Exploring TIMP2 genetics and CSF levels in Parkinson's disease: biomarkers of neurodegeneration and ageing.

PURPOSE: Matrix metalloproteinases (MMPs) regulate extracellular matrix remodeling and are implicated in neurodegeneration and brain ageing. Tissue inhibitor of metalloproteinase-2 (TIMP2) has been associated with hippocampal plasticity and cognitive function. We investigated whether cerebrospinal fluid (CSF) TIMP2 levels and genetic variants are associated with clinical features in Parkinson's disease (PD) and its continuum with dementia with Lewy bodies (DLB), with a particular focus on ageing-related processes. METHODS: CSF TIMP2 levels were analyzed in 480 patients with PD, 67 patients with DLB and 16 control participants. PD patients were stratified by GBA1 mutation status. Cross-sectional analyses included clinical scales and established CSF biomarkers (β-amyloid 1-42, h-TAU, p-TAU, neurofilament light chain (NfL) and α-synuclein). Longitudinal analyses assessed cognitive impairment and motor progression using TIMP2 tertiles and selected single nucleotide polymorphisms (SNPs) within the TIMP2 gene. RESULTS: CSF TIMP2 levels were positively associated with age and correlated with markers of neurodegeneration. Higher levels were observed in male PD patients compared to females and in female DLB GBA1 patients compared to controls. TIMP2 levels were not significantly associated with incidence or time to cognitive impairment. Higher TIMP2 levels were linked to increased postural instability in PD GBA1 patients. Exploratory genetic analyses suggested that specific SNPs (rs1384364, rs8068674) were associated with more favorable cognitive outcomes or delayed motor progression. CONCLUSIONS: CSF TIMP2 levels primarily reflect ageing-related processes associated with neurodegeneration rather than disease-specific effects. Genetic variation in TIMP2 may contribute to clinical heterogeneity. These findings support a role of extracellular matrix-related ageing mechanisms in PD and related disorders.