Abstract
MRI has emerged as one of several urgently needed candidate disease progression biomarkers for the neurodegenerative disorder amyotrophic lateral sclerosis (ALS), not least due to its unique ability to non-invasively assess structural and functional cerebral pathology. We sought to identify the extent of detectable change in cerebral MRI metrics over a more prolonged period.Analysis of multi-modal MRI data was performed in a cohort of sixteen patients (13 ALS and 3 with primary lateral sclerosis) in whom it was possible to acquire six-monthly images over two years. Structural brain changes were assessed using voxel-based morphometry of grey matter and shape analysis of sub-cortical grey matter structures, tract-based spatial statistics of diffusion tensor imaging (DTI) metrics optimized for longitudinal analysis in the white matter, as well as whole brain voxel-wise statistics of DTI metrics. Changes in resting state functional MRI (rs-fMRI) were investigated via independent component and dual regression analyses of functional connectivity (FC), controlled for confounding effects of grey matter decline. Both linear changes with time and brain changes correlated with revised ALS functional rating score (ALSFRS-R) decline were studied.Widespread and progressive reductions in grey matter were observed in the precentral gyri and posterior cingulate cortex, as well as progressive local atrophy of the thalamus, caudate, and pallidum bilaterally, and right putamen, hippocampus and amygdala. The most prominent DTI tract-based changes were in the superior longitudinal fasciculi and corpus callosum. More widespread areas of DTI changes included the thalami and caudate nuclei, hippocampi and parahippocampal gyri, insular cortices, anterior and posterior cingulate gyri, frontal operculum and cerebellum. FC decreases were noted between the sensorimotor resting state network and the frontal pole, between a network comprising both thalami and an area in the visual cortex, in relation to both time from baseline and ALSFRS-R decline. FC increases between the left primary motor cortex and left fronto-parietal network were seen for both statistical approaches.A longer period of follow-up, though necessarily involving more slowly-progressive cases, demonstrated widespread changes in both grey and white matter structural MRI measures. The mixed picture of regional decreases and increases in FC is compatible with compensatory change, in what should be viewed as a brain-based disease characterised by larger-scale disintegration of motor and frontal projection cerebral networks.
Highlights
Amyotrophic lateral sclerosis (ALS) is a uniquely destructive and typically rapidly progressive neurodegenerative disorder, with a median survival of 30 months from symptom onset
In a large structural magnetic resonance imaging (MRI) study conducted by our group, analysis of diffusion tensor imaging (DTI) data showed limited increase in axial and mean diffusivity in a corpus callosum region of interest, as well as minor axial diffusivity increases in the left corticospinal tract (CST) over a minimum of six months, while voxel-based morphometry (VBM) analysis revealed widespread grey matter volume decreases in motor and frontotemporal regions, thalami and caudate heads bilaterally (Menke et al, 2014)
Intra-subject midway space registration Before conducting the analyses described in the following paragraphs, each patient's MRI images for all time points were registered to a common ‘midway’ space in order to avoid potential registration-related bias
Summary
Amyotrophic lateral sclerosis (ALS) is a uniquely destructive and typically rapidly progressive neurodegenerative disorder, with a median survival of 30 months from symptom onset. The causes of ALS are protean and complex, with effective therapy remaining elusive, in part due to the lack of objective biomarkers of disease activity and progression against which to assess candidates (Turner and Benatar, 2015). While the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) remains the leading outcome measure in therapeutic trials, it has significant limitations (Proudfoot et al, 2016). MRI has emerged as one of several biomarker candidates that could assist differential diagnosis and patient stratification, and offer a probe for the investigation of natural disease progression and the effectiveness of therapeutic approaches (Turner et al, 2011, Turner and Verstraete, 2015)
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