Amyotrophic lateral sclerosis and multiple sclerosis associated neuroinflammation : nationwide epidemiological studies on etiology, comorbidities, and treatment

Abstract: Amyotrophic lateral sclerosis (ALS) is a relatively rare but fatal neurodegenerative disease characterized by progressive muscle paralysis, due to loss of upper and lower motor neurons. Signs of neuroinflammation have been reported in ALS, however it is still unknown whether neuroinflammation is a cause or a consequence of the motor neuron dysfunction. Neuroinflammation may also be one of the mechanisms underlying the overlap between ALS and other neurological, neuromuscular, and psychiatric disorders. Among neuromuscular disorders, the most studied disorder in association with ALS is multiple sclerosis (MS). MS is a complex disease of the central nervous system (CNS) characterized by chronic inflammation, demyelination, and neurodegeneration. A link between MS and psychiatric disorders has also been proposed. In this thesis we explored the associations of different correlates of neuroinflammation, including physical and cognitive fitness in early life (Study I), neurodegenerative and psychiatric disorders (Study II), neuromuscular diseases (Study III), depression and antidepressants use (Study IV) with the risks of either ALS or MS. In Study I, we investigated the association between physical and cognitive fitness in young adulthood with future risk of ALS. The study population included 1,838,376 Swedish men aged 17-20. Information on physical fitness, body mass index (BMI), intelligence quotient (IQ), and stress resilience was retrieved from the Swedish Conscription Register between 1968 and 2010. Information on subsequent ALS diagnosis was retrieved from the Swedish Patient Register. There were 439 incident cases of ALS during follow-up. Higher physical fitness was associated with an increased risk of ALS before age 45, while higher BMI tended to be associated with a lower risk of ALS at all ages. Higher IQ was associated with an increased risk of ALS at age 56 and onwards, whereas higher stress resilience was associated with a lower risk of ALS at age 55 and earlier. These results indicate that physical fitness, BMI, IQ, and stress resilience in young adulthood are associated with the development of early onset ALS. In Study II, we examined the risk of neurodegenerative and psychiatric disorders among individuals with ALS, compared to individuals free of the disease. The study population included 3,648 individuals with ALS and 36,480 age-, sex-, and county-of-birth-matched controls from the general population. In addition, we estimated the risk of neurodegenerative and psychiatric diseases among the relatives of ALS patients, compared to the relatives of the controls, to assess the potential contribution of familial factors. Individuals with previous neurodegenerative or psychiatric diseases had an increased risk of ALS, compared to individuals who did not have these diseases. After diagnosis, ALS patients had increased risks of neurodegenerative or psychiatric diseases, compared to individuals free of ALS. First-degree relatives of individuals with ALS had higher risk of neurodegenerative diseases compared to relatives of controls. Children of ALS patients had higher risk of psychiatric disorders, compared to children of controls. The increased risk of neurodegenerative disorders among relatives of ALS patients may be attributable to the overlapping etiopathogenesis of different neurodegenerative diseases. The increased risk of psychiatric disorders among ALS patients and their children may be due to non-motor symptoms of ALS or a severe stress response after the diagnosis of ALS. In Study III, we aimed at validating the co-occurrence of ALS and other neuromuscular diseases, investigating the temporal relationship between the diagnoses and clinical characteristics of patients with both ALS and other neuromuscular diseases. Using information from the Swedish Patient Register, we identified all patients diagnosed with ALS in Sweden between 1991 and 2014, who had also a concurrent MS, myasthenia gravis (MG), inflammatory polyneuropathies (IP), or dermatopolymyositis (DMPM). The group included 263 patients. We validated medical records for 92% of these patients to confirm the overlap. Then, we compared patients with a confirmed overlap (N=28) with an independent sample of patients with only ALS (N=271). Among the patients with a validated overlap, 12 had a confirmed diagnosis of MS, nine a confirmed diagnosis of MG, four a confirmed diagnosis of IP, and three a confirmed diagnosis of DMPM. Seventy-nine percent of the patients with a confirmed overlap had these diagnoses prior to ALS. Compared to patients with only ALS, patients with a confirmed overlap were older at symptoms onset, had higher prevalence of bulbar onset, but used riluzole and non-invasive ventilation less frequently. These results show that neuroinflammation around the motor unit might trigger ALS in a small subgroup of patients. In Study IV, we estimated the risk of depression and antidepressants prescription among patients with relapsing-remitting MS (RRMS) and explored the bi-directional relationship between different disease modulatory therapies (DMTs) and depression or antidepressants use. We included 4,867 patients with RRMS who were diagnosed in Sweden between January 2005 and September 2018 and did not have a diagnosis of depression or antidepressants prescription before initiation of their first DMT. We compared the risk of depression (defined by diagnosis or antidepressants prescription) in relation to different DMTs, using interferons as the reference and examined DMT discontinuation or relapse in relation to depression. RRMS patients treated with rituximab had a decreased risk of depression, compared to patients treated with interferons. No differences were found for other DMTs examined (dimethyl fumarate, fingolimod, and natalizumab), compared to interferons. Depression was not associated with the risk of DMT discontinuation or MS relapse. These results provide evidence for a lower risk of depression among RRMS patients treated with rituximab, compared to interferons. In conclusion, results from the studies included in this thesis support the notion that neuroinflammation might precede the onset of ALS. In addition, different neurodegenerative diseases might share common disease mechanisms including neuroinflammation. The reduced risk of depression in relation to treatment with rituximab among patients with RRMS also suggests that neuroinflammation might underlie the link between psychiatric disorders and neurodegenerative diseases because rituximab may modulate both the MS- and depression- related inflammation.

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