Characterizing the pathophysiological mechanisms of early disease in amyotrophic lateral sclerosis using multimodal neuroimaging
Creators: Dey, Avyarthana
Publisher: name: University of Alberta Library
Year: 2024

<p>Amyotrophic lateral sclerosis (ALS) is a, neurodegenerative disorder which is characterized by progressive impairment of the upper motor neurons in the brain and lower motor neurons in the brainstem and spinal cord. The disease is ultimately fatal with death eventually resulting from aspiration pneumonia. The motor neuronal impairment results in clinical signs such as muscle weakness, increased muscle tone and reflexes, and muscular atrophy and fasciculations. Cognitive impairment, recognized as a correlate of frontotemporal lobar degeneration, may occur concurrently with  the disease process in ALS. Despite the recognition of corticospinal tract and corpus callosal degeneration as hallmarks of white matter microstructural impairment, the functional connectivity alterations of the default mode and sensorimotor cerebral networks as hallmarks of gray matter impairments, and alterations in concentrations of excitatory and inhibitory neurochemicals as well as neurochemical markers of neuronal health, there is an inadequate understanding of the relationship between these independent observations across various measurement modalities as well as an inadequate understanding of the pathophysiological mechanisms underlying such disease characteristics. This makes accurate stratification of patients based on disease pathophysiology challenging, and hinders the study of targeted therapeutic interventions or inclusion in clincial trials. In addition, due to the stringency of inclusion criteria for clinical drug trials, some patients are deemed ineligible for inclusion based on a decline in their clinical measures. </p>

<p>Therefore, this thesis aimed to characterize markers of early disease using an approach that stratifies patients based on interindividual similarities in disease pathophysiology using neuroimaging instead of clinical measures. In order to assess the performance of such neuroimaging-based measures against clinically-defined methods, a comparison of clinical and functional neuroimaging measures is performed in Chapter 2. This study provides evidence of better sensitivity of the imaging-derived method of patient stratification over the clinically-defined method. The next step is to perform an evaluation of network-based evolution of disease pathophysiology in clinically-defined and imaging-derived patient subgroups. These evaluations were performed in Chapters 3 and 4. Chapter 3 was able to demonstrate that longitudinal network connectivity alterations were present in both motor and extra-motor networks in the comprehensive ALS cohort as well as in the clinically-defined patient subgroups. Additionally, an assessment of cerebral function in this chapter revealed that brain regions participating in motor encoding have altered longitudinal functional connectivities in the motor imagery network in early disease and in the action observation network in advanced disease. In chapter 4, distinct disease evolution patterns were identified in imaging-derived patient subgroups. While one subgroup had a more severe (advanced pathophysiological) disease with a predominantly motor phenotype, the other subgroup had a less severe (early pathophysiological) disease with a motor-frontotemporal phenotype. Clinical features of the disease in both patient subgroups correlated with their network characteristics. The longitudinal patterns of network functional alterations in patients stratified by both clinically-defined and imaging-derived criteria are suggestive of the role of the motor network in the disease process. Therefore, identifying the neuroanatomical basis of motor network impairment might help provide clues to the biological mechanisms underlying functional impairment of the upper motor neurons. Chapter 5 performed an assessment of the neuroanatomical features of white matter microstructure and neurochemical concentrations within the foot region of the primary motor cortex homunculus. As expected, a correlation was observed between reduced neurochemical concentrations of N-acetyl aspartate (a marker of neuronal health) and reduced foot tapping scores in ALS. Furthermore, these clinically-relevant neurochemical concentrations demonstrated both positive and negative associations with reduced motor cortex functional connectivity. </p>

<p>In sum, the evidence presented in this thesis highlights that the connectivity of the motor network plays a vital role in ALS disease pathophysiology, thereby corroborating the extensive evidence in the literature. Specifically, the evidence in this thesis suggests that the pathophysiological disease mechanisms manifest differently in ALS patients, and these differences are apparent when distinct patient stratification criteria are used. However, this thesis also highlights the lack of congruence between the various criteria used in this thesis to stratify patients. This is indicative of a gap in biological-phenotypic coherence of pathophysiological disease characterization, which remains a major player in the lack of identification of an effective biomarker for disease monitoring in the clinical setting.</p>