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

Longitudinal imaging in C9orf72 mutation carriers: Relationship to phenotype

Expansion mutations in the C9orf72 gene may cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or mixtures of the two clinical phenotypes. Different imaging findings have been described for C9orf72-associated diseases in comparison with sporadic patients with the same phenotypes, but it is uncertain whether different phenotypes have a common genotype-associated imaging signature. To address this question, 27 unrelated C9orf72 expansion mutation carriers (C9+) with varied phenotypes, 28 age-matched healthy controls and 22 patients with sporadic ALS (sALS) underwent 3T MRI scanning and clinical phenotyping. Measures of brain volumes and cortical thickness were extracted from T1 images. Compared to healthy controls and sALS patients, symptomatic C9+ subjects had greater ventricular volume loss and thalamic atrophy for age, with diffuse, patchy cortical thinning. Asymptomatic carriers did not differ from controls. C9+ ALS and ALS-FTD patients had less thinning of the motor cortex than sALS patients, but more thinning in extramotor regions, particularly in frontal and temporal lobes. C9+ ALS patients differed from sporadic ALS patients in the thickness of the superior frontal gyrus and lateral orbitofrontal cortex. Thickness of the precentral gyrus was weakly correlated with the revised ALS functional rating scale. Thickness of many cortical regions, including several frontal and temporal regions, was moderately correlated with letter fluency scores. Letter fluency scores were weakly correlated with ventricular and thalamic volume. To better understand how imaging findings are related to disease progression, nineteen C9+ subjects and 23 healthy controls were scanned approximately 6 months later. Ventricular volume increased in C9+ patients with FTD and ALS-FTD phenotypes and remained stable in asymptomatic C9+ subjects. We conclude that diffuse atrophy is a common underlying feature of disease associated with C9orf72 mutations across its clinical phenotypes. Ventricular enlargement can be measured over a 6-month time frame, and appears to be faster in patients with cognitive impairment

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

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

Double immunofluorescent labeling of ferritin-rich microglia in the dorsolateral white matter from the spinal cord of an ALS patient.

<p>Immunostaining for ferritin in green (A) and CD68, a marker of microglia, in red (B) labeling showed co-localization (<i>arrows</i>) in yellow (D, merge) indicating increased microglial ferritin in the corticospinal tract from the spinal cord of an ALS patient. (C) DAPI immunofluorescence, in blue, shows nuclear labeling. Scale bar, 30 mm.</p

Histological staining for iron with Perl's DAB stain in the motor cortex.

<p>The panels show comparable planes of section through the precentral gyrus of brains from the second ALS patient (A), and from the Alzheimer (B) and Parkinson (C) patients. The arrowheads indicate the pial surface. The arrows indicate the gray-white junction. (A) Low power magnification showing iron accumulation in the middle and deeper layers of cortical gray matter, and at the gray-white junction in a 51-year-old ALS patient. At higher power (D, E) the staining is present in cells with irregular processes suggestive of microglia in the ALS motor cortex. The lower portion of panel A shows the post-central gyrus with relatively little iron staining. The iron staining was more diffuse within the motor cortex of Alzheimer (B) and Parkinson (C) patients and was also present in the subcortical white matter. Scale bars, 1 mm (A–C), 10 µm (D, E).</p

Immunohistochemistry of cellular inclusions and iron histology in an ALS patient.

<p>(A) Ubiquitin reactive neuronal cytoplasmic inclusion with a filamentous appearance (<i>arrow</i>) in motor cortical neuron. (B, C) The neuronal cytoplasmic inclusions (<i>arrows</i>) were reactive with TDP-43 (B) and phosphorylated TDP-43 (C). Glial cell inclusions (B, <i>white arrow heads</i>) were also TDP-43 positive. (D) Spinal motor neurons (<i>arrow heads</i>) did not show iron accumulation with Perls' DAB stain which was present in erythrocytes in the same section (<i>arrows</i>). Scale bar, 100 mm (A–C); 20 mm (D).</p

<i>Ex vivo</i> 7T MRI and corresponding pathology in ALS.

<p>7T MRI signal change corresponded to iron accumulation in deeper layers of the cortical gray in the hand knob in an ALS patient. Each panel shows an axial slice of the precentral gyrus, with the cortical gray matter boundaries indicated by arrows, and the central sulcus and postcentral gyrus below. (A) R₂^* map showed patchy hyperintensity in the precentral gray. Scale bar represents R₂^* value in Hz. (B) Gradient echo magnitude image showed hypointensity in the corresponding region. Pixels correlate to acquisition voxels. (C) Low power micrographs show iron accumulation in the middle and deep layers of the motor cortex with Perls' DAB stain. (D) The luxol fast blue stain showed myelin pallor in the subcortical white matter of the precentral gyrus compared to the postcentral gyrus. Scale bar, 1 mm.</p

Frequency of hypointensity grade in the hand knob of the motor cortex.

<p>(A) Higher grades of hypointensity in the hand knob region on 3T FLAIR MRI occurred with greater frequency in ALS patients (<i>black bars</i>) than in healthy controls (<i>gray bars</i>). (B) Higher grades of hypointensity on 3T FLAIR MRI was associated with higher upper motor neuron impairment score (UMN-IS). Each dot represents the grade for one hemisphere and the UMN-IS score for the contralateral limb. Line indicates mean for group. Hypointensity was rated grade 0 (absent), grade 1 (present, mild), and grade 2 (present, marked). The UMN-IS is graded from 0–5 with normal function = 0, and higher scores indicating greater UMN impairment.</p

3T and 7T MRI in ALS and healthy control.

<p>3T and 7T brain MRI signal changes in the motor cortex hand knob differed between ALS patients (A, B, C) and healthy controls (D, E, F). Cortical hypointensity (<i>arrows</i>) is shown to be present in an ALS patient (Patient 2, age 51) and not in a healthy control on 3T FLAIR (A, D) and 7T gradient echo magnitude images (B, E). These areas corresponded to hyperintensity in the 7T R₂^* maps (C, F). Scale bar represents R₂^* value in Hz.</p