Molecular imaging biomarkers in familial frontotemporal lobar degeneration: Progress and prospects

Abstract

Familial frontotemporal lobar degeneration (FTLD) is a pathologically heterogeneous group of neurodegenerative diseases with diverse genotypes and clinical phenotypes. Three major mutations were reported in patients with familial FTLD, namely, progranulin (GRN), microtubule-associated protein tau (MAPT), and the chromosome 9 open reading frame 72 (C9orf72) repeat expansion, which could cause neurodegenerative pathological changes years before symptom onset. Noninvasive quantitative molecular imaging with PET or single-photon emission CT (SPECT) allows for selective visualization of the molecular targets in vivo to investigate brain metabolism, perfusion, neuroinflammation, and pathophysiological changes. There was increasing evidence that several molecular imaging biomarkers tend to serve as biomarkers to reveal the early brain abnormalities in familial FTLD. Tau-PET with ¹⁸F-flortaucipir and ¹¹C-PBB3 demonstrated the elevated tau position in patients with FTLD and also showed the ability to differentiate patterns among the different subtypes of the mutations in familial FTLD. Furthermore, dopamine transporter imaging with the ¹¹C-DOPA and ¹¹C-CFT in PET and the ¹²³I-FP-CIT in SPECT revealed the loss of dopaminergic neurons in the asymptomatic and symptomatic patients of familial FTLD. In addition, PET imaging with the ¹¹C-MP4A has demonstrated reduced acetylcholinesterase (AChE) activity in patients with FTLD, while PET with the ¹¹C-DAA1106 and ¹¹C-PK11195 revealed an increased level of microglial activation associated with neuroinflammation even before the onset of symptoms in familial FTLD. ¹⁸F-fluorodeoxyglucose (FDG)-PET indicated hypometabolism in FTLD with different mutations preceded the atrophy on MRI. Identifying molecular imaging biomarkers for familial FTLD is important for the in-vivo assessment of underlying pathophysiological changes with disease progression and future disease-modifying therapy. We review the recent progress of molecular imaging in familial FTLD with focused on the possible implication of these techniques and their prospects in specific mutation types.

Keywords: C9orf72; GRN; MAPT; biomarkers; familial frontotemporal lobar degeneration; molecular imaging.