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. New clinical criteria, CSF, MRI, and PET biomarkers 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.

Keywords: Alzheimer’s disease; Gene therapy; Immunotherapy; Progressive supranuclear palsy; Tau-PET; Tauopathy.

Fig. 1

The importance of autopsy confirmation in improvement of diagnosis and treatment of tauopathies. Figure depicts clinicopathological associations of the three main FTLD-Tau neuropathologies found at autopsy with clinical syndromes. Solid lines represent the strongest associations (i.e., PiD with bvFTD, CBD with CBS, and PSP with PSPS) and dashed lines represent less frequent associations. Color shading of clinical phenotype boxes depict the relative frequencies of neuropathologies found at autopsy in each syndrome (red FTLD-Tau, blue FTLD-TDP, yellow AD) and photomicrographs in each neuropathology box depict characteristic inclusion morphologies (PiD Pick bodies, CBD astrocytic plaque, PSP tufted astrocyte). Schematic illustrates how detailed multimodal evaluations of patients with longitudinal clinical, biofluid, and neuroimaging assessments followed to autopsy can improve existing clinical criteria for detection of FTLD-Tau and differentiation from other neurodegenerative diseases and provide tissue validation for biomarkers obtained during life. Autopsy tissues also provide critical source of human-derived pathogenic tau species for use in animal/cell models of disease and therapeutic response to accelerate the development of disease modifying therapies. naPPA non-fluent agrammatic variant of primary progressive aphasia, svPPA semantic variant of primary progressive aphasia