White matter changes in the perforant path area in patients with amyotrophic lateral sclerosis.

OBJECTIVE: The aim of this study was to test the hypothesis that white matter degeneration of the perforant path - as part of the Papez circuit - is a key feature of amyotrophic lateral sclerosis (ALS), even in the absence of frontotemporal dementia (FTD) or deposition of pTDP-43 inclusions in hippocampal granule cells. METHODS: We used diffusion Magnetic Resonance Imaging (dMRI), polarized light imaging (PLI) and immunohistochemical analysis of post mortem hippocampus specimens from controls (n = 5) and ALS patients (n = 14) to study white matter degeneration in the perforant path. RESULTS: diffusion Magnetic Resonance Imaging demonstrated a decrease in fractional anisotropy (P = 0.01) and an increase in mean diffusivity (P = 0.01) in the perforant path in ALS compared to controls. PLI-myelin density was lower in ALS (P = 0.05) and correlated with fractional anisotropy (r = 0.52, P = 0.03). These results were confirmed by immunohistochemistry; both myelin (proteolipid protein, P = 0.03) and neurofilaments (SMI-312, P = 0.02) were lower in ALS. Two out of the fourteen ALS cases showed pTDP-43 pathology in the dentate gyrus, but with comparable myelination levels in the perforant path to other ALS cases. CONCLUSION: We conclude that degeneration of the perforant path occurs in ALS patients and that this may occur before, or independent of, pTDP-43 aggregation in the dentate gyrus of the hippocampus. Future research should focus on correlating the degree of cognitive decline to the amount of white matter atrophy in the perforant path.

Dentatorubrothalamic tract localization with postmortem MR diffusion tractography compared to histological 3D reconstruction.

Diffusion-weighted imaging (DWI) tractography is a technique with great potential to characterize the in vivo anatomical position and integrity of white matter tracts. Tractography, however, remains an estimation of white matter tracts, and false-positive and false-negative rates are not available. The goal of the present study was to compare postmortem tractography of the dentatorubrothalamic tract (DRTT) by its 3D histological reconstruction, to estimate the reliability of the tractography algorithm in this specific tract. Recent studies have shown that the cerebellum is involved in cognitive, language and emotional functions besides its role in motor control. However, the exact working mechanism of the cerebellum is still to be elucidated. As the DRTT is the main output tract it is of special interest for the neuroscience and clinical community. A postmortem human brain specimen was scanned on a 7T MRI scanner using a diffusion-weighted steady-state free precession sequence. Tractography was performed with PROBTRACKX. The specimen was subsequently serially sectioned and stained for myelin using a modified Heidenhain-Woelke staining. Image registration permitted the 3D reconstruction of the histological sections and comparison with MRI. The spatial concordance between the two modalities was evaluated using ROC analysis and a similarity index (SI). ROC curves showed a high sensitivity and specificity in general. Highest measures were observed in the superior cerebellar peduncle with an SI of 0.72. Less overlap was found in the decussation of the DRTT at the level of the mesencephalon. The study demonstrates high spatial accuracy of postmortem probabilistic tractography of the DRTT when compared to a 3D histological reconstruction. This gives hopeful prospect for studying structure-function correlations in patients with cerebellar disorders using tractography of the DRTT.