Longitudinal Assessment of TDP43 Mouse Brain with Non‐invasive MRI and MRS
Authors: Liu Haiying , Su Susan 
Published: June 2021

Background

The TAR DNA binding protein, TDP‐43, has been recently identified to play a pathogenic role in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It has been shown that TDP43 mice expressing hTDP‐43DNLS develop a set of phenotypes reminiscent of ALS within few weeks. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) offer a set of quantitative and multi‐modal assessment options that can be exploited to investigate neurodegeneration non‐invasively in animal models of ALS.

Objectives

To establish a non‐invasive imaging based assessment protocol of brain pathology, which can be effectively used in monitoring disease progression and treatment effects in animal models of ALS; To characterize the progression of TDP 43 mice comprehensively with non‐invasive MRI and MRS.

Methods

rNLS8 mice (TDP43 mice) were used in the study. When doxycycline (Dox), a suppressor of expression of human TDP‐43 (hTDP‐43) harboring a defective nuclear localization signal (ΔNLS) under the control of the neurofilament heavy chain promoter, was taken off, the mice started to express hTDP‐43DNLS in the brain and spinal cord. In the study, TDP43 and WT mice (N=3/group) were monitored and compared. In order to practically monitor mice longitudinally, a set of MR imaging and spectroscopy methods were implemented on a Bruker Biospec 7T/20cm MRI scanner (Bruker Biospin, Ettlingen, Germany). A receive‐only mouse brain RF coil array was used in the study to maximize the signal to noise ratio. A high‐resolution volume‐metric imaging method was used to image mouse brain morphology over time, while a spatially‐localized MR spectroscopy method (TE=10ms) was used to assess neurochemistry. The imaging and behavior measurements were performed at baseline, 2, 4, and 6 weeks. Mouse brain volume was calculated from 3‐dimensional MRI brain images. Various brain metabolites were quantified from the resulting mouse brain MR spectra, using LC‐Model (Version 6.3‐1K, LCMODEL Inc).

Results

After induction of hTDP‐43DNLS synthesis, TDP43 mouse body weight started to fall, and at week 4 difference between TDP43 and WT became significant (p<0.015). At the same time, MRI showed that CSF spaces in TDP43 mouse brain gradually enlarged over time compared to its baseline. And, the corresponding TDP43 mouse brain volume was found to decline significantly in comparison to WT (p<0.005). Furthermore, several brain metabolites were observed to exhibit significant differences between the two groups at week 6. These metabolites normalized to creatine were (TDP43 vs WT): NAA (0.80+/−0.02 vs 1.05+/−0.06, p<0.02), Cho (0.217+/−0.007 vs 0.276+/−0.010, p<0.004), Glx (1.329+/−0.033 vs 1.843+/−0.070, p<0.003).

Conclusions

Using MRI and MRS based methods, we were able to closely follow the impact of disease progression on brain morphology and neurochemistry non‐invasively in these TDP43 mice. Considering each mouse had its own baseline, this approach provided an improved statistical power for detecting changes. More importantly studies performed this way could require less mice. In future studies, we will utilize the same approach in treatment studies to assess the efficacy of therapies. Furthermore, this approach can allow other valuable assessments of CNS pathologies, such as edema, stroke, micro‐hemorrhage, white‐matter integrity, etc. More importantly, all these quantitative changes detected can be modeled pharmacologically with and without dosing.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.