Imaging findings associated with cognitive performance in primary lateral sclerosis and amyotrophic lateral sclerosis

Abstract

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.

Keywords: Diffusion tensor imaging; Executive function; Motor neuron disease.

Fig. 1

FA maps with color overlays showing the white matter tracts included in the analysis. Tracts were segmented by atlas analysis. The evaluated tracts were the uncinate fasciculus (UNC), SLF, SFO, IFO, PTR, and the fornix (Fx). The corpus callosum was segmented into three portions: the genu, body, and splenium (GCC, BCC, and SCC). The cingulum was segmented into the portion underlying the cingulate cortex (CGC) and a parahippocampal portion (CGH).

Fig. 2

Cognitive test scores in ALS and PLS patients. a DRS-2 total raw scores for each patient. Values above 133 (dashed line) are considered normal according to reference values. b Scaled scores for the five domains of the DRS-2. Group means ± SD are shown. The DRS-2 scaled scores were significantly less in ALS patients than in PLS patients (ANOVA, p < 0.001). c, d Scaled scores on selected D-KEFS subtests for ALS patients (c) and PLS patients (d) fulfilling the consensus criteria for cognitive impairment (ALSci) compared to patients without cognitive impairment (means ± SD).

Fig. 3

Sagittal (a) and axial (b-f) views of FA maps with color overlays of white matter structures with significant associations between DTI metrics and neuropsychological tests as listed in table 4. a Axial slices are shown in radiological convention with the left brain on the right, body of the corpus callosum (BCC). b, c SFO. d Splenium of the corpus callosum (SCC). e PTRs. f SLF. Scale denotes uncorrected p value, and thresholds below 0.01 are shown.

Fig. 4

Axial (a, b), coronal (c), and sagittal (d) views of FA maps with color overlays of white matter structures with significant associations between DTI metrics and particular neuropsychological tests as listed in table 4. The DRS-2 memory subscore was associated with AD of the IFO bilaterally (a), and the right PTR was associated with the memory score and letter fluency (b). Other fluency subscores were associated with diffusion properties of the splenium of the corpus callosum (SCC) (c) and the parahippocampal portion of the left cingulum (CGH) (d). Scale denotes uncorrected p value, and thresholds below 0.01 are shown.

Fig. 5

Volumetric differences between patients and healthy controls. Axial T1-weighted images with overlaid results of VBM analysis show a cluster with reduced gray matter volume in the right perirolandic area in ALS patients (a) and a cluster with reduced gray matter volume in the right motor cortex in PLS patients (b).