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Grandjean J, Schroeter A, He P, Tanadini M, Keist R, Krstic D, Konietzko U, Klohs J, Nitsch RM, Rudin M. Early alterations in functional connectivity and white matter structure in a transgenic mouse model of cerebral amyloidosis. J Neurosci. 2014 Oct 8;34(41):13780-9. PubMed.
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Bio-Imaging Lab, University of Antwerp
Grandjean and colleagues used resting-state functional MRI (rsfMRI) techniques in ArcAβ and wild-type mice at different time points across their lifespan to investigate the relation between functional connectivity disruptions and amyloid pathology. They observed compromised development of functional connectivity between sensory-motor regions during the first months of postnatal life along with structural changes in the brain.
In a previous study at the Bio-Imaging Lab, we demonstrated that functional connectivity disruptions could be observed in the APP/PS1 mouse model of amyloidosis (Shah et al., 2013). The APP/PS1 mice show a rapid onset and progression of amyloid pathology, with the first amyloid plaques appearing around 6-8 weeks of age in the cortex (Radde et al., 2006). In our study, the APP/PS1 and wild-type mice were investigated with rsfMRI at the age of 18-19 months, when amyloid plaques are extensively present throughout the entire brain. The next logical step after this proof-of-concept study was to investigate functional connectivity alterations at earlier stages and even before the onset of amyloid plaque development. The rationale behind this idea is the fact that soluble forms of Aβ are known to exert toxic effects at the level of the synapses (Mucke and Selkoe, 2012), thus it would seem plausible to observe functional changes before amyloid plaques even develop. This is further supported by the observation of cognitive dysfunctions before the onset of plaque development in some mouse models of amyloidosis (Dodart et al., 1999; Knobloch et al., 2007; Westerman et al., 2002).
In line with this idea, the most promising result of the study of Grandjean and colleagues is that functional connectivity disruptions could already be observed before the onset of amyloid plaques. The ArcAβ mice develop intracellular punctate deposits of Aβ at the age of 6 months, but overt amyloid plaque formation and cerebral amyloid angiopathy (CAA), i.e. deposits of amyloid in the vessel walls, only develop between 9-15 months of age. The first cognitive deficits, however, start at 6 months of age (Knobloch et al., 2007), strongly suggesting that stages earlier than overt amyloid plaque formation might be the cause of the observed memory disruptions. The early functional connectivity deficits were observed mainly in sensory-motor regions, suggesting that these regions are the most vulnerable to amyloid pathology. This is in contrast with findings in Alzheimer’s disease patients where the default-mode-network (DMN) seems to be the most vulnerable to AD pathology. Grandjean and colleagues explain this discrepancy by the DMN being the metabolically most active network in humans and the sensory regions being metabolically as demanding as the cingulate regions in rodents. We strongly believe that conclusions of any rsfMRI results must be made taking into account the characteristics of the mouse model and the anesthesia regime that is used. Therefore, studies in different mouse models of amyloidosis with different patterns of disease progression and the use of different anesthesia regimes might provide even more insight into which brain regions are specifically vulnerable and how this can be related to amyloid pathology.
Resting-state functional MRI has proven to be a nice technique to detect functional changes in humans and rats. Recently, more and more resting-state functional MRI studies are also being performed in mice and mouse models of disease. The main advantages of this technique are its non-invasive character and short acquisition times, rendering it favorable in terms of translation to the clinic. Considering the existence of numerous interesting mouse models of disease, it is of great importance to optimize this technique in healthy mice and mouse models. This study by Grandjean and colleagues nicely shows how resting-state functional MRI can contribute to identifying early stage functional alterations in mouse models of disease.
References:
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