In Vivo Morphological Changes in Animal Models of Amyotrophic Lateral Sclerosis and Alzheimer's‐Like Disease: MRI Approach

Abstract

Magnetic resonance imaging (MRI) is the only noninvasive technique that provides structural information on both cell loss and metabolic changes. After reviewing all the results obtained in clinical studies, reliable biomarkers in neurological diseases are still lacking. Diffusional MRI, MR spectroscopy, and the assessment of regional atrophy are promising approaches, but they cannot be simultaneously used on a single patient. Thus, for further research progress, reliable animal models are needed. To this aim, we have used the clinical MRI to assess neurodegenerative processes in the hSOD-1 G93A ALS rat model and in the trimethyltin (TMT)-treated model of Alzheimer's-like disease. T2-weighted (T2W) hyperintensive neurodegenerative foci were found in the brainstem of the ALS rat with apparent lateral ventricle dilation (T1W-hypointensity vs. T2W-hyperintensity). Degenerative processes in these areas were also confirmed by confocal images of GFAP-positive astrogliosis. MRI after i.v.i. of magnetic anti-CD4 antibodies indicated an accumulation of inflammatory cells near dilated ventricles. TMTtreated rats also revealed the dilation of lateral ventricles. Expected deterioration in the hippocampus was not observed by clinical MRI, but immunocytochemistry could reveal significant redistribution of macroand microglia in this structure. In both models, Gd-DTPA contrast revealed a compromised blood brain barrier that may serve as the passage for inflammatory immune cells in the vicinity of dilated lateral ventricles. Moreover, in both models the midbrain region of the dorsal hippocampus was the target of BBB compromise, thus revealing a potentially vulnerable point that can be the primary target of neurodegeneration in the central nervous system.

Microglia centered pathogenesis in ALS: insights in cell interconnectivity

“…Thus, the human mSOD1 murine model is the most widely used in the evaluation of the involved molecular targets, biomarkers and novel drugs/treatments for ALS. Apart from developing loss of MNs and symptoms that resemble human ALS by mSOD1, the model evidences molecular links between genetic and non-genetic cases of ALS (Andjus et al, 2009; Synofzik et al, 2010). To note, that non-genetic perturbations of the wild-type (wt) SOD1 protein may lead to SOD1 misfolding with a conformation much similar to genetic SOD1 variants (Cereda et al, 2006).…”

“…The interaction between all these components provides a sustainable environment for neural function while restricting permeability and transport. Alterations in barrier properties and dynamics were observed in transgenic SOD1 rats (Andjus et al, 2009; Nicaise et al, 2009). In particular, it was noticed a reduction of endothelial tight junctions (Zhong et al, 2008), together with the disruption of the neurovascular unit and up-regulation of MMP-9 (Miyazaki et al, 2011) prior to MN degeneration.…”

Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

“…Pathophysiology of ALS is poorly understood and likely multifactorial. Proposed starting points for this complex disease targeting the motor neuron population include mitochondrial dysfunction, intracellular protein aggregation, disturbances of RNA metabolism, extracellular toxic environment, impairment at the level of axonal transport and at the neuromuscular synapse (reviewed by [81] ), together with extrinsic events: blood-brain barrier breakdown, glial cell reaction/dysfunction and neuroinflammation [82][83][84][85][86][87][88] . It is known that dying motor neurons influence surrounding cells, of which astrocytes are most commonly investigated.…”

Targeting Progressive Neuroaxonal Injury

“…[84][85][86] Similarly, brain atrophy has been used as an indicator of neuroaxonal injury in PD, AD and ALS. [76,87,88] However, the degree of change in these measures over a 1-year observation period tends to be small. For example, in untreated MS subjects the percentage decrease in brain volume that occurs in 1 year is between 0.5% and 1.0%, with some patients showing no change while others show more dramatic changes.…”