title: Better understanding of progressive multiple sclerosis
Creators: name: Zhang, Y
Publisher: name: University of Tasmania
Year: 2020

description: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating and neurodegenerative disease of the central nervous system. The majority (85–90%) of people with MS initially have relapsing-remitting MS (RRMS), of whom a majority go on to develop secondary progressive MS (SPMS), while 10‑15% of people with MS present with primary progressive MS (PPMS). Despite dramatic progress in treatments and understanding in RRMS, the story in progressive MS (SPMS &amp; PPMS) remains comparatively disappointing, partly because of a lack of sensitive progression measures and the comparatively small numbers of people with PPMS. There is a need for new low-burden measures of MS progression, as well as large epidemiological studies that can stratify by MS phenotype. Understanding the progression of MS also requires an understanding of the interplay between genes and environmental factors. This thesis aimed to improve the understanding of progressive MS and MS progression. It included four original studies using two datasets. The first three studies used the Australian Multiple Sclerosis Longitudinal Study which has roughly 3,000 active participants from around Australia. The fourth study used the Ausimmune Longitudinal Study which is a prospective cohort study that followed cases from the Ausimmune Study for up to 5 years at the time of this analysis. The first study examined the concurrent and predictive validity, stability and responsiveness of single-item 0-10 numeric MS Symptom Scores (MSSymS) for six patient-reported MS symptoms - walking difficulties, fatigue, pain, feelings of anxiety, feelings of depression, and vision problems. With two years of symptom data, I found the MSSymS performed equally well compared to validated comparison measures like Patient-Determined Disease steps, Fatigue Severity Scale, and Hospital Anxiety and Depression Scale. The second study examined differences in outcomes between progressive-onset MS (PPMS) and relapse-onset MS (RRMS &amp; SPMS). I found that people with progressive-onset MS were significantly worse off on nearly all patient-reported outcomes, including MS symptoms, disability, disability progression over the preceding year, and quality of life, persisting after accounting for confounding factors such as age and disease duration. The differences were most pronounced early in the disease course. This work highlights the importance of early intervention and a focus on specific symptomatic treatments of progressive-onset MS. The third study examined the symptoms that had the largest impact on health-related quality of life (HRQoL) measured using the Assessment of Quality of Life with eight dimensions (AQoL-8D) and European Quality of Life with five dimensions and five levels for each dimension (EQ-5D-5L) and how they differed by MS phenotype. I found that the strongest single predictor for the AQoL-8D and EQ-5D-5L were feelings of depression, pain, and walking difficulties, irrespective of MS phenotype. Reducing these symptoms may have the largest impact on improving the HRQoL in all MS phenotypes of people with MS. The fourth study examined the role of lipid- or body mass index (BMI)-related genetic polymorphisms in MS progression. I found that five lipid polymorphisms and one BMI polymorphism were nominally associated with disability progression. A cumulative genetic risk score (CGRS) of the five lipid polymorphisms model explained 16% of the variance in disability progression in this cohort, and the model of the combination of the CGRS and the lipid variable explained more than 25% of the variance in disability progression. This highlights the significant joint effect (gene-environment) of the lipid-genetic factor and lipids profile on MS progression, and indicate that lipid-related polymorphisms and tagged genes as potential points of intervention to moderate disability progression. In summary, this thesis presents a range of studies capturing validity, epidemiology as well as genetics. The findings assist in guiding disease and symptom management among people with progressive MS and is a step towards a better understanding of progressive MS.