Is Tau the Initial Pathology in Dopaminergic Nigrostriatal Degeneration? Studies in Parkinsonism and Parkinson’s Disease

Abstract

While Parkinson ′ disease(PD) remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that PD consists of multiple pathologies, but it is unclear which occurs first and which are responsible for the nigrostriatal degeneration. For the past number of years, we have been studying a well-characterized cohort of subjects with motor impairment that we have termed mild motor deficits (MMD). Motor deficits were determined on a modified and validated Unified Parkinson ′ Disease Rating Scale III (UPDRS III), but they occur to a degree insufficient to diagnose PD. We consider this population to have prodromal PD. However, in past studies, cases in this cohort had a selection bias as both a clinical syndrome in between no motor deficits and PD, plus nigral Lewy pathology as defined post-mortem, were required for inclusion. Therefore, in this study, we only based inclusion on a clinical phenotype intermediate between no motor impairment and PD. Then, we divided this group further based upon whether or not they had a synucleinopathy. Here we demonstrate that loss of nigral dopaminergic neurons, loss of putamenal dopaminergic innervation, loss of TH-phenotype in the substantia nigra and putamen, and changes in axonal transport occur equally in groups with and without nigral alpha-synuclein aggregates. Indeed, the common feature of these two groups is that both have similar degrees of AT8-expressing phospho-tau, a pathology not seen in the nigrostriatal system of aged-matched controls. These finding were confirmed with early (CP13) and late (PHF1) tau markers. This suggests that the initiation of nigrostriatal dopaminergic neurodegeneration occurs independently of alpha-synuclein aggregation and is likely tau mediated.

Perspective on the current state of the LRRK2 field

“…They suggest that tau is not an independent disease factor in LRRK2 PD, but is associated with the degree of α-synuclein pathology and progression to dementia 101 . Moreover, there is recent data that goes one step further, suggesting that the initiation of dopaminergic neurodegeneration occurs independently of α-synuclein aggregation and is likely tau mediated 102 . The lower incidence of α-synuclein pathology has recently been addressed in ante-mortem CSF samples using α-synuclein seeding amplification assays 94 , 103 , where positive signal was observed in only 40–78% of LRRK2 mutation carriers.…”

“…It could be beneficial to stratify the mutation carriers based on these pathologies with respect to future clinical trials, particularly if additional data were to emerge that provides clearer links between disease progression and one or more co-pathologies. The availability of Tau imaging agents 102 and the potential utility of blood-based assays to measure specific Tau species 104 , could enable this, indeed there are already efforts to image Tau in G2019S subjects (ClinicalTrials.gov Identifier: NCT04557865).…”