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 (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.

Keywords: C9orf72; GRN; MAPT; familial frontotemporal lobar degeneration; imaging biomarker; presymptomatic.

Figure 1

Coronal T1-weighted magnetic resonance imaging (MRI). Brain MRIs (coronal T1-weighted images) of the three familiar FTLD mutation carriers who progressed from the asymptomatic to the symptomatic stage are shown in the timeline with years before and after conversion. 0 indicates the actual symptom onset time point. (A) A male patient with MAPT N279K mutation whose first clinical manifestation was difficulties in remembering street names and people's names with Kokmen short test of mental status (36/38) at age 43. Two years after symptom onset, his forgetfulness progressed, with resting tremor in the left lower limbs, as well as some impulsivity and disinhibition, and was diagnosed with bvFTD and Parkinsonism. Five years after symptom onset, his cognitive function, parkinsonism, and behavior changes significantly worsened and mostly by motor impairment. Focal adjacent mesial temporal lobe atrophy mainly in the right side was observed 5 years before symptom onset and became bilateral hippocampal atrophy with generalized cerebral atrophy most marked in the bilateral parietotemporal regions. The structural brain change seems to be slower than his clinic symptom progression. (B) A male patient GRN mutation carrier whose first clinical manifestation was word-finding difficulties at age 68. Two years after symptom onset, his word-finding difficulties progressed, with additional executive dysfunction, forgetfulness, and tendency to repeat questions. He also had apathy, irritability, and dysphoria, and was diagnosed with mixed PPA/bvFTD syndrome. Asymmetrical (left greater than right) atrophy was observed 6 years before symptom onset, and became progressively asymmetric affecting the frontal, temporal, and parietal lobes as he aged. (C) A male patient C9orf72 mutation carrier whose first clinical manifestation was a change in motivation, spontaneity, and empathy at age 73 and was diagnosed as behavior MCI. After 4 years from symptom onset, his behavior change slightly progressed with subtleties in empathy, emotional blunting, irritability, and subtle apathy, still diagnosed as behavior MCI. While his clinic symptoms seem to be stable, the moderate parenchymal volume loss was observed 8 years before symptom onset most involved in the frontal and temporal areas, and progressed affecting the whole brain with greatest atrophy in the fronto-temporal regions as he aged.