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.

Disparate and shared transcriptomic signatures associated with cortical atrophy in genetic bvFTD

“…In MAPT-bvFTD, cholinergic, dopaminergic and GABAergic neurotransmitters are important contributors in predicting brain atrophy. Individuals with pathogenic variants in MAPT gene were observed with dopaminergic dysfunction 32 . MAPT pathogenic variants may trigger alterations in GABAergic signaling and synaptic function, leading to pathogenesis of tauopathies 33 .…”

Tau; One Protein, So Many Diseases

“…The specific mutation site affects the outcome, as shown for mutations in exon 10 that can affect the microtubulebinding affinity of the protein and change the ratio of 3R:4R in adults. Even intronic mutations in MAPT (e.g., intron 10) may affect tau protein structure and the isoform ratio, resulting in pathogenic tau formation [54,55]. To date, no association between MAPT mutations and PTMs in tau protein has been discovered [56].…”