Pathogenesis of Frontotemporal Lobar Degeneration: Insights From Loss of Function Theory and Early Involvement of the Caudate Nucleus

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.

Keywords: TDP-43 proteinopathies; amyotrophic lateral sclerosis; caudate nucleus; frontotemporal lobar degeneration; fused in sarcoma/translated in liposarcoma; loss of function; marmoset; tau proteins.

FIGURE 1

Proposed pathways of FUS-associated FTLD pathogenesis. Loss of FUS function is involved in the early phenotypic pathomechanism of FTLD/ALS. Loss of FUS function in the nucleus, such as aberrant interaction with SFPQ, causes an imbalance in tau isoforms, which subsequently affects adult neurogenesis, phosphorylated tau accumulation, and neurodegeneration (Ishigaki et al., 2017). However, loss of FUS in the dendritic spine reduces the stability of GluA1 and SynGAP mRNA. This synaptic protein reduction impairs the maturation of spines (Udagawa et al., 2015; Yokoi et al., 2017). The two FUS-mediated molecular pathways lead to behavioral impairments, including emotional defects mimicking those observed in FTLD patients.

FIGURE 2

Structural and network changes and pathologic involvement of glutamatergic striatal inputs from the cortices and striatal efferent system across the sporadic ALS-FTD spectrum. MRI studies demonstrated structural and network changes of caudate nucleus across the sporadic ALS-FTD-spectrum as follows: (1) Gray matter volume loss was the most significant in the caudate head in ALS-FTD patients relative to controls. (2) TBSS analysis showed significantly decreased FA values in widespread white matter, particularly surrounding the caudate nucleus in patients with ALS-CD and ALS-FTD, relative to controls (3) Probabilistic diffusion tractography from the head of the caudate nucleus showed extensive decreased connectivity in not only ALS-FTD and ALS-CD but also in ALS-NC. FTLD-TDP patients showed a significant reduction in the axon terminals of the glutamatergic cortical-striatal projection neurons at the caudate head and putamen, as quantified by VGLUT-1 immunohistochemistry. ALS patients showed decreased loss of VGLUT-1-positive axon terminals predominantly in the putamen. CN-positive efferent neurons from the striatum were markedly involved in the following order: ALS < FTD-MND < FTD. The striatal neuronal loss was more predominant in the caudate head than in the putamen. All FTLD-TDP patients exhibited a significant reduction in axon terminals of striatal efferent neurons immunohistochemically assessed by substance-P and enkephalin in the SNr/GPi and GPe. In particular, losses of substance-P-positive projections to the SNr and GPi were consistently severe. Similar findings were obtained in ALS-TDP patients but were mild to moderate. ALS-NC, ALS- normal cognitive; ALS-CD, ALS-cognitive deficiency; ALS-FTD, ALS with frontotemporal dementia; FTD, frontotemporal dementia; FWEc, family-wise error corrected at the cluster level for multiple comparisons; FA, fractional anisotropy; RD, radial diffusivity; TFCE, threshold-free cluster enhancement; TBSS, tensor-based spatial statistics. FTLD-TDP, TAR DNA-binding protein-43 kDa-related frontotemporal lobar degeneration (FTLD-TDP); ALS, amyotrophic lateral sclerosis; FTD, frontotemporal dementia; FTD-MND, FTD with motor neuron disease; VGLUT-1, anti-vesicular glutamate transporter-1; SNr, nigra pars reticulate; GP, globus pallidus (GP); GPi, internal segment of GP; GPe, external segment of GP; CN, calcineurin.