Association between cardiometabolic diseases and the risk and progression of motor neuron diseases in Sweden: a population-based case-control study

Charilaos Chourpiliadis; Anikó Lovik; Christina Seitz; Yihan Hu; Jing Wu; Petter Ljungman; Rayomand Press; Kristin Samuelsson; Caroline Ingre; Fang Fang

doi:10.1016/j.lanepe.2024.101173

Association between cardiometabolic diseases and the risk and progression of motor neuron diseases in Sweden: a population-based case-control study

Lancet Reg Health Eur. 2024 Dec 10:49:101173. doi: 10.1016/j.lanepe.2024.101173. eCollection 2025 Feb.

Authors

Charilaos Chourpiliadis¹, Anikó Lovik^{1

2}, Christina Seitz¹, Yihan Hu¹, Jing Wu¹, Petter Ljungman^{1

3}, Rayomand Press^{4

5}, Kristin Samuelsson^{4

5}, Caroline Ingre^{4

5}, Fang Fang¹

Affiliations

¹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
² Institute of Psychology, Leiden University, Leiden, the Netherlands.
³ Department of Cardiology and Clinical Physiology, Danderyd Hospital, Stockholm, Sweden.
⁴ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁵ Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.

Abstract

Background: The evidence on the link between cardiometabolic diseases (CMDs) and motor neuron diseases (MNDs) remains inconsistent. We aimed to determine whether there is an association of CMDs, namely, any cardiovascular disease, cardiac arrhythmia, heart failure, thromboembolic disease, hypertension, cerebrovascular disease, ischemic heart disease, diabetes mellitus type 2, and hypercholesterolemia with the risk and progression of MNDs.

Methods: We included 1463 MND patients (amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive spinal muscular atrophy (PSMA), and unspecified MND) diagnosed from January 1, 2015, to July 1, 2023, in Sweden according to the Swedish Motor Neuron Disease Quality Registry (i.e., cases), up to 5 MND-free population controls per case (N = 7311) who were individually matched to the cases on age and sex, and the full siblings (N = 2002) and spouses (N = 1220) of MND patients (i.e., relative controls). Conditional logistic regression models were used to estimate the risk of MND diagnosis in relation to previous CMDs, through comparing MND patients to population controls or relative controls. MND patients were followed from diagnosis to assess the role of pre-diagnostic CMDs on disease progression. A joint longitudinal-survival model was used to estimate risk of mortality (or use of invasive ventilation) in relation to CMDs after taking into account the longitudinal changes of ALS functional rating scale-revised (ALSFRS-R) in the time-to-event analysis. Hierarchical clustering with the Ward's linkage and a dissimilarity matrix created by Gower's method was used to identify clusters of MND patients with distinct phenotypes.

Findings: Among the CMDs studied, a history of diabetes mellitus type 2 (OR 0.75; 95% CI 0.62, 0.93) or hypercholesterolemia (OR 0.82; 95% CI 0.71, 0.94) more than one year before diagnosis was associated with a lower risk for MNDs. The associations persisted for more than five years before MND diagnosis. MND patients with a history of any cardiovascular disease (HR 1.43; 95% CI 1.13, 1.81), arrhythmia (HR 1.42; 95% CI 1.04, 1.93), heart failure (HR 1.79; 95% CI 1.02, 3.14), hypertension (HR 1.41; 95% CI 1.12, 1.77), or hypercholesterolemia (HR 1.28; 95% CI 1.01, 1.62) had an increased mortality risk, compared to others, after taking into consideration the longitudinal changes in ALSFRS-R. Cluster analysis identified two clusters of MND patients, where one cluster demonstrated higher age, worse functional status, and higher prevalence of CMDs at the time of diagnosis as well as a higher mortality and faster functional decline during follow-up, compared to the ones included in the other cluster.

Interpretation: Diabetes mellitus type 2 and hypercholesterolemia were associated with a lower future risk of MND. On the other hand, most of the CMDs were indicative of a poor disease progression after an MND diagnosis.

Funding: European Research Council, US Center for Disease Control and Prevention, Swedish Research Council.

Keywords: Amyotrophic lateral sclerosis; Cardiac arrhythmia; Cardiometabolic diseases; Cerebrovascular disease; Diabetes mellitus type 2; Heart failure; Hypercholesterolemia; Hypertension; Ischemic heart disease; Thromboembolic disease.