Pre-mortem Imaging Research Articles

Crystal Violet Selectively Detects Aβ Oligomers but Not Fibrils In Vitro and in Alzheimer's Disease Brain Tissue.

Deposition of extracellular Amyloid Beta (Aβ) and intracellular tau fibrils in post-mortem brains remains the only way to conclusively confirm cases of Alzheimer's Disease (AD). Substantial evidence, though, implicates small globular oligomers instead of fibrils as relevant biomarkers of, and critical contributors to, the clinical symptoms of AD. Efforts to verify and utilize amyloid oligomers as AD biomarkers in vivo have been limited by the near-exclusive dependence on conformation-selective antibodies for oligomer detection. While antibodies have yielded critical evidence for the role of both Aβ and tau oligomers in AD, they are not suitable for imaging amyloid oligomers in vivo. Therefore, it would be desirable to identify a set of oligomer-selective small molecules for subsequent development into Positron Emission Tomography (PET) probes. Using a kinetics-based screening assay, we confirm that the triarylmethane dye Crystal Violet (CV) is oligomer-selective for Aβ42 oligomers (AβOs) grown under near-physiological solution conditions in vitro. In postmortem brains of an AD mouse model and human AD patients, we demonstrate that A11 antibody-positive oligomers but not Thioflavin S (ThioS)-positive fibrils colocalize with CV staining, confirming in vitro results. Therefore, our kinetic screen represents a robust approach for identifying new classes of small molecules as candidates for oligomer-selective dyes (OSDs). Such OSDs, in turn, provide promising starting points for the development of PET probes for pre-mortem imaging of oligomer deposits in humans.

Abstract PO1-06-06: Underestimation of metastatic spread in patients with lobular breast cancer: results from the post-mortem tissue donation program UPTIDER

Abstract Background: Invasive lobular carcinoma (ILC) accounts for 15% of all invasive breast cancers (BC) and has a peculiar metastatic spread in comparison to BC of no-special type. Since ILC is less likely to disrupt normal tissue architecture and is usually non-mass forming, imaging of ILC lesions entails many challenges. Insights into pathologic versus radiological metastatic invasion can lead to better diagnostic and monitoring tools for patients with ILC. Here, we compare microscopical findings during autopsy with clinical findings prior to death in patients with metastatic ILC included in our post-mortem tissue donation program UPTIDER (NCT04531696). Methods: UPTIDER was started in November 2020 in University Hospitals Leuven/KU Leuven with inclusion of patients with stage IV BC who were willing to participate. One of the predefined subgroups consisted of patients with primary pure (i.e. not mixed) ILC. Samples were taken from different macroscopically invaded and non-invaded sites. Clinical data on disease progression, imaging, biochemistry and treatment regimens were extracted from patient files. The number of samples that were preregistered as pathological served as a surrogate for lesions that were seen on imaging performed during the treatment of the patient. These samples are compared to microscopical findings of the autopsy. Results: Since the start of UPTIDER, an autopsy has been performed on 6 patients with pure ILC (26.1% of all autopsies). Median age at initial diagnosis was 52 years (range: 37 – 80 years). Three patients (50.0%) had stage IV disease at diagnosis, the others relapsed on average 162.7 months (range: 55 – 358 months) after initial diagnosis. The average time between clinical occurrence of metastases and death was 44.8 months (range: 15 – 83 months). Median number of treatment lines for stage IV disease was 5 (median endocrine lines 2; median chemotherapy regimens 3.5). To follow disease evolution, computed tomography of thorax and abdomen was used for 4 (66.7%) patients and whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) for the remaining 2 (33.3%). Median time between last premortem imaging and death was 5.9 weeks (range: 1.6 – 16.6 weeks). At autopsy, a median of 26 unique metastases (range: 12-36) were sampled per patient. Table 1 gives an overview on the unique microscopically invaded metastases that were sampled per patient. Only 47.3% of the sampled unique metastases was preregistered. Of all unique metastases, 26.7% appeared macroscopically normal during autopsy. Tissues that appeared normal but turned out to be microscopically infiltrated included liver, stomach, adrenal glands, heart, pericardium, visceral and subcutaneous fat tissue. There were 2 patients with normal appearing, microscopically infiltrated livers. In these patients, elevation of γGT and transanimases was seen in the months prior to death. Conclusions: The disease burden of metastatic ILC reported on premortem imaging does not reflect the microscopical findings at autopsy. One of the priorities of metastatic ILC research should be the development of diagnostic tools to better estimate the extent of the disease. Future analyses of the performed postmortem MRIs in our study can aid in improving the interpretation of WB-DWI/MRI for patients with ILC. For now, clinicians should consider that unexplained clinical and/or biochemical findings might indicate progression of ILC. Table 1: patient overview on performed imaging and unique metastases sampled during autopsy CT = computed tomography; ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; pt = patient; WB-DWI MRI = whole-body diffusion-weighted magnetic resonance imaging *exclusion of samples of patient 2012 since no preregistration was performed for this patient due to unexpected death Citation Format: Karen Van Baelen, Gitte Zels, Maxim De Schepper, Marion Maetens, Josephine Van Cauwenberge, Tatjana Geukens, Kristien Borremans, François Richard, Amena Mahdami, Ha-Linh Nguyen, Sophia Leduc, Anirudh Pabba, Ann Smeets, Ines Nevelsteen, Patrick Neven, Hans Wildiers, Vincent Vandecaveye, Wouter Van Den Bogaert, Giuseppe Floris, Christine Desmedt. Underestimation of metastatic spread in patients with lobular breast cancer: results from the post-mortem tissue donation program UPTIDER [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-06.

Comparison between pre-mortem and post-mortem cadaveric images for use with augmented reality headsets during dissection.

Medical training has undergone many transformations to incorporate diagnostic imaging along side anatomical education. Post-mortem computed tomography (CT) scanning of body donors prior to dissection has been proposed. However, it poses challenges secondary to the embalming process and other post-mortem physiological changes that significantly alter the imaging quality. The purposes of this study were to compare the accuracy of pathology identification on pre- and post-mortem CT scans of body donors and to assess the integration of those scans in a dissection-based course, where these images were overlaid onto body donors using augmented reality (AR). Participants in this study included 35 fourth year medical students, 5 radiology residents and 3 radiologists. A convergent, parallel mixed methods design was employed with quantitative measures that included statistical analyses of a double-blinded comparison of pathological lesions recognition, on both image sets, the group responses to a study participant survey and the login access data from imaging repository. The study also included qualitative analysis of post-elective structured interviews. The double-blinded comparison revealed that staff radiologists can only identify, on post-mortem images, 54.8% of the pathologies that they were able to detect on the pre-mortem scans. Analyses of the surveys and login access data reveal that 60% of radiology residents and 56% of students preferred pre-mortem scans and used those scans more often than post-mortem scans (67 access vs 36, respectively). However, post-mortem scans were significantly preferred when used to overlay onto body donors using AR (p = 0.0047). These results show that post-mortem imaging can be valuable alongside pre-mortem imaging, as they represent the most concordance between the anatomical structures and pathologies seen on the images and what is being dissected.

Functional MRI Correlates of Carbon Dioxide Chemosensing in Persons With Epilepsy.

ObjectivesSudden unexpected death in epilepsy (SUDEP) is a catastrophic epilepsy outcome for which there are no reliable premortem imaging biomarkers of risk. Percival respiratory depression is seen in monitored SUDEP and near SUDEP cases, and abnormal chemosensing of raised blood carbon dioxide (CO2) is thought to contribute. Damage to brainstem respiratory control and chemosensing structures has been demonstrated in structural imaging and neuropathological studies of SUDEP. We hypothesized that functional MRI (fMRI) correlates of abnormal chemosensing are detectable in brainstems of persons with epilepsy (PWE) and are different from healthy controls (HC).MethodsWe analyzed fMRI BOLD activation and brain connectivity in 10 PWE and 10 age- and sex-matched HCs during precisely metered iso-oxic, hypercapnic breathing challenges. Segmented brainstem responses were of particular interest, along with characterization of functional connectivity metrics between these structures. Regional BOLD activations during hypercapnic challenges were convolved with hemodynamic responses, and the resulting activation maps were passed on to group-level analyses. For the functional connectivity analysis, significant clusters from BOLD results were used as seeds. Each individual seed time-series activation map was extracted for bivariate correlation coefficient analyses to study changes in brain connectivity between PWE and HCs.Results(1) Greater brainstem BOLD activations in PWE were observed compared to HC during hypercapnic challenges in several structures with respiratory/chemosensing properties. Group comparison between PWE vs. HC showed significantly greater activation in the dorsal raphe among PWE (p < 0.05) compared to HCs. (2) PWE had significantly greater seed-seed connectivity and recruited more structures during hypercapnia compared to HC.SignificanceThe results of this study show that BOLD responses to hypercapnia in human brainstem are detectable and different in PWE compared to HC. Increased dorsal raphe BOLD activation in PWE and increased seed-seed connectivity between brainstem and adjacent subcortical areas may indicate abnormal chemosensing in these individuals. Imaging investigation of brainstem respiratory centers involved in respiratory regulation in PWE is an important step toward identifying suspected dysfunction of brainstem breathing control that culminates in SUDEP and deserve further study as potential imaging SUDEP biomarkers.

Cardiac Findings in Fetal and Pediatric Autopsies: A 15-Year Retrospective Review

Introduction: Congenital heart defects (CHDs) carry significant morbidity and mortality in pediatric patients. This study determined the spectrum of CHDs based on fetal and pediatric autopsies. Methods: Autopsy reports over a 15-year period were reviewed. Postmortem findings were correlated with echocardiography records. Results: From 608 autopsies, 119 cases with CHDs were identified (11% of fetal, 53% of neonatal, 18% of infant, and 4.5% of childhood autopsies). Persistent left superior vena cava was the most common individual defect. 41% of cases had extracardiac malformations. 18.5% of cases had chromosomal abnormalities. Prenatal echocardiography was available in 52 cases, showing 85% correlation with autopsy findings. Defects missed by echocardiography were generally of mild severity. Conclusion: Postmortem examination is important to delineate the anatomy of CHDs, and recognize extracardiac malformations for identification of possible genetic syndromes. This information can be used for parental counseling and for assessment of accuracy of pre-mortem imaging studies.

The artefacts of death: CT post-mortem findings.

Post-mortem CT is an increasingly used tool for investigating cause of death. While sharing many similarities with pre-mortem imaging, a number of unique artefacts occur at post-mortem CT, and these have the potential to mask underlying disease processes. It is vital that the artefacts associated with the process of dying and decompositional changes are recognised to avoid misdiagnosis. The following pictorial review discusses and illustrates the important and common post-mortem changes.

The Anatomy of a Novel Malformation of the Cardinal Vein System

Anomalies of the cardinal vein system (CVS) are uncommon but if unidentified can lead to life-threatening complications. We report a case with a novel malformation of the CVS. Autopsy with in situ dissection of heart and large vessels in a 25-day-old infant was performed. The infant was diagnosed with congenital heart disease, and systemic venous malformations were suspected by imaging. Correlation between premortem imaging and postmortem anatomy was performed. The superior and inferior left venous systems developed abnormally. A persistent left superior vena cava (PLSVC) drained into the right atrium via the coronary sinus. A persistent left inferior vena cava (PLIVC) continued with the hemiazygos vein (HV), which drained into the PLSVC. The innominate vein was absent. The left renal vein was connected to the HV. Two common iliac veins were identified. The left drained into the PLIVC and the right into the right inferior vena cava (IVC). Perinatal echocardiography identified only the dilated HV draining to an LSVC and a small IVC. Congenital heart disease included hypoplastic left ventricle with hypoplastic aortic arch and subaortic stenosis, which were diagnosed by fetal ultrasound. Remodeling of components of CVS takes place during development, and unknown mechanisms guide this process. Defects of this process can lead to variable malformations, as demonstrated by this case. To our knowledge, the combination of complex malformations of both superior and IVC systems that extends to the common iliac veins has not been reported. We recommend identifying vascular anomalies in situ during autopsy before anatomic relationships are altered.

IMAGING DIAGNOSIS-NASAL SEPTAL AND LARYNGEAL CYST-LIKE MALFORMATIONS IN A THOROUGHBRED WEANLING COLT DIAGNOSED USING ULTRASONOGRAPHY AND MAGNETIC RESONANCE IMAGING

A foal was examined for abnormal upper airway noise. Endoscopically, there were narrowed nasal passages and an extralumenal mass of the cranial trachea. Using ultrasonography and magnetic resonance (MR) imaging of the larynx and cranial cervical trachea, irregular margins of the laryngeal cartilages and first tracheal ring containing areas consistent with fluid were identified. In MR images, a widened nasal septum was seen that contained material consistent with fluid. Postmortem examination confirmed the diagnosis of nasal septal, laryngeal, and cranial cervical tracheal cyst-like lesions. This is a unique congenital condition, in which premortem imaging was instrumental in defining the abnormalities.

Cavitating Otosclerosis

Despite the high prevalence of otosclerosis and its having long been a subject of scrutiny, cavitary changes in otosclerosis are rare and not well known. Here, we describe and introduce into the literature the unusual histologic and radiologic findings of cavitation and its possible clinical relevance in patients with advanced cochlear otosclerosis. Cases with clinical otosclerosis and presence of cavitation were selected from our temporal bone collection and correlated with premortem imaging and clinical manifestations. Two cases of cochlear otosclerosis presented with a clinical syndrome possibly attributed to the existence of a cavity within the otosclerotic foci. Cavitating otosclerosis is a not well-known occurrence in patients with advanced cochlear otosclerosis, and it is a possible cause of a "third window" syndrome and surgical complications.

NOVEMBER 2007 CASE 1: AN 80‐YEAR‐OLD MAN WITH A RING‐ENHANCING RIGHT BASAL GANGLIA LESION

Cerebral phaeohyphomycosis is a rare diagnosis that designates a central nervous system (CNS) infection by dematiaceous fungi. These organisms most commonly cause cutaneous infections in humans, but much less commonly, they cause CNS disease with evidence of neurotropism. We describe here the clinical course and post-mortem findings in a fatal case of cerebral phaeohyphomycosis occurring in an 80-year-old man. He had a long and complex past medical history and approximately 7 weeks prior to his death, he presented to an outside institution with imaging findings reported to be consistent with a cerebrovascular accident. He was treated with thrombolytic therapy and sent to a rehabilitation program. Approximately 2 weeks prior to his death, he was transferred to our institution with worsening chronic heart failure symptoms. Imaging after admission showed a ring-enhancing lesion and the differential diagnosis shifted to include a primary neoplasm vs. an abscess. There was a downward clinical course and neurosurgical biopsy was declined secondary to predicted poor outcome. A full autopsy was performed and confirmed the pre-mortem imaging findings of a cerebral abscess with multiple satellite lesions. The histologic and microbiologic findings were characteristic of cerebral phaeohyphomycosis. Microbiological features and disease characteristics of these organisms as well as incidence and populations affected are also discussed.