Diffusion Tensor Imaging Evaluation of Corticospinal Tract Hyperintensity in Upper Motor Neuron-Predominant ALS Patients

Amyotrophic lateral sclerosis (ALS) patients with predominant upper motor neuron (UMN) signs occasionally have hyperintensity of corticospinal tract (CST) on T2- and proton-density-(PD-) weighted brain images. Diffusion tensor imaging (DTI) was used to assess whether diffusion parameters along intracranial CST differ in presence or absence of hyperintensity and correspond to UMN dysfunction. DTI brain scans were acquired in 47 UMN-predominant ALS patients with (n = 21) or without (n = 26) CST hyperintensity and in 10 control subjects. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured in four regions of interests (ROIs) along CST. Abnormalities (P < 0.05) were observed in FA, AD, or RD in CST primarily at internal capsule (IC) level in ALS patients, especially those with CST hyperintensity. Clinical measures corresponded well with DTI changes at IC level. The IC abnormalities suggest a prominent axonopathy in UMN-predominant ALS and that tissue changes underlying CST hyperintensity have specific DTI changes, suggestive of unique axonal pathology

Motor neuronopathy with dropped hands and downbeat nystagmus: A distinctive disorder? A case report

BACKGROUND: Eye movements are clinically normal in most patients with motor neuron disorders until late in the disease course. Rare patients are reported to show slow vertical saccades, impaired smooth pursuit, and gaze-evoked nystagmus. We report clinical and oculomotor findings in three patients with motor neuronopathy and downbeat nystagmus, a classic sign of vestibulocerebellar disease. CASE PRESENTATION: All patients had clinical and electrodiagnostic features of anterior horn cell disease. Involvement of finger and wrist extensors predominated, causing finger and wrist drop. Bulbar or respiratory dysfunction did not occur. All three had clinically evident downbeat nystagmus worse on lateral and downgaze, confirmed on eye movement recordings using the magnetic search coil technique in two patients. Additional oculomotor findings included alternating skew deviation and intermittent horizontal saccadic oscillations, in one patient each. One patient had mild cerebellar atrophy, while the other two had no cerebellar or brainstem abnormality on neuroimaging. The disorder is slowly progressive, with survival up to 30 years from the time of onset. CONCLUSION: The combination of motor neuronopathy, characterized by early and prominent wrist and finger extensor weakness, and downbeat nystagmus with or without other cerebellar eye movement abnormalities may represent a novel motor neuron syndrome

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With ALS

To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results: Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898)

Corticospinal Tract and Related Grey Matter Morphometric Shape Analysis in ALS Phenotypes: A Fractal Dimension Study

A pathological hallmark of amyotrophic lateral sclerosis (ALS) is corticospinal tract (CST) degeneration resulting in upper motor neuron (UMN) dysfunction. No quantitative test is available to easily assess UMN pathways. Brain neuroimaging in ALS promises to potentially change this through identifying biomarkers of UMN dysfunction that may accelerate diagnosis and track disease progression. Fractal dimension (FD) has successfully been used to quantify brain grey matter (GM) and white matter (WM) shape complexity in various neurological disorders. Therefore, we investigated CST and whole brain GM and WM morphometric changes using FD analyses in ALS patients with different phenotypes. We hypothesized that FD would detect differences between ALS patients and neurologic controls and even between the ALS subgroups. Neuroimaging was performed in neurologic controls (n = 14), and ALS patients (n = 75). ALS patients were assigned into four groups based on their clinical or radiographic phenotypes. FD values were estimated for brain WM and GM structures. Patients with ALS and frontotemporal dementia (ALS-FTD) showed significantly higher CST FD values and lower primary motor and sensory cortex GM FD values compared to other ALS groups. No other group of ALS patients revealed significant FD value changes when compared to neurologic controls or with other ALS patient groups. These findings support a more severe disease process in ALS-FTD patients compared to other ALS patient groups. FD value measures may be a sensitive index to evaluate GM and WM (including CST) degeneration in ALS patients

Quantitative Brain MRI Metrics Distinguish Four Different ALS Phenotypes: A Machine Learning Based Study

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease whose diagnosis depends on the presence of combined lower motor neuron (LMN) and upper motor neuron (UMN) degeneration. LMN degeneration assessment is aided by electromyography, whereas no equivalent exists to assess UMN dysfunction. Magnetic resonance imaging (MRI) is primarily used to exclude conditions that mimic ALS. We have identified four different clinical/radiological phenotypes of ALS patients. We hypothesize that these ALS phenotypes arise from distinct pathologic processes that result in unique MRI signatures. To our knowledge, no machine learning (ML)-based data analyses have been performed to stratify different ALS phenotypes using MRI measures. During routine clinical evaluation, we obtained T1-, T2-, PD-weighted, diffusion tensor (DT) brain MRI of 15 neurological controls and 91 ALS patients (UMN-predominant ALS with corticospinal tract CST) hyperintensity, n = 21; UMN-predominant ALS without CST hyperintensity, n = 26; classic ALS, n = 23; and ALS patients with frontotemporal dementia, n = 21). From these images, we obtained 101 white matter (WM) attributes (including DT measures, graph theory measures from DT and fractal dimension (FD) measures using T1-weighted), 10 grey matter (GM) attributes (including FD based measures from T1-weighted), and 10 non-imaging attributes (2 demographic and 8 clinical measures of ALS). We employed classification and regression tree, Random Forest (RF) and also artificial neural network for the classifications. RF algorithm provided the best accuracy (70–94%) in classifying four different phenotypes of ALS patients. WM metrics played a dominant role in classifying different phenotypes when compared to GM or clinical measures. Although WM measures from both right and left hemispheres need to be considered to identify ALS phenotypes, they appear to be differentially affected by the degenerative process. Longitudinal studies can confirm and extend our findings

Data from: Variation in non-invasive ventilation use in amyotrophic lateral sclerosis

Objective: We sought to examine prevalence and predictors of non-invasive ventilation (NIV) in a composite cohort of amyotrophic lateral sclerosis (ALS) patients followed in a clinical trials setting (PRO-ACT database). Methods: NIV initiation and status were ascertained from response to question 12 of the revised ALS functional rating scale (ALSFRS-R). Factors affecting NIV use in patients with forced vital capacity (FVC) ≤ 50% of predicted were examined. Predictors of NIV were evaluated by Cox proportional hazard models and generalized linear mixed models. Results: Among 1,784 patients with 8,417 simultaneous ALSFRS-R and FVC% measures, NIV was used by 604 (33.9%). Of 918 encounters when FVC% ≤ 50%, NIV was reported in 482 (52.5%). Independent predictors of NIV initiation were lower FVC% (hazard ratio HR 1.27, 95% CI: 1.17-1.37 for 10% drop), dyspnea (HR 2.62, 95% CI: 1.87-3.69), orthopnea (HR 4.09, 95% CI: 3.02-5.55), lower bulbar and gross motor subscores of ALSFRS-R (HRs 1.09 (95% CI: 1.03-1.14) and 1.13 (95% CI: 1.07-1.20) respectively, per point), and male sex (HR 1.73, 95% CI: 1.31-2.28). Adjusted for other variables, bulbar onset did not significantly influence time to NIV (HR 0.72 (95% CI: 0.47-1.08)). Considerable unexplained variability in NIV use was found. Conclusion: NIV use was lower than expected in this ALS cohort that was likely to be optimally managed. Absence of respiratory symptoms and female sex may be barriers to NIV use. Prospective exploration of factors affecting adoption of NIV may help bridge this gap and improve care in ALS