scholarly journals Disruption of the white matter structural network and its correlation with baseline progression rate in patients with sporadic amyotrophic lateral sclerosis

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Wenbin Li ◽  
Qianqian Wei ◽  
Yanbing Hou ◽  
Du Lei ◽  
Yuan Ai ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
White Matter ◽  
Clustering Coefficient ◽  
Single Subject ◽  
Progression Rate ◽  
Motor Systems ◽  
Structural Network ◽  
Structural Networks ◽  
Healthy Participants ◽  
Lateral Sclerosis

Abstract Objective There is increasing evidence that amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease impacting large-scale brain networks. However, it is still unclear which structural networks are associated with the disease and whether the network connectomics are associated with disease progression. This study was aimed to characterize the network abnormalities in ALS and to identify the network-based biomarkers that predict the ALS baseline progression rate. Methods Magnetic resonance imaging was performed on 73 patients with sporadic ALS and 100 healthy participants to acquire diffusion-weighted magnetic resonance images and construct white matter (WM) networks using tractography methods. The global and regional network properties were compared between ALS and healthy subjects. The single-subject WM network matrices of patients were used to predict the ALS baseline progression rate using machine learning algorithms. Results Compared with the healthy participants, the patients with ALS showed significantly decreased clustering coefficient Cp (P = 0.0034, t = 2.98), normalized clustering coefficient γ (P = 0.039, t = 2.08), and small‐worldness σ (P = 0.038, t = 2.10) at the global network level. The patients also showed decreased regional centralities in motor and non-motor systems including the frontal, temporal and subcortical regions. Using the single-subject structural connection matrix, our classification model could distinguish patients with fast versus slow progression rate with an average accuracy of 85%. Conclusion Disruption of the WM structural networks in ALS is indicated by weaker small-worldness and disturbances in regions outside of the motor systems, extending the classical pathophysiological understanding of ALS as a motor disorder. The individual WM structural network matrices of ALS patients are potential neuroimaging biomarkers for the baseline disease progression in clinical practice.

scholarly journals White matter structural network abnormalities underlie executive dysfunction in amyotrophic lateral sclerosis

2016 ◽  
Vol 38 (3) ◽  
pp. 1249-1268 ◽  
Author(s):  
Dennis Dimond ◽  
Abdullah Ishaque ◽  
Sneha Chenji ◽  
Dennell Mah ◽  
Zhang Chen ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
White Matter ◽  
Executive Dysfunction ◽  
Structural Network ◽  
Lateral Sclerosis

scholarly journals Multimodal longitudinal study of structural brain involvement in amyotrophic lateral sclerosis

Neurology ◽  
2020 ◽  
Vol 94 (24) ◽  
pp. e2592-e2604 ◽  
Author(s):  
Hannelore K. van der Burgh ◽  
Henk-Jan Westeneng ◽  
Renée Walhout ◽  
Kevin van Veenhuijzen ◽  
Harold H.G. Tan ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
White Matter ◽  
Gray Matter ◽  
White Matter Integrity ◽  
Progression Rate ◽  
Lateral Sclerosis ◽  
Over Time ◽  
Structural Brain ◽  
Cerebral Degeneration

ObjectiveTo understand the progressive nature of amyotrophic lateral sclerosis (ALS) by investigating differential brain patterns of gray and white matter involvement in clinically or genetically defined subgroups of patients using cross-sectional, longitudinal, and multimodal MRI.MethodsWe assessed cortical thickness, subcortical volumes, and white matter connectivity from T1-weighted and diffusion-weighted MRI in 292 patients with ALS (follow-up: n = 150) and 156 controls (follow-up: n = 72). Linear mixed-effects models were used to assess changes in structural brain measurements over time in patients compared to controls.ResultsPatients with a C9orf72 mutation (n = 24) showed widespread gray and white matter involvement at baseline, and extensive loss of white matter integrity in the connectome over time. In C9orf72-negative patients, we detected cortical thinning of motor and frontotemporal regions, and loss of white matter integrity of connections linked to the motor cortex. Patients with spinal onset displayed widespread white matter involvement at baseline and gray matter atrophy over time, whereas patients with bulbar onset started out with prominent gray matter involvement. Patients with unaffected cognition or behavior displayed predominantly motor system involvement, while widespread cerebral changes, including frontotemporal regions with progressive white matter involvement over time, were associated with impaired behavior or cognition. Progressive loss of gray and white matter integrity typically occurred in patients with shorter disease durations (<13 months), independent of progression rate.ConclusionsHeterogeneity of phenotype and C9orf72 genotype relates to distinct patterns of cerebral degeneration. We demonstrate that imaging studies have the potential to monitor disease progression and early intervention may be required to limit cerebral degeneration.

scholarly journals Cerebrospinal Fluid Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis

Diagnostics ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1210
Author(s):  
Júlia Costa ◽  
Marta Gromicho ◽  
Ana Pronto-Laborinho ◽  
Conceição Almeida ◽  
Ricardo A. Gomes ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cerebrospinal Fluid ◽  
Motor Neurons ◽  
Neurological Diseases ◽  
Disease Diagnosis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Progression Rate ◽  
Therapeutic Trials ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease that affects motor neurons controlling voluntary muscles. Survival is usually 2–5 years after onset, and death occurs due to respiratory failure. The identification of biomarkers would be very useful to help in disease diagnosis and for patient stratification based on, e.g., progression rate, with implications in therapeutic trials. Neurofilaments constitute already-promising markers for ALS and, recently, chitinases have emerged as novel marker targets for the disease. Here, we investigated cerebrospinal fluid (CSF) chitinases as potential markers for ALS. Chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1), chitinase-3-like protein 2 (CHI3L2) and the benchmark marker phosphoneurofilament heavy chain (pNFH) were quantified by an enzyme-linked immunosorbent assay (ELISA) from the CSF of 34 ALS patients and 24 control patients with other neurological diseases. CSF was also analyzed by UHPLC-mass spectrometry. All three chitinases, as well as pNFH, were found to correlate with disease progression rate. Furthermore, CHIT1 was elevated in ALS patients with high diagnostic performance, as was pNFH. On the other hand, CHIT1 correlated with forced vital capacity (FVC). The three chitinases correlated with pNFH, indicating a relation between degeneration and neuroinflammation. In conclusion, our results supported the value of CHIT1 as a diagnostic and progression rate biomarker, and its potential as respiratory function marker. The results opened novel perspectives to explore chitinases as biomarkers and their functional relevance in ALS.

scholarly journals Significance of Serological Markers in Neurological Function and Progression Rate of Amyotrophic Lateral Sclerosis

2021 ◽  
Author(s):  
Xiaowen Chen ◽  
Junrong Li ◽  
Yingying Lv ◽  
Wei Zhang ◽  
xiujian Xu ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Creatine Kinase ◽  
Uric Acid ◽  
Total Cholesterol ◽  
Cystatin C ◽  
Control Group ◽  
Progression Rate ◽  
Cholesterol Levels ◽  
Als Patients ◽  
Lateral Sclerosis

Abstract Objective The present study was to investigate the significance of creatinine, uric acid, creatine kinase, total cholesterol, triglyceride, HCY (Homocysteine), and cystatin C in neurological function and progression rate of amyotrophic lateral sclerosis. Methods According to the diagnostic criteria of EI-Escorial (2000), 103 patients with ALS were enrolled. All patients were given corresponding serological tests at the initial diagnosis. The Revised ALS Functional Rating Scale (ALSFRS-R) and Disease Progression Rate (DPR) were evaluated. The detected indexes in blood tests included creatinine, uric acid, creatine kinase, total cholesterol, triglycerides, homocysteine, and cystatin C. All data were input into the computer, and the data analysis was performed by SPSS22.0 statistical software.Results 1. There were significant differences in creatinine, uric acid, creatine kinase,
total cholesterol, HCY and cystatin C between the two groups (P<0.05). The levels of uric acid and creatinine of ALS group were lower than those of the control group, and the levels of creatine kinase, total cholesterol, triglyceride, HCY and cystatin C were higher than that in the control group.
2. The results from correlation analysis demonstrated that there was a significant correlation between ALSFRS-R and creatinine (P<0.01), the correlation coefficient was 0.567 (positive correlation); There was also a significant correlation between DPR and creatinine (P<0.01), and the correlation coefficient was -0.808 (negative correlation). The correlations of DPR with triglyceride and total cholesterol were significantly negative correlated (P<0.05), with -0.201 and -0.210 of correlation coefficients, respectively. The remaining indexes did not show any correlation with ALSFRS-R and DPR.
Conclusions 1. Uric acid and creatinine of ALS patients were lower than that in healthy people. Creatine kinase, triglyceride, total cholesterol, HCY, and cystatin C in ALS patients were higher than those in health controls. There were significant metabolic abnormalities in ALS patients.
2. Creatinine level is an independent risk factor affecting ALSFRS-R. The creatinine and total cholesterol levels are also the independent risk factors affecting DPR. Creatinine and total cholesterol levels could be used as reliable indicators to evaluate the ALSFRS-R and DPR of ALS patients.

scholarly journals Role of Blood Neurofilaments in the Prognosis of Amyotrophic Lateral Sclerosis: A Meta-Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan-ni Zhou ◽  
You-hong Chen ◽  
Si-qi Dong ◽  
Wen-bo Yang ◽  
Ting Qian ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Meta Analysis ◽  
Progression Rate ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Risk Of Death ◽  
Disease Progression Rate ◽  
Als Patients ◽  
Lateral Sclerosis

Background: Neurofilaments in cerebrospinal fluid (CSF) and in blood are considered promising biomarkers of amyotrophic lateral sclerosis (ALS) because their levels can be significantly increased in patients with ALS. However, the roles of neurofilaments, especially blood neurofilaments, in the prognosis of ALS are inconsistent. We performed a meta-analysis to explore the prognostic roles of blood neurofilaments in ALS patients.Methods: We searched all relevant studies on the relationship between blood neurofilament levels and the prognosis of ALS patients in PubMed, Embase, Scopus, and Web of Science before February 2, 2021. The quality of the included articles was assessed using the Quality in Prognosis Studies (QUIPS) scale, and R (version 4.02) was used for statistical analysis.Results: Fourteen articles were selected, covering 1,619 ALS patients. The results showed that higher blood neurofilament light chain (NfL) levels in ALS patients were associated with a higher risk of death [medium vs. low NfL level: HR = 2.43, 95% CI (1.34–4.39), p &lt; 0.01; high vs. low NfL level: HR = 4.51, 95% CI (2.45–8.32), p &lt; 0.01]. There was a positive correlation between blood phosphorylated neurofilament heavy chain (pNfH) levels and risk of death in ALS patients [HR = 1.87, 95% CI (1.35–2.59), p &lt; 0.01]. The levels of NfL and pNfH in blood positively correlated with disease progression rate (DPR) of ALS patients [NfL: summary r = 0.53, 95% CI (0.45–0.60), p &lt; 0.01; pNfH: summary r = 0.51, 95% CI (0.24–0.71), p &lt; 0.01].Conclusion: The blood neurofilament levels can predict the prognosis of ALS patients; specifically, higher levels of blood neurofilaments are associated with a greater risk of death.

scholarly journals A Natural History Comparison of SOD1-Mutant Patients with Amyotrophic Lateral Sclerosis between Chinese and German Populations

2021 ◽  
Author(s):  
Lu Tang ◽  
Johannes Dorst ◽  
Lu Chen ◽  
Xiaolu Liu ◽  
Yan Ma ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Large Scale ◽  
Age Of Onset ◽  
Diagnostic Delay ◽  
Chinese Patients ◽  
Common Mutation ◽  
Progression Rate ◽  
Causative Gene ◽  
Sod1 Mutant ◽  
Lateral Sclerosis

Abstract Background: The gene coding the Cu/Zn superoxide dismutase ( SOD1 ) was the first-identified causative gene of amyotrophic lateral sclerosis (ALS), and the second most common genetic cause for ALS worldwide. The promising therapeutic approaches targeting SOD1 mutations are on the road. The purpose of the present study was to compare the mutational and clinical features of Chinese and German patients with ALS carrying mutations in SOD1 gene, which will facilitate the strategy and design of SOD1 -targeted trials.Methods: Demographic and clinical characteristics were collected from two longitudinal cohorts in China and Germany. Chinese and German patients carrying SOD1 mutations were compared with regard to mutational distribution, age of onset, site of onset, body mass index (BMI) at diagnosis, diagnostic delay, progression rate, and survival.Results: A total of 66 Chinese and 84 German patients with 69 distinct SOD1 mutations were identified. The most common mutation in both populations was p.His47Arg. It was found in 8 Chinese and 2 German patients and consistently showed a slow progression of disease in both countries. Across all mutations, Chinese patients showed a younger age of onset (43.9 vs 49.9 years, p=0.002), a higher proportion of young-onset cases (62.5% vs 30.7%, p<0.001) and a lower BMI at diagnosis (22.8 vs 26.0, p<0.001) compared to German patients. Although riluzole intake was less frequent in Chinese patients (28.3% vs 81.3%, p<0.001), no difference in survival between populations was observed (p=0.90). Across both cohorts, female patients had a longer diagnostic delay (15.0 vs 11.0 months, p=0.01) and a prolonged survival (248.0 vs 60.0 months, p=0.005) compared to male patients.Conclusions: Our data demonstrate the distinct mutational and clinical spectrums of SOD1 -mutant patients in Asian and European populations. Clinical phenotypes seem to be primarily influenced by mutation-specific, albeit not excluding ethnicity-specific factors. Further large-scale transethnical studies are needed to clarify determinants and modifiers of SOD1 phenotypes.

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