Elham Bayat

Iron accumulation in deep cortical layers accounts for MRI signal abnormalities in ALS: Correlating 7 tesla MRI and pathology

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.

White matter alterations differ in primary lateral sclerosis and amyotrophic lateral sclerosis

Primary lateral sclerosis is a sporadic disorder characterized by slowly progressive corticospinal dysfunction. Primary lateral sclerosis differs from amyotrophic lateral sclerosis by its lack of lower motor neuron signs and long survival. Few pathological studies have been carried out on patients with primary lateral sclerosis, and the relationship between primary lateral sclerosis and amyotrophic lateral sclerosis remains uncertain. To detect in vivo structural differences between the two disorders, diffusion tensor imaging of white matter tracts was carried out in 19 patients with primary lateral sclerosis, 18 patients with amyotrophic lateral sclerosis and 19 age-matched controls. Fibre tracking was used to reconstruct the intracranial portion of the corticospinal tract and three regions of the corpus callosum: the genu, splenium and callosal fibres connecting the motor cortices. Both patient groups had reduced fractional anisotropy, a measure associated with axonal organization, and increased mean diffusivity of the reconstructed corticospinal and callosal motor fibres compared with controls, without changes in the genu or splenium. Voxelwise comparison of the whole brain white matter using tract-based spatial statistics confirmed the differences between patients and controls in the diffusion properties of the corticospinal tracts and motor fibres of the callosum. This analysis further revealed differences in the regional distribution of white matter alterations between the patient groups. In patients with amyotrophic lateral sclerosis, the greatest reduction in fractional anisotropy occurred in the distal portions of the intracranial corticospinal tract, consistent with a distal axonal degeneration. In patients with primary lateral sclerosis, the greatest loss of fractional anisotropy and mean diffusivity occurred in the subcortical white matter underlying the motor cortex, with reduced volume, suggesting tissue loss. Clinical measures of upper motor neuron dysfunction correlated with reductions in fractional anisotropy in the corticospinal tract in patients with amyotrophic lateral sclerosis and increased mean diffusivity and volume loss of the corticospinal tract in patients with primary lateral sclerosis. Changes in the diffusion properties of the motor fibres of the corpus callosum were strongly correlated with changes in corticospinal fibres in patients, but not in controls. These findings indicate that degeneration is not selective for corticospinal neurons, but affects callosal neurons within the motor cortex in motor neuron disorders.

Imaging Findings Associated with Cognitive Performance in Primary Lateral Sclerosis and Amyotrophic Lateral Sclerosis

Introduction: Executive dysfunction occurs in many patients with amyotrophic lateral sclerosis (ALS), but it has not been well studied in primary lateral sclerosis (PLS). The aims of this study were to (1) compare cognitive function in PLS to that in ALS patients, (2) explore the relationship between performance on specific cognitive tests and diffusion tensor imaging (DTI) metrics of white matter tracts and gray matter volumes, and (3) compare DTI metrics in patients with and without cognitive and behavioral changes. Methods: The Delis-Kaplan Executive Function System (D-KEFS), the Mattis Dementia Rating Scale (DRS-2), and other behavior and mood scales were administered to 25 ALS patients and 25 PLS patients. Seventeen of the PLS patients, 13 of the ALS patients, and 17 healthy controls underwent structural magnetic resonance imaging (MRI) and DTI. Atlas-based analysis using MRI Studio software was used to measure fractional anisotropy, and axial and radial diffusivity of selected white matter tracts. Voxel-based morphometry was used to assess gray matter volumes. The relationship between diffusion properties of selected association and commissural white matter and performance on executive function and memory tests was explored using a linear regression model. Results: More ALS than PLS patients had abnormal scores on the DRS-2. DRS-2 and D-KEFS scores were related to DTI metrics in several long association tracts and the callosum. Reduced gray matter volumes in motor and perirolandic areas were not associated with cognitive scores. Conclusion: The changes in diffusion metrics of white matter long association tracts suggest that the loss of integrity of the networks connecting fronto-temporal areas to parietal and occipital areas contributes to cognitive impairment.

Psychiatric aspects of amyotrophic lateral sclerosis (ALS).

Amyotrophic lateral sclerosis (ALS) is a progressive disorder characterized by degeneration of motor neurons. Given the severe nature of ALS, many believed that patients would suffer from a high level of depression and a low quality of life. However, research into the psychological health of patients with ALS has shown that this is not the case. This article reviews the state of current knowledge as it pertains to the psychological health of ALS patients in four broad areas: quality of life, personality characteristics, emotional reactions, and end-of-life choices.

Amyotrophic lateral sclerosis: An emerging era of collaboratie gene discovery

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered. However, most forms of the disease are not obviously familial. Recent advances in human genetics have enabled genome-wide analyses of single nucleotide polymorphisms (SNPs) that make it possible to study complex genetic contributions to human disease. Genome-wide SNP analyses require a large sample size and thus depend upon collaborative efforts to collect and manage the biological samples and corresponding data. Public availability of biological samples (such as DNA), phenotypic and genotypic data further enhances research endeavors. Here we discuss a large collaboration among academic investigators, government, and non-government organizations which has created a public repository of human DNA, immortalized cell lines, and clinical data to further gene discovery in ALS. This resource currently maintains samples and associated phenotypic data from 2332 MND subjects and 4692 controls. This resource should facilitate genetic discoveries which we anticipate will ultimately provide a better understanding of the biological mechanisms of neurodegeneration in ALS.

Underrecognized anomaly: Proximal Martin-Gruber anastomosis at the elbow

Purpose: A proximal Martin-Gruber anastomosis (MGA) is an underrecognized anomaly and can mimic ulnar neuropathy at the elbow on electrodiagnostic testing. Martin-Gruber anastomosis is mainly recognized as a crossover from median nerve or its branches to ulnar nerve at the forearm, but may occur at the elbow (proximal MGA). The authors report their experience with MGA at the elbow. Methods: Using standard nerve conduction techniques, the authors prospectively detected electrodiagnostic evidence of a proximal MGA at the elbow over the course of 4 years. An accompanying ulnar neuropathy was diagnosed based on clinical findings, focal conduction slowing, and needle electromyography. Results: A proximal MGA involving branch of ulnar nerve was detected in 16 cases. The detection of proximal MGA to the first dorsal interosseous muscles was more sensitive than to the adductor digiti minimi muscles in their series. Conclusions: A proximal MGA is an underrecognized anomaly. This study is the largest series for proximal MGA in the literature. The authors recommend considering proximal MGA in any cases of ulnar neuropathy at the elbow, especially if the apparent conduction block is not associated with slowing of conduction velocity, and a discrepancy between clinical and electrodiagnostic findings is present.

Ulnar neuropathy with prominent proximal Martin-Gruber anastomosis

Martin-Gruber anastomosis (MGA) is the most common nerve anastomosis in the upper extremities and it crosses from the median nerve to the ulnar nerve. Proximal MGA is an under recognized anastomosis between the ulnar and median nerves at or above the elbow and should not be missed during nerve conduction studies. We presented two patients with ulnar neuropathy mimicking findings including numbness and tingling of the 4th and 5th digits and mild weakness of intrinsic hand muscles. However, both cases had an apparently remarkable conduction block between the below- and above-elbow sites that was disproportionate to their clinical findings. To explain this discrepancy, a large MGA was detected with stimulation of the median nerve at the elbow. Thus, proximal MGA should be considered in ulnar neuropathy at the elbow when apparent conduction block or/and discrepancy between clinical and electrodiagnostic findings is found.

Autoantibody Testing of Autoimmune Neuromuscular Junction, Hyperexcitability, and Muscle Disorders

Serological evaluation for neuromuscular disorders expands commensurate with understanding of their autoimmune etiology. In myasthenia gravis (MG) and Lambert-Eaton syndrome (LES) and stiff person syndrome (SPS), there is a clear link between an autoantibody and disease pathogenesis, while the association of autoantibodies and inflammatory myopathies is less clear. Despite the uncertainty of the pathogenic role of autoantibodies in certain disorders, their detection may be useful in diagnosis and prognosis. This chapter reviews use of serological evaluation in diagnosis of neuromuscular junction disorders, hyperexcitability syndromes, and inflammatory muscle diseases.