An automatic pipeline for PET/MRI attenuation correction validation in the brain

PURPOSE: Challenges in PET/MRI quantitative accuracy for neurological uses arise from PET attenuation correction accuracy. We proposed and evaluated an automatic pipeline to assess the quantitative accuracy of four MRI-derived PET AC methods using analytically simulated PET brain lesions and ROIs as ground truth for PET activity. METHODS: Our proposed pipeline, integrating a synthetic lesion insertion tool and the FreeSurfer neuroimaging framework, inserts simulated spherical and brain ROIs into PET projection space, reconstructing them via four PET MRAC techniques. Utilizing an 11-patient brain PET dataset, we compared the quantitative accuracy of four MRACs (DIXON, DIXONbone, UTE AC, and DL-DIXON) against the gold standard PET CTAC, evaluating MRAC to CTAC activity bias in spherical lesions and brain ROIs with and without background activity against original (lesion free) PET reconstructed images. RESULTS: The proposed pipeline yielded accurate results for spherical lesions and brain ROIs, adhering to the MRAC to CTAC pattern of original brain PET images. Among the MRAC methods, DIXON AC exhibited the highest bias, followed by UTE, DIXONBone, and DL-DIXON showing the least. DIXON, DIXONbone, UTE, and DL-DIXON showed MRAC to CTAC biases of - 5.41%, - 1.85%, - 2.74%, and 0.08% respectively for ROIs inserted in background activity; - 7.02%, - 2.46%, - 3.56%, and - 0.05% for lesion ROIs without background; and - 6.82%, - 2.08%, - 2.29%, and 0.22% for the original brain PET images\u27 16 FreeSurfer brain ROIs. CONCLUSION: The proposed pipeline delivers accurate results for synthetic spherical lesions and brain ROIs, with and without background activity consideration, enabling the evaluation of new attenuation correction approaches without utilizing measured PET emission data. Additionally, it offers a consistent method to generate realistic lesion ROIs, potentially applicable in assessing further PET correction techniques

Immunogenicity and Protective Efficacy against Murine Tuberculosis of a Prime-Boost Regimen with BCG and a DNA Vaccine Expressing ESAT-6 and Ag85A Fusion Protein

Heterologous prime-boost regimens utilizing BCG as a prime vaccine probably represent the best hope for the development of novel tuberculosis (TB) vaccines. In this study, we examined the immunogenicity and protective efficacy of DNA vaccine (pcD685A) expressing the fusion protein of Ag85A and ESAT-6 (r685A) and its booster effects in BCG-immunized mice. The recombinant r685A fusion protein stimulated higher level of antigen-specific IFN-γ release in tuberculin skin test- (TST-) positive healthy household contacts of active pulmonary TB patients than that in TST-negative population. Vaccination of C57BL/6 mice with pcD685A resulted in significant protection against challenge with virulent Mycobacterium tuberculosis H37Rv when compared with the control group. Most importantly, pcD685A could act as a BCG booster and amplify Th1-type cell-mediated immunity in the lung of BCG-vaccinated mice as shown the increased expression of IFN-γ. The most significant reduction in bacterial load of both spleen and lung was obtained in mice vaccinated with BCG prime and pcD685A DNA booster when compared with BCG or pcD685A alone. Thus, our study indicates that pcD685A may be an efficient booster vaccine against TB with a strong ability to enhance prior BCG immunity

Self-Supervised Deep Equilibrium Models for Inverse Problems with Theoretical Guarantees

Deep equilibrium models (DEQ) have emerged as a powerful alternative to deep unfolding (DU) for image reconstruction. DEQ models-implicit neural networks with effectively infinite number of layers-were shown to achieve state-of-the-art image reconstruction without the memory complexity associated with DU. While the performance of DEQ has been widely investigated, the existing work has primarily focused on the settings where groundtruth data is available for training. We present self-supervised deep equilibrium model (SelfDEQ) as the first self-supervised reconstruction framework for training model-based implicit networks from undersampled and noisy MRI measurements. Our theoretical results show that SelfDEQ can compensate for unbalanced sampling across multiple acquisitions and match the performance of fully supervised DEQ. Our numerical results on in-vivo MRI data show that SelfDEQ leads to state-of-the-art performance using only undersampled and noisy training data

Neuroinflammation and amyloid deposition in the progression of mixed Alzheimer and vascular dementia

BACKGROUND: Alzheimer\u27s disease (AD) and vascular contributions to cognitive impairment and dementia (VCID) pathologies coexist in patients with cognitive impairment. Abnormal amyloid beta (Aβ) deposition is the hallmark pathologic biomarker for AD. Neuroinflammation may be a pathophysiological mechanism in both AD and VCID. In this study, we aimed to understand the role of neuroinflammation and Aβ deposition in white matter hyperintensities (WMH) progression and cognitive decline over a decade in patients with mixed AD and VCID pathologies. METHODS: Twenty-four elderly participants (median [interquartile range] age 78 [64.8, 83] years old, 14 female) were recruited from the Knight Alzheimer Disease Research Center. RESULTS: Fifteen participants (62.5%) had mixed AD (positive PiB) and VCID (at least one vascular risk factor) pathologies. Elevated CONCLUSIONS: Neuroinflammation and Aβ deposition may represent two distinct pathophysiological pathways, and both independently contributed to the progression of cognitive impairment in mixed AD and VCID pathologies. Neuroinflammation, but not Aβ deposition, contributed to WMH volume and progression

Intracranial aneurysms in sickle cell disease are associated with hemodynamic stress and anemia

Although hemodynamic stress plays a key role in aneurysm formation outside of sickle cell disease (SCD), its role is understudied in patients with SCD. We hypothesized that tissue-based markers of hemodynamic stress are associated with aneurysm presence in a prospective SCD cohort. Children and adults with SCD, with and without aneurysms, underwent longitudinal brain magnetic resonance imaging/magnetic resonance angiography (MRA) to assess cerebral blood flow (CBF) and oxygen extraction fraction (OEF). Baseline characteristics were recorded. In the subgroup of adults, stepwise mixed-effect logistic regression examined clinical variables, CBF, and OEF as predictors of aneurysm presence. Cumulative rates of new aneurysm formation were estimated using Kaplan-Meier analyses. Forty-three aneurysms were found in 27 of 155 patients (17%). Most aneurysms were ≤3 mm and in the intracranial internal carotid artery. On univariate analysis, older age (P = .07), lower hemoglobin (P = .002), higher CBF (P = .03), and higher OEF (P = .02) were associated with aneurysm presence. On multivariable analysis, age and CBF remained independently associated with aneurysm presence. Seventy-six patients (49% of enrollment) received follow-up MRAs (median, 3.5 years). No aneurysm grew or ruptured, however, 7 new aneurysms developed in 6 patients. The 3-year cumulative rate of aneurysm formation was 3.5%. In 155 patients with SCD, 17% had intracranial aneurysms. Three-year aneurysm formation rate was 3.5%, although limited by small longitudinal sample size and short follow-up duration. Aneurysm presence was associated with elevated CBF in adults, as a tissue-based marker of cerebral hemodynamic stress. Future studies may examine the predictive role of CBF in aneurysm development in SCD

Interferon-alpha responsible EPN3 regulates hepatitis B virus replication

Hepatitis B virus (HBV) infection remains a major health problem worldwide, and the current antiviral therapy, including nucleoside analogs, cannot achieve life-long cure, and clarification of antiviral host immunity is necessary for eradication. Here, we found that a clathrin-binding membrane protein epsin3 (EPN3) negatively regulates the expression of HBV RNA. EPN3 expression was induced by transfection of an HBV replicon plasmid, and reduced HBV-RNA level in hepatic cell lines and murine livers hydrodynamically injected with the HBV replicon plasmid. Viral RNA reduction by EPN3 was dependent on transcription, and independent from epsilon structure of viral RNA. Viral RNA reduction by overexpression of p53 or IFN-α treatment, was attenuated by knockdown of EPN3, suggesting its role downstream of IFN-α and p53. Taken together, this study demonstrates the anti-HBV role of EPN3. The mechanism how it decreases HBV transcription is discussed

PET/MR Imaging Biomarkers for Cerebral Small Vascular Diseases: Tissue Oxygenation Stress and Neuroinflammation

Fifty million people are affected by dementia worldwide. Cerebral small vessel disease (CSVD) often leads to vascular contributions to cognitive impairment and dementia (VCID), the second leading cause of dementia after Alzheimer’s disease (AD), accounting for up to 45% of dementia. White matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) imaging and disrupted white matter microstructure on diffusion tensor imaging (DTI) have been widely used as biomarkers to evaluate CSVD. The pathogenesis underlying CSVD is not well understood. It has been postulated that exposure to risk factors, including hypertension, diabetes, and smoking over years injures small arterioles, impairs autoregulation and leads to chronic hypoxia-ischemia. Elevated oxygen extraction fraction (OEF) is a signature of tissue oxygenation stress. A magnetic resonance imaging (MRI) measured OEF (MR-OEF) will provide direct evidence of tissue oxygenation stress in the development of CSVD. Neuroinflammation may also be a pathophysiological mechanism for CSVD. Systemic serum and cerebrospinal fluid markers of inflammation, including C-reactive protein and matrix metalloproteases, are elevated in patients with CSVD. While systemic biomarkers are indirect measures of neuroinflammation, positron emission tomography (PET) imaging using 11C-PK11195, a radioligand that binds to the 18 kDa translocator protein located on the membrane of microglia and astrocytes, allows measuring regional neuroinflammation directly. The overarching goal of this dissertation is to develop combined PET and MR imaging methods to investigate cerebral tissue oxygenation stress and neuroinflammation, two critical pathogenic factors for CSVD. Specific method developments and their applications include 1) PET/MR attenuation correction (AC) and PET/MR AC repeatability; 2) repeatability of regional MR-OEF, cerebral blood flow (CBF) measurements in healthy young participants and elderly participants with CSVD; 3) MR-OEF validation using 15O PET imaging; 4) association between tissue hypoxia-ischemia and white matter structural and micro-structural impairments; 5) roles of neuroinflammation and amyloid deposition in the progression of the mixed AD and VCID pathology. In combined PET/MR imaging, AC is crucial for accurate quantitative PET. However, MR signal does not provide information on electron density needed for PET AC. In this dissertation, we first developed and evaluated a deep learning-based approach to convert MR to pseudo computed tomography (pCT) for accurate PET/MR AC. This approach achieves highly accurate and repeatable PET/MR AC at both regional and voxel levels while taking a short processing time and is well-suited for longitudinal PET/MR clinical studies. Our lab previously developed a noninvasive MRI approach that can provide voxel-wise OEF maps using standard MRI scanners without ionizing radiation. Thus far, this approach has not been validated directly against the 15O PET measurement in human subjects, and its test-retest repeatability remains unclear. To establish MR-OEF as a fully validated and robust imaging biomarker for CSVD, we aimed to validate this approach on a hybrid PET/MR system that allows simultaneous PET and MR image acquisition and evaluate its test-retest repeatability in healthy young participants and elderly participants with CSVD. Moreover, we compared MR-measured CBF to 15O-H2O PET measurements. We then investigated the association between chronic hypoxia-ischemia, measured by regional OEF and CBF and white matter injury in elderly participants with and without vascular risk factors using MRI in a cross-sectional study. We found that elevated MR-OEF was associated with greater WMH lesion burden and microstructural disruption (measured by DTI metrics). Our results suggested that chronic hypoxia-ischemia may contribute to CSVD pathogenesis and may be an imaging biomarker which helps identify individuals at risk for CSVD progression. Finally, we explored the roles of neuroinflammation and amyloid beta (Aβ) deposition (a key pathologic biomarker for AD) in WMH progression and cognitive decline over a decade in participants with mixed AD and VCID pathologies using PET and MRI in a longitudinal study. Our results suggested that neuroinflammation and Aβ deposition may represent two distinct pathophysiological pathways, both of which independently contributed to the progression of cognitive impairment in mixed AD and VCID pathologies. Neuroinflammation, but not Aβ deposition, contributed to WMH volume and progression

Anodal transcranial direct current stimulation over the right primary somatosensory cortex increases cough reflex sensitivity: a pilot randomised controlled crossover trial

Background The cough reflex is a protective reflex of the human body. Increases or decreases in cough reflex sensitivity may be related to chronic cough, aspiration pneumonia and other diseases. The right primary somatosensory cortex (RS1) is the main activation centre for the urge to cough. Here, we discuss the effects of transcranial direct current stimulation (tDCS) of RS1 on the cough reflex and urge to cough. In addition, we explored the role of the left dorsolateral prefrontal cortex (lDLPFC) in cough using tDCS. Methods 24 healthy young adults completed this pilot randomised controlled crossover experiment. Each person was tested three times, receiving, in random order, anodal tDCS of RS1 or lDLPFC or sham stimulation. The current intensity was set to 2 mA, the stimulation time was 30 min and the interval between any two stimuli was ≥1 week. After each intervention, the citric acid cough challenge test was used immediately to assess the urge to cough and cough reflex sensitivity. Results The cough reflex thresholds, expressed as LogC2 and LogC5, were significantly reduced after RS1 anodal stimulation compared to sham stimulation, accompanied by increased urge-to-cough sensitivity (urge-to-cough log–log slope 1.19±0.40 point·L·g−1 versus 0.92±0.33 point·L·g−1, p=0.001), but the threshold for the urge to cough did not change significantly. There were no significant changes in the urge to cough and cough reflex sensitivity after tDCS anodal lDLPFC stimulation. Conclusion Anodal tDCS stimulation of the RS1 can increase urge-to-cough sensitivity and reduce cough reflex threshold. The effects of tDCS on cough reflex, as well as the underlying mechanisms driving those effects, should be explored further

Distinct Transcriptional Responses of Skeletal Muscle to Short-Term Cold Exposure in Tibetan Pigs and Bama Pigs

Piglets are susceptible to cold, and piglet death caused by cold stress leads to economic losses in the pig industry in cold areas. Skeletal muscle plays a key role in adaptive thermogenesis in mammals, but the related mechanism in pigs is unclear. In this study, cold-tolerant Tibetan pigs and cold-sensitive Bama pigs were subjected to either a cold environment (4 °C) or a room temperature environment (25 °C) for 3 days. The biceps femoris (BF) and longissimus dorsi muscle (LDM) were collected for phenotypic analysis, and the BF was used for genome-wide transcriptional profiling. Our results showed that Tibetan pigs had a higher body temperature than Bama pigs upon cold stimulation. RNA-seq data indicated a stronger transcriptional response in the skeletal muscle of Tibetan pigs upon cold stimulation, as more differentially expressed genes (DEGs) were identified with the same criteria (p 2). In addition, distinct pathway signaling patterns in skeletal muscle upon cold exposure were found between the breeds of pigs. Mitochondrial beta-oxidation-related genes and pathways were significantly upregulated in Tibetan pigs, indicating that Tibetan pigs may use fatty acids as the primary fuel source to protect against cold. However, the significant upregulation of inflammatory response- and glycolysis-related genes and pathways in the skeletal muscle of Bama pigs suggested that these pigs may use glucose as the primary fuel source in cold environments. Together, our study revealed the distinct transcriptional responses of skeletal muscle to cold stimulation in Tibetan pigs and Bama pigs and provided novel insights for future investigation of the cold adaptation mechanism in pigs