The Present and the Future of Neuroimaging in Amyotrophic Lateral Sclerosis

Abstract

SUMMARY:In patients with ALS, conventional MR imaging is frequently noninformative, and its use has been restricted to excluding other conditions that can mimic ALS. Conversely, the extensive application of modern MR imagingϪbased techniques to the study of ALS has undoubtedly improved our understanding of disease pathophysiology and is likely to have a role in the identification of potential biomarkers of disease progression. This review summarizes how new MR imaging technology is changing dramatically our understanding of the factors associated with ALS evolution and highlights the reasons why it should be used more extensively in studies of disease progression, including clinical trials.ABBREVIATIONS: ALS ϭ amyotrophic lateral sclerosis; ALSFRS ϭ ALS Functional Rating Scale; Cho ϭ choline; Cr ϭ creatine; CST ϭ corticospinal tract; DTI ϭ diffusion tensor imaging; FA ϭ fractional anisotropy; FLAIR ϭ fluid-attenuated inversion recovery; fMRI ϭ functional MR imaging; FTD ϭ frontotemporal dementia; FUS/TLS ϭ fused in sarcoma/translocated in liposarcoma gene; GM ϭ gray matter; 1 H-MR spectroscopy ϭ proton MR spectroscopy; L ϭ left; LMN ϭ lower motor neuron; MD ϭ mean diffusivity; mIns ϭ myo-inositol; MT ϭ magnetization transfer; MTR ϭ MT ratio; NAA ϭ N-acetylaspartate; ns ϭ not significant; PD ϭ proton density; R ϭ right; SOD1 ϭ superoxide dismutase 1; SPM ϭ statistical parametric mapping; TDP-43 ϭ TAR DNA-binding protein gene; UMN ϭ upper motor neuron; VBM ϭ voxel-based morphometry; WM ϭ white matter A LS, also known as motor neuron disease, is a neurodegenerative disorder characterized by a progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, brain stem, and spinal cord. The phenotypic expression of ALS is highly heterogeneous and determined by 4 elements: 1) body region of onset, 2) relative mix of UMN and LMN involvement, 3) rate of progression, and 4) cognitive impairment.1 In approximately 5%-10% of patients, the disease is inherited; 20% of these individuals have a mutation of the SOD1 gene; approximately 2%-5%, of the TARDBP (TDP-43) gene; and 2%-4%, of the FUS/TLS gene. 2Most patients with ALS, however, have no obvious family history and have sporadic ALS.2 To date, the only specific marker of sporadic ALS is the presence of inclusions staining positively for ubiquitin and TDP-43 in degenerating motor neurons. 3Despite technical advances in medicine in the last century, the diagnosis of sporadic ALS relies on the interpretation of clinical symptoms and signs (ie, signs suggestive of combined UMN and LMN degeneration, together with disease progression compatible with a neurodegenerative disorder). Paraclinical and laboratory tests are used only to exclude "ALS-mimic" syndromes. 4,5 In ALS, the absence of a disease marker for UMN and LMN involvement has 2 main negative consequences. First, the delay from onset of the disease to diagnosis of ALS can vary between 13 and 18 months 6,7

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

“…Modern imaging modalities such as diffusion tensor imaging [59,60], magnetic resonance spectroscopy [61,62], functional magnetic resonance imaging [63], and 18 Ffludeoxyglucose positron emission tomography [64,65] are emerging as potential biomarkers of disease progression. Unique imaging characteristics on magnetic resonance spectroscopy, functional magnetic resonance imaging, and 18 Ffludeoxyglucose positron emission tomography may aid in diagnosis [61][62][63][64].…”

“…Unique imaging characteristics on magnetic resonance spectroscopy, functional magnetic resonance imaging, and 18 Ffludeoxyglucose positron emission tomography may aid in diagnosis [61][62][63][64]. Findings on diffusion tensor imaging also correlate with ALS phenotypes [59], disease severity scales, and disease duration [60].…”

Neuroimaging in Amyotrophic Lateral Sclerosis

“…However, some of these findings have also been reported in normal controls [26]. The frequency of hyperintense lesions in the CST of patients with ALS varies significantly in different studies and does not correlate with clinical scores [26,28].…”

“…In patients with ALS, conventional MRI is used principally to exclude other pathologies, such as cerebral lesions, skull base lesions, cervical spondylotic myelopathy, other myelopathy, conus lesions, and thoracolumbar/sacral radiculopathy [7,26,27]. Once diseases mimicking ALS are ruled out, subtle neuroimaging signs that are supportive of ALS are looked into.…”

“…Hyperintensity along the CST on T2-weighted or fluidattenuated inversion recovery images is most readily identified in the posterior limb of the internal capsule (PLIC) and may also be seen in the centrum semiovale and ventral brain stem [26,27]. However, some of these findings have also been reported in normal controls [26].…”