A specific biomarker for amyotrophic lateral sclerosis: Quantitative susceptibility mapping.

OBJECTIVE: Accurate and timely diagnosis of amyotrophic lateral sclerosis (ALS) is a diagnostic challenge given the lack of specific diagnostic and imaging biomarkers as well as the significant clinic overlap with mimic syndromes. We hypothesize that MR quantitative susceptibility mapping (QSM) can help differentiate ALS from mimic diagnoses. METHODS: In a blinded retrospective study of MRIs with QSM from 2015 to 2018, we compared motor cortex susceptibility along the hand and face homunculi in ALS patients and patients with similar clinical presentations. Inclusion required a confirmed ALS or a mimic diagnosis. Comparative groups included age-matched patients with MRIs performed for non-motor neuron symptoms that were reported as normal or demonstrated leukoaraiosis. Quantitative susceptibility values were compared with ANOVA and Tukey-Kramer (post-hoc). ROC analysis and Youden's index were used to identify optimal cutoff values. RESULTS: Fifty ALS, 35 mimic, and 70 non-motor neuron symptom patients (35 normal, 35 leukoaraiosis) were included. Hand and face homunculus mean susceptibility values were significantly higher in the ALS group compared to the mimic (p=0.001, p=0.004), leukoaraiosis (p<0.001, p=0.003), and normal (p<0.001, p<0.001) groups. ROC curve analysis comparing ALS to mimics resulted in an area under the curve of 0.71 and 0.67 for the hand and face homunculus measurements, respectively. In differentiating ALS from mimics, Youden's index showed 100% specificity and 36% sensitivity for hand homunculus measurements. CONCLUSIONS: QSM has diagnostic potential in the assessment of suspected ALS patients, demonstrating very high specificity in differentiating ALS from mimic diagnoses.

Diffusion tensor imaging and quantitative susceptibility mapping as diagnostic tools for motor neuron disorders.

PURPOSE: Diffusion tensor imaging (DTI) and quantitative susceptibility mapping (QSM) have been proposed as methods to aid in the diagnosis of amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), both diseases affecting upper motor neurons. We test the performance of DTI and QSM alone and in combination to distinguish patients with diseases affecting upper motor neurons (ALS/PLS) from patients with other motor symptom-predominant neurologic disorders. METHODS: 3.0 Tesla MRI with DTI and QSM in patients referred to a subspecialty neurology clinic for evaluation of motor symptom-predominant neurologic disorders were retrospectively reviewed. Corticospinal tract fractional anisotropy and maximum motor cortex susceptibility were measured. Subjects were categorized by diagnosis and imaging metrics were compared between groups using Student's t-tests. Receiver operating characteristic curves were generated for imaging metrics alone and in combination. RESULTS: MRI scans for 43 patients with ALS or PLS and 15 patients with motor symptom predominant, non-upper motor neuron disease (mimics) were reviewed. Fractional anisotropy was lower (0.57 vs. 0.60, p < 0.01) and maximum motor cortex magnetic susceptibility higher (64.4 vs. 52.7, p = 0.01) in patients with ALS/PLS compared to mimics. There was no significant difference in area under the curve for these metrics alone (0.73, 0.63; p > 0.05) or in combination (0.75; p > 0.05). CONCLUSION: We found significant differences in DTI and QSM metrics in patients with diseases affecting upper motor neurons (ALS/PLS) compared to mimics, but no significant difference in the performance of these metrics in diagnosing ALS/PLS compared to mimics.

Perceptions of sexuality in individuals with Amyotrophic Lateral Sclerosis (ALS) and their treating clinicians.

INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) may not affect an individual's sexual function directly, but it can indirectly impact their sexual activity. Sexual partners often become caregivers, diminishing sexuality within a relationship. This can result in decline of quality of life. OBJECTIVE: The study aimed to explore the perspectives of individuals with ALS and their treating clinicians regarding the importance of sexuality in rehabilitation within a multidisciplinary ALS center. We hypothesize that individuals with ALS will express the need for sexuality-related discussions as a therapy. METHOD: Electronic 11-item questionnaires were anonymously completed by individuals with ALS (n = 21) and ALS healthcare professionals (n = 81) between August 2014 to June 2016. Descriptive statistics were performed in STATA 14. RESULTS: Majority (90%, n = 92) of respondents stated that ALS impacts the sexuality of an individual with ALS, and agreed that sexuality-related discussion is needed as a complementary therapy. Over 75% of clinicians reported they were not familiar with any strategies or interventions to help the patients. CONCLUSION: ALS indirectly affects sexuality, thus confirming the need for promoting awareness regarding sexuality-related topics among individuals with ALS and healthcare professionals. ALS multidisciplinary clinics need to improve their delivery of care to address sexual rehabilitation as a complementary therapy.

Pyrimethamine significantly lowers cerebrospinal fluid Cu/Zn superoxide dismutase in amyotrophic lateral sclerosis patients with SOD1 mutations.

OBJECTIVE: Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose-dependent SOD1 reduction in cell culture systems. A previous phase 1 trial showed pyrimethamine lowers SOD1 levels in leukocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to familial amyotrophic lateral sclerosis (fALS/SOD1). METHODS: A multicenter (5 sites), open-label, 9-month-duration, dose-ranging study was undertaken to determine the safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF in fALS/SOD1. All participants underwent 3 lumbar punctures, blood draw, clinical assessment of strength, motor function, quality of life, and adverse effect assessments. SOD1 levels were measured in erythrocytes and CSF. Pyrimethamine was measured in plasma and CSF. Appel ALS score, ALS Functional Rating Scale-Revised, and McGill Quality of Life Single-Item Scale were measured at screening, visit 6, and visit 9. RESULTS: We enrolled 32 patients; 24 completed 6 visits (18 weeks), and 21 completed all study visits. A linear mixed effects model showed a significant reduction in CSF SOD1 at visit 6 (p < 0.001) with a mean reduction of 13.5% (95% confidence interval [CI] = 8.4-18.5) and at visit 9 (p < 0.001) with a mean reduction of 10.5% (95% CI = 5.2-15.8). INTERPRETATION: Pyrimethamine is safe and well tolerated in ALS. Pyrimethamine is capable of producing a significant reduction in total CSF SOD1 protein content in patients with ALS caused by different SOD1 mutations. Further long-term studies are warranted to assess clinical efficacy. Ann Neurol 2017;81:837-848.

Quantitative susceptibility mapping of the motor cortex in amyotrophic lateral sclerosis and primary lateral sclerosis.

OBJECTIVE: The diagnosis of amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) is often difficult because of a lack of disease biomarkers. The purpose of this study was to investigate quantitative susceptibility mapping (QSM) of the motor cortex as a potential quantitative biomarker for the diagnosis of ALS and PLS. MATERIALS AND METHODS: From a retrospective database, QSM images of 16 patients with upper motor neuron disease (nine men [56%], seven women; mean age, 56.3 years; 12 with ALS, four with PLS) and 23 control patients (13 men [56%], 10 women; mean age, 56.6 years) were reviewed. Two neuroradiologists, blinded to diagnosis, qualitatively assessed QSM, T2- and T2*-weighted, and T2-weighted FLAIR images. Relative motor cortex susceptibility was calculated by subtraction of adjacent white matter and CSF signal intensity from mean motor cortex susceptibility on the axial image most representative of the right- or left-hand lobule, and ROC analysis was performed. The Fisher exact and Student t tests were used to evaluate for statistical differences between the groups. RESULTS: Qualitatively, QSM had greater diagnostic accuracy than T2-weighted, T2*-weighted, or T2-weighted FLAIR imaging for the diagnosis of ALS and PLS. Quantitatively, relative motor cortex susceptibility was found to be significantly greater in patients with motor neuron disease than in control patients (46.0 and 35.0 ppb; p < 0.001). ROC analysis showed an AUC of 0.88 (p < 0.0001) and an optimal cutoff value of 40.5 ppb for differentiating control patients from patients with ALS or PLS (sensitivity, 87.5%; specificity, 87.0%). CONCLUSION: QSM is a sensitive and specific quantitative biomarker of iron deposition in the motor cortex in ALS and PLS.

REM behavior disorder associated with familial amyotrophic lateral sclerosis.

The association between RBD and synucleinopathies is well known. However, the association between RBD and other neuromuscular diseases has not been as well described. Our case study describes two siblings with familial ALS, confirmed by the identification of the L84F mutation in the SOD1 gene, and RDB. We hope this case study will promote future studies on the prevalence of this association and will stimulate research in identifying the underlying pathogenic mechanism.

Differential gene expression in patients with amyotrophic lateral sclerosis.

Our objective was to analyze gene expression pattern in muscles from patients with amyotrophic lateral sclerosis (ALS) and multifocal motor neuropathy (MMN) compared to controls. Biopsied skeletal muscles from three ALS, three MMN and three control subjects had total RNA extracted and subjected to genome-wide gene expression analysis using Affymetrix GeneChip Exon 1.0 ST array. The most significant expression pattern differences were confirmed with RT-PCR in four additional ALS patients. Results showed that over 3000 genes were identified across the groups using q < 10%. Among 50 genes that were overexpressed only in the ALS group were: leucine-rich repeat kinase-2, follistatin, collagen type XIX alpha-1, ceramide kinase-like, sestrin-3 and CXorf64. No genes were significantly overexpressed in MMN alone. Underexpressed genes only in ALS included actinin α3, fructose-1,6-bisphosphatase-2 and homeobox C10; whereas only in MMN: hemoglobin A1 and CXorf64. Ankyrin repeat domain-1 was overexpressed in both groups. Underexpressed genes in both groups included myosin light chain kinase-2, enolase-3 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-1. Validation analysis using RT-PCR confirmed the data for leucine-rich repeat kinase-2, follistatin, collagen type XIX alpha-1, ceramide kinase-like, sestrin-3 and CXorf64. In conclusion, there is differential tissue-specific gene expression in patients with ALS relative to MMN and controls. Further studies are necessary to evaluate the identified genes in larger patient groups and different tissues.