Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine

Abstract

Frontotemporal lobar degeneration (FTLD) comprises two main classes of neurodegenerative diseases characterized by neuronal/glial proteinaceous inclusions (ie. proteinopathies) including tauopathies (i.e. FTLD-Tau) and TDP-43 proteinopathies (i.e. FTLD-TDP) while other very rare forms of FTLD are known such as FTLD with FUS pathology (FTLD-FUS). This review focuses mainly on FTLD-Tau and FLTD-TDP, which may present as several clinical syndromes: a behavioral/dysexecutive syndrome (behavioral-variant frontotemporal dementia); language disorders (primary progressive aphasia variants); and motor disorders (amyotrophic lateral sclerosis, corticobasal syndrome, progressive supranuclear palsy syndrome). There is considerable heterogeneity in clinical presentations of underlying neuropathology and current clinical criteria do not reliably predict underlying proteinopathies ante-mortem. In contrast, molecular etiologies of hereditary FTLD are consistently associated with specific proteinopathies. These include MAPT mutations with FTLD-Tau and GRN, C9orf72, VCP and TARDBP with FTLD-TDP. The last decade has seen a rapid expansion in our knowledge of the molecular pathologies associated with this clinically and neuropathologically heterogeneous group of FTLD diseases. Moreover, in view of current limitations to reliably diagnose specific FTLD neuropathologies prior to autopsy, we summarize the current state of the science in FTLD biomarker research including neuroimaging, biofluid and genetic analyses. We propose that combining several of these biomarker modalities will improve diagnostic specificity in FTLD through a personalized medicine approach. The goals of these efforts are to enhance power for clinical trials focused on slowing or preventing progression of spread of tau, TDP-43 and other FTLD-associated pathologies and work towards the goal of defining clinical endophenotypes of FTD.

Semi-Automated Digital Image Analysis of Pick’s Disease and TDP-43 Proteinopathy

“…A direct comparison of the percent of total pathological burden finds a double-dissociation, where PiD has a lower percent of total pathology in STG whereas FTLD-TDPC has a lower total percent in MFG (Table 2). These preliminary associations in our pilot study suggest that FTLD neuropathological subtypes may have subtle differences in the pattern of disease in bvFTD, which could have potential clinical implications for improved diagnostics of underlying neuropathology (i.e., development of endophenotypes) (Irwin et al 2015). Future studies in larger samples of bvFTD, including other forms of FTLD-Tau and FTLD-TDP, will help to confirm these observations.…”

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

“…Biomarkers discriminating FTLD pathological subtypes are strongly needed for the selection of patients in drug trials targeting the specific proteinopathies 6, 7. We have assessed and validated the clinical performance of novel CSF biomarkers identified previously12 for discrimination of FTLD pathological subtypes and nondemented controls using two independent CSF cohorts coming from different centers.…”

“…Thus, the FTLD‐TDP group was enriched with FTLD patients with amyotrophic lateral sclerosis (FTLD‐ALS, n  = 7), associated with TDP43 pathology 15. FTLD cases with tau neuropathology (FTLD‐Tau, n  = 20) were selected based on autopsy ( n  = 2), MAPT mutations ( n  = 2),6 and familial history of autopsy confirmed FTLD‐Tau ( n  = 1). The FTLD‐Tau group was also enriched with CSF from patients with FTLD‐Plus syndromes related to tau pathology such as progressive supranuclear palsy (FTLD‐PSP, n  = 10) or corticobasal syndrome (FTLD‐CBS, n  = 5) 16, 17.…”

“…However, the clinical presentation of the FTLD pathological subtypes is heterogeneous and overlapping 5. So far, there are still no effective early biomarkers available to discriminate FTLD and its two main pathological subtypes, hampering the selection of appropriate patients for clinical trials targeting the specific proteinopathy (i.e., Tau or TDP43) 6, 7…”

Multimodal imaging evidence of pathology-mediated disease distribution in corticobasal syndrome

“…It is possible that prospective assessments of neuropsychological tests and motor evaluations may yield a deeper endophenotype of CBS that can be used to screen individuals for likely forms of underlying pathology. 30 Future studies are necessary in an independent cohort to evaluate the sensitivity and specificity of asymmetric rigidity, along with our observed dissociation between neuroimaging features, for improving the diagnosis of underlying pathology in CBS.…”