Network diffusion model predicts neurodegeneration in limb-onset amyotrophic lateral sclerosis

The trans-neural propagation of phosphorylated 43-kDa transactive response DNA-binding protein (pTDP-43) contributes to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS). We investigated whether Network Diffusion Model (NDM), a biophysical model of spread of pathology via the brain connectome, could capture the severity and progression of neurodegeneration (atrophy) in ALS. We measured degeneration in limb-onset ALS patients (n=14 at baseline, 12 at 6-months, and 9 at 12 months) and controls (n=12 at baseline) using FreeSurfer analysis on the structural T1-weighted Magnetic Resonance Imaging (MRI) data. The NDM was simulated on the canonical structural connectome from the IIT Human Brain Atlas. To determine whether NDM could predict the atrophy pattern in ALS, the accumulation of pathology modelled by NDM was correlated against atrophy measured using MRI. The cross-sectional analyses revealed that the network diffusion seeded from the inferior frontal gyrus (pars triangularis and pars orbitalis) significantly predicts the atrophy pattern in ALS compared to controls. Whereas, atrophy over time with-in the ALS group was best predicted by seeding the network diffusion process from the inferior temporal gyrus at 6-month and caudal middle frontal gyrus at 12-month. Our findings suggest the involvement of extra-motor regions in seeding the spread of pathology in ALS. Importantly, NDM was able to recapitulate the dynamics of pathological progression in ALS. Understanding the spatial shifts in the seeds of degeneration over time can potentially inform further research in the design of disease modifying therapeutic interventions in ALS.

Improved survival in amyotrophic lateral sclerosis patients following autologous bone marrow mononuclear cell therapy: a long term 10-year retrospective study

Background:Promising results from previous studies using cell therapy have paved the way for an innovative treatment option for amyotrophic lateral sclerosis (ALS). There is considerable evidence of immune and inflammatory abnormalities in ALS. Bone marrow mononuclear cells (BMMNCs) possess immunomodulatory properties and could contribute to slowing of disease progression.Objective:Aim of our study was to evaluate the long-term effect of autologous BMMNCs combined with standard treatment on survival duration in a large population and to evaluate effect of type of onset and hormonal status on survival duration in the intervention group.Methods:This controlled, retrospective study spanned over 10 years, 5 months; included 216 patients with probable or definite ALS, 150 in intervention group receiving autologous BMMNCs and standard treatment, and 66 in control group receiving only standard treatment. The estimated survival duration of control group and intervention group was computed and compared using Kaplan Meier analysis. Survival duration of patients with different types of onset and hormonal status was compared within the intervention group.Results:None of the patients reported any major adverse events related to cell administration or the procedure. Kaplan Meier analysis estimated survival duration in the intervention group to be 91.7 months while 49.7 months in the control group (p = 0.008). Within the intervention group, estimated survival was significantly higher (p = 0.013) in patients with limb onset (102.3 months) vs. bulbar onset (49.9 months); premenopausal women (93.1 months) vs. postmenopausal women (57.6 months) (p = 0.002); and preandropausal men (153.7 months) vs. postandropausal males (56.5 months) (p = 0.006).Conclusion:Cell therapy using autologous BMMNCs along with standard treatment offers a promising and safe option for ALS with the potential of long term beneficial effect and increased survival. Limb onset patients, premenopausal women and men ≤ 40 years of age demonstrated better treatment efficacy.

Clinical Experience of Edaravone in Amyotrophic Lateral Sclerosis

Objective: To describe clinical experience with edaravone in ALS over a period of 12 months Methods:The current study retrospectively investigated characteristics in a group of patients (n=31) with ALS who underwent edaravone treatment. Information including age, gender, race, and site of onset of symptoms were collected for all patients. Adverse events with edaravone therapy was documented where available. Results:The average age of the patients observed was 62.09 years, with 18 males and 13 females. 18 patients had limb onset, 12 bulbar onset, and 1 diaphragmatic onset. 7 of the 31 patients discontinued treatment at the end of one year. The average age of patients who discontinued edaravone was 65.71 years, of whom which 3 had limb onset, 3 bulbar onset, and 1 diaphragmatic onset. No perceived benefit, port complications, systemic bacteremia, and development of atrial fibrillation were documented as reasons for discontinuation of therapy.Conclusion: Edaravone is well tolerated in ALS patients at the end of one year. Lack of perceived benefit and port related complications are common reasons for discontinuation of treatment