Imaging Biomarkers Research Articles

Research on imaging biomarkers for chronic subdural hematoma recurrence.

This study utilizes radiomics to explore imaging biomarkers for predicting the recurrence of chronic subdural hematoma (CSDH), aiming to improve the prediction of CSDH recurrence risk. Analyzing CT scans from 64 patients with CSDH, we extracted 107 radiomic features and employed recursive feature elimination (RFE) and the XGBoost algorithm for feature selection and model construction. The feature selection process identified six key imaging biomarkers closely associated with CSDH recurrence: flatness, surface area to volume ratio, energy, run entropy, small area emphasis, and maximum axial diameter. The selection of these imaging biomarkers was based on their significance in predicting CSDH recurrence, revealing deep connections between postoperative variables and recurrence. After feature selection, there was a significant improvement in model performance. The XGBoost model demonstrated the best classification performance, with the average accuracy improving from 46.82% (before feature selection) to 80.74% and the AUC value increasing from 0.5864 to 0.7998. These results prove that precise feature selection significantly enhances the model's predictive capability. This study not only reveals imaging biomarkers for CSDH recurrence but also provides valuable insights for future personalized treatment strategies.

Elevated serum sodium is linked to increased amyloid-dependent tau pathology, neurodegeneration, and cognitive impairment in Alzheimer's disease.

Vascular dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD). While sodium is essential for maintaining vascular function, its role in AD pathology remains unclear. We included 353 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI), assessing serum sodium levels, cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers, magnetic resonance imaging (MRI), and cognitive function. An independent sample (N = 471) with available CSF sodium-related proteins and AD biomarkers was also included. Associations between serum sodium levels and AD pathology, neurodegeneration, and cognition were evaluated using linear regression models. Spearman's correlation analyses assessed the relationships between CSF sodium-related proteins and AD biomarkers. Higher serum sodium levels were associated with increased AD pathology, reduced hippocampal volume, and greater cognitive decline (all p < 0.05). The relationship between serum sodium and amyloid PET was evident in several AD-susceptible brain regions, including the neocortex and limbic system. Individuals with high serum sodium exhibited higher tau pathology, lower hippocampal volume, and more severe cognitive decline per unit increase in amyloid PET compared to those with low serum sodium (all p < 0.05). Among the 14 CSF sodium-related proteins, which were inter-correlated, six were significantly correlated with CSF AD pathology and amyloid PET, while two were correlated with hippocampal volume and cognitive function, with sodium channel subunit beta-2 (SCN2B) and sodium channel subunit beta-3 (SCN3B) showing the strongest correlations. These findings underscore the crucial role of serum sodium in AD progression, highlighting a potential network of sodium dysregulation involved in AD pathology. Targeting sodium may offer a novel therapeutic approach to slowing AD progression, particularly by impeding the progression of amyloid-related downstream events.

Role of tumor-specific and whole-body imaging biomarkers for prediction of recurrence in patients with stage III colorectal cancer.

Imaging biomarkers are emerging as non-invasive predictors of cancer prognosis and clinical outcome. We assessed tumor-specific ("radiomics") and body composition imaging features ("morphomics") extracted from baseline pre-treatment CT for prediction of recurrence in patients with stage III colorectal cancer (CRC). Patients with newly diagnosed stage III CRC were enrolled in this prospective observational study. Patients with available preoperative scans were included (N = 101). The tumor, if visible, was manually segmented and first-order radiomics features were extracted with a commercially available software. The morphomics features (reflecting muscle, fat, and bone characteristics) were extracted in a standardized fashion using a proprietary software and the values were adjusted and normalized based on a reference standard. Time to recurrence was the final outcome. Correlation between demographics, clinical features, radiomics, and morphomics features and outcome were assessed using univariate and multivariate tests as well as Kaplan-Meier and log-rank tests. Morphomic analysis was performed in all 101 patients. 60 patients had discrete tumors suitable for radiomics analysis. These patients had lower ECOG score (p < 0.05), more muscle mass (p > 0.05), and lower fat density (p > 0.05) compared to the patients in whom radiomics analysis could not be performed. Pathological stage (HR: 2.69; p = 0.03), CEA level after surgery (HR: 1.11 for 1ng/mL; p < 0.005), bone mineral density (HR: 1.01 for 1 Hounsfield Unit; p < 0.01), and tumor skewness (HR: 0.33 for 1 unit; p < 0.05) had association with recurrence based on both univariate and multivariate analyses. A model using Cox's regression analyses was able to divide the patients into low-, medium-, and high-risk for recurrence. Both radiomics and morphomics features were independently associated with the risk of CRC recurrence and, when combined, each contributed valuable information to explain risk of recurrence. Clinical trial.gov NCT02842203. Patient recruitment occurred between 22/07/2016 and 18/03/2020.

Longitudinal Magnetic Resonance Imaging in Asymptomatic C9orf72 Mutation Carriers Distinguishes Phenoconverters to Amyotrophic Lateral Sclerosis or Amyotrophic Lateral Sclerosis With Frontotemporal Dementia.

We prospectively studied asymptomatic C9orf72 mutation carriers, identifying those developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). We enrolled 56 asymptomatic family members (AFM) with a C9orf72 mutation (AFM C9+), 132 non-carriers (AFM C9-), and 359 population-based controls. Using 3 T magnetic resonance imaging, we measured cortical thickness, gyrification, and subcortical volumes longitudinally. Linear mixed-effects models on non-converting AFM C9+ scans (n = 107) created a reference for these measurements, establishing individual atrophy patterns. Atrophy patterns from presymptomatic phenoconverters (n = 10 scans) served as a template for group comparisons and similarity assessments. Similarity with phenoconverters was quantified using Dice similarity coefficient (DSC) for cortical and Kullback-Leibler similarity (KLS) for subcortical measures. Using longitudinal similarity assessments, we predicted when participants would reach the average similarity level of phenoconverters at their first post-onset scan. Five AFM C9+ converted to ALS or ALS-FTD. Up to 6 years before symptoms, these phenoconverters exhibited significant atrophy in frontal, temporal, parietal, and cingulate cortex, along with smaller thalamus, hippocampus, and amygdala compared to other AFM C9+. Some non-converted AFM C9+ had high DSC and KLS, approaching values of phenoconverters, whereas others, along with AFM C9- and controls, had lower values. At age 80, we predicted 27.9% (95% confidence interval, 13.2-40.1%) of AFM C9+ and no AFM C9- would reach the same DSC as phenoconverters. Distinctive atrophy patterns are visible years before symptom onset on presymptomatic scans of phenoconverters. Combining baseline and follow-up similarity measures may serve as a promising imaging biomarker for identifying those at risk of ALS or ALS-FTD. ANN NEUROL 2024.

Mechanism and significance of diffusion restriction followed by calcification in high-grade glioma treated with bevacizumab

In this study, we focused on calcification and diffusion restriction, which sometimes appear around the resection cavity or periventricular white matter in patients with high-grade glioma (HGG) treated with bevacizumab (BVZ), as candidate imaging biomarkers for BVZ treatment efficacy. We investigated the timing of the appearance of diffusion restriction and calcification using magnetic resonance imaging and computed tomography in 35 patients with newly diagnosed or recurrent HGG treated with BVZ. In 17 (48.6%) patients, calcification was identified around the resection cavity or periventricular white matter at a median of 12 months after the initiation of BVZ treatment. Patients with calcification had significantly longer progression-free survival (16 vs. 7 months; p = 0.0023) and overall survival (36 vs. 12 months; p = 0.0006) than those without calcification. Histopathological examination revealed the presence of scattered microcalcifications within areas of necrosis, which suggested dystrophic calcification induced by BVZ. Diffusion-restricted lesions that appeared in patients with calcification had significantly lower apparent diffusion coefficients than those in patients without calcifications, indicating the presence of treatment-related necrosis but not hypercellularity. In conclusion, the radiological finding of diffusion restriction followed by calcification could be a potential imaging biomarker for favorable clinical course in patients with HGG treated with BVZ.

Enhancing preoperative diagnosis of pancreatic ductal adenocarcinoma and mass-forming chronic pancreatitis: a study on normalized conventional MR imaging parameters.

To assess the utility of signal intensity ratio (SIR) in distinguishing between mass-forming chronic pancreatitis (MFCP) and pancreatic ductal adenocarcinoma (PDAC), thereby reducing unnecessary pancreatectomies or delayed diagnosis brought by misdiagnosis. This retrospective study included 170 participants (34 with MFCP and 136 with PDAC) who underwent radical pancreatic surgery and were diagnosed via specimen pathology. The study group was carefully selected with a 1:4 ratio matching for sex, age, and operation time between two entities. T1 SIR, T2 SIR, arterial phase (AP) SIR, portal venous phase (VP) SIR, delay phase (DP) SIR, DWI0-50 SIR, and DWI500-1000 SIR, were calculated by dividing the signal intensity of lesions by that of the paraspinal muscle, serving as a reference organ. Intraclass Correlation Coefficient (ICC) was estimated to evaluate the intraobserver and interobserver reliability. Wilcoxon tests were employed for univariate analysis, and receiver operating characteristic (ROC) curves were generated to determine optimal cutoff points and AUC values for selected predictors. A tenfold cross-validation method was applied to validate the robustness of the results. The ICC demonstrated excellent correlation for both intraobserver and interobserver(ICCs > 0.8). T1 SIR, AP SIR, VP SIR, and DP SIR were significantly lower in the PDAC group compared to the MFCP group, and exhibited good independent predictive properties with the sensitivities of 61.8, 61.8, 70.6, and 73.5%, specificities of 66.2, 68.4, 59.6, and 55.9%, and AUCs of 0.620, 0.659, 0.670, and 0.668, respectively, hovering around 0.7. The tenfold cross-validation confirmed the reliability and robustness of our findings, with consistent AUC, sensitivity, specificity, and 95% confidence intervals over 1000 iterations. T1 SIR, AP SIR, VP SIR, and DP SIR show promise as potential imaging biomarkers for distinguishing between MFCP and PDAC.

Altered callosal morphology in post stroke cognitive impairment.

Stroke is the second leading cause of death and cognitive impairment. Post-stroke cognitive impairment (PSCI) is one of the most common sequelae among stroke survivors, yet its underlying neural mechanisms remain largely unclear. The corpus callosum (CC) plays a crucial role in interhemispheric integration and hemispheric segregation, with changes in CC morphology potentially overlapping with the spectrum of PSCI. This study aimed to investigate the morphological changes in the CC and their diagnostic value in PSCI patients. Structural MRI, neurobehavioral, and clinical data were collected from 104 PSCI patients and 54 demographically matched healthy controls. Significant reductions in CC area, circularity, and genu thickness were observed in PSCI patients, with these changes strongly correlating with global cognitive function. Subgroup analysis revealed that CC circularity significantly decreased when lesions were located in the posterior circulation, while both CC area and circularity markedly decreased with anterior circulation lesions. Receiver Operating Characteristic analyses identified the midbody areas of the CC as having high diagnostic value, with area under the curve values of 0.748 and 0.746, respectively. Further validation analyses suggest that the transcallosal fibers in these CC subregions are connected to the premotor, dorsal attention, and frontoparietal system. These findings show that areal CC atrophy in PSCI patients, particularly in regions with transcallosal connections to the premotor cortex and frontoparietal network, parallels global cognitive impairment. This suggests that CC morphology may serve as a potential imaging marker for the diagnosis and prognosis of PSCI.

Early α-synuclein/synapsin III co-accumulation, nigrostriatal dopaminergic synaptopathy and denervation in the MPTPp mouse model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by the loss of nigrostriatal dopaminergic neurons and the presence of Lewy bodies (LB), intraneuronal inclusions mainly composed of α-synuclein (α-Syn) fibrils. Compelling evidence supports that, in PD brains, synapses are the sites where neurodegeneration initiates several years before the manifestation of motor symptoms. Furthermore, the amount of α-Syn deposited at synaptic terminals is several orders greater than that constituting LB. This hints that pathological synaptic α-Syn aggregates may be the main trigger for the retrograde synapse-to-cell body degeneration pattern characterizing early prodromal phases of PD. Identifying reliable biomarkers of synaptopathy is therefore crucial for early diagnosis. Here, we studied the alterations of key dopaminergic and non-dopaminergic striatal synaptic markers during the initial phases of axonal and cell body degeneration in mice subjected to 3 or 10 administrations of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine + probenecid (MPTPp), a model for early prodromal PD. We found that MPTPp administration resulted in progressive deposition of α-Syn, advancing from synaptic terminals to axons and dopaminergic neuron cell bodies. This was accompanied by marked co-accumulation of Synapsin III (Syn III), a synaptic protein previously identified as a component of α-Syn fibrils in post-mortem PD brains and as a main stabilizer of α-Syn aggregates, as well as very early and severe reduction of vesicular monoamine transporter 2 (VMAT2), dopamine transporter (DAT) and tyrosine hydroxylase (TH) immunoreactivity in nigrostriatal neurons. Results also showed that striatal α-Syn accumulation and VMAT2 decrease, unlike other markers, did not recover following washout from 10 MPTPp administrations, supporting that these changes were precocious and severe. Finally, we found that early changes in striatal α-Syn, Syn III, VMAT2 and DAT observed following 3 MPTPp administrations, correlated with nigrostriatal neuron loss after 10 MPTPp administrations. These findings indicate that α-Syn/Syn III co-deposition characterizes very early stages of striatal dopaminergic dysfunction in the MPTPp model and highlight that VMAT2 and Syn III could be two reliable molecular imaging biomarkers to predict dopamine neuron denervation and estimate α-Syn-related synaptopathy in prodromal and early symptomatic phases of PD.

Quantitative MRI in Childhood Neuroblastoma: Beyond the Assessment of Image-defined Risk Factors.

Neuroblastoma commonly occurs in children. MRI is a radiation-free imaging modality and has played an important role in identifying image-defined risk factors of neuroblastoma, providing necessary guidance for surgical resection and treatment response evaluation. However, image-defined risk factors are limited to providing structural information about neuroblastoma. With the evolution of MRI technologies, quantitative MRI can not only help assess image-defined risk factors but can also quantitatively reflect the biologic features of neuroblastoma in a noninvasive manner. Therefore, compared with anatomic imaging, these emerging quantitative MRI technologies are expected to provide more imaging biomarkers for the management of neuroblastoma. This review article discusses the current applications of quantitative MRI technologies in evaluating childhood neuroblastoma. Keywords: Pediatrics, MR-Functional Imaging, Children, MRI, Neuroblastoma, Quantitative Imaging © RSNA, 2024.

Machine Learning Assessment of Background Parenchymal Enhancement in Breast Cancer and Clinical Applications: A Literature Review

Background Parenchymal Enhancement (BPE) on breast MRI holds promise as an imaging biomarker for breast cancer risk and prognosis. The ability to identify those at greatest risk can inform clinical decisions, promoting early diagnosis and potentially guiding strategies for prevention such as risk-reduction interventions with the use of selective estrogen receptor modulators and aromatase inhibitors. Currently, the standard method of assessing BPE is based on the Breast Imaging-Reporting and Data System (BI-RADS), which involves a radiologist’s qualitative categorization of BPE as minimal, mild, moderate, or marked on contrast-enhanced MRI. This approach can be subjective and prone to inter/intra-observer variability, and compromises accuracy and reproducibility. In addition, this approach limits qualitative assessment to 4 categories. More recently developed methods using machine learning/artificial intelligence (ML/AI) techniques have the potential to quantify BPE more accurately and objectively. This paper will review the current machine learning/AI methods to determine BPE, and the clinical applications of BPE as an imaging biomarker for breast cancer risk prediction and prognosis.

Multimodal MRI changes associated with non-motor symptoms of rapid eye movement sleep behaviour disorder in Parkinson's disease patients.

Parkinson's disease (PD), a prevalent neurodegenerative disorder, assumes a more adverse prognosis when accompanied by rapid eye movement sleep disorder (RBD). Non-motor symptoms, particularly sleep and emotional disturbances, significantly impair patients' quality of life. This study aimed to investigate the neuroimaging underpinnings of PD-RBD using structural and functional magnetic resonance imaging (MRI) and to explore the associations between these imaging biomarkers and non-motor symptoms. Brain scans were acquired from 33 PD patients without and 21 with probable RBD (PD-pRBD). Comparative analyses were performed to evaluate structural and functional alterations between the two groups. Additionally, the correlations between neuroimaging metrics and clinical assessment scales were assessed. PD-pRBD patients demonstrated more pronounced grey matter atrophy, particularly in the putamen and insula. Functional MRI revealed decreased amplitude of low-frequency fluctuations (ALFF) in the bilateral posterior cingulate cortex and left precuneus of PD-pRBD patients. Furthermore, reduced functional connectivity (FC) was observed in specific regions of the whole brain and within the default mode network (DMN) in PD-pRBD. Notably, a negative correlation was found between mean ALFF values in the left posterior cingulate cortex of PD-pRBD patients and Hamilton Depression Rating Scale scores. PD-pRBD is characterized by more severe grey matter loss and functional MRI abnormalities compared to PD alone. Dysfunction of the posterior cingulate cortex is implicated in more pronounced affective impairments, providing novel insights into the complex pathophysiology of PD-RBD.

The Relevance of Spinal Muscular Atrophy Biomarkers in the Treatment Era

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder that currently has an approved treatment for all forms of the disease. Previously, biomarkers were primarily used for diagnostic purposes, such as detecting the presence of the disease or determining a specific clinical type of SMA. Currently, with the availability of therapy, biomarkers have become more valuable due to their potential for prognostic, predictive, and pharmacodynamic applications. This review describes the most promising physiological, functional, imaging and molecular biomarkers for SMA, derived from different patients’ tissues. The review summarizes information about classical biomarkers that are already used in clinical practice as well as fresh findings on promising biomarkers that have been recently disclosed. It highlights the usefulness, limitations, and strengths of each potential biomarker, indicating the purposes for which each is best suited and when combining them may be most beneficial.

Phase II study of uPAR-PET/CT for staging of primary breast cancer in comparison with ultrasound and fine needle biopsies

Accurate initial staging of patients with breast cancer is essential for planning optimal treatment strategies. However, currently, no imaging modality is able to detect lymph node metastases preoperatively with sufficient reliability; therefore, the N status depends on the sentinel node procedure for ~ 70% of patients. In a prospective clinical trial of breast cancer patients, we compared head-to-head uPAR-PET/CT with current standard-of-care, ultrasound (US) and fine needle biopsy (FNB) as staging methods. Forty-nine patients (48 women and 1 man) with biopsy-proven early breast cancer underwent uPAR-PET/CT prior to surgery. All image data were analyzed by two separate teams, each consisting of a highly experienced certified specialist in nuclear medicine and a highly experienced certified specialist in radiology for visualization of primary tumor lesions and detection of lymph node and distant metastases. Histopathological assessment and verification of malignancy in the excised tissues (primary tumors and lymph nodes) were considered standard-of-truth. On a per patient basis, uPAR PET/CT demonstrated a sensitivity of 94% [CI: 83–99%] for detecting the primary tumor (both teams). For the detection of axillary lymph nodes the pooled sensitivity of uPAR PET/CT was 33.3% [CI: 16.5–54.0%], specificity 87.0% [CI: 66.4–97.2%] and accuracy 58.0% [CI: 43.2–71.8%]. In comparison, the standard-of-care preoperative clinical staging algorithm with US and FNB had a sensitivity of 41% [CI: 22–61%] and specificity of 100% [CI: 85–100%] for axillary lymph node metastases. We conclude that the results do not support the use of uPAR PET/CT for staging in breast cancer patients. However, the finding that 94% of primary tumors were uPAR-PET positive may be encouraging for pursuing uPAR theranostics in localized disease. Additionally, other potential applications, such as using uPAR-PET as a prognostic imaging biomarker of tumor aggressiveness, remain to be investigated.

Patient-specific prostate tumour growth simulation: a first step towards the digital twin

Prostate cancer (PCa) is a major world-wide health concern. Current diagnostic methods involve Prostate-Specific Antigen (PSA) blood tests, biopsies, and Magnetic Resonance Imaging (MRI) to assess cancer aggressiveness and guide treatment decisions. MRI aligns with in silico medicine, as patient-specific image biomarkers can be obtained, contributing towards the development of digital twins for clinical practice. This work presents a novel framework to create a personalized PCa model by integrating clinical MRI data, such as the prostate and tumour geometry, the initial distribution of cells and the vasculature, so a full representation of the whole prostate is obtained. On top of the personalized model construction, our approach simulates and predicts temporal tumour growth in the prostate through the Finite Element Method, coupling the dynamics of tumour growth and the transport of oxygen, and incorporating cellular processes such as proliferation, differentiation, and apoptosis. In addition, our approach includes the simulation of the PSA dynamics, which allows to evaluate tumour growth through the PSA patient’s levels. To obtain the model parameters, a multi-objective optimization process is performed to adjust the best parameters for two patients simultaneously. This framework is validated by means of data from four patients with several MRI follow-ups. The diagnosis MRI allows the model creation and initialization, while subsequent MRI-based data provide additional information to validate computational predictions. The model predicts prostate and tumour volumes growth, along with serum PSA levels. This work represents a preliminary step towards the creation of digital twins for PCa patients, providing personalized insights into tumour growth.

Overcoming the Challenges of Hyperpolarizing Substrates with Parahydrogen‐Induced Polarization in an MRI System

Hyperpolarization of 13C nuclei in biomolecules and their administration as imaging agents enables in‐vivo monitoring of metabolism. This approach has demonstrated potential for deriving imaging biomarkers for cancer detection, differentiation, and therapy efficacy assessment. The in situ generation of polarized substrates using a permanent addition of parahydrogen to an unsaturated precursor inside the bore of an MRI system used for subsequent imaging circumvents the need for a dedicated external polarizer. This approach reduces polarization loss associated with sample transfer, minimizes hardware requirements and cost, and results in reduced spatial requirements. However, performing INEPT‐like pulsed sequences for heteronuclear spin‐order transfer in the bore of an MRI system is challenged by poor uniformity of static and excitation magnetic field and molecular convection during the polarization transfer. Therefore, here we characterize these effects, implement a robust modification to the pulse sequence, and measure experimentally the polarization improvement upon modification of the sequence. After rigorous optimization of the parameters, we obtained a 13C polarization of 44.5% for 50 mM of the 1‐13C site of ethyl acetate‐d6. Our parahydrogen‐induced polarization approach enhances the accessibility to hyperpolarized MRI, circumventing the need for an external polarizer.

Imaging modalities for atraumatic shoulder hypermobility: a scoping review.

Objective measures from imaging studies have the potential to assist in timely diagnosis of atraumatic shoulder hypermobility to better guide management. The aim of this scoping review is to examine imaging modalities and techniques used to characterize atraumatic shoulder hypermobility. MEDLINE, EMBASE, SPORTDiscus, Cochrane Library, and Web of Science were searched up to May 2024 for any primary study investigating imaging findings seen in atraumatic shoulder hypermobility. Patients with unilateral instability were excluded given its frequent association with traumatic origin. Eighteen observational studies met inclusion criteria. Results were divided into outcomes relating to capsular redundancy, glenohumeral anatomy, and muscle activation. Five studies using magnetic resonance arthrography (MRA) demonstrated statistically significant increases in capsular cross-sectional area (CSA), while a significant superior capsular elongation was reported by two studies in patients with multidirectional instability (MDI). Labrocapsular distance, glenocapsular ratio, and the presence of a combined sail and triangle sign on MRA were highly sensitive and specific parameters for identifying MDI. There were inconsistent findings for alterations of glenohumeral anatomy. Ultrasound assessments of acromiohumeral distance (AHD) were significantly increased in patients with MDI, but not in shoulders with hypermobility alone. Similarly, muscle activity measured by electromyography or glenohumeral translations differed significantly in patients with MDI, but not in those with hypermobility alone. Radiographic markers of capsular redundancy (e.g., CSA, labrocapsular distance, glenocapsular ratio), AHD, and muscular activity are useful in the diagnosis of MDI. However, there are no definitive imaging markers for diagnosing atraumatic shoulder hypermobility without MDI.

Clinical significance of MRI-measured olfactory bulb height as an imaging biomarker of idiopathic Parkinson's disease.

This study aimed to determine whether the olfactory bulb height (OBH) measured using magnetic resonance imaging (MRI) has clinical utility as an imaging biomarker in the evaluation of patients with idiopathic Parkinson's disease (iPD) through its correlation with movement impairment. This retrospective study included cognitively intact patients with suspected parkinsonism. All participants underwent T2-weighted imaging to measure OBH. Logistic regression was used to determine whether OBH was an independent risk factor for distinguishing iPD patients from disease controls, and its relation with clinical parameters related to motor impairment, including clinical laterality, modified Hoehn and Yahr (HY) stage, and Unified Parkinson's Disease Rating Scale (UPDRS) III score, was investigated. Based on the final clinical diagnosis, 79 patients with iPD and 16 disease controls were included. The mean OBH was significantly smaller in iPD than in disease controls (p < 0.0001). OBH was a significant independent predictor of iPD, with a cutoff of 1.52 mm. In the comparison among the ipsilateral, contralateral side of iPD with clinical laterality, and disease control group, the OBH of the disease control group was significantly larger than both the ipsilateral and contralateral sides (P < 0.05). However, there was no significant difference in OBH between the ipsilateral and contralateral sides (p > 0.05). OBH according to HY stage was significantly smaller in HY stage 2-3 groups than in the disease control group (p < 0.001). The correlation analysis between UPDRS III and OBH showed a mild negative correlation (r = -0.32, p = 0.013). MRI-measured OBH is decreased in iPD regardless of age and sex and may be correlated with the progression of motor symptoms in the iPD.

Cardiovascular effects of BRAF and MEK inhibitors in patients with melanoma: a prospective study incorporating risk scores, cardiac biomarkers and cardiovascular magnetic resonance imaging

Abstract Background BRAF and MEK inhibitors have revolutionised treatment for patients with BRAF-mutated melanoma. Unfortunately, they are associated with cardiovascular adverse effects including hypertension and cancer-therapy related cardiac dysfunction (CTRCD). The ‘real world’ incidence and risk factors for these adverse effects are poorly described. Purpose To characterise the incidence and risk factors for BRAF and MEK inhibitor-associated hypertension and CTRCD in a prospective ‘real world’ setting. Methods Prospective, observational, cohort study of patients with melanoma treated with BRAF and MEK inhibitors at a regional cancer hospital network (March 2021 - May 2023). Comprehensive assessment was performed at baseline, 4, 12 and 24 weeks following start of treatment, including home and clinic blood pressure assessment, serial echocardiography, stress-perfusion cardiovascular magnetic resonance imaging (CMR) and humoral biomarkers (Figure 1). CTRCD was defined as mild, moderate or severe in line with International Cardio-Oncology Society (IC-OS) definitions. Hypertension was defined as 7 day average home blood pressure of ≥135/85 mmHg or the initiation or escalation of anti-hypertensive therapy. Baseline cardiotoxicity risk stratification was performed using the ESC Cardio-Oncology guideline-recommended tool. Results 61 participants were enrolled. 48% developed BRAF/MEK inhibitor associated hypertension. 46% of participants developed CTRCD and, of these, 24 (86%) were classified as mild, 3 (11%) moderate and 1 (3%) severe. Left ventricular ejection fraction (LVEF) during follow up is shown in Figure 2. All participants with moderate and severe CTRCD also had BRAF/MEK inhibitor associated hypertension. After stratification with the baseline risk assessment tool, no patient in the ‘low risk’ group developed moderate or severe CTRCD. Baseline elevated NT-proBNP (&amp;gt;125pg/mL), history of left ventricular systolic dysfunction and atrial fibrillation were associated with the development of CTRCD. 20 participants underwent stress perfusion CMR at baseline, 4 and 24 weeks. 25% had a drop in LVEF to &amp;lt;50% but only 5% had a co-existing LVEF ≥10% from baseline to fulfil criteria for the diagnosis of moderate CTRCD. Conclusion BRAF and MEK inhibitor-associated hypertension and CTRCD is common, with a higher incidence in this ‘real world’ prospective cohort than observed in clinical trials. The majority of CTRCD was ‘mild’ and the long term sequalae of this remains unknown. No patients considered to be at low baseline risk for CTRCD using the ESC-recommended risk stratification tool developed moderate or severe CTRCD. These findings support the use of routine blood pressure surveillance in this group as well as baseline risk stratification to guide appropriate imaging surveillance of cardiac function.Figure 1.Schedule of study visitsFigure 2.LV function/CTRCD over time

Long-term safety and efficacy of antibody ALXN2220 for depletion of cardiac amyloid transthyretin: results of treatment beyond 12 months in the open-label extension of study NI006-101

Abstract Introduction ALXN2220 (formerly NI006) is an investigational human monoclonal antibody in development for the treatment of transthyretin-mediated amyloid cardiomyopathy (ATTR-CM). ALXN2220 is designed to deplete cardiac amyloid transthyretin (ATTR) deposits in patients with ATTR-CM on top of standard of care. Data from the first-in-human, ascending dose study NI006-101 show that ALXN2220 is safe and well tolerated. A reduction of surrogate markers of cardiac amyloid load and cardiac biomarkers was observed in participants receiving doses of ≥ 10mg/kg of ALXN2220 over a period of 12 months of treatment. Purpose Long-term safety, tolerability and efficacy of ALXN2220 treatment beyond 12 months was studied in a prolonged Open-Label Extension (OLE) of the NI006-101 study. Methods Participants completing 12 months in dose cohorts ≤ 30 mg/kg were allowed to receive additional 6 to 12 monthly open-label ALXN2220 infusions with up-titration of all participants to 30 mg/kg. Cardiac biomarkers were measured centrally, and serial cardiac imaging was performed with echocardiography and cardiac MRI or scintigraphy. Results Out of 27 participants completing 12 months, 23 (18 ATTRwt, all male, median age 70 years at screening (range 28-83)) continued treatment in the prolonged OLE. Median number of infusions of ALXN2220 received and median time followed across the full study were 20 infusions (range 11-24) and 125 weeks (range 83-153). Overall adherence to treatment was high in the prolonged OLE, 97% of planned infusions administered, 87% of participants received all planned doses. No severe or serious adverse events were considered related to ALXN2220 or resulted in the discontinuation during OLE, and no events of cytokine release syndrome or thrombocytopenia were observed. None of the participants had anti-drug antibodies throughout the trial. Cardiac biomarkers (NT-proBNP, troponin) and cardiac imaging indicated continued treatment effects beyond 12 months and supported the up-titration of participants who previously received lower doses of ALXN2220. Conclusions Up-titration and long-term treatment at a dose level of 30 mg/kg in the OLE was safe and well tolerated, with overall good adherence to treatment. Cardiac imaging and cardiac biomarker data indicated continued treatment effects beyond 12 months and supported the up-titration of patients to 30 mg/kg.

Cardiac MRI traits linked to cardiomyopathy mutations in phenotype naive carriers

Abstract Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are prevalent forms of cardiomyopathies, characterised by changes in cardiac structure and function, associated with an increased risk of atrial fibrillation (AF), heart failure (HF), and sudden cardiac death (SCD). Due to these potential life-threatening consequences close monitoring of genetic mutation carriers of HCM and DCM, is important. However, disease onset in these subjects is highly variable, with a substantial subset of people only developing disease late-in-life, or not at all, making risk stratification challenging. We set out to identify cardiac MRI (CMR) based imaging biomarkers of HCM and DCM carriership in phenotype naïve individuals, which were benchmarked against associations with AF and HF. CMR and whole genome sequencing (n: 42,723) data were sourced from a UK biobank sample free of heart failure at the time of CMR measurements. A previously validated deep learning(DL) network was used to derive 22 CMR traits(1). Adjusted cox regression models were used to determine the CMR associations with the onset of heart failure and atrial fibrillation, providing empirical validation of the DL CMR network. Univariable and multivariable generalised linear models were employed to identify associations with genetic carriership conditional on cardiac risk factors. 14 and 19 CMR measurements were associated with the time until HF (274 cases), AF (704 cases), respectively. These variables included left-ventricle (LV) ejection fraction (EF), LV end systolic volume (ESV), Right-ventricular (RV) EF and right atrial (RA) EF. Using WGS data we identified 154 people with an HCM mutation and 220 with a DCM mutation, where HCM carriership associated with five and DCM with four CMR traits. This included RA-EF (OR 1.26 95%CI 1.10; 1.45), and RV-EF (OR 1.41 95%CI 1.23;1,63) for HCM, and LV-EF (OR 0.72 95%CI 0.62; 0.84), and RV stroke volume (OR 0.75 95CI 0.62; 0.91) for DCM. By combining deep learning of CMR with large sample size WGS we were able to identify cardiac imaging biomarkers of HCM and DCM carriership in apparently healthy subjects. This could prove relevant for early identification and monitoring of phenotype naïve people.