Tag Archives: therapy

In vivo MRI/MRS longitudinal study of immunotherapy in Alzheimer’s

Progression of Alzheimer’s disease and effect of scFv-h3D6 immunotherapy in the 3xTg-AD mouse model: An in vivo longitudinal study using Magnetic Resonance Imaging and Spectroscopy by Güell-Bosch J, Lope-Piedrafita S, Esquerda-Canals G, Montoliu-Gaya L, and Villegas S. NMR in Biomedicine 33(5):e4263; DOI: 10.1002/nbm.4263.

Alzheimer’s disease (AD) is an incurable disease that affects most of the 47 million people estimated as living with dementia worldwide. The main histopathological hallmarks of AD are extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein.  In recent years, Aβ-immunotherapy has been revealed as a potential tool in AD treatment. One strategy consists of using single-chain variable fragments (scFvs), which avoids the fragment crystallizable (Fc) effects that are supposed to trigger a microglial response, leading to microhemorrhages and vasogenic edemas, as evidenced in clinical trials with bapineuzumab. The scFv-h3D6 generated by our research group derives from this monoclonal antibody, which targets the N-terminal of the Aβ peptide and recognizes monomers, oligomers and fibrils.

In this study, 3xTg-AD mice were intraperitoneally and monthly treated with 100 μg of scFv-h3D6 (a dose of ~3.3 mg/kg) or PBS, from 5 to 12 months of age (-mo), the age at which the mice were sacrificed and samples collected for histological and biochemical analyses. During treatments, four monitoring sessions using magnetic resonance imaging and spectroscopy (MRI/MRS) were performed at 5, 7, 9, and 12 months of age. MRI/MRS techniques allow, in a non-invasive manner, to draw an in vivo picture of concrete aspects of the pathology and to monitor its development across time. Compared with the genetic background, 3xTg-AD mice presented a smaller volume in almost all cerebral regions and ages examined, an increase in both the intra and extracellular Aβ1-42 at 12-mo, and an inflammation process at this age, in both the hippocampus (IL-6 and mIns) and cortex (IL-6). In addition, treatment with scFv-h3D6 partially recovered the values in brain volume, and Aβ, IL-6, and mIns concentrations, among others, encouraging further studies with this antibody fragment.

Metronomic treatment in immunocompetent preclinical glioblastoma

“Metronomic treatment in immunocompetent preclinical GL261 glioblastoma: effects of cyclophosphamide and temozolomide” by by L. Ferrer-Font,  N. Arias-Ramos, S. Lope-Piedrafita, M. Julià-Sapé , M. Pumarola, C. Arús  and A. P. Candiota. NMR Biomed. 2017. DOI: 10.1002/nbm.3748. 

Glioblastoma (GBM) causes poor survival in patients even when applying aggressive treatment. In preceding years, efforts have focused in new therapeutic regimens with conventional drugs to activate immune responses that may enhance tumor regression and prevent regrowth, as for example the “metronomic” approaches.

We have evaluated whether metronomic CPA or TMZ administration could increase survival in orthotopic GL261 in C57BL/6 mice, an immunocompetent model. Longitudinal in vivo studies with CPA (140 mg/Kg) or TMZ (range 140-240 mg/Kg) metronomic administration (every 6 days) were performed in tumor-bearing mice. Tumor evolution was monitored at 7T with T2-weighted MRI, Diffusion weighted imaging and MRSI-based nosological images of response to therapy. Obtained results demonstrated that both treatments resulted in increased survival (38.6+21.0 days, n=30) compared to control (19.4+2.4 days, n=18). Also, it was found a clear edema appearance during chemotherapeutic treatment suggesting inflammatory associated processes. The necropsy performed in mice cured from GBM after high TMZ cumulative dosage (980-1400 mg/Kg) revealed lymphoma incidence.

Multi-Slice MRSI Analysis of Therapy Response in Preclinical Glioblastoma

Metabolomics of Therapy Response in Preclinical Glioblastoma: A Multi-Slice MRSI-Based Volumetric Analysis for Noninvasive Assessment of Temozolomide Treatment” by N. Arias-Ramos, L. Ferrer-Font,  S. Lope-Piedrafita,  V. Mocioiu, M. Julià-Sapé , M. Pumarola, C. Arús  and A. P. Candiota. Metabolites, 2017, 18;7(2). pii: E20. DOI: 10.3390/metabo7020020.

Glioblastoma (GBM) is the most common and aggressive glial primary tumor with a survival average of 14-15 months, even after application of standard treatment. Non-invasive surrogate biomarkers of therapy response may be relevant for improving patient survival. Nosological images of therapy response using a semi-supervised source extraction approach in preclinical GBM based on single slice Magnetic Resonance Spectroscopic Imaging (MRSI) was previously describe by our group. However, because of GBM heterogeneity, relevant response information could be missed just by studying one slice. Therefore, the goal of this work was to acquire 3D-like information from preclinical GBM under a longitudinal treatment protocol, using a multi-slice MRSI approach.

Nosological maps were obtained based on semi-supervised convex Non-negative Matrix Factorization and each voxel was colored according to the contribution to the spectral pattern of each one of the three sources or characteristic spectral patterns: Normal brain, actively proliferating tumour or responding tumour.

Heterogeneous response levels were observed and three arbitrary groups of treated animals were defined as: high response, intermediate response, and low response. Histopathological studies showed an inverse correlation between the responding pattern level and Ki67 proliferation rate.


Stroke Therapy in Mice

PLoSONEcover“Factors Secreted by Endothelial Progenitor Cells Enhance Neurorepair Responses after Cerebral Ischemia in Mice” by Rosell, A., Morancho, A., Navarro-Sobrino, M., Martínez-Saez, E., Hernández-Guillamon, M., Lope-Piedrafita, S., Barceló, V., Borrás, F., Penalba, A., García-Bonilla, L., Montaner, J. PLoS ONE 8 (2013), e73244. DOI: 10.1371/journal.pone.0073244

Cell therapy with endothelial progenitor cells (EPCs) has emerged as a promising strategy to regenerate the brain after stroke. Continue reading Stroke Therapy in Mice