Association between cardiometabolic diseases and the risk and progression of motor neuron diseases in Sweden: a
Charilaos Chourpiliadis1, Anikó Lovik1,2, Christina Seitz1
1Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Insights
Diabetes and high cholesterol may lower motor neuron disease risk. However, cardiovascular diseases are linked to poorer MND progression and increased mortality. Further research is needed.
Area of Science:
- Neurology
- Cardiology
- Epidemiology
Background:
- Inconsistent evidence links cardiometabolic diseases (CMDs) with motor neuron diseases (MNDs).
- CMDs include various cardiovascular conditions, diabetes mellitus type 2, and hypercholesterolemia.
- Understanding this association is crucial for predicting MND risk and progression.
Purpose of the Study:
- To investigate the association between CMDs and the risk of developing MND.
- To determine if pre-diagnostic CMDs influence MND progression and mortality.
- To identify distinct MND patient phenotypes based on CMD prevalence.
Main Methods:
- A registry-based case-control study in Sweden included 1463 MND patients and 7311 population controls.
- Conditional logistic regression analyzed MND risk in relation to prior CMDs.
- Longitudinal-survival models assessed CMDs' impact on mortality and functional decline (ALSFRS-R).
- Hierarchical clustering identified MND patient subgroups.
Main Results:
- Diabetes mellitus type 2 and hypercholesterolemia were associated with a reduced risk of MND.
- Cardiovascular disease, arrhythmia, heart failure, and hypertension increased mortality risk post-MND diagnosis.
- Cluster analysis revealed distinct MND patient groups with varying CMD prevalence and prognosis.
Conclusions:
- Certain CMDs, like diabetes and hypercholesterolemia, may have a protective effect against MND development.
- Conversely, prevalent CMDs are indicators of poorer MND prognosis and increased mortality.
- Identifying CMDs can aid in stratifying MND patients for tailored management.
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.
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