Imaging Biomarkers for Neurodegeneration in Presymptomatic Familial Frontotemporal Lobar Degeneration

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 ( 1 H 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 [ 18 F]-fluorodeoxyglucose (FDG) has demonstrated the glucose hypometabolism in the presymptomatic stage of familial FTLD. Also, a novel PET ligand, 18 F-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.

Differential early subcortical involvement in genetic FTD within the GENFI cohort

“…In about a third of the cases it is associated with an autosomal dominant inherited mutation in one of three genes: microtubule-associated protein tau ( MAPT ), progranulin ( GRN ), and chromosome 9 open reading frame 72 ( C9orf72 ) ( Warren et al, 2013 ). For each of these genetic groups, there is evidence of a differential pattern of cortical atrophy ( Chen and Kantarci, 2020 ), with changes occurring presymptomatically, up to twenty years before estimated phenoconversion ( Rohrer et al, 2015 , Cash et al, 2018 ). Whilst these studies have been highly informative in describing the presence of brain changes in presymptomatic stages of the disease, they have focused less on subcortical structures, and in particular, they have not investigated specific subregions within the deep grey matter.…”

Multiparametric magnetic resonance imaging and positron emission tomography findings in neurodegenerative diseases: Current status and future directions

“…MAPT and GRN gene mutations are associated with tauopathies (3R/4R/mixed-tau) and TDP-43 protein aggregation, respectively. 52,53 Related FTD disorders include ALS, progressive supranuclear palsy syndrome (PSP), and corticobasal syndrome. 52,53 The neuropathology underlying these clinical syndromes is multifaceted and does not correlate well with the clinical phenotype.…”

“…52,53 Related FTD disorders include ALS, progressive supranuclear palsy syndrome (PSP), and corticobasal syndrome. 52,53 The neuropathology underlying these clinical syndromes is multifaceted and does not correlate well with the clinical phenotype. It leads to struggles in the early and reliable diagnosis and treatment of FTLD.…”

“…C9orf72 gene carriers show widespread WM alterations in the frontal lobe (UF, inferior longitudinal fasciculus), corticospinal tract (CST), corona-radiata, and thalamic radiation, CC, cingulum, and cerebellar peduncles. 53…”

“…In contrast, asymptomatic GRN mutation carriers showed right medial frontal hypometabolism. 53,62 To differentiate bvFTD from other NDDs, the addition of FDG-PET information to sMRI increases sensitivity from 70% to 96%, albeit with lower specificity (73% from 93%). 63 FDG-PET based anterior DMN integrity accurately differentiated bvFTD and AD patients with higher accuracy (94%), supporting metabolic connectivity imaging as a promising diagnostic tool.…”