Infections in the risk and prognosis of multiple sclerosis and amyotrophic lateral sclerosis

<p dir="ltr">Neurodegenerative diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) are incurable, progressive, and heterogeneous. In MS, autoimmune T- and B-cell attacks against central-nervous-system myelin initiate focal demyelination, axonal injury, and gliosis, leading to clinically evident relapses that may evolve into slowly progressive disability even without further overt inflammation. ALS, by contrast, is characterized by selective degeneration of upper and lower motor neurons accompanied by cytoplasmic TDP-43 aggregation, microglial activation, oxidative stress, and metabolic dysregulation, typically culminating in progressive muscle weakness and respiratory failure within 3-5 years of onset. Although a dysregulated immune response and low-grade neuroinflammation are well-recognized components of both conditions, the contribution of infections to their initiation and course remains unclear. In this thesis, we investigated the bidirectional links between infections and MS and ALS, including post-diagnosis infection risk (Study I), impact of infections on MS progression under different treatments (Study II), role of hospital-treated infections in ALS risk and prognosis (Study III), and subclinical infections detected via a serological screening in ALS (Study IV).</p><p dir="ltr">In Study I, we conducted both a community-based matched cohort and a twin study, using data from the UK Biobank and Swedish Twin Registry (UK Biobank: 2023 MS, 2200 Alzheimer's disease [AD], 3050 Parkinson's disease [PD] patients, and their individually matched healthy controls; Swedish Twin Registry: 230 twin pairs for the analysis of MS, 885 for AD, and 626 for PD). The aim was to investigate the incidence of serious infections following a diagnosis of MS, AD and PD, as well as the contribution of post-diagnostic infections on mortality after diagnosis of these conditions. Patients with MS, AD or PD exhibited significantly higher rates of hospital-treated infections after diagnosis compared to their matched healthy controls. Notably, an elevation in infection risk was already evident during the years preceding the diagnosis of these conditions, suggesting that immune alterations or preclinical disease processes may contribute to this early vulnerability. Causal mediation analysis indicated that infections experienced after diagnosis explained only a modest portion of the excess mortality risk associated with these diseases. In other words, while individuals with MS (and AD and PD) are more susceptible to infections, these infections only partially mediate the observed increase in mortality.</p><p dir="ltr">In Study II, we conducted a nationwide registry-based cohort study in Sweden to examine infection risk and disability worsening in MS patients receiving different disease-modifying therapies. This study included over 16,000 MS treatment episodes, comprising 8,759 with the B-cell-depleting antibody rituximab and 7,561 with injectable interferon-ß or glatiramer acetate (IFN/GA). Rituximab-treated patients had approximately double the risk of hospital-treated infections compared to those treated with IFN/GA. Hospital-treated infections were significantly associated with disability worsening, measured as an increase in the Expanded Disability Status Scale scores; this association was most pronounced in progressive MS and in patients treated with IFN/GA. Among patients with relapsing-remitting MS treated with IFN/GA, an inpatient-treated infection was associated with greater subsequent disability progression after adjustment for relapses and MRI activity, whereas no such association was observed in patients treated with rituximab. These findings highlight a trade-off between infection risk and disease control, namely that, to optimize long-term outcomes, clinicians must balance the risk of infection against the benefit of preventing disease progression. Highly effective therapies such as rituximab increase susceptibility to infections but offer superior protection against the accumulation of disability in MS.</p><p dir="ltr">In Study III, we conducted a nationwide nested case-control study using data from the Swedish Motor Neuron Disease Quality Registry to assess the role of infections in ALS. We identified all individuals newly diagnosed with ALS in Sweden between 2015 and 2023 and matched each case to three control groups: population controls and unaffected full siblings and spouses of ALS patients, thereby accounting for potential confounding by shared genetic and environmental factors between family members. The analysis showed that individuals who developed ALS were more likely to have a history of hospital-treated infections prior to diagnosis than controls, including population, sibling, and spouse controls. This finding suggests that previous serious infections are associated with an elevated risk of ALS, independent of familial background. Moreover, ALS patients with an experience of pre-diagnostic infections tended to present more frequently bulbar onset, lower functional status, and higher levels of anxiety and depressive symptoms at diagnosis. Following ALS diagnosis, the occurrence of a hospital-treated infection was associated with a higher mortality risk in ALS patients, whereas pre-diagnostic infections were not.</p><p dir="ltr">In Study IV, we used a multiplex serological screening to identify infectious exposures linked to ALS. Within the ALSrisc Study (Biomarkers and Risk Factors for Amyotrophic Lateral Sclerosis), we analyzed blood samples from 500 incident ALS patients and three control groups (105 sibling controls, 170 spouse controls, and 106 mimic controls with other neurological disorders) for antibodies to a broad panel of common pathogens. A higher overall pathogen burden, defined as the total number of seropositive pathogens, was associated with an increased ALS risk. Seropositivity of specific pathogens, particularly Helicobacter pylori and Chlamydia trachomatis, showed the strongest association with case status; other notable pathogens included human herpesvirus 2 (HHV-2), Epstein-Barr virus (EBV/HHV-4), HHV-6B, and Toxoplasma gondii. ALS patients with antibodies to these pathogens also tended to have poorer clinical profiles, including lower functional status at diagnosis; however, we found no strong evidence that these infections influenced post-diagnosis survival.</p><p dir="ltr">In conclusion, this thesis clarifies the bidirectional relationship between infections and both MS and ALS, highlighting an increased infection susceptibility before and after diagnosis as well as an impact of infection on the risk and progression of these diseases. These findings add novel evidence suggesting infections as modifiable elements that may shape neurodegenerative trajectories and represent potential targets for the development of new therapeutic approaches.</p><h3>List of scientific papers</h3><p dir="ltr">I. Yihan Hu, Kejia Hu, Huan Song, Yudi Pawitan, Fredrik Piehl, Fang Fang. Infections among individuals with multiple sclerosis, Alzheimer's disease and Parkinson's disease. Brain Commun. 2023;5(2):fcad065. <a href="https://doi.org/10.1093/braincomms/fcad065" rel="noreferrer" target="_blank">https://doi.org/10.1093/braincomms/fcad065</a></p><p dir="ltr">II. Yihan Hu, Thomas Frisell, Peter Alping, Huan Song, Yudi Pawitan, Fang Fang, Fredrik Piehl. Hospital-Treated Infections and Risk of Disability Worsening in Multiple Sclerosis. Ann Neurol. 2024;96(4):694-703. <a href="https://doi.org/10.1002/ana.27026" rel="noreferrer" target="_blank">https://doi.org/10.1002/ana.27026</a></p><p dir="ltr">III. Yihan Hu, Charilaos Chourpiliadis, Caroline Ingre, Viktor H. Ahlqvist, Jiangwei Sun, Huan Song, Yudi Pawitan, Fredrik Piehl, Fang Fang. Hospital-treated infections and the risk and prognosis of amyotrophic lateral sclerosis: A population-based study. J Intern Med. 2025 Aug 5. <a href="https://doi.org/10.1111/joim.70008" rel="noreferrer" target="_blank">https://doi.org/10.1111/joim.70008</a></p><p dir="ltr">IV. Yihan Hu, Caroline Ingre, Birgitta E. Michels, Christina Seitz, Rayomand Press, Kristin Samuelsson, John Andersson, Huan Song, Yudi Pawitan, Pentti J. Tienari, Pascal Falter-Braun, Fredrik Piehl, Tim Waterboer, Fang Fang. Infections and risk and prognosis of amyotrophic lateral sclerosis: a serological screening. [Manuscript]</p>