Familial frontotemporal lobar degeneration

Abstract

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia, and is characterized by neurodegeneration of the frontal and temporal lobes. The disease typically presents with behavioral disturbances and language difficulties that occur before the age of 65 years. An autosomal dominant familial form of FTLD can be caused by mutations in microtubule-associated protein tau or progranulin, and the chromosome 9 open reading frame 72 repeat expansion. There currently is no therapy available to prevent or cure FTLD. In order to develop a disease-modifying therapy, knowledge concerning the pathophysiological process is crucial to identify proper treatment targets. The familial forms of FTLD can teach us a lot about the disease process by enabling us to explore clinical and pathological characteristics in relation to genetic defects. In this thesis we have expanded knowledge genetic forms of FTLD by reporting clinical and pathological characteristics of a novel GRN mutation and the C9orf72 repeat expansion. Moreover, we have demonstrated that using several MRI techniques, including diffusion tensor imaging, resting-state fMRI, and arterial spin labeling, brain changes can be detected in the presymptomatic stage of FTLD. Therefore, these measures might provide sensitive biomarkers for the earliest stages of FTLD in upcoming clinical trials with disease-modifying agents.