Exploring Potential Biomarkers for Amyotrophic Lateral Sclerosis Using Postmortem In Situ Magnetic Resonance Imaging

There is an urgent need for reliable magnetic resonance imaging (MRI) biomarkers for the diagnosis, prognosis or therapy management of amyotrophic lateral sclerosis (ALS). The aim of this study was to explore potential biomarkers for ALS by conducting postmortem (PM) in situ MRI, allowing for a non-invasive evaluation of the disease's end-stage without the effects of formalin fixation. PM in situ MRI whole-brain scans of five deceased patients with clinically definite ALS and seven deceased healthy controls (HC) without known neurological disorders were performed at 3 Tesla. Fractional anisotropy, mean diffusivity, T₁, T₂ and T₂* were assessed for cortex, deep grey matter, white matter, whole brain and hippocampus. For the validation of the MRI DTI data, the focus was placed on the hippocampus, where the myelin density was evaluated by analysing histological samples from the dentate gyrus. A custom python script was developed for the quantification of the myelin density in histological data. Comparing ALS to HC values suggested potential reductions of mean diffusivity, T₁ (after outlier removal) and T₂* in white matter and of T₂ in deep grey matter in the ALS group. Furthermore, mean diffusivity was potentially reduced in the hippocampus of patients with ALS (after outlier removal), whereas no difference in myelin density was found by histopathological assessment. The results of this exploratory study suggest potential differences in diffusivity and relaxometry between PM in situ brains of patients with ALS and HC. Understanding these variations at the end-stage of ALS might contribute to the development of novel MRI prognostic and diagnostic biomarkers for ALS. However, larger sample sizes and complementary histological examinations are needed to confirm these results and to clarify the underlying mechanisms.