Work packages

WP1: AD and Inflammation: The goal of WP1 is to study the interaction between soluble amyloid, inflammation and synaptic loss in AD. We hypothesize that the soluble form of amyloid rather than amyloid plaques are of interest in AD, inducing inflammatory cascades, toxicity at the level of the synapses and possibly affecting the vascular response function and blood brain barrier integrity. It is thought that accumulation of soluble amyloid leads to inflammatory cascades and exerts toxic effects on the synapses. Moreover, reduced cerebral perfusion, whether or not related to pathological soluble amyloid accumulation, has been suggested as an additional risk factor that could contribute to exacerbation of neuro-inflammatory or neuro-toxic effects of soluble amyloid. In view of the complex interplay (and possible synergism) between the multiple pathological processes, a combined approach involving a multi-modal battery of in vivo and ex vivo imaging is essential to obtain more insight into the (molecular) processes and mechanisms behind AD. To this end, brains of transgenic AD mice will be studied longitudinally by in vivo MRI functional connectivity, metabolic changes (7, 8), vascular responses (9) and optical imaging (10, 11). A subset of the obtained in vivo MRI data will be co-registered with ex-vivo mass spectroscopy-based molecular images. As such a fingerprint of morphological, functional and molecular changes during AD will be established. These insights might lead to both identification of novel targets for therapeutic interventions and development of early stage non-invasive biomarkers of AD. Furthermore, this WP aims to investigate the interaction between soluble amyloid, inflammation, synaptic loss and vascular responsiveness in AD.

 

WP2: Maximizing Regeneration after Brain Lesions: The Role of Stem Cells and Inflammation After Stroke: The goal of WP2 is to understand better the interrelationship between stem cell grafts and inflammatory activity following cerebral lesions for the purpose of developing a preclinical, robust regenerative therapy for stroke. The hypothesis is that there is a time window of preferred stem cell implantation during lesion evolution (12, 13). This time window will be strongly influenced by the phase of the inflammatory activity, whether it is detrimental or constructive, modulating the vitality and survival of the graft. We further hypothesize that the interaction between inflammatory cells (microglia, infiltrating monocytes) and the stem cell graft will influence the regenerative capacity of the stem cells. This again will probably have major impact on functional outcome and, thus, in essence, on the therapeutic value of the stem cell-mediated regenerative strategy. Experiments will be performed using non-invasive imaging techniques to characterize the time profile of the lesion development, of the fate of the stem cell graft after intracerebral implantation and of the activity of infiltrating monocytes/macrophages and microglia during this process. To achieve this goal, cells need to be labelled according to their function of interest to be studied. We have developed and established various cell labelling strategies covering cell localization, cell vitality and cell differentiation, for detection by MRI and optical imaging (14). Furthermore, functional deficit and functional improvement of the affected animals will be assessed. For this purpose, we have established both stimulus-based fMRI to screen the sensorimotor system, and resting state fMRI to characterize disturbance and recovery of functional network connectivity in the various phases of the lesion evolution.

 

WP3: GBM and the Immune Response: The aim of this work package is to test a potential new combination therapy for a type of aggressive and malignant brain tumour. Despite wide surgical resection and improvements in radio- and chemotherapies, the prognosis of patients with GBM remains extremely poor. New approaches that allow tumour specific targeting and extensive intra-tumoural distribution must be developed in order to achieve efficient therapeutic delivery of anti-cancer compounds (15). Furthermore, there is also an immunosuppressive barrier to overcome through accumulation of regulatory T cells (Tregs) which is induced by GBM. Our hypothesis is that by combining stem cell migration and nanoparticle-based payloads of therapeutic agents, GBM can be targeted.

 

WP4: TBI and Repair: Despite being a major burden on society, no treatment at present exists that can promote recovery in patients with TBI. Cell therapy is the most promising intervention that could change the lives of millions of patients affected by TBI. Combining imaging technologies, such as MRI together with optical imaging, are key in ensuring that the cell implantation is accurate, that no ill effects follow grafting and to understanding the mechanism of recovery. In order to reach this goal of stem cell implantation into the lesioned brain, we have brought together an inter-disciplinary team that will work together to better understand the mechanisms of the cells’ functions in the host organ, and the cells’ interaction within the area of lesion tissue. Recently an in vivo cryogenic brain injury mouse model was developed at LUMC to monitor dead cells (16, 17). This same model will also be used in this project to study neuronal stem cell migration and differentiation, and to develop new therapeutic strategies for TBI.

 

WP5: Migraine-Related Hyperexcitability as a Risk Factor for Stroke Evolution: The goal of this work package is to identify, and intervene with, the underlying molecular and neurobiological mechanisms by which migraine influences stroke susceptibility and the evolution of brain damage after stroke. Migraine is a very common paroxysmal neurovascular brain disorder that is characterized by disabling attacks of headache and associated neurological symptoms. Neuronal hyperexcitability and a subsequent increased susceptibility to cortical spreading depression (CSD) play a central role in migraine pathophysiology (18,19). Following ischemic stroke in patients, the occurrence of peri-infarct depolarizations with associated electrolytic and neurovascular changes are expected to worsen stroke outcome (20). Migraine is an independent risk factor for stroke (21), but the underlying mechanisms of the co-morbidity are not known. We hypothesize that migraine-related mechanisms (i.e. increased neuronal excitability and enhanced susceptibility for spreading depression) negatively influences stroke evolution. More precise, stroke outcome will be worsened as a result of migraine-linked pathological changes that include altered brain electrolyte composition (e.g. pH, K+), increased inflammation and structural neuronal plasticity changes that result in further enhanced brain excitability and impaired recovery from stroke events.

 

WP6: High Resolution MSI: The objective of this work package is to utilize high structural resolving power offered by ion mobility mass spectrometry and high resolution mass spectrometry to elucidate local molecular signalling pathways on complex biological surfaces. Resolving molecular structures in the gas-phase is a key capability required for the fundamental understanding of signalling processes in diseases. Often biomolecules are structurally investigated after isolation and purification. In this research theme we intend to perform these structural investigations directly on biomolecules in their native cellular or tissue environment using mass spectrometry based molecular imaging techniques and correlate these histopathological results with in-vivo PET and MRI. Of particular interest is how small regulatory molecules as well as larger protein folding complexes interact and influence local structural changes that occur in or even trigger diseases described in previous work packages such as AD, generic neurodegenerative disorders and cancer. Mass spectrometry based label-free molecular imaging (22) of intact biomolecules from biological surfaces needs the further development of new desorption, ionization and dissociation techniques to facilitate localization and identification of the tissue surface biomolecules. The concerted application of different high resolution MSI modalities on brain tissue surfaces will provide a global insight into the different molecular structures involved in disease signalling, inflammation and tissue regeneration.

 

WP7: Multispectral Optoacoustic Imaging of the Brain:The aim of this work package is to provide project partners and the wider scientific community with a new tool for in vivo optical visualization of brain pathophysiology at high resolution. To this end, Multispectral Optoacoustic Tomography (MSOTTM) methods will be developed and characterized for brain imaging (23). Our particular objectives will be to develop multiplexed multimodal cell imaging, functional imaging of the brain as well as quantitative imaging of pathological biomarkers relevant to, in particular, AD, stroke and migraine. MSOTTM is an emerging modality that overcomes the primary challenge in deep-tissue optical imaging: photon scattering. By detecting optical absorption via ultrasound emitted by the photoacoustic effect, optoacoustic tomography can pinpoint molecular signals within deep tissue layers at an unprecedented spatial resolution (tens to hundreds of microns). Multispectral excitation allows MSOTTM to identify different endogenous (e.g. haemoglobin, melanin) and exogenous (e.g. fluorescent dyes, nanoparticles) chromophores by means of their unique spectral absorption signatures. We have recently demonstrated basic brain imaging capabilities in mice using MSOT. This includes real-time visualization of optical contrast perfusion, dynamic changes in blood oxygenation and characterization of GBM (haemoglobin changes and exogenous contrast).

References:

 

  1. Jonckers E., Van Audekerke J., De Visscher G., Van der Linden A., Verhoye M. Functional connectivity fMRI of the rodent brain: comparison of functional connectivity networks in rat and mouse. PLOS ONE 2011; 6: e18876.

  2. Shah D., Jonckers E., Bigot C., Vanhoutte G., Verhoye M., Van der Linden A. The use of resting state functional MRI to assess functional connectivity in a mouse model of Alzheimer’s disease (abstract) 5th annual World Molecular Imaging Congress. Dublin Ireland. 2012.

  3. Kober F., Duhamel G., Callot V. (2011) Cerebral perfusion MRI in mice. Methods Mol Biol771:117-38

  4. Klohs J., Deistung A., Schweser F., Grandjean J., Dominietto M., Waschkies C., Nitsch RM., Knuesel I., Reichenbach JR., Rudin M. (2011) Detection of cerebral microbleeds with quantitative susceptibility mapping in the ArcAbeta mouse model of cerebral amyloidosis. J Cereb Blood Flow Metab. 2011;;31(12):2282-92

  5. Grillon E., Provent P., Montigon O., Segebarth C., Rémy C., Barbier EL. (2008) Blood-brain barrier permeability to manganese and to Gd-DOTA in a rat model of transient cerebral ischaemia.NMR Biomed. 2008; Jun;21(5):427-36.

  6. Weber R., Ramos-Cabrer P., Justicia C., Wiedermann D., Strecker C., Sprenger C., Hoehn M. Early prediction of functional recovery after experimental stroke. Journal of Neuroscience 2008; 28, 1022-1029

  7. Ramos-Cabrer P., Justicia C., Wiedermann D., Hoehn, M. Stem cell mediation of functional recovery after stroke in the rat. PLoS One 2010; 5, e12779

  8. Seehafer JU.,Farr TD., Kalthoff D., Wiedermann D., Hoehn M. No increase of the BOLD fMRI signal with higher field strength: implications for brain activation studies. Journal of Neuroscience 2010; 30: 5234-5241

  9. Auffinger B, Thaci B, Nigam P, Rincon E, Cheng Y, Lesniak MS. New therapeutic approaches for malignant glioma: in search of the Rosetta stone. F1000 Med Rep. 2012; 4:18. Epub 2012

  10. Smith BA, Xie BW, van Beek ER, Que I, Blankevoort V, Xiao S, Cole EL, Hoehn M, Kaijzel EL, Löwik CW, Smith BD. Multicolor fluorescence imaging of traumatic brain injury in a cryolesion mouse model. ACS Chem Neurosci. 2012; 18;3(7):530-7. Epub 2012 Apr 7

  11. Xie, BW, Park D, Van Beek ER, Blankevoort V, Orabi Y, Que I, Kaijzel EL, Chan A, Hogg PJ & Lowik CMGM. Cell Death and Disease 2012: 3, e_; doi:10.1038/cddis.2012.207; In Press

  12. Aurora SK, Wilkinson F. The brain is hyperexcitable in migraine. Cephalalgia. 2007 Dec;27(12):1442-53.

  13. van den Maagdenberg AM, Haan J, Terwindt GM, Ferrari MD. Migraine: gene mutations and functional consequences. Curr Opin Neurol 2007;20:299-305.

  14. Dreier JP. The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med 2011;17:439-47

  15. Stam AH, Haan J, van den Maagdenberg AM, Ferrari MD, Terwindt GM. Migraine and genetic and acquired vasculopathies. Cephalalgia 2009a;29 :1006-17

  16. Chughtai K and Heeren RM. Mass Spectrometric Imaging for biomedical tissue analysis. Chem. Rev. 2010; 110:3237-3277

  17. Xie, BW, Park D, Van Beek ER, Blankevoort V, Orabi Y, Que I, Kaijzel EL, Chan A, Hogg PJ & Lowik CMGM. Cell Death and Disease 2012: 3, e_; doi:10.1038/cddis.2012.207; In Press

  18. Aurora SK, Wilkinson F. The brain is hyperexcitable in migraine. Cephalalgia. 2007 Dec;27(12):1442-53.

  19. van den Maagdenberg AM, Haan J, Terwindt GM, Ferrari MD. Migraine: gene mutations and functional consequences. Curr Opin Neurol 2007;20:299-305.

  20. Dreier JP. The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med 2011;17:439-47

  21. Stam AH, Haan J, van den Maagdenberg AM, Ferrari MD, Terwindt GM. Migraine and genetic and acquired vasculopathies. Cephalalgia 2009a;29 :1006-17

  22. Chughtai K and Heeren RM. Mass Spectrometric Imaging for biomedical tissue analysis. Chem. Rev. 2010; 110:3237-3277

  23. Ntziachristos V, Razansky D. Molecular imaging by means of multispectral optoacoustic tomography (MSOT). Chem Rev. 2010 May 12;110(5):2783-94

News

Publications

Adamczak J. et al. (2015).
Poststroke angiogenesis, Con: Dark side of angiogenesis.
- DOI: 10.1161/STROKEAHA.114.007642
Keuters M. et al. (2015).
Transcranial direct current stiumulation promotes the mobility of engrafted NSCs in the rat brain.
- doi: 10.1002/nbm.3244
Škrášková K. et al. (2015)
Precise anatomical localization of accumulated lipids in Mfp2 deficient murine brains through automated registration of SIMS images to the Allen Brain Atlas.
- doi: 10.1007/s13361-015-1146-6
Tzoumas S. et al.
Spatiospectral denoising framework for multispectral optoacoustic imaging based on sparse signal representation.
- doi: 10.1118/1.4893530
Tzoumas S. et al.
Immune cell imaging using multi-spectral optoacoustic tomography.
- doi: 10.1364/OL.39.003523
Shah D et al. (2015)
Acute modulation of the cholinergic system in the mouse brain detected by pharmacological resting-state functional MRI.
- doi: 10.1016/j.neuroimage.2015.01.009

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Project BRAINPATH is supported by, and carried out within the FP7 Programme IAPP, funded by the EC

 

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