We searched PubMed (1966, to March 31, 2014), Embase (1980, to March 31, 2014), and the Cochrane Library (April, 1996, to March 31, 2014) for the search terms “amyotrophic lateral sclerosis” or “motor neuron disease” or “primary lateral sclerosis” in combination with “imaging”, “neuroimaging”, “magnetic resonance imaging”, “positron emission tomography”, “single photon emission computed tomography”, “diffusion tensor imaging”, “voxel based morphometry”, and “spectroscopy”. Further
ReviewNeuroimaging in amyotrophic lateral sclerosis: insights into structural and functional changes
Introduction
Amyotrophic lateral sclerosis (ALS) is a disorder of adult life characterised by progressive degeneration of upper and lower motor neurons and the frontal cortex. The cause of ALS is still unknown and no disease-modifying treatments are available, apart from the anti-glutamatergic drug riluzole, which increases survival by about 2–3 months without affecting muscle strength.1 Up to 10% of patients with ALS inherit a genetic mutation, whereas the other 90% of cases occur sporadically in the population.2 The most common ALS-related genes in white populations are C9orf72, SOD1, TARDBP, and FUS, which account for about two-thirds of cases of familial ALS.2 Diagnosis of ALS is largely based on its clinical presentation, progression of symptoms, and exclusion of other diseases, supported by neurophysiological and neuroimaging examinations.3, 4
There is an increasing awareness that ALS is a clinically and pathogenically heterogeneous disease.5 Several different phenotypes of ALS exist, ranging from pure upper motor neuron disease (primary lateral sclerosis) to pure lower motor neuron disease (progressive muscular atrophy), with several demographically (age and sex) and prognostically different intermediate forms (flail arm, flail leg, prevalent upper motor neuron, and bulbar ALS).6 Moreover, up to 50% of patients with ALS have cognitive deficits, again with a range of different clinical presentations, ranging from overt frontotemporal dementia (FTD) to cognitive impairment below the diagnostic threshold for FTD (pure executive, pure non-executive, or pure behavioural impairment).7, 8 MRI, PET, and SPECT have been used variously in about 200 ALS studies (appendix). The contribution of imaging to the understanding of ALS cannot be overlooked, since it has enabled study of the brains of patients with ALS in vivo and, to a lesser extent, longitudinally. There are three main areas of neuroimaging research. First, anatomical and functional changes in ALS have been identified on structural (MRI) and functional (functional MRI [fMRI], PET, and SPECT) neuroimaging, including the spread of cortical and subcortical lesions. The extensive application of structural magnetic-resonance-based techniques (panel) has improved our understanding of ALS pathophysiology and the mechanisms underlying the progressive degenerative process. These findings have also given some insight into the dysfunction of local and distant neural circuits in the various phases of the disease. Second, MRI and radiotracers have been used to identify CNS alterations that could be used to improve ALS diagnostic accuracy with clinically useful sensitivity and specificity. Third, these techniques are being used to assess promising biomarkers of progression of motor and non-motor lesions, which will be used in both clinical (as markers of prognosis in a patient) and research settings (as biological markers for assessing the efficacy of experimental treatments).
Section snippets
Structural T1-weighted imaging
Structural T1-weighted MRI enables detailed analysis of focal brain atrophy, which is a key feature of patients with ALS. Cross-sectional voxel-based morphometry studies have yielded inconsistent results regarding the presence of atrophy in the primary motor cortex or premotor cortex in ALS and the extent of extra-motor atrophy, largely because of differences in sample sizes, image preprocessing, and statistical analysis, but also because of the clinical, cognitive, and genetic characteristics
Resting-state fMRI
Several resting-state fMRI studies of ALS reported significantly decreased functional connectivity within the sensorimotor network21, 22, 23, 24, 25 and in brain networks related to cognition and behaviour,21, 22, 24, 26, 27 in keeping with the altered motor and extramotor structural connectivity. Other studies have identified regions of increased functional connectivity, including somatosensory and extra-motor areas (figure 2; appendix).9, 24, 25, 26, 27, 28, 29, 30 Two scenarios have been
Neuroimaging as a diagnostic marker of ALS
In patients with ALS, conventional MRI is frequently not informative and its diagnostic use is restricted to exclusion of other mimic disorders.3, 4 Although the detection of corticospinal tract hyperintensities on conventional MRI and the presence of a T2-hypointense rim in the primary motor cortex can support a pre-existing suspicion of ALS, they are neither sensitive nor specific for ALS and are not recommended for a firm diagnosis.88
Findings from some studies suggested cortical thinning of
Pitfalls of MRI and radiotracer imaging studies
Despite great achievements, most published studies have several pitfalls (table). Some of the differences in reported results might be because of clinical and demographic characteristics of patients, particularly the variable duration of the disease at the time of MRI and PET or SPECT (ranging from 6 months to 180 months)—ie, patients are at different stages of the disease. Neurobiological evidence that the different involvement of cortical bulbar and spinal motor neurons from an early stage in
Conclusions and future directions
MRI and radiotracer imaging are powerful and rapidly evolving imaging techniques that allow the assessment of the involvement of brain structures and functions in ALS in vivo. Although conceptually and methodologically different, their findings tend be concordant (figure 6). There is substantial anatomical and functional damage of the primary motor cortex, associated with damage to the corpus callosum (in particular, the middle and posterior parts). The degeneration of corticospinal tracts and
Search strategy and selection criteria
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Contributed equally