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ABSTRACT & COMMENTARY
By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports no financial relationships relevant to this field of study.
SYNOPSIS: Diffusion tensor magnetic resonance imaging of the brain and spinal cord, which measures the integrity of white-matter fiber tracks, can improve the sensitivity and specificity of amyotrophic lateral sclerosis diagnosis.
SOURCE: Kassubek J, et al. Diffusion tensor imaging analysis of sequential spreading of disease in amyotrophic lateral sclerosis confirms patterns of TDP-43 pathology. Brain 2014;137:1733-1740.
Based on 76 autopsies, and using distribution patterns of phosphorylated 43 kDa TAR DNA-binding protein, four neuropathological stages of amyotrophic lateral sclerosis (ALS) have recently been defined by Brettschneider et al.1 ALS was found to progress in a sequential regional pattern, with stage 1 lesions observed in the agranular motor cortex; brainstem cranial motor nuclei of nerves V, VII, and XII; and in spinal cord anterior horn cells, with stage 2 involvement seen in the prefrontal neocortex (middle frontal gyrus), brainstem reticular formation, precerebellar nuclei, and red nucleus. In stage 3, abnormalities were found in the prefrontal gyrus rectus and orbital gyri, postcentral neocortex, and striatum, and stage 4 changes were seen in anteromedial portions of the temporal lobe, including the hippocampal formation. An in vivo approach to assessing this spread of TDP-43 pathology is measurement of neuro-axonal loss in white matter fiber tracts. Using magnetic resonance imaging (MRI)-based techniques, can the ex vivo staging system be transferred to noninvasive in vivo diagnostics in ALS, thereby permitting in vivo monitoring of disease progression?
To address this question, 111 patients (68 men, 43 women) with clinically definite or probable, mild-to-moderate, sporadic ALS, based on revised El Escorial criteria,2 underwent clinical and laboratory examination, including MRI imaging using a 1.5T (n = 78) or 3.0T (n = 33) scanner, with 74 healthy, age-matched controls used for comparison. No one in either group had other medical, neurologic, or psychiatric issues. MRI images were examined by a fiber-tracking approach to analyze five tracts-of-interest that represent the white matter correlates of the four stages of ALS: the corticospinal tract (stage 1), the corticorubral and corticopontine tracts (stage 2), the corticostriatal pathway (stage 3), the proximal portion of the perforant path (stage 4), and two reference pathways originating from the corpus callosum and optic tract. Postprocessing and statistical analysis comprised whole brain-based spatial statistics, the t-test, staging categorization of a decision alogorithm, and calculation of axial and radial diffusivity, with false discovery rate corrected at P < 0.05.
Using region of interest analysis, ALS patients could be differentiated from controls using the 1.5T MRI with 78% sensitivity and 69% specificity, and using the 3.0T MRI by 82% and 68%, respectively. Tract-wise fractional anisotropy statistics found similar sensitivity and specificity results: 79% and 71% for the former, and 79% and 73% for the latter, respectively. In the entire cohort, distinction between ALS and controls was greatest at stage 1 for the corticospinal tract. Staging pattern identification could be performed at the individual patient level. In ALS, it is possible to image stages of disease in predefined tract structures in vivo using tract of interest-based tensor diffusion MRI technique, permitting in vivo monitoring of disease progression.
Diffusion tensor imaging (DTI) of the cervical spinal cord in ALS patients may disclose corticospinal abnormalities not seen on conventional MRI. Among 24 patients with probable or definite ALS, conventional cervical spinal cord MRI was unremarkable. In contrast, fractional anisotropy was significantly lower and apparent diffusion coefficient correlates were significantly greater than those of 16 age-matched controls when examining the lateral corticospinal tracts bilaterally. No correlation between abnormal DTI parameters and clinical findings was seen. Quantitative DTI can disclose subtle abnormalities in the lateral corticospinal tracts even in "MRI normal-appearing" cervical spinal cord of ALS patients and may be used to assist in the diagnosis of ALS.3