Association of long-term glycemic variability with longitudinal motor and nonmotor progression in patients with Parkinson’s disease: an 8-year follow-up

Abstract Background Although recent evidence suggests that glycemic variability (GV) has a negative impact on neurodegeneration, its role in Parkinson’s disease (PD) remains unclear. Objective To explore the association between long-term GV and longitudinal motor and nonmotor progression in patients with PD and to uncover the disease-specific and nonspecific mechanisms underlying this association. Methods We used data obtained from the Parkinson’s Progression Markers Initiative cohort. Three hundred seventy-seven patients with early untreated PD underwent annual motor and nonmotor assessments covering neuropsychiatric, sleep-related, and autonomic symptoms for up to 8 years of follow-up. Dopamine transporter (DAT) imaging results and cerebrospinal fluid (CSF) marker levels, including α-synuclein, β-amyloid 1–42, total tau, phosphorylated tau181, and neurofilament light chain (NfL) were collected at baseline and for up to 6 years of follow-up. We defined GV as the intra-individual visit-to-visit variability in annual fasting blood glucose levels. Results With respect to motor symptoms, a greater GV was associated with a greater increase in postural instability/gait difficulty scores (P = .001) and a greater risk of developing freezing of gait (P = .002). With respect to nonmotor symptoms, higher GV was associated with a steeper decrease in Montreal Cognitive Assessment (P < .001) and semantic fluency test (P = .002) scores and a greater increase in Geriatric Depression Scale scores (P = .001). With respect to DAT imaging and CSF biomarkers, increased GV was associated with a greater increase in CSF NfL levels (P = .001) but not with other biomarker changes. Conclusion Our findings suggest that increased GV is related to unfavourable motor and nonmotor outcomes in patients with PD. However, we did not identify the specific mechanisms underlying these GV-related effects, despite its association with more severe neurodegeneration.