Cerebrospinal fluid tau and disease progression in early Parkinson's disease: an 8-year longitudinal study.

Objective: To explore whether CSF phosphorylated tau-181 (P-tau181) and total tau (T-tau) are associated with disease progression in early PD patients.

Methods: We analyzed 8-year longitudinal clinical data from 368 early, drug-naive PD patients and 185 matched controls from the Parkinson's Progression Markers Initiative cohort. CSF P-tau181 and T-tau were measured over 5 years, while CSF α-synuclein was measured over 3 years. Dopamine transporter (DAT) imaging was performed at baseline and at 1, 2, and 4 years.

Results: PD patients exhibited significantly lower CSF P-tau181, T-tau and P-tau181/T-tau ratio than controls at each visit. Higher baseline CSF P-tau181 predicted greater increases in Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III (estimate: 0.067, P < 0.001) and Montreal Cognitive Assessment (MoCA) scores (estimate: -0.010, P = 0.009). Similarly, higher baseline CSF T-tau predicted greater increases in MDS-UPDRS III (estimate: 0.005, P < 0.001) and MoCA scores (estimate: -0.001, P = 0.013). Higher baseline P-tau181/T-tau ratio predicted greater increases in MDS-UPDRS III (estimate: 0.552, P < 0.001) but was not significantly associated with changes in MoCA scores (estimate: -0.052, P = 0.114). CSF P-tau181 (estimate = 84.889, P < 0.001), T-tau (estimate = 8.297, P < 0.001) and P-tau181/T-tau ratio (estimate = 263.425, P < 0.001) were positively correlated with CSF α-synuclein but not correlated with striatal DAT uptake.

Conclusions: Elevated baseline CSF P-tau181, T-tau and P-tau181/T-tau ratio in early PD patients predict accelerated motor deterioration, with P-tau181 and T-tau also predicting cognitive decline, potentially through interactions with α-synuclein. However, the direct role of tau on nigrostriatal dopaminergic degeneration remains uncertain.