGE2 and/or PGD2 or other combinations of prostaglandin secretion may be applied as a method to differentiate MDE from healthy subjects or treated MDE from healthy subjects. For example, if subjects are being screened for enrolment in an antidepressant trial and a requirement is to have a diagnosis of treatment resistant MDE, a useful screening tool to verify the interview based information would be to measure prostaglandin levels such as PGE2 and PGD2 in blood and determine if they are low and similar to what is observed in treatment resistant MDE. Similarly, as a component of a diagnostic panel, measurement of prostaglandins in blood such as PGE2 and PGD2, could be included to aid in the diagnosis of MDE.
  • Microglia secrete prostaglandins and data presented here show that this is altered during MDD and is further altered during treatment of MDD. Serum level of both PGE2 and PGD2 are reduced in MDD and further reduced during treatment of MDD. PGD2 is often undetectable in the treated depressed subjects as compared to the healthy controls. Figure 2 shows data of both serum PGE2 levels and PGD2 levels (the latter as detectable or not).
  • microglia When microglia are activated, their morphology changes and their propensity to secrete cytokines and prostaglandins changes. Activated microglia, as measured by elevated TSPO VT, may occur in treatment resistant MDE. Microglia secrete prostaglandins.
  • Figure 3 is a graph sampling depressed subjects currently receiving antidepressant treatment (people most likely eligible to receive an additional anti-inflammatory medication). The results suggest the ratio of serum PGE2 to PGF2alpha is predictive/indicative of brain inflammation (TSPO VT).
  • subjects undergoing antidepressant treatment such as monoamine raising medications, such as serotonin and norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, dopamine reuptake inhibitors, monoamine receptor binding treatments (such as, but not limited to trazodone, mirtazapine, Vortioxetine, aripiprazole), who wish to know whether they have evidence of brain inflammation, could measure the ratio of blood PGE2 to PGF2alpha to ascertain whether this is likely or not.
  • monoamine raising medications such as serotonin and norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, dopamine reuptake inhibitors, monoamine receptor binding treatments (such as, but not limited to trazodone, mirtazapine, Vortioxe
  • This information could be used as a predictor/indicator of treatment response to treatment interventions that are anti-inflammatory, such as a treatment that reduces microglial activation, or an inflammatory modulating treatment, which induces microglia or other inflammatory cells to function in a more curative or restorative manner, or a treatment that influences the downstream effects of inflammation, such as a prostaglandin synthesis inhibitor (like a COX-1 or COX-2 inhibitor), or monoamine oxidase B inhibitor.
  • a prostaglandin synthesis inhibitor like a COX-1 or COX-2 inhibitor
  • monoamine oxidase B inhibitor monoamine oxidase B inhibitor
  • Measures of blood PGE2 to PGF2alpha might also be used as a monitoring approach to determine whether continuation of an antidepressant treatment would be helpful; since a high ratio of PGE2 to PGF2alpha indicates brain inflammation, it would indicate that active disease is present and that it would be important to continue such treatment.
  • Antidepressant treatments could include monoamine raising medications, such as: serotonin and norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, dopamine reuptake inhibitors, monoamine receptor binding treatments (such as, but not limited to trazodone, mirtazapine, Vortioxetine, aripiprazole); or anti -inflammatory or inflammation modulating treatments that are intended to improve depressed mood.
  • monoamine raising medications such as: serotonin and norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, dopamine reuptake inhibitors, monoamine receptor binding treatments (such as, but not limited to trazodone, mirtazapine, Vortioxetine, aripiprazole); or anti -inflammatory or inflammation modulating
  • HDRS Hamilton Depression Rating Scale
  • AD antidepressant
  • BMI body mass index
  • MDD major depressive disorder
  • MDE major depressive episode
  • N number
  • na not applicable
  • SD standard deviation
  • TSPO translocator protein
  • R 2 refers to the proportion of variance attributable to the model, one adjusted for number of predictors.
  • ACC anterior cingulate cortex
  • ANCOVA analysis of covariance
  • DLPFC dorsolateral prefrontal cortex
  • HAB high-affinity binding
  • MAB mixed-affinity binding
  • MDD major depressive disorder
  • MPFC medial prefrontal cortex
  • OFC orbitofrontal cortex
  • PFC prefrontal cortex
  • TSPO VT translocator protein density measured by distribution volume
  • VLPFC ventrolateral PFC.
  • MDD subjects were subdivided into those with duration of untreated MDD greater than or equal to 10 years and those less than or equal to 9 years duration of untreated MDD. With the sample of healthy subjects, this created three groups: long duration of untreated MDD, shorter duration of untreated MDD, and health.
  • R 2 refers to the proportion of variance attributable to the model, one adjusted for number of predictors.
  • ACC anterior cingulate cortex
  • ANCOVA analysis of covariance
  • DLPFC dorsolateral prefrontal cortex
  • HAB high-affinity binding
  • MAB mixed-affinity binding
  • MDD major depressive disorder
  • MPFC medial PFC
  • OFC orbitofrontal cortex
  • TSPO VT translocator protein density measured by distribution volume
  • VLPFC ventrolateral PFC.
  • aValues are expressed as mean (SD). Analyses of variance with regional TSPO VT as the dependent variable was done and the least significant difference test was applied towards differences in TSPO VT between the long duration group and the other two groups.
  • ACC anterior cingulate cortex
  • DLPFC dorsolateral prefrontal cortex
  • MPFC medial prefrontal cortex
  • SD standard deviation
  • TSPO translocator protein
  • TSPO VT translocator protein density
  • OFC orbitofrontal cortex
  • VLPFC ventrolateral prefrontal cortex
  • yrs years.
  • HAB high affinity binders (Alal47/Alal47); MAB, mixed affinity binders (Alal47/Thrl47) of the single nucleotide polymorphism rs6971 of the TSPO gene.
  • a clinically meaningful response refers to as an increase in to the number of points on the Hamilton Depression Rating Scale, for example, 1, 2, 3, 4, 5 or more points.
  • TSPO V T 14% to 18% per decade.
  • the DSM V addresses progression by differentiating between single and multiple episode.
  • duration of untreated MDD may reflect a more precise measure since elevated TSPO VT is best interpreted as reflecting greater levels of microglial activation.
  • the increased TSPO expression in mammalian brain after diverse paradigms like stroke, neurotoxins, and lipopolysaccharide administration, 25a ' 26a has a temporal course that closely matches the increased expression of other markers of microglial activation rather than astroglial activation.
  • Microglial activation is a well-established quantitative response to brain injury in neurodegenerative conditions.
  • microglial activation itself is implicated in the generation of depressive behaviors in humans and rodents through mechanisms such as the diversion of tryptophan metabolism to kynurenine, stimulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor resistance. 27a
  • microglial activation is a marker of advancing disease and is implicated in depressive symptoms it may be advantageous to clinically investigate and categorize chronologically advanced MDD differently.
  • the linear predictors are of similar magnitude in the opposite direction. It may be advantageous to develop superior strategies to target microglial activation such as minocycline administration or vagal nerve stimulation for which rapid effects are reported in rodents, 28a ' 29a although presently it is not yet known whether these interventions, once modified for dose and method of administration, would effectively reduce microglial activation in humans.
  • microglial activation in regards to therapeutic strategies for greater TSPO VT, although microglial activation is associated with depressive behaviors, microglial activation also spans a broad range of function of which some may be useful, hence modulating microglial function rather than reducing microglial activation may be the best therapeutic strategy.
  • investigations of the role of TSPO are ongoing, hence, while it is clear that increased microglial activation is most strongly associated with greater TSPO expression, ' minor contributions from astroglial activation are possible and in the future, other mechanisms that influence TSPO expression may be identified.
  • Wilson AA Wilson AA
  • Garcia A Parkes J, et al. Radiosynthesis and initial evaluation of [18FJ-FEPPA for PET imaging of peripheral benzodiazepine receptors.
  • Sluzewska A Rybakowski J, Bosmans E, et al. Indicators of immune activation in major depression. Psychiatry Res. 1996 Oct 16;64(3): 161-7.
  • Rapoport MJ Depression following traumatic brain injury: epidemiology, risk factors and management. CNS Drugs. Feb 1 ;26(2): 111-21.

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Abstract

L'invention concerne des procédés, des compositions et des kits permettant l'évaluation du niveau d'inflammation cérébrale chez des sujets déprimés et l'évaluation, la prévention ou l'inhibition de l'avancement chronologique de la dépression, y compris la neuroprogression. Les procédés impliquent des tests sanguins, comprenant la quantification de la prostaglandine sanguine E2 (PGE2), de la prostaglandine D2 (PGD2), ou d'une combinaison de ces dernières ; ou des balayages de tomographie par émission de positrons (TEP), comprenant la mesure de la liaison de la protéine translocatrice (TSPO).
PCT/CA2018/050081 2017-01-24 2018-01-24 Procédés, compositions et kits d'évaluation d'une inflammation cérébrale dans la dépression et de conditions associées Ceased WO2018137028A1 (fr)

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CN112185518A (zh) * 2020-09-25 2021-01-05 上海交通大学医学院附属仁济医院 一种tspo转位蛋白pet探针在神经炎症中的显影方法

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WO2016112467A1 (fr) * 2015-01-15 2016-07-21 Centre For Addiction And Mental Health Mesure périphérique d'une inflammation cérébrale centrale, ses marqueurs et ses utilisations

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WO2016112467A1 (fr) * 2015-01-15 2016-07-21 Centre For Addiction And Mental Health Mesure périphérique d'une inflammation cérébrale centrale, ses marqueurs et ses utilisations

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YIRMIYA ET AL.: "Depression as a microglial disease", TRENDS IN NEUROSCIENCE, vol. 38, no. 10, October 2015 (2015-10-01), pages 637 - 658, XP055523410 *

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CN112185518A (zh) * 2020-09-25 2021-01-05 上海交通大学医学院附属仁济医院 一种tspo转位蛋白pet探针在神经炎症中的显影方法

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