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. 2018 Jul 12;12:473. doi: 10.3389/fnins.2018.00473

FIGURE 2.

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.