Structural MRI has several key advantages for the measurement of brain atrophy in preclinical studies of disease-modifying therapeutics for neurodegenerative diseases:
- Non-invasive, in vivo measures without confounds associated with tissue manipulation (e.g. extraction, fixation, processing)
- Opportunity for longitudinal measures in the same animal
- Often the first biomarker to show disease progression (before conventional fluid & tissue markers)
- Can obtain readouts from the in-life phase that can serve as go/no-go decision points for additional analyses
- Allows for evaluation of the brain regions that are specifically affected in a particular disease model
In vivo MRI brain atrophy measures can be complemented by NfL measures in the plasma and CSF (also a clinically-translational biomarker), as well as by appropriate, quantitative immunohistochemistry or immunofluorescence markers on post-mortem tissue sections. Through this "multi-modality" strategy, a high degree of sensitivity and specificity can be realized.
In summary, MRI measures can be a cost-effective and time-efficient means of evaluating modulation of brain atrophy by potential disease-modifying therapeutic agents. We have demonstrated the high level of sensitivity of volumetric loss and cortical thinning in mouse models of ALS and Parkinson's disease that we routinely use in therapeutic efficacy studies.
MRI is widely used in CNS clinical trials, ranging from exploratory studies to large-scale, global, multicenter, Phase 3 studies. The ability to identify potential disease-modifying effects on MRI brain atrophy during preclinical studies presents a unique opportunity to de-risk future clinical trials and identify potential reliable biomarkers and endpoints.