Disease-Modifying Therapies in Frontotemporal Lobar Degeneration

Frontotemporal Lobar Degeneration (FTLD) is characterized by behavioral changes, executive dysfunctions, and language impairment, sustained by different neuropathological patterns. The collective efforts of clinical, pathological and genetic studies have recently opened new insights into the underpinnings of pathological mechanisms of this complex disorder. Different types of inclusions define the new conceptual framework for FTLD classification. Up to now, Tau (FTLDTau-positive), TAR DNA-binding protein (TDP43, FTLD Tau-negative TDP43-positive) have been recognized as the most frequent neuropathological hallmarks of FTLD. In some clinical cases, monogenic forms are identified, mainly due to Microtubule Associated Protein (MAPT) or Granulin (GRN) mutations. No treatments for FTLD are available yet, and off-label medications are commonly used to treat behavioralsymptoms. However, several studies testing potential modifying treatments on the basis of neuropathological inclusions are ongoing. With regard to FTLD-Tau positive, inhibitors of Tau kinases or manipulation of Tau-processing pathways have been proposed. On the other hand, progranulin haploinsuffciency associated with GRN mutations, has been counteracted by specific pharmacological treatments. Finally, new insights into pathological processing of TDP-43 and other key-molecules involved in FTLD, such as hyperphosphorylation and ubiquitination, and their consequent translocation from nucleus to cytoplasm, and their role as RNA-binding proteins, open new perspectives for a growing number of potential therapeutic targets. In this continuously evolving field, the aim of the present review is to summarize the new findings on molecular targets and modifying therapies in FTLD.