Martin Schneider

All Publications

• Biomarkers. Alzheimer's & dementia : the journal of the Alzheimer's Association Dai, E., Schneider, M. K., Zhou, X., Shailja, S., Zeineh, M., McNab, J. A. 2025; 21 Suppl 2: e101616

  Abstract

  Diffusion MRI is a promising approach to detecting brain microstructure changes associated with neurodegeneration. Unfortunately, diffusion tensor imaging (DTI) only provides limited specificity as it relies solely on single-dimensional diffusion encoding. Multi-dimensional diffusion encoding (MDE) is an emerging method for more specific brain microstructure mapping with advanced diffusion-encoding waveform design and modeling. However, MDE typically decreases the diffusion-encoding efficiency and SNR, resulting in relatively low voxel resolution (>2 mm isotropic). We aim to develop an MDE protocol of 1.8 mm isotropic with a clinically feasible scan time using an optimized MDE waveform design and an SNR-efficient readout, for studying brain microstructure changes in neurodegeneration. Moreover, we evaluate the scan-rescan reproducibility of the developed MDE protocol.A customized MDE sequence was developed by jointly using two different diffusion-encoding waveforms: linear and spherical tensor-valued diffusion encoding (LTE and STE). An SNR-efficient multi-band multi-shot EPI sequence and reconstruction were used for data readout. Three cognitively normal elderly subjects (1F/2M, aged 62∼70 y/o) were scanned on a 3T GE scanner equipped with a UHP gradient coil. Detailed parameters are listed in Table 1. Quantitative diffusion metrics were calculated, including mean diffusivity (MD), microscopic fractional anisotropy (μFA), anisotropic and isotropic mean kurtosis (MKa and MKi). Each subject was scanned twice to assess reproducibility, in the left and right hippocampal cingulum bundle and fornix (using FSL XTRACT) and global white matter/gray matter (using FSL FAST).High-quality quantitative diffusion metric maps are achieved with the developed MDE protocol (Figure 1). Pearson correlation coefficients (marked in Figure 2) range from r=0.951-0.995 for MD, μFA, MKa, and MKi in the global GM and WM, left and right hippocampal cingulum and fornix (Figure 2).We have developed a MDE protocol of 1.8 mm isotropic and demonstrated its high scan-rescan reproducibility, globally and in four critical WM regions for cognitive function. The achieved 1.8 mm isotropic resolution, together with a large slice coverage (∼70 mm) within a clinically feasible scan time (∼13 min), sets the foundation for more specifically mapping brain microstructure changes in critical brain regions (e.g., the medial temporal lobe) to capture neurodegeneration.

  View details for DOI 10.1002/alz70856_101616

  View details for PubMedID 41444150

• Alzheimer's Imaging Consortium. Alzheimer's & dementia : the journal of the Alzheimer's Association Dai, E., Schneider, M. K., Zhou, X., Shailja, S., Zeineh, M., McNab, J. A. 2025; 21 Suppl 8 (Suppl 8): e109814

  Abstract

  Diffusion MRI is a promising approach to detecting brain microstructure changes associated with neurodegeneration. Unfortunately, diffusion tensor imaging (DTI) only provides limited specificity as it relies solely on single-dimensional diffusion encoding. Multi-dimensional diffusion encoding (MDE) is an emerging method for more specific brain microstructure mapping with advanced diffusion-encoding waveform design and modeling. However, MDE typically decreases the diffusion-encoding efficiency and SNR, resulting in relatively low voxel resolution (>2 mm isotropic). We aim to develop an MDE protocol of 1.8 mm isotropic with a clinically feasible scan time using an optimized MDE waveform design and an SNR-efficient readout, for studying brain microstructure changes in neurodegeneration. Moreover, we evaluate the scan-rescan reproducibility of the developed MDE protocol.A customized MDE sequence was developed by jointly using two different diffusion-encoding waveforms: linear and spherical tensor-valued diffusion encoding (LTE and STE). An SNR-efficient multi-band multi-shot EPI sequence and reconstruction were used for data readout. Three cognitively normal elderly subjects (1F/2M, aged 62∼70 y/o) were scanned on a 3T GE scanner equipped with a UHP gradient coil. Detailed parameters are listed in Table 1. Quantitative diffusion metrics were calculated, including mean diffusivity (MD), microscopic fractional anisotropy (μFA), anisotropic and isotropic mean kurtosis (MKa and MKi). Each subject was scanned twice to assess reproducibility, in the left and right hippocampal cingulum bundle and fornix (using FSL XTRACT) and global white matter/gray matter (using FSL FAST).High-quality quantitative diffusion metric maps are achieved with the developed MDE protocol (Figure 1). Pearson correlation coefficients (marked in Figure 2) range from r=0.951-0.995 for MD, μFA, MKa, and MKi in the global GM and WM, left and right hippocampal cingulum and fornix (Figure 2).We have developed a MDE protocol of 1.8 mm isotropic and demonstrated its high scan-rescan reproducibility, globally and in four critical WM regions for cognitive function. The achieved 1.8 mm isotropic resolution, together with a large slice coverage (∼70 mm) within a clinically feasible scan time (∼13 min), sets the foundation for more specifically mapping brain microstructure changes in critical brain regions (e.g., the medial temporal lobe) to capture neurodegeneration.

  View details for DOI 10.1002/alz70862_109814

  View details for PubMedID 41433887

  View details for PubMedCentralID PMC12725733

• UltraFlex: Iterative Model-Based Ultrasonic Flexible-Array Shape Calibration IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL Frey, B. N., Hyun, D., Simson, W., Zhuang, L., Hashemi, H. S., Schneider, M., Dahl, J. J. 2025; 72 (11): 1462-1475

  Abstract

  UltraFlex is an iterative model-based ultrasonic flexible-array shape calibration framework that uses automatic differentiation. This work evaluates array shape calibration model performance while examining multiple image quality metrics: speckle brightness, envelope entropy, coherence factor, lag-one coherence, common-midpoint correlation coefficient (CMCC), and common-midpoint phase error (CMPE). The accuracy of these image quality metrics was evaluated on simulated phantoms using a variety of array shapes. Experimental phantom and in vivo liver datasets were also investigated using transducers with known geometries. While speckle brightness, envelope entropy, and coherence factor enable model convergence under many conditions, lag-one coherence, CMCC, and CMPE enable more accurate element position estimations and improved visual ultrasound image focusing quality. Furthermore, the models based on the CMCC and phase-error quality metrics are the most robust against additive white noise while achieving median mean Euclidean errors (MEEs) of 3.7 μm for simulation, 29.7 μm for phantom, and 69.0 μm for in vivo liver data. These array shape calibration results show promise for future development of experimental flexible- and wearableultrasonic arrays.

  View details for DOI 10.1109/TUFFC.2025.3627525

  View details for Web of Science ID 001629793500002

  View details for PubMedID 41171672

• Spatial transcriptomic analysis drives PET imaging of tight junction protein expression in pancreatic cancer theranostics. Nature communications Wang, J., Seo, J. W., Kare, A. J., Schneider, M., Pandrala, M., Tumbale, S. K., Raie, M. N., Engudar, G., Zhang, N., Guo, Y., Zhong, X., Ferreira, S., Wu, B., Attardi, L. D., Pratx, G., Iagaru, A., Brunsing, R. L., Charville, G. W., Park, W. G., Ferrara, K. W. 2024; 15 (1): 10751

  Abstract

  Molecular imaging using positron emission tomography (PET) provides sensitive detection and mapping of molecular targets. While cancer-associated fibroblasts and integrins have been proposed as targets for imaging of pancreatic ductal adenocarcinoma (PDAC), herein, spatial transcriptomics and proteomics of human surgical samples are applied to select PDAC targets. We find that selected cancer cell surface markers are spatially correlated and provide specific cancer localization, whereas the spatial correlation between cancer markers and immune-related or fibroblast markers is low. Claudin-4 expression increases ~16 fold in cancer as compared with normal pancreas, and tight junction localization confers low background for imaging in normal tissue. We develop a peptide-based molecular imaging agent targeted to claudin-4 with accumulation to ~25% injected activity per cubic centimeter (IA/cc) in metastases and ~18% IA/cc in tumors. Our work motivates a data-driven approach to selection of molecular targets.

  View details for DOI 10.1038/s41467-024-54761-6

  View details for PubMedID 39737976

  View details for PubMedCentralID 10236159

• Combined near infrared photoacoustic imaging and ultrasound detects vulnerable atherosclerotic plaque. Biomaterials Schneider, M. K., Wang, J., Kare, A., Adkar, S. S., Salmi, D., Bell, C. F., Alsaigh, T., Wagh, D., Coller, J., Mayer, A., Snyder, S. J., Borowsky, A. D., Long, S. R., Lansberg, M. G., Steinberg, G. K., Heit, J. J., Leeper, N. J., Ferrara, K. W. 2023; 302: 122314

  Abstract

  Atherosclerosis is an inflammatory process resulting in the deposition of cholesterol and cellular debris, narrowing of the vessel lumen and clot formation. Characterization of the morphology and vulnerability of the lesion is essential for effective clinical management. Here, near-infrared auto-photoacoustic (NIRAPA) imaging is shown to detect plaque components and, when combined with ultrasound imaging, to differentiate stable and vulnerable plaque. In an ex vivo study of photoacoustic imaging of excised plaque from 25 patients, 88.2% sensitivity and 71.4% specificity were achieved using a clinically-relevant protocol. In order to determine the origin of the NIRAPA signal, immunohistochemistry, spatial transcriptomics and spatial proteomics were co-registered with imaging and applied to adjacent plaque sections. The highest NIRAPA signal was spatially correlated with bilirubin and associated blood-based residue and with the cytoplasmic contents of inflammatory macrophages bearing CD74, HLA-DR, CD14 and CD163 markers. In summary, we establish the potential to apply the NIRAPA-ultrasound imaging combination to detect vulnerable carotid plaque and a methodology for fusing molecular imaging with spatial transcriptomic and proteomic methods.

  View details for DOI 10.1016/j.biomaterials.2023.122314

  View details for PubMedID 37776766

• Photoacoustic tomography versus cone-beam computed tomography versus micro-computed tomography: Accuracy of 3D reconstructions of human teeth. PloS one Schneider, S. J., Höhne, C., Schneider, M., Schmitter, M. 2022; 17 (12): e0274818

  Abstract

  In this in-vitro study, teeth were imaged using photoacoustic tomography (PAT), cone-beam computed tomography (CBCT), and micro-computed tomography (μ-CT). The study had aim: to identify the best wavelength for PAT images to determine the accuracy of the three imaging methods, and to determine whether PAT images of teeth can achieve acceptable reconstruction quality.Nineteen human mandibular single-rooted incisors were extracted from patients with trauma or periodontitis. To determine the best wavelength for acquiring photoacoustic images, all 19 teeth were scanned in vitro with PAT, using different laser wavelengths between 680 and 960 nm. The images were analyzed using image analysis software. To assess the accuracy of PAT and compare it with the accuracy of CBCT, each tooth was also scanned in vitro using CBCT and the reference standard technique of μ-CT. Subsequently, three different three-dimensional models, one for each imaging technique, were created for each tooth. Finally, the three different three-dimensional models acquired for the same tooth were matched and analyzed regarding volume and surface.The highest quality tooth images were achieved using the 680 nm wavelength, which showed the best contrast ratio. The full geometry of the dental root (μ-CT compared with PAT) could be visualized with relative standard deviations of 0.12 mm for the surface and -7.33 mm3 for the volume (n = 19). The full geometry of the dental root (μ-CT compared with CBCT) could be visualized with relative standard deviations of 0.06 mm for the surface and -14.56 mm3 for the volume (n = 19). The difference between the PAT-μ-CT group and CBCT-μ-CT group regarding the total average of the root surface area was not significant (p>0.06).Images, which were acquired using PAT at 680nm showed the best contrast ration, enabling the identification of dentin, cementum and the dental pulp. No significant differences were found between the PAT-μ-CT group and CBCT-μ-CT group regarding the total average of the RSA and the total volume. Thus, three-dimensional reconstructions based on in-vitro PAT are already of acceptable reconstruction quality.

  View details for DOI 10.1371/journal.pone.0274818

  View details for PubMedID 36534651

• Superiorized Photo-Acoustic Non-NEgative Reconstruction (SPANNER) for Clinical Photoacoustic Imaging. IEEE transactions on medical imaging Steinberg, I. n., Kim, J. n., Schneider, M. K., Hyun, D. n., Zlitni, A. n., Hooper, S. M., Klap, T. n., Sonn, G. A., Dahl, J. J., Kim, C. n., Gambhir, S. S. 2021; PP

  Abstract

  Photoacoustic (PA) imaging can revolutionize medical ultrasound by augmenting it with molecular information. However, clinical translation of PA imaging remains a challenge due to the limited viewing angles and imaging depth. Described here is a new robust algorithm called Superiorized Photo-Acoustic Non-NEgative Reconstruction (SPANNER), designed to reconstruct PA images in real-time and to address the artifacts associated with limited viewing angles and imaging depth. The method utilizes precise forward modeling of the PA propagation and reception of signals while accounting for the effects of acoustic absorption, element size, shape, and sensitivity, as well as the transducer's impulse response and directivity pattern. A fast superiorized conjugate gradient algorithm is used for inversion. SPANNER is compared to three reconstruction algorithms: delay-and-sum (DAS), universal back-projection (UBP), and model-based reconstruction (MBR). All four algorithms are applied to both simulations and experimental data acquired from tissue-mimicking phantoms, ex vivo tissue samples, and in vivo imaging of the prostates in patients. Simulations and phantom experiments highlight the ability of SPANNER to improve contrast to background ratio by up to 20 dB compared to all other algorithms, as well as a 3-fold increase in axial resolution compared to DAS and UBP. Applying SPANNER on contrast-enhanced PA images acquired from prostate cancer patients yielded a statistically significant difference before and after contrast agent administration, while the other three image reconstruction methods did not, thus highlighting SPANNER's performance in differentiating intrinsic from extrinsic PA signals and its ability to quantify PA signals from the contrast agent more accurately.

  View details for DOI 10.1109/TMI.2021.3068181

  View details for PubMedID 33755561

• A Distinct Role of the Autonomic Nervous System in Modulating the Function of Lymphatic Vessels under Physiological and Tumor-Draining Conditions CELL REPORTS Bachmann, S. B., Gsponer, D., Montoya-Zegarra, J. A., Schneider, M., Scholkmann, F., Tacconi, C., Noerrelykke, S. F., Proulx, S. T., Detmar, M. 2019; 27 (11): 3305-+

  Abstract

  Lymphatic vessels (LVs) are important in the regulation of tissue fluid homeostasis and the pathogenesis of tumor progression. We investigated the innervation of LVs and the response to agonists and antagonists of the autonomic nervous system in vivo. While skin-draining collecting LVs express muscarinic, α1- and β2-adrenergic receptors on lymphatic endothelial cells and smooth muscle cells, intestinal lacteals express only β-adrenergic receptors and muscarinic receptors on their smooth muscle cells. Quantitative in vivo near-infrared imaging of the exposed flank-collecting LV revealed that muscarinic and α1-adrenergic agonists increased LV contractility, whereas activation of β2-adrenergic receptors inhibited contractility and initiated nitric oxide (NO)-dependent vasodilation. Tumor-draining LVs were expanded and showed a higher innervation density and contractility that was reduced by treatment with atropine, phentolamine, and, most potently, isoproterenol. These findings likely have clinical implications given the impact of lymphatic fluid drainage on intratumoral fluid pressure and thus drug delivery.

  View details for DOI 10.1016/j.celrep.2019.05.050

  View details for Web of Science ID 000470993200017

  View details for PubMedID 31189113

  View details for PubMedCentralID PMC6581737

• An in vivo wound healing model for the characterization of the angiogenic process and its modulation by pharmacological interventions. Scientific reports Schneider, M. K., Ioanas, H. I., Xandry, J., Rudin, M. 2019; 9 (1): 6004

  Abstract

  Angiogenesis during wound healing is essential for tissue repair and also affected during cancer treatment by anti-angiogenic drugs. Here, we introduce a minimally invasive wound healing model in the mouse ear to assess angiogenesis with high spatiotemporal resolution in a longitudinal manner in vivo using two-photon microscopy in mice expressing GCaMP2 in arterial endothelial cells. The development of vascular sprouts occurred in a highly orchestrated manner within a time window of 8 days following wounding. Novel sprouts developed exclusively from the distal stump of the transsected arteries, growing towards the proximal arterial stump. This was in line with the incidence of Ca2+ transients in the arterial endothelial cells, most probably a result of VEGF stimulation, which were more numerous on the distal part. Functional analysis revealed perfusion across the wound site via arterial sprouts developed between days 6 and 8 following the incision. At day 8, proximal and distal arteries were structurally and functionally connected, though only 2/3 of all sprouts detected were actually perfused. Treatment with the FDA approved drug, sunitinib, the preclinical drug AZD4547, as well as with the combination of the two agents had significant effects on both structural and functional readouts of neo-angiogenesis. The simplicity and high reproducibility of the model makes it an attractive tool for elucidating migratory activity, phenotype and functionality of endothelial cells during angiogenesis and for evaluating specific anti-angiogenic drug interventions.

  View details for DOI 10.1038/s41598-019-42479-1

  View details for PubMedID 30979919

  View details for PubMedCentralID PMC6461656

• EMMPRIN and its ligand Cyclophilin A as novel diagnostic markers in inflammatory cardiomyopathy INTERNATIONAL JOURNAL OF CARDIOLOGY Seizer, P., Geisler, T., Bigalke, B., Schneider, M., Klingel, K., Kandolf, R., Stellos, K., Schreieck, J., Gawaz, M., May, A. E. 2013; 163 (3): 299–304

  Abstract

  During inflammatory cardiomyopathy matrix metalloproteinases are crucially involved in cardiac remodeling. The aim of the present study was to investigate whether the "extracellular matrix metalloproteinase inducer" EMMPRIN (CD147) and its ligand Cyclophilin A (CyPA) are upregulated in inflammatory cardiomyopathy and may serve as diagnostic markers. Therefore, a series of 102 human endomyocardial biopsies were analyzed for the expression of EMMPRIN and CyPA and correlated with histological and immunohistological findings.Endomyocardial biopsies were stained for EMMPRIN and CyPA in addition to standard histology (HE, Trichrom) and immunohistological stainings (MHC-II, CD68, CD3). 39 (38.2%) biopsies met the immunohistological criteria of an inflammatory cardiomyopathy. EMMPRIN, which was predominantly expressed on cardiomyocytes, was slightly (but significantly) upregulated in non inflammatory cardiomyopathies compared to normal histopathological findings and highly upregulated in inflammatory cardiomyopathy compared to both non inflammatory cardiomyopathy and normal histopathology. In contrast, CyPA reveals no enhanced expression in non inflammatory cardiomyopathies and a highly enhanced expression in inflammatory cardiomyopathy, where it is closely associated with leucocytes infiltrates. We found a strong correlation between both EMMPRIN and CyPA with the expression of MHC-II molecules (correlation coefficient 0.475 and 0.527, p<0.05). Moreover, we found a correlation for both EMMPRIN and CyPA with CD68 (correlation coefficient 0.393 and 0.387, p<0.05) and CD3 (correlation coefficient 0.360 and 0.235, p<0.05).EMMPRIN is enhanced in both inflammatory and non inflammatory cardiomyopathies and can serve as a marker of myocardial remodeling. CyPA may represent a novel and specific marker for cardiac inflammation.

  View details for DOI 10.1016/j.ijcard.2011.06.049

  View details for Web of Science ID 000315156000019

  View details for PubMedID 21724278