Abstract
BackgroundAmyotrophic lateral sclerosis (ALS) is a clinically and histopathologically heterogeneous neurodegenerative disorder, in which therapy is hindered by the rapid progression of disease and lack of biomarkers. Magnetic resonance imaging (MRI) has demonstrated its potential for detecting the pathological signature and tracking disease progression in ALS. However, the microstructural and molecular pathological substrate is poorly understood and generally defined histologically. One route to understanding and validating the pathophysiological correlates of MRI signal changes in ALS is to directly compare MRI to histology in post mortem human brains.ResultsThe article delineates a universal whole brain sampling strategy of pathologically relevant grey matter (cortical and subcortical) and white matter tracts of interest suitable for histological evaluation and direct correlation with MRI. A standardised systematic sampling strategy that was compatible with co-registration of images across modalities was established for regions representing phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) patterns that were topographically recognisable with defined neuroanatomical landmarks. Moreover, tractography-guided sampling facilitated accurate delineation of white matter tracts of interest. A digital photography pipeline at various stages of sampling and histological processing was established to account for structural deformations that might impact alignment and registration of histological images to MRI volumes. Combined with quantitative digital histology image analysis, the proposed sampling strategy is suitable for routine implementation in a high-throughput manner for acquisition of large-scale histology datasets. Proof of concept was determined in the spinal cord of an ALS patient where multiple MRI modalities (T1, T2, FA and MD) demonstrated sensitivity to axonal degeneration and associated heightened inflammatory changes in the lateral corticospinal tract. Furthermore, qualitative comparison of R2* and susceptibility maps in the motor cortex of 2 ALS patients demonstrated varying degrees of hyperintense signal changes compared to a control. Upon histological evaluation of the same region, intensity of signal changes in both modalities appeared to correspond primarily to the degree of microglial activation.ConclusionThe proposed post mortem whole brain sampling methodology enables the accurate intraindividual study of pathological propagation and comparison with quantitative MRI data, to more fully understand the relationship of imaging signal changes with underlying pathophysiology in ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a clinically and histopathologically heterogeneous neurodegen‐ erative disorder, in which therapy is hindered by the rapid progression of disease and lack of biomarkers
Distinct phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) distribution patterns have been proposed for behavioural variant frontotemporal dementia (FTD) [12], the most common form of FTD overlapping with ALS [26]
Serial histology sections stained for axonal myelin (PLP) and neurofilament content (SMI-312) were mapped to the corresponding Magnetic resonance imaging (MRI) plane that represents the region of interest, spared from pathology, from an ALS patient (ALS 1) (Fig. 9)
Summary
Amyotrophic lateral sclerosis (ALS) is a clinically and histopathologically heterogeneous neurodegen‐ erative disorder, in which therapy is hindered by the rapid progression of disease and lack of biomarkers. Amyotrophic lateral sclerosis (ALS) is a typically rapidly progressive, fatal neurodegenerative disorder that is genetically and phenotypically heterogeneous. It is primarily characterised by selective degeneration of upper and lower motor neurons [1]. Quantitative susceptibility mapping has demonstrated potential as a biomarker of upper motor neuron dysfunction in ALS [6,7,8]. These MRI markers are non-specific and generally known to be influenced by several aspects of tissue related to neuropathology. MRI-histology correlation analysis in post mortem tissue offers a platform to discover the histological underpinnings of MRI signal changes
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