In this retrospective case series analysis, we found the prevalence of metabolic syndrome to be higher in our NZ cohort of MND patients compared with the general NZ population. Moreover, the presence of metabolic syndrome was associated with significantly worsened survival in MND, even after adjustment for age, gender, and ethnicity.

In our MND cohort, 34 patients (33%) had metabolic syndrome (33% of NZ Europeans, 46% of Māori), which is relatively high compared with the general NZ prevalence of 26% (16% of Europeans, 32% of Māori) that was observed by a large cross-sectional survey (Gentles et al. 2007). The much higher prevalence of metabolic syndrome amongst NZ Europeans in our MND cohort, compared to a neighbouring population, was striking. Although speculative, this finding may indicate that patients with metabolic syndrome are somehow metabolically predisposed to developing MND. Given the disposition of both metabolic syndrome and MND towards prominent metabolic and mitochondrial abnormalities, mitochondria dysfunction may constitute the underlying, shared pathology that predisposes a person to both disorders.

In our MND cohort, mean survival was significantly reduced in patients with metabolic syndrome compared to patients without metabolic syndrome (38 vs. 61 months). Even after adjusting for age, gender, and ethnicity, 5-year survival rates were significantly worse amongst the metabolic syndrome patients compared to those without metabolic syndrome (21% vs. 38%, hazard ratio 1.68). This considerable difference in survival time suggests a patient’s metabolic status may influence the rate of their MND progression. It has long been known that metabolic and mitochondria dysfunction are present during the early stages of ALS, which is associated with glucose intolerance (Ionǎşescu and Luca 1964; Nagano et al. 1979; Reyes et al. 1984), as well as inefficient adenosine triphosphate (ATP) production, increased oxidative stress, and a reduced ability to maintain energy and protein homeostasis (Smith et al. 2019; Valbuena et al. 2016), all of which could contribute to a more rapid progression of the degenerative process. Despite the substantial evidence of metabolic dysfunction in ALS, there have been conflicting reports on the effect of metabolic risk factors on ALS incidence and prognosis (Brito et al. 2019; Chiò et al. 2009; Dupuis et al. 2008; Kioumourtzoglou et al. 2015; O’Reilly et al. 2013; Mitchell et al. 2015; Moglia et al. 2017; Rafiq et al. 2015; Seelan et al. 2014; Sun et al. 2015; Tsai et al. 2019). However, most of these studies assessed individual factors without considering their combined interactive effect, and many of them performed little or no adjustment for factors known to affect incidence and survival (such as age, gender, and ethnicity). When assessed individually, the components of metabolic syndrome in our cohort were not associated with a significant difference in survival, which suggests that an overall combined metabolic risk profile, rather than individual risk factors, is the crucial factor associated with a worsened outcome. Importantly, nearly all the patients in our cohort passed away due to progression of their MND, rather than an unrelated disorder (except 1 patient, who died of a myocardial infarction rather than their MND), which argues against the possibility that patients with metabolic syndrome died as a result of the metabolic syndrome itself.

Although we detected a significant mean survival difference between NZ European and Māori patients with MND (50 vs. 94 months), the 5-year survival rates showed a non-significant (albeit borderline) trend towards prolonged survival in the latter population. This trend was an unexpected finding, particularly since the Māori patients in our cohort showed a higher prevalence of metabolic syndrome compared with European patients. Although this finding is interesting, given the small number of Māori patients in our cohort (11 patients), it is difficult to draw definitive conclusions about any potential impact of ethnicity on survival.

There were several strengths to this study. It is the first study to examine metabolic syndrome and its association with MND. Moreover, despite using stringent criteria for defining metabolic syndrome in our study population, we nevertheless found a significantly increased prevalence of metabolic syndrome in our cohort compared to the general NZ population.

Our study also had several limitations. First, since retrospective studies are unable to identify causal relationships, we are unable to comment on causality. Second, there were some limitations with respect to how the metabolic data was collected - given that it is not standard practice in our neurology department for MND patients to have either their weight circumference or fasting glucose level measured, we had to use surrogate markers, such as BMI (as a substitute for waist circumference) and HbA1c (for the fasting glucose level). Third, given the low number of Māori patients in our cohort, there was insufficient power to make any firm conclusions with respect to the observed survival differences based on ethnicity.

In conclusion, we have shown that metabolic syndrome is highly prevalent amongst MND patients in the Waikato region of NZ compared with the general NZ population. Moreover, metabolic syndrome is associated with considerably worsened survival in MND. These findings strengthen the possibility that metabolic and mitochondria dysfunction may be the crucial factors underlying the pathogenesis of MND. Although further observational studies are needed to corroborate our findings, prospective clinical trials will be crucial to determine whether therapies aimed at enhancing mitochondria function are capable of mitigating the pathological process in MND.