Much is likely to change in the treatment of FTD. Beyond completion of the ongoing memantine trials (), as well as possible clarification of the role of cholinesterase inhibitors, the most important changes are likely to include the introduction of rational drug therapies intended to slow or stop disease progression. These therapies will most likely be protein-specific, growing directly out of basic science studies of FTLD-tau, FTLD-TDP and FTLD-FUS.
One exciting example is the introduction of drugs aimed at preventing tau aggregation. Such therapy could potentially offer disease-modifying benefits in both AD and in a subset of FTD syndromes, including some cases of bvFTD and most cases of PNFA (). One such agent, the microtubule-interacting peptide NAPVSIPQ (NAP, also referred to as davunetide or AL-108) reduced tau neuropathology in a mouse model [60
], and it is now in a Phase II randomized, double-blind, placebo-controlled trial for patients with predicted FTLD-tau pathology (NCT01056965 [101
]). Methylene blue is another agent that has been investigated for its potential to reduce tau aggregation and slow AD [61
]; a clinical trial of this agent in FTD is planned. Other potential therapeutic interventions include inhibition of enzymes that contribute to tau phosphorylation (glycogen synthase kinase-3β [GSK3β] or cyclin-dependent protein kinase 5), manipulation of tau-processing pathways (e.g., ubiquitination), reduction of tau expression and other approaches [29
]. Lithium and valproic acid, both inhibitors of GSK3β, have entered clinical trials as neuroprotective treatments for AD, FTD and other tauopathies (NCT00088387, NCT00703677, NCT01055392, NCT00385710 and NCT00071721 [101
Frontotemporal lobar degeneration-TDP neuropathology results in some cases from low levels of another protein, known as progranulin. Loss-of-function mutations in the progranulin gene result in a haploinsufficiency of the protein and cause familial, autosomal-dominant FTD with FTLD-TDP [65
]. Although the exact function of progranulin is unknown, normalizing protein levels could be a potential therapeutic strategy. Recently, microRNA-29b was demonstrated to enhance progranulin expression in vitro
]. Other possible therapeutic strategies include reducing TDP-43 hyperphosphorylation, ubiquitination, cleavage and translocation from nucleus to cytoplasm [6
As protein-specific therapies emerge, accurate in vivo
diagnosis will be essential. In particular, tools that can differentiate FTD-tau from FTD-TDP are needed, since most future disease-modifying agents are likely to be targeted towards one pathway or the other. Neuroimaging will play a critical role in this effort [68
]. Recently, a large, longitudinal study patterned after and complementary to the Alzheimer’s Disease Neuroimaging Initiative (ADNI) began recruiting patients with FTD to undergo sophisticated neuroimaging, with a goal of characterizing the brain functionally and structurally over time, as well as developing spinal fluid biomarkers that may correspond to the underlying molecular pathogenesis. The hope is that this study will yield, not only new information on brain–behavior correlates, but also strategies for identifying the underlying proteinopathy in specific patients and to monitor the response to emerging treatments.
With luck, the vacuum that currently exists in FTD-dedicated therapeutics may begin to fill.