Emerging Diagnostic and Therapeutic Strategies for Tauopathies

Abstract

Purpose of Review Tauopathies represent a spectrum of incurable and progressive age-associated neurodegenerative diseases that currently are diagnosed definitively only at autopsy. Few clinical diagnoses, such as classic Richardson’s syndrome of progressive supranuclear palsy, are specific for underlying tauopathy and no clinical syndrome is fully sensitive to reliably identify all forms of clinically manifest tauopathy. Thus, a major unmet need for the development and implementation of tau-targeted therapies is precise antemortem diagnosis. This article reviews new and emerging diagnostic therapies for tauopathies including novel imaging techniques and biomarkers and also reviews recent tau therapeutics. Recent Findings Building evidence from animal and cell models suggests that prion-like misfolding and propagation of pathogenic tau proteins between brain cells are central to the neurodegenerative process. These rapidly growing developments build rationale and motivation for the development of therapeutics targeting this mechanism through altering phosphorylation and other post-translational modifications of the tau protein, blocking aggregation and spread using small molecular compounds or immunotherapy and reducing or silencing expression of the MAPT tau gene. Summary New clinical criteria, CSF, MRI, and PET bio-markers will aid in identifying tauopathies earlier and more accurately which will aid in selection for new clinical trials which focus on a variety of agents including immunotherapy and gene silencing.

Manganese-Enhanced Magnetic Resonance Imaging: Overview and Central Nervous System Applications With a Focus on Neurodegeneration

“…Confirmed diagnoses for tauopathies cannot be made until post-mortem examination confirms histopathology. This major obstacle in the diagnosis of tauopathies compounds with the problem that appropriate therapies for one type of tauopathy likely will not be effective for another (Coughlin and Irwin, 2017), establishing the importance of identifying the tauopathy as early as possible.…”

Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1

“…It has been shown by many groups that cerebrospinal fluid (CSF) levels of tau and pTyr181 tau increase in AD but not in various other tauopathies, compared to normal controls [58–60]. This consistent finding suggests that extracellular tau is unlikely to be an important component of tau pathogenesis in non-AD tauopathies.…”

Novel monoclonal antibodies targeting the microtubule-binding domain of human tau

“…At present, there are no effective therapeutic strategies available to target tauopathies [ 36 ]. There have been numerous failures in anti-Aβ therapies for AD [ 37 ], and the correlation between cognitive decline and tau pathology in human AD [ 5 ] has driven interest to target tau pathology in AD.…”