Compressing Binary Decision Diagrams

The paper introduces a new technique for compressing Binary Decision Diagrams in those cases where random access is not required. Using this technique, compression and decompression can be done in linear time in the size of the BDD and compression will in many cases reduce the size of the BDD to 1-2 bits per node. Empirical results for our compression technique are presented, including comparisons with previously introduced techniques, showing that the new technique dominate on all tested instances.Comment: Full (tech-report) version of ECAI 2008 short pape

Imaging Neurodegenerative Metabolism in Amyotrophic Lateral Sclerosis with Hyperpolarized [1-13C]pyruvate MRI

The cause of amyotrophic lateral sclerosis (ALS) is still unknown, and consequently, early diagnosis of the disease can be difficult and effective treatment is lacking. The pathology of ALS seems to involve specific disturbances in carbohydrate metabolism, which may be diagnostic and therapeutic targets. Magnetic resonance imaging (MRI) with hyperpolarized [1-(13)C]pyruvate is emerging as a technology for the evaluation of pathway-specific changes in the brain’s metabolism. By imaging pyruvate and the lactate and bicarbonate it is metabolized into, the technology is sensitive to the metabolic changes of inflammation and mitochondrial dysfunction. In this study, we performed hyperpolarized MRI of a patient with newly diagnosed ALS. We found a lateralized difference in [1-(13)C]pyruvate-to-[1-(13)C]lactate exchange with no changes in exchange from [1-(13)C]pyruvate to (13)C-bicarbonate. The 40% increase in [1-(13)C]pyruvate-to-[1-(13)C]lactate exchange corresponded with the patient’s symptoms and presentation with upper-motor neuron affection and cortical hyperexcitability. The data presented here demonstrate the feasibility of performing hyperpolarized MRI in ALS. They indicate potential in pathway-specific imaging of dysfunctional carbohydrate metabolism in ALS, an enigmatic neurodegenerative disease

Lactate saturation limits bicarbonate detection in hyperpolarized 13 C-pyruvate MRI of the brain

PURPOSE: To investigate the potential effects of [1‐(13)C]lactate RF saturation pulses on [(13)C]bicarbonate detection in hyperpolarized [1‐(13)C]pyruvate MRI of the brain. METHODS: Thirteen healthy rats underwent MRI with hyperpolarized [1‐(13)C]pyruvate of either the brain (n = 8) or the kidneys, heart, and liver (n = 5). Dynamic, metabolite‐selective imaging was used in a cross‐over experiment in which [1‐(13)C]lactate was excited with either 0° or 90° flip angles. The [(13)C]bicarbonate SNR and apparent [1‐(13)C]pyruvate‐to‐[(13)C]bicarbonate conversion (k (PB)) were determined. Furthermore, simulations were performed to identify the SNR optimal flip‐angle scheme for detection of [1‐(13)C]lactate and [(13)C]bicarbonate. RESULTS: In the brain, the [(13)C]bicarbonate SNR was 64% higher when [1‐(13)C]lactate was not excited (5.8 ± 1.5 vs 3.6 ± 1.3; 1.2 to 3.3–point increase; p = 0.0027). The apparent k (PB) decreased 25% with [1‐(13)C]lactate saturation (0.0047 ± 0.0008 s(−1) vs 0.0034 ± 0.0006 s(−1); 95% confidence interval, 0.0006–0.0019 s(−1) increase; p = 0.0049). These effects were not present in the kidneys, heart, or liver. Simulations suggest that the optimal [(13)C]bicarbonate SNR with a TR of 1 s in the brain is obtained with [(13)C]bicarbonate, [1‐(13)C]lactate, and [1‐(13)C]pyruvate flip angles of 60°, 15°, and 10°, respectively. CONCLUSIONS: Radiofrequency saturation pulses on [1‐(13)C]lactate limit [(13)C]bicarbonate detection in the brain specifically, which could be due to shuttling of lactate from astrocytes to neurons. Our results have important implications for experimental design in studies in which [(13)C]bicarbonate detection is warranted

Enabling SENSE accelerated 2D CSI for hyperpolarized carbon-13 imaging

As hyperpolarized (HP) carbon-13 (13C) metabolic imaging is clinically translated, there is a need for easy-to-implement, fast, and robust imaging techniques. However, achieving high temporal resolution without decreasing spatial and/or spectral resolution, whilst maintaining the usability of the imaging sequence is challenging. Therefore, this study looked to accelerate HP 13C MRI by combining a well-established and robust sequence called two-dimensional Chemical Shift Imaging (2D CSI) with prospective under sampling and SENSitivity Encoding (SENSE) reconstruction. Due to the low natural abundance of 13C, the sensitivity maps cannot be pre-acquired for the reconstruction. As such, the implementation of sodium (23Na) sensitivity maps for SENSE reconstructed 13C CSI was demonstrated in a phantom and in vivo in the pig kidney. Results showed that SENSE reconstruction using 23Na sensitivity maps corrected aliased images with a four-fold acceleration. With high temporal resolution, the kidney spectra produced a detailed metabolic arrival and decay curve, useful for further metabolite kinetic modelling or denoising. Metabolic ratio maps were produced in three pigs demonstrating the technique’s ability for repeat metabolic measurements. In cases with unknown metabolite spectra or limited HP MRI specialist knowledge, this robust acceleration method ensures comprehensive capture of metabolic signals, mitigating the risk of missing spectral data

Detection of increased pyruvate dehydrogenase flux in the human heart during adenosine stress test using hyperpolarized [1-13C]pyruvate cardiovascular magnetic resonance imaging

BACKGROUND: Hyperpolarized (HP) [1-(13)C]pyruvate cardiovascular magnetic resonance (CMR) imaging can visualize the uptake and intracellular conversion of [1-(13)C]pyruvate to either [1-(13)C]lactate or (13)C-bicarbonate depending on the prevailing metabolic state. The aim of the present study was to combine an adenosine stress test with HP [1-(13)C]pyruvate CMR to detect cardiac metabolism in the healthy human heart at rest and during moderate stress. METHODS: A prospective descriptive study was performed between October 2019 and August 2020. Healthy human subjects underwent cine CMR and HP [1-(13)C]pyruvate CMR at rest and during adenosine stress. HP [1-(13)C]pyruvate CMR images were acquired at the mid-left-ventricle (LV) level. Semi-quantitative assessment of first-pass myocardial [1-(13)C]pyruvate perfusion and metabolism were assessed. Paired t-tests were used to compare mean values at rest and during stress. RESULTS: Six healthy subjects (two female), age 29 ± 7 years were studied and no adverse reactions occurred. Myocardial [1-(13)C]pyruvate perfusion was significantly increased during stress with a reduction in time-to-peak from 6.2 ± 2.8 to 2.7 ± 1.3 s, p = 0.02. This higher perfusion was accompanied by an overall increased myocardial uptake and metabolism. The conversion rate constant (k(PL)) for lactate increased from 11 ± 9 *10(–3) to 20 ± 10 * 10(–3) s(−1), p = 0.04. The pyruvate oxidation rate (k(PB)) increased from 4 ± 4 *10(–3) to 12 ± 7 *10(–3) s(−1), p = 0.008. This increase in carbohydrate metabolism was positively correlated with heart rate (R(2) = 0.44, p = 0.02). CONCLUSIONS: Adenosine stress testing combined with HP [1-(13)C]pyruvate CMR is feasible and well-tolerated in healthy subjects. We observed an increased pyruvate oxidation during cardiac stress. The present study is an important step in the translation of HP [1-(13)C]pyruvate CMR into clinical cardiac imaging. Trial registration EUDRACT, 2018-003533-15. Registered 4th of December 2018, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-003533-1

A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency

The established causal genes in Alzheimer’s disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease’s initial preclinical phase. Mutations in SORL1, encoding the endosome recycling receptor SORLA, are found in 2%–3% of individuals with early-onset AD, and SORL1 haploinsufficiency appears to be causal for AD. To test whether SORL1 can function as an AD causal gene, we use CRISPR-Cas9-based gene editing to develop a model of SORL1 haploinsufficiency in Göttingen minipigs, taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young adult minipigs is found to phenocopy the preclinical in vivo profile of AD observed with APP, PSEN1, and PSEN2, resulting in elevated levels of β-amyloid (Aβ) and tau preceding amyloid plaque formation and neurodegeneration, as observed in humans. Our study provides functional support for the theory that SORL1 haploinsufficiency leads to endosome cytopathology with biofluid hallmarks of autosomal dominant AD