Esther Verstraete

Motor Network Degeneration in Amyotrophic Lateral Sclerosis: A Structural and Functional Connectivity Study

Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by motor neuron degeneration. How this disease affects the central motor network is largely unknown. Here, we combined for the first time structural and functional imaging measures on the motor network in patients with ALS and healthy controls. Methodology/Principal Findings Structural measures included whole brain cortical thickness and diffusion tensor imaging (DTI) of crucial motor tracts. These structural measures were combined with functional connectivity analysis of the motor network based on resting state fMRI. Focal cortical thinning was observed in the primary motor area in patients with ALS compared to controls and was found to correlate with disease progression. DTI revealed reduced FA values in the corpus callosum and in the rostral part of the corticospinal tract. Overall functional organisation of the motor network was unchanged in patients with ALS compared to healthy controls, however the level of functional connectedness was significantly correlated with disease progression rate. Patients with increased connectedness appear to have a more progressive disease course. Conclusions/Significance We demonstrate structural motor network deterioration in ALS with preserved functional connectivity measures. The positive correlation between functional connectedness of the motor network and disease progression rate could suggest spread of disease along functional connections of the motor network.

Neuroimaging in amyotrophic lateral sclerosis

The catastrophic system failure in amyotrophic lateral sclerosis is characterized by progressive neurodegeneration within the corticospinal tracts, brainstem nuclei and spinal cord anterior horns, with an extra-motor pathology that has overlap with frontotemporal dementia. The development of computed tomography and, even more so, MRI has brought insights into neurological disease, previously only available through post-mortem study. Although largely research-based, radionuclide imaging has continued to provide mechanistic insights into neurodegenerative disorders. The evolution of MRI to use advanced sequences highly sensitive to cortical and white matter structure, parenchymal metabolites and blood flow, many of which are now applicable to the spinal cord as well as the brain, make it a uniquely valuable tool for the study of a multisystem disorder such as amyotrophic lateral sclerosis. This comprehensive review considers the full range of neuroimaging techniques applied to amyotrophic lateral sclerosis over the last 25 years, the biomarkers they have revealed and future developments.

Structural MRI reveals cortical thinning in amyotrophic lateral sclerosis

Objectives Amyotrophic lateral sclerosis (ALS) is a fatal disease characterised by combined upper and lower motor neuron degeneration. An early and accurate diagnosis is important for patient care and might facilitate the search for a more effective therapy. MRI was used to study the whole cortical mantle, applying an unbiased surface based approach to identify a marker of upper motor neuron involvement in ALS. Methods Surface based cortical morphology analyses were performed on structural, 3T MRI data of 45 patients with ALS and 25 matched healthy controls in a case control study design. These analyses consisted of measuring cortical thickness, surface area and volume. The effects of disease progression were examined by correlating cortical measures with progression rate and by longitudinal measures in 20 patients. Results Cortical morphology analyses revealed specific thinning in the precentral gyrus, considered the primary motor cortex, in patients with ALS compared with controls (p=6.3×10−8). Surface area was reduced in the right inferior parietal region (p=0.049) and volume—the product of cortical thickness and surface area—was reduced in the right precentral gyrus (p=0.031). From these findings, it appears that cortical thickness is superior in detecting the degenerative effects of ALS. Relative cortical thinning in temporal regions was related to faster clinical progression (right inferior temporal gyrus: p=3.3×10−4). Conclusions Cortical thinning of the primary motor cortex might be a diagnostic marker for upper motor neuron degeneration in ALS. Relative thinning in temporal regions was associated with a rapidly progressive disease course.

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

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. Hum Brain Mapp 35:1351–1361, 2014.

Correlation between structural and functional connectivity impairment in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized by progressive loss of motor function. While the pathogenesis of ALS remains largely unknown, imaging studies of the brain should lead to more insight into structural and functional disease effects on the brain network, which may provide valuable information on the underlying disease process. This study investigates the correlation between changes in structural connectivity (SC) and functional connectivity (FC) of the brain network in ALS. Structural reconstructions of the brain network, derived from diffusion weighted imaging (DWI), were obtained from 64 patients and 27 healthy controls. Functional interactions between brain regions were derived from resting‐state fMRI. Our results show that (i) the most structurally affected connections considerably overlap with the most functionally impaired connections, (ii) direct connections of the motor cortex are both structurally and functionally more affected than connections at greater topological distance from the motor cortex, and (iii) there is a strong positive correlation between changes in SC and FC averaged per brain region (r = 0.44, P < 0.0001). Our findings indicate that structural and functional network degeneration in ALS is coupled, suggesting the pathogenic process affects both SC and FC of the brain, with the most prominent effects in SC. Hum Brain Mapp 35:4386–4395, 2014.

Cortical thickness in ALS: towards a marker for upper motor neuron involvement

Objective Examine whether cortical thinning is a disease-specific phenomenon across the spectrum of motor neuron diseases in relation to upper motor neuron (UMN) involvement. Methods 153 patients (112 amyotrophic lateral sclerosis (ALS), 19 patients with a clinical UMN phenotype, 22 with a lower motor neuron (LMN) phenotype), 60 healthy controls and 43 patients with an ALS mimic disorder were included for a cross-sectional cortical thickness analysis. Thirty-nine patients with ALS underwent a follow-up scan. T1-weighted images of the brain were acquired using a 3 T scanner. The relation between cortical thickness and clinical measures, and the longitudinal changes were examined. Results Cortical thickness of the precentral gyrus (PCG) was significantly reduced in ALS (p=1.71×10−13) but not in mimic disorders (p=0.37) or patients with an LMN phenotype (p=0.37), as compared to the group of healthy controls. Compared to patients with ALS, patients with a UMN phenotype showed an even lower PCG cortical thickness (p=1.97×10−3). Bulbar scores and arm functional scores showed a significant association with cortical thickness of corresponding body regions of the motor homunculus. Longitudinal analysis revealed a decrease of cortical thickness in the left temporal lobe of patients with ALS (parahippocampal region p=0.007 and fusiform cortex p=0.001). Conclusions PCG cortical thinning was found to be specific for motor neuron disease with clinical UMN involvement. Normal levels of cortical thickness in mimic disorders or LMN phenotypes suggest that cortical thinning reflects pathological changes related to UMN involvement. Progressive cortical thinning in the temporal lobe suggests recruitment of non-motor areas, over time.

Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial.

Objectives To determine the safety and efficacy of lithium for the treatment of amyotrophic lateral sclerosis (ALS) in a randomised, placebo controlled, double blind, sequential trial. Methods Between November 2008 and June 2011, 133 patients were randomised to receive lithium carbonate (target blood level 0.4–0.8 mEq/l) or placebo as add-on treatment with riluzole. The primary endpoint was survival, defined as death, tracheostomal ventilation or non-invasive ventilation for more than 16 h/day. Secondary outcome measures consisted of the revised ALS Functional Rating Scale and forced vital capacity. Analysis was by intention to treat and according to a sequential trial design. Results 61 patients reached a primary endpoint, 33 of 66 in the lithium group and 28 of 67 patients in the placebo group. Lithium did not significantly affect survival (cumulative survival probability of 0.73 in the lithium group (95% CI 0.63 to 0.86) vs 0.75 in the placebo group (95% CI 0.65 to 0.87) at 12 months and 0.62 in the lithium group (95% CI 0.50 to 0.76) vs 0.67 in the placebo group (95% CI 0.56 to 0.81) at 16 months). Secondary outcome measures did not differ between treatment groups. No major safety concerns were encountered. Conclusions This trial, designed to detect a modest effect of lithium, did not demonstrate any beneficial effect on either survival or functional decline in patients with ALS. Trial registration number NTR1448. Name of trial registry: Lithium trial in ALS.

What Does Imaging Reveal About the Pathology of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is now recognised to be a heterogeneous neurodegenerative syndrome of the motor system and its frontotemporal cortical connections. The development and application of structural and functional imaging over the last three decades, in particular magnetic resonance imaging (MRI), has allowed traditional post mortem histopathological and emerging molecular findings in ALS to be placed in a clinical context. Cerebral grey and white matter structural MRI changes are increasingly being understood in terms of brain connectivity, providing insights into the advancing degenerative process and producing candidate biomarkers. Such markers may refine the prognostic stratification of patients and the diagnostic pathway, as well as providing an objective assessment of changes in disease activity in response to future therapeutic agents. Studies are being extended to the spinal cord, and the application of neuroimaging to unaffected carriers of highly penetrant genetic mutations linked to the development of ALS offers a unique window to the pre-symptomatic landscape.

Subcortical structures in amyotrophic lateral sclerosis

The aim of this study was to assess the involvement of deep gray matter, hippocampal subfields, and ventricular changes in patients with amyotrophic lateral sclerosis (ALS). A total of 112 ALS patients and 60 healthy subjects participated. High-resolution T1-weighted images were acquired using a 3T MRI scanner. Thirty-nine patients underwent a follow-up scan. Volumetric and shape analyses of subcortical structures were performed, measures were correlated with clinical parameters, and longitudinal changes were assessed. At baseline, reduced hippocampal volumes (left: p = 0.007; right: p = 0.011) and larger inferior lateral ventricles (left: p = 0.013; right: p = 0.041) were found in patients compared to healthy controls. Longitudinal analyses demonstrated a significant decrease in volume of the right cornu ammonis 2/3 and 4/dentate gyrus and left presubiculum (p = 0.002, p = 0.045, p < 0.001), and a significant increase in the ventricular volume in the lateral (left: p < 0.001; right: p < 0.001), 3rd (p < 0.001) and 4th (p = 0.001) ventricles. Larger ventricles were associated with a lower ALSFRS-R score (p = 0.021). In conclusion, ALS patients show signs of neurodegeneration of subcortical structures and ventricular enlargement. Subcortical involvement is progressive and correlates with clinical parameters, highlighting its role in the neurodegenerative process in ALS.

TDP-43 plasma levels are higher in amyotrophic lateral sclerosis

Abstract Our objective was to investigate TDP-43 plasma levels in patients with amyotrophic lateral sclerosis (ALS). TDP-43 has been identified as a major component of protein inclusions in the brain of patients with ALS; mutations in the corresponding gene (TARDBP) have also been identified. Although increased TDP-43 levels have been reported in the cerebrospinal fluid, plasma levels have not yet been assessed in patients with ALS. TDP-43 levels were quantified by sandwich ELISA in plasma of 219 patients and 100 controls. In addition, we sequenced exon 6 of TARDBP, and performed longitudinal TDP-43 plasma measurements in a subset of patients. Results showed that TDP-43 plasma levels were significantly increased in patients with ALS (p = 0.023) and we found a positive correlation with age in patients and controls. Longitudinal measurements of TDP-43 plasma levels showed an increase in only one patient, with stable levels in five others. Three TARDBP variations were identified in the ALS group (1.7%), but the association with TDP-43 plasma levels was ambiguous. In conclusion, our data indicate that TDP-43 plasma levels may have potential as a marker for ALS. A genotype-phenotype relationship could not, however, be established in this cohort.