CSF phospho-tau levels at Parkinson’s disease onset predict the risk for development of motor complications

Background: Motor complications (MC), including fluctuations, represent a disabling milestone of Parkinson’s disease (PD) course, although the underlying early pathophysiological mechanisms remain unclear. We therefore investigated whether the biological profile at PD onset, as defined through a panel of CSF biomarkers, may predispose to the development of MC. Methods: We conducted a dual-center retrospective longitudinal study involving 131 de novo (DN) PD patients (newly diagnosed, untreated). At baseline, patients were evaluated by motor and non-motor scores, and the measurement of CSF total α-synuclein (α-syn), total and phosphorylated-181-tau (t-tau, p-tau), amyloid-β42 and amyloid-β40 (Aβ42, Aβ40) levels, p-tau/t-tau, Aβ42/Aβ40, and p-tau/Aβ42 ratios. According to the successive development of MC, patients were classified as “with MC” (wMC) or “without MC” (noMC). A control group of 107 controls was also collected. Variables were compared between groups, adjusting for main covariates; ROC and Cox analyses evaluated predictive values. Results: The DN PD cohort was followed for 57 (± 18) months, with 38 (29%) patients developing MC. At baseline, DN patients showed lower CSF total α-syn and t-tau levels than controls. The wMC group had higher p-tau, p-tau/t-tau, and p-tau/Aβ42 ratios than noMC. The p-tau/t-tau ratio best predicted MC development; above the cutoff of 0.148, MC were 2.6 times more likely with 81% sensitivity and 61% specificity (AUC = 0.79). Conclusions: Elevated CSF p-tau/t-tau ratio in DN PD patients predicts higher MC risk, supporting biomarker-based stratification for patients at onset. Our findings also highlight Alzheimer’s co-pathology, especially tauopathy, as a key factor in shaping PD motor progression from early stages.