Tauopathies as clinicopathological entities.

Tauopathies are a class of neurodegenerative disorders characterized by neuronal and/or glial inclusions composed of the microtubule-binding protein, tau. Several lines of evidence suggest tau aggregation is central to the neurodegenerative process in tauopathies. First, recent animal and cell model studies find abnormally-modified tau alone may be transmitted between adjacent neurons and spread to anatomically connected brain regions to recapitulate human disease. Further, staging efforts in human autopsy cases suggest a sequential distribution of tau aggregation in the central nervous system that could reflect this observed cell-to-cell transmission of pathogenic tau species in animal models. Finally, pathogenic mutations in the MAPT gene encoding tau protein cause hereditary forms of tauopathy. Clinically, tauopathies can present with a range of phenotypes that include both movement- and cognitive/behavioral-disorders (i.e. frontotemporal dementia spectrum disorders) or non-specific amnestic symptoms in advanced age. A major limitation is that current clinical diagnostic criteria for these disorders do not reliably differentiate underlying tauopathy from other neurodegenerative diseases, such as TDP-43 proteinopathies. Thus, current research efforts are focused on improving the ante mortem diagnosis of tauopathies, including pre-clinical stages of disease, as many therapeutic strategies for emerging disease-modifying therapies focus on preventing abnormal folding and spread of tau pathology.