Dopamine Metabolite Biomarkers and Testing for Disease Modification in Parkinson Disease

Abstract

efits (as assessed by changes in scores of the Mini-Mental State Examination and the Bristol Activities of Daily Living scale) in a cohort of persons with a diagnosis of early AD. The rationale for the investigation of minocycline stems from preclinical evidence supporting the notion that the drug targets critical determinants of AD-like β-amyloid, hyperphosphorylated tau, and microglia activation and neuroinflammation.Disappointingly, but possibly not surprisingly, the drug failed to prove beneficial effects. However, we believe that valuable information can be still inferred from the study. The authors proposed 3 mechanisms (negligible contribution of neuroinflammation in the early stages of AD, insufficient drug dosage, and modest and undetectable effects) that may have negatively affected the positive effects of the compound.In our opinion, an additional angle should be considered: the association of minocycline activity with metalloproteinases. Matrix metalloproteinases (MMPs) are a broad class of calcium-and zinc-dependent endopeptidases involved in matrix remodeling and the modulation of cell-matrix interaction. Among the 24 MMPs identified, minocycline is a potent inhibitor of This inhibitory activity is critical, as MMP-9 is highly expressed in the central and peripheral nervous system and is integral in the modulation of brain development as well as neurodegenerative processes. Preclinical data indicate that MMP-9 is released in a neuronal activity-dependent manner and contributes to learning, memory, and neuronal plasticity by promoting dendritic spine remodelling. 3 Furthermore, MMP-9 contributes to the cleavage of the brainderived neurotrophic factor (BDNF) into its mature, active, counterpart. 4 Preclinical and clinical data indicate that alterations of BDNF-associated signaling largely affect the neurodegenerative and cognitive aspects of AD. 5 Thus, it is quite possible that, in the study by Howard and colleagues, 1 the beneficial effects of minocycline have been occluded by the drug-driven MMP-dependent inhibition of the BDNF neurotrophic drive.This possibility should be tested if the authors have collected blood samples from the study participants. The analysis should be conducted because pinpointing the failure to a drug-driven negative modulation of BDNF signaling may help to further highlight the need to therapeutically address the modulation of this critical process.