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 (i.e., 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 toward the goal of defining clinical endophenotypes of FTD.

Figure 1. TDP-43 Mediated Neurodegeneration in FTLD-TDP/ALS

Pathological TDP-43 translocation from the nucleus (red) to the cytoplasmic compartment occurs in sporadic disease and hereditary cases with C9orf72, TARDBP, GRN, and VCP mutations. VCP mutation cases also have intranuclear TDP-43 inclusions (not shown). C9orf72 mutation is associated with additional RNA foci in the nucleus (green) and cytoplasmic di-peptide repeat inclusions (blue), but the specific association with neurodegeneration is currently unclear. Neuron-to-neuron transmission is the likely mechanism for the non-random pattern of spread of neurodegeneration. These processes are linked to RNA dysfunction and abnormal proteostasis, ultimately leading to neuronal cell loss and/or muscle denervation from lower motor neuron loss. Drug-development efforts to slow or halt this process may provide novel disease modifying therapies in the future.

Figure 2. Neuropathological subtypes of FTLD

Photomicrographs of FTLD-Tau (a–f) and FTLD-TDP (g–k). Images illustrate characteristic inclusion bodies including neocortical (a) round tau-positive Pick-bodies (arrows) in PiD, (b) tufted-astrocytes (arrows) in PSP, (c) astrocytic plaques (asterisk) in CBD, (d) tau-positive neuronal inclusions (arrows) and threads (asterisk) in FTLD-Tau with a MAPT mutation (p.P301L), (e) tau-positive grains (arrows) in limbic cortex in AGD, (f) extracellular ghost tangles (asterisks) in the cornu ammonis in tangle predominant dementia or primary age-related tauopathy (PART). Neocortical sections illustrate in g-j FTLD-TDP morphological subtype A (g) with superficial layer short dystrophic neurites (arrows) and neuronal cytoplasmic inclusions (asterisks) containing pathological TDP-43, (h) subtype B with mainly cytoplasmic inclusions (asterisks), (i) subtype C with long dystrophic neurites (arrows), (j) and subtype D with superficial layer lentiform intranuclear inclusions (asterisks) and short dystrophic neurites (arrows) while (k) shows skein-like inclusions (arrows) in anterior horn cell in ALS. Scale bar= 100 µm.

Figure 3. Genetic Associations in FTLD/ALS

Relative frequencies of neuropathological subtypes and associated molecular etiologies of FTLD and ALS are depicted. FTLD-Tau represents roughly 45% of all FTLD and mutations in MAPT are the sole known cause of hereditary forms of this disorder. FTLD-TDP accounts for roughly 50% of all FTLD and hereditary forms are associated with pathogenic mutations in GRN, C9orf72, TARDBP and VCP and rare other genes. ALS is associated with TDP-43 neuropathology in >95% of cases and there is considerable clinicopathological and genetic overlap of FTLD-TDP and ALS as demonstrated by the overlapping Venn diagrams. Placement of gene names reflect these associations, with FTLD-ALS/ALS cases more associated with C9orf72 and TARDBP while less commonly linked to VCP and rarely GRN. TARDBP is rarely associated with FTLD without co-morbid ALS. A minority of ALS is associated with pathogenic mutations in SOD1 and FUS, while FTLD-FUS also may occur a sporadic condition. Extremely rare cases of FTLD (other) are associated with pathogenic mutations in CHMP2B and FTLD-U neuropathology.

Figure 4. Clinicopathological and Genetic Associations in FTLD/ALS

The schematic portrays relative frequencies of neuropathological subtypes of FTLD and pathogenic mutations associated with FTD clinical phenotypes arranged with predominant cognitive syndromes above and predominant motor disorders below (CBS is intermediate with largely mixed cognitive/motor features). Common associations between syndromes (i.e. ALS-bvFTD, PSP-naPPA) are identified with solid lines and dashed line represent less common co-morbid syndromes (i.e. ALS-naPPA, PSP-bvFTD, CBS-bvFTD). FTLD-Tau pathology (red) is found in virtually all PSP cases and the majority of naPPA. FTLD-Tau is also found in a significant proportion of CBS and bvFTD and rare in svPPA. TDP-43 pathology (blue) is found in almost all ALS and the majority of svPPA, while roughly half of bvFTD cased harbor FTLD-TDP at autopsy while FTLD-TDP pathology is less commonly found in naPPA and CBS. Atypical presentations of AD are seen in a significant proportion of CBS and less commonly in svPPA and naPPA, but very rarely in bvFTD. Finally, a small percentage of ALS has FUS or SOD-1 (green) pathology at autopsy and FUS is a rare substrate for bvFTD. Genetic etiologies linked to clinical phenotypes are written below in order of frequency; svPPA is largely a sporadic condition.

Figure 5. Tau-Mediated Neurodegeneration in FTLD-Tau

Tau misfolding and aggregation into to beta-pleated sheet containing oligomers and fibrils occurs in familial FTLD-Tau due to MAPT mutations and in FTLD-Tau. This process results in loss of microtubule binding function and formation of cytosolic tau inclusions (red). Animal- and cell-model data suggest neuron-to-neuron transmission is central to disease pathogenesis and propagation. This process leads to multiple areas of cell-dysfunction (boxes).