Diabetes Linked With Increased Levels of Neurofilament Light, Neuroaxonal Damage in Parkinson Disease

Thomas Foltynie, MD, PhD, MRCP

Confirming previous reports, new post hoc data from a recently published study showed an association between Parkinson disease (PD), diabetes mellitus (DM), and more severe neuroaxonal damage.¹

The analysis, which included 280 patients with PD, 29 of whom suffered from prevalent type 2 diabetes, found significant associations between neurofilament light (NfL) and patients’ diabetic status (coefficient, 0.82; 95% CI, 0.45-1.19; P <.0001). Using regression models, these associations persisted (coefficient, 0.52; 95% CI, 0.18-0.86; P = .003) after adjustment for age, BMI, and vascular risk factors such as history of angina, myocardial infarction, stroke, hypertension, and hypercholesterolemia.

"[Type 2 DM] and PD share several pathological processes encompassing neuroinflammation, lysosomal dysfunction, mitochondrial dysfunction, and the development of central insulin resistance that leads to neurodegeneration,” senior investigator Thomas Foltynie, PhD, professor of neurology, UCL London, and colleagues wrote. “Disentangling the mechanistic factors that contribute to this more rapidly progressive axonal damage is of critical importance in the development of disease-modifying therapies for PD."

The Tracking Parkinson’s study, first published online in July 2022, aimed to determine if blood biomarkers and genetic status are useful in addition to clinical measures for prognostic modelling in PD. Less than a few months later, the new analysis included a previously defined subgroup of the trial to explore the relationship between serum NfL and diabetes. The findings of the MARK-PD study, which first linked diabetes and high hemoglobin (HbA1c) to increased neuroaxonal damage and cognitive impairment in patients with PD, were a consideration for conducting this current study.

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Differences between groups were compared using Kruskal-Wallis tests for continuous data and X2 tests for categorical data, whereas the association between NfL and DM was further explored using univariate and multivariate linear regression analyses. All told, those with PD and DM were older (74.1 years [±7.7] vs 68.1 years [±8.7]; P <.001) and had higher BMIs (31.1 [±5.7] vs 27.1 [±4.4]; P <.001). Additionally, more patients with DM had coexistent vascular risk factors (P = .032) and had higher serum NfL levels (39.5 [±18.9] vs 29.6 [±16.0]; P <.001) than those without DM.

In June 2022, data from a subcohort of the MARK-PD study including 195 patients with PD with available HbA1c measurements were published.2 In unadjusted linear regression analysis, prevalent diabetes or HbA1c levels were inversely associated with cognition, assessed using Montreal Cognitive Assessment (MoCA) scores; however, this association only remained significant for prevalent diabetes after adjustment. Furthermore, investigators found a significant association of prevalent diabetes with Hoehn and Yagr stages in unadjusted and age- and BMI-adjusted models, which revealed only a trend after adjustment for vascular risk factors (P = .079).²

Additional data from unadjusted regression models showed that diabetes was associated with higher serum NfL levels in patients with PD, which remained significant after adjustment for BMI, prevalent hypertension, hypercholesterolemia, and history of history. Although HbA1c levels were significantly correlated with NfL levels in age and BMI-adjusted models, this association revealed only a trend after adjustment for vascular risk factors. Investigators from the MARK-PD study concluded that, "Taken together, our data suggest increased neuroaxonal damage in PD patients with diabetes independent of vascular risk factors, whereas the association of high HbA1c with neuroaxonal damage is not independent of vascular risk factors. Hyperglycemia might explain some, but not all, of the association of diabetes with PD."²

REFERENCES
1. Vijaratnam N, Lawton M, Real R, et al. Diabetes and neuroaxonal damage in Parkinson’s disease. Mov Disord. Published online July 20, 2022. doi:10.1002/mds.29067
2. Uyar M, Lezius S, Buhmann C, et al. Diabetes, glycated hemoglobin (HbA1c) and neuroaxonal damage in Parkinson disease (MARK-PD study). Mov Disord. 2022;37(6):1299-1304. doi:10.1002/mds.29009