Monitoring spinal muscular atrophy with three-dimensional optoacoustic imaging.

BACKGROUND: Spinal muscular atrophy is a progressive neuromuscular disorder and among the most frequent genetic causes of infant mortality. While recent advancements in gene therapy provide the potential to ameliorate the disease severity, there is currently no modality in clinical use to visualize dynamic pathophysiological changes in disease progression and regression after therapy. METHODS: In this prospective diagnostic clinical study, ten pediatric patients with spinal muscular atrophy and ten age- and sex-matched controls have been examined with three-dimensional optoacoustic imaging and clinical standard examinations to compare the spectral profile of muscle tissue and correlate it with motor function (ClinicalTrials.gov: NCT04115475). FINDINGS: We observed a reduced optoacoustic signal in muscle tissue of pediatric patients with spinal muscular atrophy. The reduction in signal intensity correlated with disease severity as assessed by grayscale ultrasound and standard motor function tests. In a cohort of patients who received disease-modifying therapy prior to the study, the optoacoustic signal intensity was similar to healthy controls. CONCLUSIONS: This translational study provides early evidence that three-dimensional optoacoustic imaging could have clinical implications in monitoring disease activity in spinal muscular atrophy. By visualizing and quantifying molecular changes in muscle tissue, disease progression and effects of gene therapy can be assessed in real time. FUNDING: The project was funded by ELAN Fonds (P055) at the University Hospital of the Friedrich-Alexander-Universität (FAU) Erlangen-Nurnberg to A.P.R.

Hybrid ultrasound and single wavelength optoacoustic imaging reveals muscle degeneration in peripheral artery disease.

Peripheral arterial disease (PAD) leads to chronic vascular occlusion and results in end organ damage in critically perfused limbs. There are currently no clinical methods available to determine the muscular damage induced by chronic mal-perfusion. This monocentric prospective cross-sectional study investigated n = 193 adults, healthy to severe PAD, in order to quantify the degree of calf muscle degeneration caused by PAD using a non-invasive hybrid ultrasound and single wavelength optoacoustic imaging (US/SWL-OAI) approach. While US provides morphologic information, SWL-OAI visualizes the absorption of pulsed laser light and the resulting sound waves from molecules undergoing thermoelastic expansion. US/SWL-OAI was compared to multispectral data, clinical disease severity, angiographic findings, phantom experiments, and histological examinations from calf muscle biopsies. We were able to show that synergistic use of US/SWL-OAI is most likely to map clinical degeneration of the muscle and progressive PAD.

Multispectral optoacoustic tomography enables assessment of disease activity in paediatric inflammatory bowel disease.

Multispectral optoacoustic tomography (MSOT) allows non-invasive molecular disease activity assessment in adults with inflammatory bowel disease (IBD). In this prospective pilot-study, we investigated, whether increased levels of MSOT haemoglobin parameters corresponded to inflammatory activity in paediatric IBD patients, too. 23 children with suspected IBD underwent MSOT of the terminal ileum and sigmoid colon with standard validation (e.g. endoscopy). In Crohn`s disease (CD) and ulcerative colitis (UC) patients with endoscopically confirmed disease activity, MSOT total haemoglobin (HbT) signals were increased in the terminal ileum of CD (72.1 ± 13.0 a.u. vs. 32.9 ± 15.4 a.u., p = 0.0049) and in the sigmoid colon of UC patients (62.9 ± 13.8 a.u. vs. 35.1 ± 16.3 a.u., p = 0.0311) as compared to controls, respectively. Furthermore, MSOT haemoglobin parameters correlated well with standard disease activity assessment (e.g. SES-CD and MSOT HbT (rs =0.69, p = 0.0075). Summarizing, MSOT is a novel technology for non-invasive molecular disease activity assessment in paediatric patients with inflammatory bowel disease.

Hybrid reflected-ultrasound computed tomography versus B-mode-ultrasound for muscle scoring in spinal muscular atrophy.

BACKGROUND AND PURPOSE: Novel light- and sound-based technologies like multispectral optoacoustic tomography (MSOT) with co-registered reflected-ultrasound computed tomography (RUCT) could add additional value to conventional ultrasound (US) for disease phenotyping in pediatric spinal muscular atrophy (SMA). The aim of this study was to investigate the quality of RUCT compared to US for qualitative and quantitative assessment of imaging neuromuscular disorders. METHODS: Subanalyzing the MSOT SMA study, 288 RUCT and 276 US images from 10 SMA patients (mean age 9.0 ± 3.7) and 10 gender- and age-matched healthy volunteers (HV; mean age 8.7 ± 4.3) were analyzed for quantitative (grayscale levels [GSLs]) and qualitative (echogenicity, distribution pattern, Heckmatt scale, and muscle texture) muscle changes. RUCT and US measures were further correlated with clinical standard motor outcomes. RESULTS: Quantitative agreement using GSLs revealed significantly higher GSLs in muscles of SMA patients compared to healthy muscles in both techniques (US mean GSL [SD] SMA vs. HV: 110.70 [27.8] vs. 68.85 [19.2], p < .0001; RUCT mean GSL [SD] SMA vs. HV: 91.81 [21.8] vs. 59.86 [8.2], p < .0001) with good correlation with motor outcome tests, respectively. Qualitative agreement between methods for muscle composition was excellent for differentiation of pathological versus healthy muscles, echogenicity, and distribution pattern, moderate for Heckmatt scale, and poor for muscle texture. CONCLUSIONS: The data suggest that RUCT may allow the assessment of basic qualitative and quantitative measures for muscular diseases with comparable results to conventional US.

Multispectral optoacoustic tomography for non-invasive disease phenotyping in pediatric spinal muscular atrophy patients.

Proximal spinal muscular atrophy (SMA) is a rare progressive, life limiting genetic motor neuron disease. While promising causal therapies are available, meaningful prognostic biomarkers for therapeutic monitoring are missing. We demonstrate handheld Multispectral Optoacoustic Tomography (MSOT) as a novel non-invasive imaging approach to visualize and quantify muscle wasting in pediatric SMA. While MSOT signals were distributed homogeneously in muscles of healthy volunteers (HVs), SMA patients showed moth-eaten optoacoustic signal patterns. Further signal quantification revealed greatest differences between groups at the isosbestic point for hemoglobin (SWL 800 nm). The SWL 800 nm signal intensities further correlated with clinical phenotype tested by standard motor outcome measures. Therefore, handheld MSOT could enable non-invasive assessment of disease burden in SMA patients.

Precision of handheld multispectral optoacoustic tomography for muscle imaging.

Photo-or optoacoustic imaging (OAI) allows quantitative imaging of target tissues. Using multi-wavelength illumination with subsequent ultrasound detection, it may visualize a variety of different chromophores at centimeter depth. Despite its non-invasive, label-free advantages, the precision of repeated measurements for clinical applications is still elusive. We present a multilayer analysis of n = 1920 imaging datasets obtained from a prospective clinical trial (NCT03979157) in n = 10 healthy adult volunteers. All datasets were analyzed for 13 single wavelengths (SWL) between 660 nm-1210 nm and five MSOT-parameters (deoxygenated/oxygenated/total hemoglobin, collagen and lipid) by a semi-automated batch mode software. Intraclass correlation coefficients (ICC) were good to excellent for intrarater (SWL: 0.82-0.92; MSOT-parameter: 0.72-0.92) and interrater reproducibility (SWL: 0.79-0.87; MSOT-parameter: 0.78-0.86), with the exception for MSOT-parameter lipid (interrater ICC: 0.56). Results were stable over time, but exercise-related effects as well as inter-and intramuscular variability were observed. The findings of this study provide a framework for further clinical OAI implementation.