Abstract
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder characterized by behavioral changes, language abnormality, as well as executive function deficits and motor impairment. In about 30–50% of FTLD patients, an autosomal dominant pattern of inheritance was found with major mutations in the MAPT, GRN, and the C9orf72 repeat expansion. These mutations could lead to neurodegenerative pathology years before clinical symptoms onset. With potential disease-modifying treatments that are under development, non-invasive biomarkers that help determine the early brain changes in presymptomatic FTLD patients will be critical for tracking disease progression and enrolling the right participants into the clinical trials at the right time during the disease course. In recent years, there is increasing evidence that a number of imaging biomarkers show the abnormalities during the presymptomatic stage. Imaging biomarkers of presymptomatic familial FTLD may provide insight into the underlying neurodegenerative process years before symptom onset. Structural magnetic resonance imaging (MRI) has demonstrated cortical degeneration with a mutation-specific neurodegeneration pattern years before onset of clinical symptoms in presymptomatic familial FTLD mutation carriers. In addition, diffusion tensor imaging (DTI) has shown the loss of white matter microstructural integrity in the presymptomatic stage of familial FTLD. Furthermore, proton magnetic resonance spectroscopy (1H MRS), which provides a non-invasive measurement of brain biochemistry, has identified early neurochemical abnormalities in presymptomatic MAPT mutation carriers. Positron emission tomography (PET) imaging with [18F]-fluorodeoxyglucose (FDG) has demonstrated the glucose hypometabolism in the presymptomatic stage of familial FTLD. Also, a novel PET ligand, 18F-AV-1451, has been used in this group to evaluate tau deposition in the brain. Promising imaging biomarkers for presymptomatic familial FTLD have been identified and assessed for specificity and sensitivity for accurate prediction of symptom onset and tracking disease progression during the presymptomatic stage when clinical measures are not useful. Furthermore, identifying imaging biomarkers for the presymptomatic stage is important for the design of disease-modifying trials. We review the recent progress in imaging biomarkers of the presymptomatic phase of familial FTLD and discuss the imaging techniques and analysis methods, with a focus on the potential implication of these imaging techniques and their utility in specific mutation types.
Highlights
Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder characterized by behavioral abnormalities, language impairment, impaired social cognition, and executive function, as well as progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), or motor neuron disease [1]
During a 10year follow-up, the rates of temporal lobe atrophy were accelerated in asymptomatic microtubuleassociated protein tau gene (MAPT) mutation carriers who were asymptomatic during follow-up, while accelerated atrophy rates in the temporal, parietal and frontal lobes were reported in MAPT mutation carriers who became symptomatic compared to non-carriers [23]
Glial activities were increased in the frontal cortex of 1 aMAPT+, the occipital cortex of 2 aMAPT+, and the posterior cingulate cortex of 1 aMAPT+
Summary
Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder characterized by behavioral abnormalities, language impairment, impaired social cognition, and executive function, as well as progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), or motor neuron disease [1]. FTLD has a strong genetic background with an autosomal dominant pattern of inheritance in about 30–50% FTLD patients [2] with major mutations in the microtubuleassociated protein tau gene (MAPT) [3], progranulin (GRN), and the repeat expansions in the chromosome 9 open reading frame 72 gene (C9orf). Mutations in the gene encoding the microtubule-associated protein tau (MAPT) on chromosome 17 was first reported in 1998 [4] and have been found in many kindreds with familial FTLD. Subtypes of MAPT mutations were associated with different types of tauopathies. These are mutations inside exon 10 (i.e., N279K, S305N, and P301L) and outside exon 10 (i.e., R406W and V337M). Mutations inside exon 10 tend to form four tandem microtubule-binding domain repeat (4R-tau) pathology rather than 3 repeat (3R-tau) pathology [9], while mutations outside exon 10 tend to form mixed 3R/4R tau pathology
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
