Present (from March 2015)

PRESENT EXCHANGES BETWEEN PARTNERS (from March 2015)

At present (March 2015) focus on and aims are

  1. The evaluation and integration of the data of the various assays (see above) with patient and clinical characteristics and to file the data in the database of RMS
  2. The identification of assay parameters, which are key elements in
    1. the pathogenesis of the disorders,
    2. the diagnosis of the disorders
    3. the prediction of an outbreak of psychiatric symptoms in individuals at risk
    4. the prediction of therapy outcome
  3. The identification and validity testing of assays and their key parameters for clinical utility, since these parameters are key elements in above described aspects of the psychiatric disorder (pathogenesis, diagnosis, disease prediction and therapy prediction).

We realize these aims in the following exchanges in which we aim at the following aspects:

EMC (recruitment Dr Barry McGuiness)

Aim: To study the inflammatory aspects and the aberrancies  in the growth and differentiation of monocytes/macrophages, T cells and neurons in an animal model of autoimmunity with mood disorders (the NOD mouse model) to find biomarkers of the mood disorder process, also taking into consideration the different stages of the disorder (pre-clinical, early and late clinical)

The animal model is necessary since we cannot study patients in every aspect, in particular not longitudinally and only for blood parameters and non-invasive imaging of the brain. Of course pathogenesis principles found in the animal model are evaluated for as much as possible in the patients.

Results:

1. The NOD mouse model shows, next to proneness for autoimmune thyroiditis and diabetes, also behavioral abnormalities in the form of higher anxiety behavior

2. The NOD mouse model shows a hypersensitivity to danger signals (i.e. LPS) with a higher sickness behavior

3. All myeloid cells, including the microglia and monocytes show proliferation, apoptosis, differentiation and maturation abnormalities (already from intra-uterine life onwards)

4. The microglia and brain tissue of the NOD mouse is deficient for neuronal growth factors

5. Brain tissue of the NOD mouse is hyper responsive to danger signals showing a higher production of pro-inflammatory cytokines

6. Various growth factors for myeloid cells and neuronal cells are deficient in the NOD mouse before disease and behavioral symptoms, and follow a dynamic pattern in time.

At present these findings are prepared for three publications. The findings in the animal model form the impetus to study in the human the lack of myeloid and neuronal growth factors in the different stages of life, even before outbreak of disease (see underneath)

WWU to RMS (Dr Laura Grosse, former Sumaski)

Aim: To analyze in an integrated fashion and file in the database the outcomes of monocyte activation, T cell subset determination, trypcat analysis and cytokines, chemokines, retroviral factors and growth factors in MDD patients (collected in WWU and EMC) to come to clinically useful biomarkers for MDD

Results:

1. Monocyte activation does occur in MDD patients, but only after 28 years of life. In these patients monocyte activation correlates with EGF and IL-6 levels in the serum. Correlation also exists with numerical deficiencies in T regulator cells, suggesting that this might be the reason for the pro-inflammatory monocyte activation in the older MDD patients.

2. Monocyte activation and T regulator cell defects are particularly prominent in older, not yet medicated melancholic MDD patients. The higher the monocyte activation, the higher the CD8+ T cytotoxic level and the lower the NK cell level, the worst the outcome is for venlafaxine or imipramine treatment.

3. Venlafaxine and imipramine raise the number of T regulatory cells in MDD patients

4. MDD patients are characterized by other defects in the lymphocyte compartment, namely numerical defects in NK cells, functional defects in the maturation of T helper cells to IL-4 and IL-17 producing cells, deficiencies in the T/NK cell growth factors IL-7 and sCD25. These defects are also evident in MDD patients under 28 years  of age.

5. Younger MDD patients of less than 28 years of age are not only characterized by these NK and T cell deficiencies, but also by a reduced expression of pro-inflammatory cytokines in their monocytes, thus by a general and partial immune deficiency.

6. Trypcat analyses and other analyses are in progress

One publication appeared in the last months

Three publications are in progress/submitted and in resubmission phase.

UMCG to RMS (Dr Benno Haarman)

Aim: To analyze in an integrated fashion and file in the database the outcomes of monocyte activation, T cell subset determination, trypcat analysis and cytokines, chemokines, retroviral factors and growth factors in a group of BD patients (collected in UMCG) and compare outcomes to MDD patients of WWU to come to clinically useful discriminating biomarkers of BD

Results:

Data are analyzed by Benno Haarman in close collaboration with Karlijn Becking.

Monocyte, T cell data and data on growth factors are presently analyzed. Specific outcomes can at present not be given.

FBP to RMS (Dr Angelica Angelova)

Aim: To analyze in an integrated fashion the outcomes of monocyte activation, T cell subset determination, trypcat analysis and cytokines, chemokines, retroviral factors and growth factors in BD and MDD patients (collected in FBP) and identify biomarkers relevant for the association of BD and MDD with thyroid autoimmune disease.

Results:

  1. TPO-antibodies, a sign of thyroid autoimmune disease are more prevalent in BD and MDD patients, in particular the high titers.
  2. Frequencies of MHC haplotypes, monocyte, T cell data and data on growth factors are presently analyzed. Specific outcomes can at present not be given.

EMC to RMS (Annemarie Wijkhuijs to RMS)

Aim: To build up the data base for all outcomes of monocyte activation, T cell subset determination, trypcat analysis and cytokines, chemokines, retroviral factors, growth factors and various clinical data of all patients under study, to make complex comparisons possible and validate biomarkers of interest across groups.

Results:

  1. At present also the assays for leukocytes and serum are performed for the LMU MDD cohort, in part treated with a combination of an anti-depressive and a COX2 inhibitor.
  2. These data are also filed in the RMS database and will thereafter be analyzed. Specific outcomes can at present not be given.
  3. Exchanges are discussed from LMU to RMS to assist in these analyses and to prepare manuscripts

PSY to EMC (Dr Jakub Tomasik)

Aim: 1. To analyze in an integrated fashion and file in the database the outcomes of monocyte activation, T cell subset determination, and analysis of cytokines, chemokines, and growth factors in schizophrenia patients (collected by EMC with the aid of Dr Wim Veling) to validate earlier found biomarkers for schizophrenia (amongst which IL-1RA and IL-10) and treatment response (molecule in the fatty acid metabolism).

2.To test leukocytes of these patients with a rostrum of different physiological stimuli to find discriminating intra cellular molecules, which are treatment targets. This series of tests is a validation series of previous found molecules in similar patients

Results: Assays are planned and the project is in the first early phases of execution.


FBP to PSY (Dr Olia Mykova)

Aim: To analyze via proteomics techniques the collected leukocytes of the series of MDD and BD patients of FBP for discriminating biomarkers.

Results: Leukocytes have been transferred to PSY from EMC (the storage place) and analyses are planned.

Outside the project similar analyses as in PSYCH-AID are presently performed on twin samples (index cases BD patients) and offspring of a bipolar parent (dr Gijsje Snijders) as well on first degree relatives of thyroid autoimmune patients (dr Elske Massolt). Data will be compared to the outcomes in the patient groups under study in PSYCH-AID.

The contours of markers predicting therapy response and outbreak of disease are beginning to appear. If continuing to be promising we will develop these biomarkers in the later phases into clinically useful assays with the help of our commercial partners PSY, APDia and Geneuro.