Frontotemporal Lobar Degeneration TDP-43-Immunoreactive Pathological Subtypes: Clinical and Mechanistic Significance

Frontotemporal lobar degeneration with TPD-43-immunoreactive pathology (FTLD-TDP) is subclassified based on the type and cortical laminar distribution of neuronal inclusions. The relevance of these pathological subtypes is supported by the presence of relatively specific clinical and genetic correlations. Recent evidence suggests that the different patterns of pathology are a reflection of biochemical differences in the pathological TDP-43 species, each of which is influenced by differing genetic factors. As a result, patient FTLD-TDP subtype may be an important factor to consider when developing biomarkers and targeted therapies for frontotemporal dementia. In this chapter, we first describe the pathological features, clinical and genetic correlations of the currently recognized FTLD-TDP subtypes. We then discuss a number of novel patterns of TDP-43 pathology. Finally, we provide an overview of what is currently known about the biochemical basis of the different FTLD-TDP subtypes and how this may explain the observed phenotypic and pathological heterogeneity.