Biomedical factors in the risk and prognosis of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a relatively rare but incurable and relentlessly progressive neurodegenerative disease, characterized by motor neuron loss in the brain and spinal cord. Majority of patients die within 3-5 years after symptom onset, commonly due to respiratory failure. Until now, except for older age, male sex, family history, and specific genetic mutations, other risk factors of ALS remain largely unknown. Alterations in energy metabolism and neuroinflammation are known features of ALS, which can be directly or indirectly modulated by human gut microbiome and microbial metabolites. Gut microbiome and microbial metabolites have also been suggested to have a role in neurodegenerative disease through modulating the process of protein misfolding and aggregations and subsequently exacerbate disease phenotype. Exploring the association of biomedical factors related to gut microbiome alteration with the risk and prognosis of ALS might therefore help to elucidate the etiology of ALS. Further, as the survival of patients with ALS varies greatly, ranging from several months to more than 10 years, identification of prognostic predictors that are routinely measured in clinical practice might help to supervise treatment and improve patient care.

The first three studies focused on the etiology of ALS. Study I examined the association between previous gastrointestinal (GI) biopsy of normal mucosa and non-specific inflammation and risk of ALS in a matched cohort study based on ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden). After excluding the first two years of follow-up after the biopsy from analysis, we found that individuals with a GI biopsy result of normal mucosa had an increased risk of ALS, compared with their matched reference individuals randomly selected from the general population. However, no risk alteration was observed for a GI biopsy result of non-specific inflammation. Besides, a GI biopsy result of normal mucosa or non-specific inflammation was not related to mortality risk in patients with ALS. Study II analysed the potential role of antibiotic use on risk of ALS in a nested case-control study conducted using several Swedish national healthcare registers. After excluding all prescriptions within one year before diagnosis, patients with ALS were more likely to have antibiotic prescriptions before diagnosis, compared with controls, and there was a dose- response relationship between numbers of antibiotic prescriptions and ALS risk. Study III explored the association between hospital-treated infection and risk of three neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and ALS, in a nested case-control study conducted in the Swedish national healthcare registers. A hospital-treated infection was associated with an increased risk of AD and PD, regardless of infection type (bacterial, viral, or other infection) and site (central nervous system, gastrointestinal, or genitourinary infection). The associations were primarily noted among individuals younger than age 60. Moreover, individuals with multiple events of hospital-treated infections before age 40 appeared to have the greatest risk of developing AD and PD. However, no association was observed for ALS.

The fourth study focused on the use of routinely measured blood markers in the prognosis of ALS. Study IV assessed the predictive role of eight commonly measured blood markers on ALS prognosis in a population-based cohort study within the SCREAM (Stockholm CREAtinine Measurement) project. At the time of diagnosis, lower serum levels of creatinine and albumin, as well as higher serum levels of C-reactive protein (CRP) and glucose, were associated with an increased risk of mortality among ALS patients. After ALS diagnosis, decreasing serum levels of creatinine and albumin or increasing serum levels of CRP and glucose were indicative of an increased mortality risk.

In conclusion, findings from this thesis work support that specific biomedical factors such as previous GI dysfunction, antibiotic use, and hospital-treated infections are associated with the later risk of ALS development, as risk factors, triggers, or prodromal symptoms. Moreover, commonly measured biomedical markers can be of predictive value in ALS prognosis.