Spinal cord gray and white matter atrophy in patients with motor neuron diseases

Motor neuron disorders (MND) are a heterogeneous group of disease of the upper (UMN) and lower motor neurons (LMN) with a wide spectrum of etiologies.
Among them, Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative MND leading to the decline of the UMN and LMN and thus, to progressive muscular spasticity and weakness. Death usually occurs from respiratory failure. Despite ever-increasing efforts in last years, there are no curative therapeutic options and disease-prolonging therapies are sparse.
In order to identify potentially effective new treatment options, valid and reliable biomarkers are needed to assess disease progression and to evaluate the effect of new therapeutic approaches. Imaging markers may serve this purpose, but so far, reliable and easily implementable imaging biomarkers for ALS are lacking. The radially acquired Averaged Magnetization Inversion Recovery Acquisitions (rAMIRA) is a novel Magnetic Resonance Imaging (MRI) technique that enables high-resolution imaging of the spinal cord (SC) gray (GM) and white matter (WM) in clinically feasible acquisitions times. Using
rAMIRA imaging, GM and WM metrics may have the potential to become new imaging markers in patients with MND.
This PhD thesis comprises three studies evaluating SC metrics in patients with MND, evaluating their potential as new imaging markers. As a first step, we investigate the SC GM atrophy as a surrogate for LMN damage in a presumably pure LMN disorder, the Post-Polio Syndrome (PPS). This work was the first implementation of the rAMIRA sequence in an MND. By essentially using PPS as a model disease, this first work built a basis for the implementation of rAMIRA in other MND. As a second step, both SC GM and WM were evaluated in a combined UMN and LMN disorder, i.e. ALS. As a third step, a new MRI sign for ALS was evaluated in patients with ALS and other non-ALS MND.
In the first study, we evaluated the SC GM in patients with PPS. We compared the cervical and thoracic SC GM of patients with PPS to healthy, age- and sex-matched controls (HC) and assessed the relationship between the SC GM at different intervertebral disc levels and the segmental muscle strength at the respective corresponding myotomes. We were able to demonstrate significant cervical and thoracic SC GM atrophy in patients with PPS and found significant correlations between SC GM areas and muscle strength at corresponding myotomes. This study provided an encouraging first step for the implementation of the rAMIRA sequence in further MND.
In the second study, we evaluated both the SC GM and WM in patients with ALS, which is a combined disorder of the UMN and LMN. Similar to the first study, we compared the cervical and thoracic SC GM and WM of patients with ALS to age- and sex-matched HC and assessed the relationship of SC GM and WM at cervical and thoracic levels with segmental muscle strength. Moreover, we analyzed the relationship between the SC GM and WM and established markers of disease progression. We were able to demonstrate significant atrophy of cervical and thoracic SC GM and WM compared to controls, and found significant correlations between GM atrophy and muscle strength at corresponding myotomes as well as significant correlations with markers of respiratory strength and overall disability.
The third study describes and evaluates an observation we made during the analyses of the data from the second study: We observed a hyperintensity of the SC corticospinal lateral tracts on rAMIRA imaging in a patient with ALS who clinically presented a predominant UMN disease type. We then observed that these hyperintensities were visible in patients with, but also in some patients without a predominant UMN ALS. Building on these observations, we identified, defined, and analyzed the presence of the sign in a group of patients with ALS, a group of HC and a control group comprised of patients with non-ALS LMN disorders. The sign showed a good sensitivity and an excellent specificity for the diagnosis of ALS. Furthermore, we performed post-mortem imaging and consecutive histopathological analysis of one patient with ALS and an UMN predominant disease type. The histopathological analysis showed a rarefaction of myelinated axons in the region of the hyperintensities observed on rAMIRA imaging.
Taken together, the results from these three projects suggest that SC metrics acquired using rAMIRA imaging show promise as potential future imaging markers in patients with MND.