Advances in Neuroimaging for Amyotrophic Lateral Sclerosis

In a review of the role of neuroimaging in ALS, researchers outlined three main areas of neuroimaging research:8

  • Anatomical and functional changes in ALS have been identified on structural (MRI), functional MRI (fMRI), PET, and SPECT neuroimaging. This includes the spread of cortical and subcortical lesions.
  • MRI and radiotracers can identify central nervous system alterations that could improve the accuracy of diagnosing ALS with sensitivity and specificity that could be used in a clinical setting.
  • These techniques are being used to assess promising biomarkers of how motor and non-motor lesions progress, which will be used as both clinical markers of prognosis and as biological markers in research evaluating how well experimental treatments are working.

In a 2014 proof-of-concept study, Bradley Foerster, MD, of the University of Michigan, and colleagues tested diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS) to accurately identify diagnostic biomarkers for ALS. Subjects included 29 ALS patients and 30 matched healthy controls. Both groups underwent MRI with MRS to measure g-aminobutyric acid (GABA) and DTI to measure fractional anisotropy (FA) of the corticospinal tract.

Researchers found that DTI FA measures combined with MRS resulted in a significant improvement in positive and negative likelihood ratios, and they concluded that the combination leads to significantly increased diagnostic accuracy in distinguishing ALS patients with well-established disease from healthy controls.5

In a review of advanced neuroimaging techniques, researchers examined potential diagnostic value of multimodal neuroimaging techniques of examining brain structure. One technique combined high resolution MRI to measure focal loss of gray or white matter, with voxel-based and surface-based morphometry (VBM and SBM). Using automated software, the acquired data was compared to normal controls to study regional differences.6

The researchers found that reports vary, with some showing reduced gray matter in motor and extramotor regions, while others only show reduced gray matter in extramotor regions. The differences are thought to be due to sample sizes, image processing, and statistical analysis, but also because of the clinical, cognitive, and genetic characteristics of patients.

In another study, Adriano Chiò, of the ALS Centre of the Department of Neuroscience of the University of Turin and Molinette Hospital, wrote “findings from large studies have shown that frontotemporal and parietal loss or thinning, which is seen in patients with ALS with normal cognitive functions, is more severe in patients with cognitive impairment and ALS-FTD than in those with only motor ALS.”1

At the same time, SBM studies of patients with ALS show that cortical thinning is a consistent alteration specific to upper motor neuron degeneration. Mimic conditions and patients with PMA do not show these cortical changes.1

While functional MRI using tasks to investigate cognitive and behavioral performance have shown increased activity in cortical regions associated with motor processing, Foerster and Verstraete concluded that that this type of measure is unlikely to result in diagnostic markers because of challenges involving quantification and standardization.

“It is expected that techniques with much higher temporal resolutions than fMRI, such as magnetoencephalography, will provide future insights into functional connectivity changes in the context of ALS,” they wrote.6

Studying neuronal receptors and protein expression in ALS is also uniquely possible with positron emission tomography (PET). Foerster and Verstraete also reviewed PET studies aimed at examining brain receptors and metabolites, including the γ- aminobutyric acid A (GABAA) receptor and the serotonergic 5-hydroxytryptamine1A receptor.

The studies reviewed showed patients with sporadic ALS had reductions in [11C]flumazenil receptor binding in the motor cortex and motor association areas. There also may be different neuronal vulnerabilities for ALS patients who have a SOD1 mutation compared with sporadic ALS, leading to differences in their cortical imaging signature.2 While promising, Foerster and Verstraete concluded that new PET agents will provide more potential biomarkers for ALS.5