UC Berkeley

Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system. Disease progression is highly variable, with very few established predictors. This dissertation focuses on several disease progression measures and hypothesized clinical, genetic, and environmental predictors.

Chapter 1 provides a general introduction to MS and highlights the background, significance, and specific aims for each study/chapter.

Chapter 2 focuses on cognitive impairment measured in a MS case-control study nested in the Kaiser Permanente Medical Care Plan, Northern California Region. This study utilizes the modified telephone interview for cognitive status (TICS-M) in a large study of MS cases and healthy controls. The aim of this study is to examine cognitive status, as measured by TICS-M, and investigate potential associations between clinical, environmental, and genetic risk factors for MS susceptibility. This study is the first to implement this brief, phone-administered assessment of cognitive status in MS patients.

Chapter 3 focuses on 52 MS genetic risk variants and their potential associations with the MS Severity Score (MSSS) in a cohort of 7,125 MS cases provided through collaboration with the International Multiple Sclerosis Genetics Consortium (IMSGC). This study aims to test association between the strongest established genetic risk variants and a well-known measure of clinical disability. This study tests each variant individually, as well as two composite scores. While no genetic risk factor is associated with MS disease disability measured using the MSSS, previously established associations between gender and age of onset with MS progression are confirmed. These results substantiate that the genetic associations between susceptibility and progression in MS are distinct.

Chapter 4 focuses on a meta-analysis of smoking and MS disease progression. To date, there is controversy in the literature regarding the effects of smoking on MS progression. This study aims to incorporate all existing studies of smoking and disease progression in MS, as measured by time to transition from relapsing remitting (RR) MS to secondary progressive (SP) MS; time to transition from clinically isolated syndrome (CIS) to clinically definite (CD) MS; time to clinical measures of ambulatory assistance; mean difference in MSSS; mean difference in expanded disability status scale (EDSS); and two MRI measures. These results support an association between smoking and acceleration of disease progression.

Finally, Chapter 5 highlights the major findings of each chapter, provides a conclusion, and suggested future directions.