Antecedent Disease and Amyotrophic Lateral Sclerosis: What Is Protecting Whom?

Abstract

Multiple studies have shown that antecedent diseases are less prevalent in amyotrophic lateral sclerosis (ALS) patients than the general age-matched population, which suggests possible neuroprotection. Antecedent disease could be protective against ALS or, conversely, the asymptomatic early physiological underpinnings of ALS could be protective against other antecedent disease. Elucidating the impact of antecedent disease on ALS is critical for assessing diagnostic risk factors, prognostic outcomes, and intervention timing. The objective of this study was to examine the relationship between antecedent conditions and ALS onset age and disease duration (i.e. survival). Medical history surveys for 1439 Emory ALS Clinic patients (Atlanta, GA, USA) were assessed for antecedent hypertension, hyperlipidemia, diabetes, obesity, asthma, arthritis, chronic obstructive pulmonary disease (COPD), thyroid, kidney, liver, and other non-ALS neurological diseases. The ALS onset age and disease duration are compared between the antecedent and non-antecedent populations using chi square, Kaplan–Meier, and ordinal logistic regression. When controlled for confounders, antecedent hypertension (high blood pressure), hyperlipidemia (high cholesterol), arthritis, COPD, thyroid disease, and non-ALS neurological disease are found to be statistically associated with a delayed ALS onset age, whereas antecedent obesity [body mass index (BMI) > 30] was correlated to earlier ALS onset age. With the potential exceptions of liver disease and diabetes (the latter without other common comorbid conditions), antecedent disease is associated with overall shorter ALS disease duration. The unique potential relationship between antecedent liver disease and longer ALS disease duration warrants further investigation, especially given liver disease was found to be a factor of 4–7 times less prevalent in ALS. Notably, most conditions associated with delayed ALS onset are also associated with shorter disease duration. Pathological homeostatic instability exacerbated by hypervigilant regulation (over-zealous homeostatic regulation due to too high regulatory feedback gains) is a viable hypothesis for explaining the early-life protection against antecedent disease and the overall lower antecedent disease prevalence in ALS patients; the later ALS onset age in patients with antecedent disease; and the inverse relationship between ALS onset age and disease duration.

Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis

“…These conflicting results may be mainly due to methodological issues concerning the design and population of the study (single ALS centre cohort , case‐control study , population‐based register study , multiple ALS centre cohort in the present study), sample size (from 111 to 1439 patients with ALS and 2354 in our study) and study duration (covering a variable period up to 15 years ). Other methodological issues concern variables that have been taken into account: diverse diseases in some studies and only arterial hypertension and other cardiovascular diseases/risk factors in other studies. In contrast, our study considered almost all possible comorbidities and clinical diagnoses as indicated by referring neurologists, conferring more comprehensiveness to the assessment of comorbidities.…”

“…To the best of our knowledge, only a few studies have considered the possible prognostic role of comorbidities related to the cardiovascular system. Hypertension was related to a late ALS onset in a cohort of 1439 patients, but none of the examined comorbidities significantly affected survival . Another study found that the presence of hypertension and coronary heart disease was associated with shorter survival at univariate analysis, findings that were not confirmed in multivariable analysis.…”

Epidemiology of Amyotrophic Lateral Sclerosis: A Population-Based Study in Israel

“…A low CKD prevalence is also consistent with ALS patients' significantly lower BMI. While there is no clear trend regarding the prevalence of comorbidities in our ALS study, the question of ‘what is protecting whom' [19] warrants further investigation.…”

Blood biomarkers of carbohydrate, lipid, and apolipoprotein metabolisms and risk of amyotrophic lateral sclerosis: A more than 20‐year follow‐up of the Swedish AMORIS cohort

“…Given their high energy demand, motor neurons may be more sensitive than other cell types to energy deficits . An unfavourable vascular risk profile (eg, obesity and type 2 diabetes) has indeed been associated with a lower risk of ALS . Increased energy need may also simply constitute a compensatory mechanism secondary to neurodegeneration.…”