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Structural brain network imaging shows expanding disconnection of the motor system in amyotrophic lateral sclerosis.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease, which primarily targets the motor system. The structural integrity of the motor network and the way it is embedded in the overall brain network is essential for motor functioning. We studied the longitudinal effects of ALS on the brain network using diffusion tensor imaging and questioned whether over time an increasing number of connections become involved or whether there is progressive impairment of a limited number of connections. The brain network was reconstructed based on "whole brain" diffusion tensor imaging data. We examined: (1) network integrity in 24 patients with ALS at baseline (T = 1) and at a more advanced stage of the disease (T = 2; interval 5.5 months) compared with a group of healthy controls and (2) progressive brain network impairment comparing patients at two time-points in a paired-analysis. These analyses demonstrated an expanding subnetwork of affected brain connections over time with a central role for the primary motor regions (P-values T = 1 0.003; T = 2 0.001). Loss of structural connectivity mainly propagated to frontal and parietal brain regions at T = 2 compared with T = 1. No progressive impairment of the initially affected (motor) connections could be detected. The main finding of this study is an increasing loss of network structure in patients with ALS. In contrast to the theory of ALS solely affecting a fixed set of primary motor connections, our findings show that the network of impaired connectivity is expanding over time. These results are in support of disease spread along structural brain connections.

SUBMITTER: Verstraete E

PROVIDER: S-EPMC6869230 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Structural brain network imaging shows expanding disconnection of the motor system in amyotrophic lateral sclerosis.

Verstraete Esther E Veldink Jan H JH van den Berg Leonard H LH van den Heuvel Martijn P MP

Human brain mapping 20130301 4

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease, which primarily targets the motor system. The structural integrity of the motor network and the way it is embedded in the overall brain network is essential for motor functioning. We studied the longitudinal effects of ALS on the brain network using diffusion tensor imaging and questioned whether over time an increasing number of connections become involved or whether there is progressive impairment of a limited number of ...[more]

PMID: 23450820

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Project description:Magnetic resonance imaging measures have been proposed as objective markers to study upper motor neuron loss in motor neuron disorders. Cross-sectional studies have identified imaging differences between groups of healthy controls and patients with amyotrophic lateral sclerosis (ALS) or primary lateral sclerosis (PLS) that correlate with disease severity, but it is not known whether imaging measures change as disease progresses. Additionally, whether imaging measures change in a similar fashion with disease progression in PLS and ALS is unclear. To address these questions, clinical and imaging evaluations were first carried out in a prospective cross-sectional study of 23 ALS and 22 PLS patients with similar motor impairment and 19 age-matched healthy controls. Clinical evaluations consisted of a neurological examination, the ALS Functional rating scale-revised, and measures of finger tapping, gait, and timed speech. Age and ALSFRS score were not different, but PLS patients had longer duration of symptoms. Imaging measures examined were cortical thickness, regional brain volumes, and diffusion tensor imaging of the corticospinal tract and callosum. Imaging measures that differed from controls in a cross-sectional vertex-wise analysis were used as regions of interest for longitudinal analysis, which was carried out in 9 of the ALS patients (interval 1.26 ± 0.72 years) and 12 PLS patients (interval 2.08 ± 0.93 years). In the cross-sectional study both groups had areas of cortical thinning, which was more extensive in motor regions in PLS patients. At follow-up, clinical measures declined more in ALS than PLS patients. Cortical thinning and grey matter volume loss of the precentral gyri progressed over the follow-up interval. Fractional anisotropy of the corticospinal tracts remained stable, but the cross-sectional area declined in ALS patients. Changes in clinical measures correlated with changes in precentral cortical thickness and grey matter volume. The rate of cortical thinning was greater in ALS patients with shorter disease durations, suggesting that thickness decreases in a non-linear fashion. Thus, cortical thickness changes are a potential imaging marker for disease progression in individual patients, but the magnitude of change likely depends on disease duration and progression rate. Differences between PLS and ALS patients in the magnitude of thinning in cross-sectional studies are likely to reflect longer disease duration. We conclude that there is an evolution of structural imaging changes with disease progression in motor neuron disorders. Some changes, such as diffusion properties of the corticospinal tract, occur early while cortical thinning and volume loss occur later.

Project description:Background and purposeAmyotrophic lateral sclerosis is a progressive motor neuron disorder that involves degeneration of both upper and lower motor neurons. In patients with amyotrophic lateral sclerosis, pathologic studies and ex vivo high-resolution MR imaging at ultra-high field strength revealed the co-localization of iron and activated microglia distributed in the deep layers of the primary motor cortex. The aims of the study were to measure the cortical thickness and evaluate the distribution of iron-related signal changes in the primary motor cortex of patients with amyotrophic lateral sclerosis as possible in vivo biomarkers of upper motor neuron impairment.Materials and methodsTwenty-two patients with definite amyotrophic lateral sclerosis and 14 healthy subjects underwent a high-resolution 2D multiecho gradient-recalled sequence targeted on the primary motor cortex by using a 7T scanner. Image analysis consisted of the visual evaluation and quantitative measurement of signal intensity and cortical thickness of the primary motor cortex in patients and controls. Qualitative and quantitative MR imaging parameters were correlated with electrophysiologic and laboratory data and with clinical scores.ResultsUltra-high field MR imaging revealed atrophy and signal hypointensity in the deep layers of the primary motor cortex of patients with amyotrophic lateral sclerosis with a diagnostic accuracy of 71%. Signal hypointensity of the deep layers of the primary motor cortex correlated with upper motor neuron impairment (r = -0.47; P < .001) and with disease progression rate (r = -0.60; P = .009).ConclusionsThe combined high spatial resolution and sensitivity to paramagnetic substances of 7T MR imaging demonstrate in vivo signal changes of the cerebral motor cortex that resemble the distribution of activated microglia within the cortex of patients with amyotrophic lateral sclerosis. Cortical thinning and signal hypointensity of the deep layers of the primary motor cortex could constitute a marker of upper motor neuron impairment in patients with amyotrophic lateral sclerosis.

Project description:Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that affects upper and lower motor neurons. Observational and intervention studies can be tracked using clinical measures such as the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) but for a complete understanding of disease progression, objective in vivo biomarkers of both central and peripheral motor pathway pathology are highly desirable. The aim of this study was to determine the utility of structural and diffusion imaging as central nervous system biomarkers compared to the standard clinical measure, ALSFRS-R, to track longitudinal evolution using three time-point measurements. N = 34 patients with ALS were scanned and clinically assessed three times at a mean of three month time intervals. The MRI biomarkers were structural T1-weighted volumes for cortical thickness measurement as well as deep grey matter volumetry, voxel-based morphometry and diffusion tensor imaging (DTI). Cortical thickness focused specifically on the precentral gyrus while quantitative DTI biomarkers focused on the corticospinal tracts. The evolution of imaging biomarkers and ALSFRS-R scores over time were analysed using a mixed effects model that accounted for the scanning interval as a fixed effect variable, and, the initial measurements and time from onset as random variables. The mixed effects model showed a significant decrease in the ALSFRS-R score, (p < 0.0001, and an annual rate of change (AROC) of - 7.3 points). Similarly, fractional anisotropy of the corticospinal tract showed a significant decrease (p = 0.009, AROC = - 0.0066) that, in turn, was driven by a significant increase in radial diffusivity combined with a trend to decrease in axial diffusivity. No significant change in cortical thickness of the precentral gyrus was found (p > 0.5). In addition, deep grey matter volumetry and voxel-based morphometry also identified no significant changes. Furthermore, the availability of three time points was able to indicate that there was a linear progression in both clinical and fractional anisotropy measures adding to the validity of these results. The results indicate that DTI is clearly a superior imaging marker compared to atrophy for tracking the evolution of the disease and can act as a central nervous biomarker in longitudinal studies. It remains, however, less sensitive than the ALSFRS-R score for monitoring decline over time.

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Structural brain network imaging shows expanding disconnection of the motor system in amyotrophic lateral sclerosis.

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Structural brain network imaging shows expanding disconnection of the motor system in amyotrophic lateral sclerosis.

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