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

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.