Metabolic disorders in the etiology of amyotrophic lateral sclerosis : an epidemiological approach

Sammanfattning: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a loss of motor neurons in the brain and spinal cord, leading to progressive muscle weakness in multiple regions of the body. No effective treatment is available and the disease progresses rapidly to death with an average survival time of 3-5 years after symptom onset. The etiology of ALS is unknown for the majority of the patients. Alterations in the carbohydrate and lipid metabolisms, together with hypermetabolism, are features of ALS patients that are not yet well characterized. Understanding the early metabolic symptoms of the disease might be a necessary step for the identification of an effective treatment. Paper I describes a nested case-control study on the association between diabetes and the future risk of ALS in the Swedish population. A total of 5,108 new ALS cases among the Swedish residents between 1991 and 2010 were identified from the National Patient Register. Through linkages to several nationwide Swedish registers five controls per case were selected from the entire Swedish population using incidence density sampling and diabetes diagnoses were identified for both cases and controls from hospital admission records, outpatient care records, prescription of antidiabetics, or a combination of the three. An overall inverse association between diabetes and risk of ALS was found. There was however a positive association between insulin-dependent diabetes before age 30 and ALS risk. Paper II describes the association between body mass index (BMI), BMI change and ALS risk and survival in the GENEVA study, a case-control study of United States military veterans. Self-reported BMI at age 25, 40 and at time of ALS diagnosis (interview for controls) was compared. Low BMI at age 40 was associated with increased risk of developing ALS and the association was stronger for cases with diagnostic delay shorter than one year. Stable or decreasing BMI between age 25 and 40 was also associated with higher risk of ALS compared to an increasing BMI. However, premorbid BMI and BMI change did not predict survival of ALS patients. Paper III describes the association between ALS risk and serum glucose, total cholesterol, LDL-C, HDL-C, triglycerides, apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I) in a Swedish populationbased cohort study. High LDL-C, apoB and the LDL-C/HDL-C and apoB/apoA-I ratios were associated with a higher incidence of ALS. These associations seemed to be mainly due to a strong association of apoB with ALS risk. High glucose level ( 6.11 mmol/L) was associated with a lower incidence of ALS. During the 10 years before diagnosis, ALS patients had increasing levels of LDL-C, HDL-C, apoB and apoA-I, whereas gradually decreasing levels of LDL-C/HDL-C and apoB/apoA-I ratios. Paper IV describes a population-based nested case-control study of 2,475 Swedish residents diagnosed with ALS during July 2006-December 2013, and 12,375 population controls. Information on filled prescriptions of antidiabetics and statins were extracted from the Swedish Prescribed Drug Register. Antidiabetics were associated with a lower ALS risk, the association was stronger for men, for individuals above age 65, and for ALS with longer disease duration. Statins were not associated with ALS risk overall, though a positive association was noted among women. The latter association was mostly explained by increased statins use during the year before ALS diagnosis. The studies presented in this thesis have taken advantage of different study designs and populations to systematically investigate the relationship between metabolic disorders and ALS risk and, to a lesser extent, progression. Therefore, they contributed substantially to fill the knowledge gap about the association between metabolic disorders and neurodegeneration in ALS. Furthermore, Paper I and Paper IV serve as excellent examples of the unique possibilities offered by the nationwide health registers in Sweden that can, when equipped with modern analytical methods, contribute to the understanding of complex diseases.