Iron Accumulation in Deep Cortical Layers Accounts for MRI Signal Abnormalities in ALS: Correlating 7 Tesla MRI and Pathology

Justin Y Kwan,Elham Bayat,Teepu Siddique,Han-Xiang Deng,John A Butman,Suh Young Jeong,Peter Van Gelderen,Lingye Chen,Jeff H Duyn,Martha M Quezado,Tracey A Rouault,James Russell,Laura E Danielian,Mary Kay Floeter,Tetsuo Ashizawa

doi:10.1371/journal.pone.0035241

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by cortical and spinal motor neuron dysfunction. Routine magnetic resonance imaging (MRI) studies have previously shown hypointense signal in the motor cortex on T2-weighted images in some ALS patients, however, the cause of this finding is unknown. To investigate the utility of this MR signal change as a marker of cortical motor neuron degeneration, signal abnormalities on 3T and 7T MR images of the brain were compared, and pathology was obtained in two ALS patients to determine the origin of the motor cortex hypointensity. Nineteen patients with clinically probable or definite ALS by El Escorial criteria and 19 healthy controls underwent 3T MRI. A 7T MRI scan was carried out on five ALS patients who had motor cortex hypointensity on the 3T FLAIR sequence and on three healthy controls. Postmortem 7T MRI of the brain was performed in one ALS patient and histological studies of the brains and spinal cords were obtained post-mortem in two patients. The motor cortex hypointensity on 3T FLAIR images was present in greater frequency in ALS patients. Increased hypointensity correlated with greater severity of upper motor neuron impairment. Analysis of 7T T2 *-weighted gradient echo imaging localized the signal alteration to the deeper layers of the motor cortex in both ALS patients. Pathological studies showed increased iron accumulation in microglial cells in areas corresponding to the location of the signal changes on the 3T and 7T MRI of the motor cortex. These findings indicate that the motor cortex hypointensity on 3T MRI FLAIR images in ALS is due to increased iron accumulation by microglia.

Highlights

A reliable objective marker of corticospinal upper motor neuron (UMN) dysfunction remains elusive despite its importance for diagnosis and monitoring of disease progression in amyotrophic lateral sclerosis (ALS)
The ALSFRS-R was lower and upper motor neuron impairment score (UMN-IS) was higher in the patient group compared with the controls (Table 1)
We suggest that the T2 shortening observed in the motor cortex on MR images of the brain in ALS patients is caused by iron accumulation within microglia

Summary

Introduction

A reliable objective marker of corticospinal upper motor neuron (UMN) dysfunction remains elusive despite its importance for diagnosis and monitoring of disease progression in amyotrophic lateral sclerosis (ALS). Reduction in the neuronal marker N-acetyl-aspartate (NAA) on proton magnetic resonance spectroscopy, decreased fractional anisotropy on diffusion tensor imaging studies, and prolongation of central motor conduction time on transcranial magnetic stimulation studies have been suggested as potential markers of corticospinal motor neuron dysfunction in ALS [2,3,4]. While these measures facilitate an improved understanding of the underlying pathophysiology, they are neither sensitive nor specific for ALS. Motor cortex hypointensity correlated with the severity of clinical UMN dysfunction in one study, and was proposed as a marker of motor neuron degeneration [6]

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