White matter changes in the perforant path in ALS Providing evidence for ALS as a multisystem disease

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Amyotrophic lateral sclerosis (ALS) is a severe, progressive and incurable motor disease. Roughly 20% of the ALS patients are affected by a level of cognitive decline that meets the criteria for behavioral frontotemporal lobe dementia (bvFTD). ALS and bvFTD share some clinical and pathological features, for example the deposition of TAR DNA binding protein 43(pTDP-43) in several brain regions that are part of the circuit of Papez. Previous literature suggests involvement of the perforant path, a white matter tract in the hippocampus that is part of the circuit of Papez in patients with both ALS and bvFTD. We hypothesize that white matter degeneration in the perforant pathway is a key feature of ALS, providing a neuronal correlate for ALS as a multisystem disorder. To verify our hypothesis we studied white matter changes in ex-vivo hippocampal blocks from patients with known ALS (n=13) and controls (n=5) using diffusion MRI. The dMRI results were evaluated using polarised light imaging (PLI), a microscopy technique sensitive to density and orientation of myelinated axons. From the same hippocampal blocks, sections were cut and stained for myelin, pTDP-43, neurofilaments and activated microglia. The dMRI results show a significant decrease in fractional anisotropy (p=0.018) and an increase in mean diffusivity (p=0.0017), axial diffusivity (p=0.023) and radial diffusivity (p=0.028) in the perforant path in ALS patients compared to controls, likely indicating a loss of fibres. The PLI retardance values within the perforant path were lower in cases compared to controls, however not significantly (p=0.16). The retardance correlates with the fractional anisotropy (p=0.04). Furthermore, an increase in dispersion was observed in ALS specimens(p=0.04), implying a less organised axonal structure. Histology data showed a (non-significant) increase in myelin (PLP) (p=0.11) and an increase in neurofilaments (SMI-312) (p=0.03) in ALS cases compared to controls. No differences were found in the amount of inflammation and two out of the 13 ALS cases exhibited pTDP-43 pathology in the hippocampus. These results demonstrate degradation of the perforant path in ALS patients, providing a potential neuronal correlate for the cognitive symptoms observed in ALS and substantiating the hypothesis that ALS and bvFTD are part of the same spectrum of diseases. Future research should focus on correlating the degree of clinically observed cognitive decline to the amount of white matter atrophy in the perforant path.
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