Amyotrophic lateral sclerosis (ALS) patients with predominant upper motor neuron (UMN) signs occasionally have hyperintensity of corticospinal tract (CST) on T2- and proton-density-(PD-) weighted brain images. Diffusion tensor imaging (DTI) was used to assess whether diffusion parameters along intracranial CST differ in presence or absence of hyperintensity and correspond to UMN dysfunction. DTI brain scans were acquired in 47 UMN-predominant ALS patients with ( ) or without ( ) CST hyperintensity and in 10 control subjects. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured in four regions of interests (ROIs) along CST. Abnormalities ( ) were observed in FA, AD, or RD in CST primarily at internal capsule (IC) level in ALS patients, especially those with CST hyperintensity. Clinical measures corresponded well with DTI changes at IC level. The IC abnormalities suggest a prominent axonopathy in UMN-predominant ALS and that tissue changes underlying CST hyperintensity have specific DTI changes, suggestive of unique axonal pathology. 1. Introduction Amyotrophic lateral sclerosis (ALS) is a progressive degeneration of motor neurons in the brain and spinal cord whose cause is unknown [1]. It is also unclear whether the motor neuron degeneration begins in the perikaryon (cell body) as a neuronopathy and proceeds anterogradely, or along the axon as an axonopathy and proceeds retrogradely. Brain motor neurons, mostly in the primary motor cortex (upper motor neurons), project their axons caudally along the corticospinal tract (CST) through the brainstem to the spinal cord where they synapse onto anterior horn cells (lower motor neurons). Progressive degeneration of these two motor neuron pools results in ALS with upper motor neuron (UMN) signs (hypertonicity, hyperreflexia, and pathologic reflexes) and lower motor neuron (LMN) signs (muscle fasciculations, atrophy, and weakness) both being required for diagnosis [1]. A certain percentage of ALS patients present with UMN-predominant disease, and few or no clinically detectable LMN signs. By El Escorial criteria, they are usually initially categorized as possible or, at most, probable with laboratory support ALS because of the limited extent of LMN findings [2]. As disease progresses, their LMN dysfunction may remain either limited in degree or become more extensive. Independent of this observation, a relatively small percentage of ALS patients display bilateral hyperintensity of the corticospinal tract (CST) on T2- and proton-density-(PD-) weighted
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