Abstract
Frontotemporal lobar degeneration (FTLD) is a group of clinically, pathologically and genetically heterogeneous neurodegenerative disorders that involve the frontal and temporal lobes. Behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA) are three major clinical syndromes. TDP-43, FUS, and tau are three major pathogenetic proteins. In this review, we first discuss the loss-of-function mechanism of FTLD. We focus on FUS-associated pathogenesis in which FUS is linked to tau by regulating its alternative splicing machinery. Moreover, FUS is associated with abnormalities in post-synaptic formation, which can be an early disease marker of FTLD. Second, we discuss clinical and pathological aspects of FTLD. Recently, FTLD and amyotrophic lateral sclerosis (ALS) have been recognized as the same disease entity; indeed, nearly all sporadic ALS cases show TDP-43 pathology irrespective of FTD phenotype. Thus, investigating early structural and network changes in the FTLD/ALS continuum can be useful for developing early diagnostic markers of FTLD. MRI studies have revealed the involvement of the caudate nucleus and its anatomical networks in association with the early phase of behavioral/cognitive decline in FTLD/ALS. In particular, even ALS patients with normal cognition have shown a significant decrease in structural connectivity between the caudate head networks. In pathological studies, FTLD/ALS has shown striatal involvement of both efferent system components and glutamatergic inputs from the cerebral cortices even in ALS patients. Thus, the caudate nucleus may be primarily associated with behavioral abnormality and cognitive involvement in FTLD/ALS. Although several clinical trials have been conducted, there is still no therapy that can change the disease course in patients with FTLD. Therefore, there is an urgent need to establish a strategy for predominant sporadic FTLD cases.
Highlights
Frontotemporal lobar degeneration (FTLD) is a clinically, genetically, and pathologically heterogeneous neurodegenerative disorder that causes selective neuronal loss and gliosis of the frontal and temporal lobes of the brain (Olney et al, 2017)
We introduce recent findings that can help detect the (1) key pathogenesis leading to neurodegeneration and (2) early structural and network changes related to early diagnosis in FTLD/amyotrophic lateral sclerosis (ALS)
These results indicate that there is a strong association between the severity of striatal efferent system involvement and the development of clinical Frontotemporal dementia (FTD), suggesting that striatal efferent changes parallel the decline of socio-cognitive performance in sporadic FTLD-TDP patients
Summary
Frontotemporal lobar degeneration (FTLD) is a clinically, genetically, and pathologically heterogeneous neurodegenerative disorder that causes selective neuronal loss and gliosis of the frontal and temporal lobes of the brain (Olney et al, 2017). Loss of FUS functionality is relevant to the pathogenesis of FTLD/ALS by demonstrating that formation of the FUS intranuclear complex with splicing factor, proline-, and glutamine-rich (SFPQ), an RNA-binding protein, in neurons is compromised by FTLD/ALS-associated mutations (Ishigaki et al, 2017). TDP-43 was observed in striatal efferent neurons, efferent tracts, or their axon terminals in the SNr, GPi, and GPe in both FTLDTDP and ALS-TDP These results indicate that there is a strong association between the severity of striatal efferent system involvement and the development of clinical FTD, suggesting that striatal efferent changes parallel the decline of socio-cognitive performance in sporadic FTLD-TDP patients. The association between behavioral abnormalities and involvement of the corticostriatal tract seeded from the caudate head in ALS and bvFTD supports the view that the caudate head and its network can be the most important target for developing disease-modifying therapy
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