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To describe the imaging findings of intimate partner violence (IPV)–related injury and to evaluate the role of longitudinal imaging review in detecting IPV. Radiology studies were reviewed in chronological order and IPV-related injuries were recorded among 400 victims of any type of abuse (group 1) and 288 of physical abuse (group 2) from January 2013 to June 2018. The likelihood of IPV was assessed as low/moderate/high based on the review of (1) current and prior anatomically related studies only and (2) longitudinal imaging history consisting of all prior studies. The first radiological study date with moderate/high suspicion was compared to the self-reported date by the victim. A total of 135 victims (33.8%) in group 1 and 144 victims (50%) in group 2 demonstrated IPV-related injuries. Musculoskeletal injury was most common (58.2% and 44.5% in groups 1 and 2, respectively; most commonly lower/upper extremity fractures), followed by neurologic injury (20.9% and 32.9% in groups 1 and 2, respectively; most commonly facial injury). With longitudinal imaging history, radiologists were able to identify IPV in 31% of group 1 and 46.5% of group 2 patients. Amongst these patients, earlier identification by radiologists was provided compared to the self-reported date in 62.3% of group 1 (median, 64 months) and in 52.6% of group 2 (median, 69.3 months). Musculoskeletal and neurological injuries were the most common IPV-related injuries. Knowledge of common injuries and longitudinal imaging history may help IPV identification when victims are not forthcoming. • Musculoskeletal injuries were the most common type of IPV-related injury, followed by neurological injuries. • With longitudinal imaging history, radiologists were able to better raise the suspicion of IPV compared to the selective review of anatomically related studies only. • With longitudinal imaging history, radiologists were able to identify IPV earlier than the self-reported date by a median of 64 months in any type of abuse, and a median of 69.3 months in physical abuse.

Purpose: This longitudinal study aims to evaluate the performance of 68 Ga-FAPI-04 and 18 F-FDG and to profile the dynamic process of tumor metastasis in a preclinical 4T1 breast cancer model. Although both of these two radioligands are wildly used in clinic, no study was reported on their performance in the longitudinal monitoring of tumor metastasis. Also, no correlation between the expression level of fibroblast activation protein (FAP) and the development of tumor metastasis has been elucidated previously. In this study, we evaluated the performance of 68 Ga-FAPI-04 and 18 F-FDG PET during the entire process of tumor metastasis, and their potential for the early diagnosis of tumor metastasis. We also clarified the correlation of uptakes as well as the signal-to-background (S/B) ratios between these two probes at different stages of tumor metastasis. Methods: Forty 4T1 metastatic breast cancer murine model were established using female BALB/c mice, followed by the longitudinal imaging with 68 Ga-FAPI-04 and 18 F-FDG once a week for up to six weeks. In vitro Hematoxylin & Eosin (H&E) and immunochemistry (IHE) staining were performed to evaluate FAP expression on the metastatic lesions. Further statistical analysis was performed to evaluate the correlation of 68 Ga-FAPI-04 and 18 F-FDG uptake (%ID/cc) at different stages of the metastasis. Results: 68 Ga-FPAI-04 holds an advantage over 18 F-FDG with higher sensitivity at the early stage of tumor metastasis. However, with the progress of tumor metastasis, uptake of 68 Ga-FAPI-04 decreases and becomes less sensitive than 18 F-FDG. There is also no direct correlation between uptake or S/B ratios of 68 Ga-FAPI-04 and 18 F-FDG during this dynamic process. Conclusion: 68 Ga-FAPI-04 is more sensitive than 18 F-FDG in detecting the early stage of tumor metastasis, but becomes less sensitive than 18 F-FDG at the late stage of tumor metastasis. We envision this result would be meaningful for the explanation of the 18 Ga-FAPI-04 and 18 F-FDG imaging both in the future clinic and preclinic studies.

BACKGROUND. Lung cancer (LC) associated with cystic airspaces is an uncommon presentation that is underrecognized on imaging. Additionally, understanding of its underlying pathology and risk factors is limited, which can contribute to delays in diagnosis. OBJECTIVE. The purpose of this analysis was to systematically review, analyze, and synthesize the medical literature to determine the imaging features of LC associated with cystic airspaces. EVIDENCE ACQUISITION. In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we included published research reporting the clinical, pathologic, and imaging features of LC associated with cystic airspaces. We then performed a pooled analysis of continuous and categoric data with respect to patient clinical characteristics, tumor pathologic features, underlying driver mutation, CT features, and evolution of these features over time. EVIDENCE SYNTHESIS. The analysis included eight original observational studies with a combined total of 341 patients with LC associated with cystic airspaces (weighted mean age, 61.8 years; range, 30-87 years; 135 women and 206 men). Most patients were current or previous smokers (127/192 [66.1%]). The most common histologic finding was adenocarcinoma (289/328 [88.1%]) followed by squamous cell carcinoma (30/328 [9.1%]). The most common driver mutations were EGFR (46/122 [37.7%]) and KRAS (21/122 [17.2%]). The cysts in LC associated with cystic airspaces commonly had nonuniform (104/114 [91.2%]) and thick (83/222 [37.4%]) walls, irregular margins (53/142 [37.3%]), and were unilocular (173/272 [63.6%]). Most cysts had a nodular component (210/328 [64.0%]). Over time, most cysts showed development or enlargement of the nodular component (61/89 [68.5%]), approximately half showed wall thickening (43/89 [48.3%]), and a minority evolved into completely solid lesions (11/89 [12.4%]). The size of the cystic component increased in 36 of 89 patients (40.4%), decreased in 28 (31.5%), and remained stable in 24 (27.0%). CONCLUSION. LC associated with cystic airspaces occurs most commonly as adeno-carcinoma and is seen in both smokers and nonsmokers. The cysts associated with LC show wall thickening and mural nodularity, which may evolve over time. LC associated with cystic airspaces can be indolent, and long-term surveillance with imaging should be considered if cysts are not resected. CLINICAL IMPACT. Familiarity with the imaging features and temporal evolution of LC associated with cystic airspaces can minimize delays in LC diagnosis. Future management guidelines should include protocols for follow-up and management of cystic lung lesions identified during diagnostic and LC screening CT.

Achondroplasia is the most common form of short-limb dwarfism. In this disorder, endochondral ossification is impaired due to gain-of-function mutation in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene. In addition to short limbs, cranial base bones are also affected leading to shortening of the skull base and to serious neurological complications associated with foramen magnum stenosis. These complications are thought to be due to the delay or premature arrest of skull base growth, caused by an accelerated ossification of the sphenooccipital (SOS) and the intraoccipital (IOS) synchondroses. Skull synchondroses consist of two opposite growth plates sharing a common reserve zone of chondrocytes. In this study, we first characterized the skull base synchondroses ossification in a mouse model of achondroplasia carrying the human G380R mutation (

Substance use disorder (SUD) is comorbid with devastating health issues, social withdrawal, and isolation. Successful clinical treatments for SUD have used social interventions. Neurons can encode drug cues, and drug cues can trigger relapse. It is important to study how the activity in circuits and embedded cell types that encode drug cues develop in SUD. Exploring shared neurobiology between social interaction (SI) and SUD may explain why humans with access to social treatments still experience relapse. However, circuitry remains poorly characterized due to technical challenges in studying the complicated nature of SI and SUD. To understand the neural correlates of SI and SUD, it is important to: (1) identify cell types and circuits associated with SI and SUD, (2) record and manipulate neural activity encoding drug and social rewards over time, (3) monitor unrestrained animal behavior that allows reliable drug self-administration (SA) and SI. Miniaturized fluorescence microscopes (miniscopes) are ideally suited to meet these requirements. They can be used with gradient index (GRIN) lenses to image from deep brain structures implicated in SUD. Miniscopes can be combined with genetically encoded reporters to extract cell-type specific information. In this mini-review, we explore how miniscopes can be leveraged to uncover neural components of SI and SUD and advance potential therapeutic interventions.

Simple Summary Mild hyperthermia is a technique that induces a local tumor temperature increase up to 43.0 °C. In this paper, we introduce three devices that could be used to apply hyperthermia in small animals in combination with intravital microscopy for the real-time visualization of in vivo intratumoral events such as drug delivery. Abstract This paper presents three devices suitable for the preclinical application of hyperthermia via the simultaneous high-resolution imaging of intratumoral events. (Pre)clinical studies have confirmed that the tumor micro-environment is sensitive to the application of local mild hyperthermia. Therefore, heating is a promising adjuvant to aid the efficacy of radiotherapy or chemotherapy. More so, the application of mild hyperthermia is a useful stimulus for triggered drug release from heat-sensitive nanocarriers. The response of thermosensitive nanoparticles to hyperthermia and ensuing intratumoral kinetics are considerably complex in both space and time. To obtain better insight into intratumoral processes, longitudinal imaging (preferable in high spatial and temporal resolution) is highly informative. Our devices are based on (i) an external electric heating adaptor for the dorsal skinfold model, (ii) targeted radiofrequency application, and (iii) a microwave antenna for heating of internal tumors. These models, while of some technical complexity, significantly add to the understanding of effects of mild hyperthermia warranting implementation in research on hyperthermia.

Convergent advances in the field of soft matter, macromolecular chemistry, and engineering have led to the development of biomaterials that possess autonomous, adaptive, and self-healing characteristics similar to living systems. These rationally designed biomaterials can surpass the capabilities of their parent material. Herein, the modification of hyaluronic acid (HA) to exhibit self-healing properties is described, and its physical and biological function both in vitro and in vivo is studied. The in vitro findings showed that self-healing HA designed to undergo self-repair improves lubrication, enhances free radical scavenging, and attenuates enzymatic degradation compared to unmodified HA. Longitudinal imaging following intraarticular injection of self-healing HA shows improved in vivo retention despite its low molecular weight. Concomitant with these functions, intraarticular injection of self-healing HA mitigates anterior cruciate ligament injury-mediated cartilage degeneration in rodents. This proof-of-concept study shows how incorporation of functional properties such as self-healing can be used to surpass the existing capabilities of biolubricants.

The outbreak of coronavirus disease 2019 (COVID-19) with the origin of the spread assumed to be located in Wuhan, China, began in December 2019, and is continuing until now. With the COVID-19 pandemic showing a progressive spread throughout the countries of the world, there is emerging interest for the potential long-term consequences of suffering from a COVID-19 pneumonia. Imaging plays a central role in the diagnosis and management of COVID-19 pneumonia, with chest X-ray examinations and computed tomography (CT) being undoubtedly the modalities most widely used, allowing for a fast and sensitive detection of infiltration patterns associated with COVID-19 pneumonia. For a better understanding of underlying pathomechanisms of pulmonary damage, longitudinal imaging series are warranted, for which CT is of limited usability due to repeated exposure of X-rays. Recent advances in MRI suggested that high-performance low-field MRI might represent a valuable method for pulmonary imaging without the need of radiation exposure. However, so far, low-field MRI has not been applied to study pulmonary damage after COVID-19 pneumonia. We present a case report of a patient who suffered from COVID-19 pneumonia using 0.55 T MRI for follow-up examinations three months after initial infection. Low-field MRI enables a precise visualization of persistent pulmonary changes including ground-glass opacities, which are consistent with CT performed on the same day. Low-field MRI seems to be feasible in the detection of pulmonary involvement in patients with COVID-19 pneumonia and may have the potential for repetitive lung examinations in monitoring the reconvalescence after pulmonary infections.

Conventional pulmonary function tests appear normal in early cystic fibrosis (CF) lung disease. Therefore, new diagnostic approaches are required that can detect CF lung disease in children and monitor treatment response. Hyperpolarized (HP) gas (129Xe and 3He) magnetic resonance imaging (MRI) is a powerful, emergent tool for mapping regional lung function and may be well suited for studying pediatric CF. HP gas MRI is well tolerated, reproducible, and it can be performed longitudinally without the need for ionizing radiation. In particular, quantification of the distribution of ventilation, or ventilation defect percent (VDP), has been shown to be a sensitive indicator of CF lung disease and correlates well with pulmonary function tests. This article presents the current state of CF diagnosis and treatment and describes the potential role of HP gas MRI for detection of early CF lung disease and following the effects of interventions. The typical HP gas imaging workflow is described, along with a discussion of image analysis to calculate VDP, dosing considerations, and the reproducibility of VDP. The potential use of VDP as an outcome measure in CF is discussed, by considering the correlation with pulmonary function measures, preliminary interventional studies, and case studies involving longitudinal imaging and pulmonary exacerbations. Finally, emerging HP gas imaging techniques such as multiple breath washout imaging are introduced, followed by a discussion of future directions. Overall, HP gas MRI biomarkers are expected to provide sensitive outcome measures that can be used in disease surveillance as well as interventional studies involving novel CF therapies.

For over 50 years, diabetic retinopathy (DR) has been classified by pathologic features seen on clinical examination and conventional retinal photographs. However, newer technology such as optical coherence tomography angiography (OCTA) now enables rapid acquisition of retinal structural and vascular information in a reliable, non-invasive, high-resolution fashion. Here, we highlight recent studies that have explored wide field swept-source OCTA (WF SS-OCTA) for the diagnosis and management of DR. Multiple studies have demonstrated the utility of WF SS-OCTA for detection of all clinically relevant features of DR. An updated DR staging system is proposed that leverages the advantages of WF SS-OCTA, including the ability to correlate detailed vascular and structural pathology over time with longitudinal imaging. WF SS-OCTA has tremendous potential for evaluating patients with DR. A new WF SS-OCTA-based staging system may be useful in routine clinical practice and for clinical trials.

Stroke profoundly disrupts cortical excitability which impedes recovery, but how it affects the function of specific inhibitory interneurons, or subpopulations therein, is poorly understood. Interneurons expressing vasoactive intestinal peptide (VIP) represent an intriguing stroke target because they can regulate cortical excitability through disinhibition. Here we chemogenetically augmented VIP interneuron excitability after stroke to show that it enhances somatosensory responses and improves recovery of paw function. Using longitudinal calcium imaging, we discovered that stroke primarily disrupts the fidelity (fraction of responsive trials) and predictability of sensory responses within a subset of highly active VIP neurons. Partial recovery of responses occurred largely within these active neurons and was not accompanied by the recruitment of minimally active neurons. Importantly, chemogenetic stimulation preserved sensory response fidelity and predictability in highly active neurons. These findings provide a new depth of understanding into how stroke and prospective therapies (chemogenetics), can influence subpopulations of inhibitory interneurons.

The purpose of this study was to analyze size and growth dynamics of focal lesions (FL) as well as to quantify diffuse infiltration (DI) in untreated smoldering multiple myeloma (SMM) patients and correlate those MRI features with timepoint and cause of progression. We investigated 199 whole-body magnetic resonance imaging (wb-MRI) scans originating from longitudinal imaging of 60 SMM patients and 39 computed tomography (CT) scans for corresponding osteolytic lesions (OL) in 17 patients. All FLs &gt, 5 mm were manually segmented to quantify volume and growth dynamics, and DI was scored, rating four compartments separately in T1- and fat-saturated T2-weighted images. The majority of patients with at least two FLs showed substantial spatial heterogeneity in growth dynamics. The volume of the largest FL (p = 0.001, c-index 0.72), the speed of growth of the fastest growing FL (p = 0.003, c-index 0.75), the DI score (DIS, p = 0.014, c-index 0.67), and its dynamic over time (DIS dynamic, p &lt, 0.001, c-index 0.67) all significantly correlated with the time to progression. Size and growth dynamics of FLs correlated significantly with presence/appearance of OL in CT within 2 years after the respective MRI assessment (p = 0.016 and p = 0.022). DIS correlated with decrease of hemoglobin (p &lt, 0.001). In conclusion, size and growth dynamics of FLs correlate with prognosis and local bone destruction. Connections between MRI findings and progression patterns (fast growing FL—OL, DIS—hemoglobin decrease) might enable more precise diagnostic and therapeutic approaches for SMM patients in the future.

Artificial intelligence (AI) has been applied with considerable success in the fields of radiology, pathology, and neurosurgery. It is expected that AI will soon be used to optimize strategies for the clinical management of patients based on intensive imaging follow-up. Our objective in this study was to establish an algorithm by which to automate the volumetric measurement of vestibular schwannoma (VS) using a series of parametric MR images following radiosurgery. Based on a sample of 861 consecutive patients who underwent Gamma Knife radiosurgery (GKRS) between 1993 and 2008, the proposed end-to-end deep-learning scheme with automated pre-processing pipeline was applied to a series of 1290 MR examinations (T1W+C, and T2W parametric MR images). All of which were performed under consistent imaging acquisition protocols. The relative volume difference (RVD) between AI-based volumetric measurements and clinical measurements performed by expert radiologists were + 1.74%, − 0.31%, − 0.44%, − 0.19%, − 0.01%, and + 0.26% at each follow-up time point, regardless of the state of the tumor (progressed, pseudo-progressed, or regressed). This study outlines an approach to the evaluation of treatment responses via novel volumetric measurement algorithm, and can be used longitudinally following GKRS for VS. The proposed deep learning AI scheme is applicable to longitudinal follow-up assessments following a variety of therapeutic interventions.

International audience; Motor neuron diseases encompass a divergent group of conditions with considerable differences in clinical manifestations, survival, and genetic vulnerability. One of the key aspects of clinical heterogeneity is the preferential involvement of upper (UMN) and lower motor neurons (LMN). While longitudinal imaging patters are relatively well characterized in ALS, progressive cortical changes in UMN,- and LMN-predominant conditions are seldom evaluated. Accordingly, the objective of this study is the juxtaposition of longitudinal trajectories in 3 motor neuron phenotypes; a UMN-predominant syndrome (PLS), a mixed UMN-LMN condition (ALS), and a lower motor neuron condition (poliomyelitis survivors). A standardized imaging protocol was implemented in a prospective, multi-timepoint longitudinal study with a uniform follow-up interval of 4 months. Forty-five poliomyelitis survivors, 61 patients with amyotrophic lateral sclerosis (ALS), and 23 patients with primary lateral sclerosis (PLS) were included. Cortical thickness alterations were evaluated in a dual analysis pipeline, using standard cortical thickness analyses, and a z-score-based individualized approach. Our results indicate that PLS patients exhibit rapidly progressive cortical thinning primarily in motor regions; ALS patients show cortical atrophy in both motor and extra-motor regions, while poliomyelitis survivors exhibit cortical thickness gains in a number of cerebral regions. Our findings suggest that dynamic cortical changes in motor neuron diseases may depend on relative UMN and/or LMN involvement, and increased cortical thickness in LMN-predominant conditions may represent compensatory, adaptive processes.

Longitudinal imaging forms an essential component in the management and follow-up of many medical conditions. The presence of lesion changes on serial imaging can have significant impact on clinical decision making, highlighting the important role for automated change detection. Lesion changes can represent anomalies in serial imaging, which implies a limited availability of annotations and a wide variety of possible changes that need to be considered. Hence, we introduce a new unsupervised anomaly detection and localisation method trained exclusively with serial images that do not contain any lesion changes. Our training automatically synthesises lesion changes in serial images, introducing detection and localisation pseudo-labels that are used to self-supervise the training of our model. Given the rarity of these lesion changes in the synthesised images, we train the model with the imbalance robust focal Tversky loss. When compared to supervised models trained on different datasets, our method shows competitive performance in the detection and localisation of new demyelinating lesions on longitudinal magnetic resonance imaging in multiple sclerosis patients. Code for the models will be made available at https://github.com/toson87/MSChangeDetection.

Purpose To investigate the relationship between disruption in different photoreceptor layers and deep capillary plexus (DCP) telangiectasias in eyes with macular telangiectasia type 2 (MacTel). Methods 35 eyes (21 patients) with MacTel imaged with optical coherence tomography angiography (OCTA) were included. Circumscribed areas of DCP telangiectasia were traced from OCTA slabs and the corresponding spectral-domain OCT (SD-OCT) slabs were used to visualize the photoreceptor layer interdigitation zone (IZ) and ellipsoid zone (EZ). IZ attenuation, IZ loss, and EZ loss were graded by reviewing en face SD-OCT slabs for hypo-reflective areas and confirming their status on cross-sectional views. Total area of photoreceptor disruption and overlap with DCP telangiectasia were evaluated with respect to OCT-based MacTel stage. Longitudinal changes were evaluated in a subset of patients with follow-up imaging. Results Overlap of DCP telangiectasia with IZ attenuation significantly decreased with MacTel severity, while overlap with IZ and EZ loss significantly increased. Overlap with IZ loss peaked in moderate MacTel (Stages 3–5). Longitudinal imaging showed that new EZ loss at 6 months was largely predicted by baseline IZ loss. Conclusions Worsening MacTel severity is characterized by greater overlap between DCP telangiectasia and zones of increasing severity of photoreceptor disruption, with EZ loss enlarging over time within areas of preexisting IZ disruption. We suggest that IZ disruption may indicate early photoreceptor dysfunction that eventually progresses to EZ loss, with IZ loss being a more reliable metric than IZ attenuation. Additional studies will be necessary to further explore long-term photoreceptor changes and evaluate their relationship with visual function in MacTel.

Highlights • PREVENT-AD is openly releasing datasets to the neuroscience community. • PREVENT-AD is a longitudinal study of older adults at-risk of Alzheimer disease. • Data include imaging, genetics, fluid biochemistry, neurosensory, cognition and more. • Data collection methods and data sharing plans for open science are described., To move Alzheimer Disease (AD) research forward it is essential to collect data from large cohorts, but also make such data available to the global research community. We describe the creation of an open science dataset from the PREVENT-AD (PResymptomatic EValuation of Experimental or Novel Treatments for AD) cohort, composed of cognitively unimpaired older individuals with a parental or multiple-sibling history of AD. From 2011 to 2017, 386 participants were enrolled (mean age 63 years old ± 5) for sustained investigation among whom 349 have retrospectively agreed to share their data openly. Repositories are findable through the unified interface of the Canadian Open Neuroscience Platform and contain up to five years of longitudinal imaging data, cerebral fluid biochemistry, neurosensory capacities, cognitive, genetic, and medical information. Imaging data can be accessed openly at https://openpreventad.loris.ca while most of the other information, sensitive by nature, is accessible by qualified researchers at https://registeredpreventad.loris.ca. In addition to being a living resource for continued data acquisition, PREVENT-AD offers opportunities to facilitate understanding of AD pathogenesis.

This study investigates the hyaloid vascular regression and its relationship to the retinal and choroidal vascular developments using optical coherence tomography angiography (OCTA). Normal and oxygen-induced retinopathy (OIR) rat eyes at postnatal day 15, 18, 21, and 24 were longitudinally imaged using OCTA. At each day, two consecutive imaging for visualizing the hyaloid vasculature and the retinal and choroidal vasculatures were conducted. The hyaloid vessel volume and the retinal and choroidal vessel densities were measured. The hyaloid vessel volumes gradually decreased during the regression, although the OIR eyes exhibited large vessel volumes at all time points. A spatial relationship between persistent hyaloid vasculature and retardation of underlying retinal vascular development was observed in the OIR eyes. Furthermore, anti-vascular endothelial growth factor (VEGF) was administered intravitreally to additional OIR eyes to observe its effect on the vascular regression and development. The VEGF injection to OIR eyes showed reduced persistent hyaloid vessels in the injected eyes as well as in the non-injected fellow eyes. This study presents longitudinal imaging of intraocular vasculatures in the developing eye and shows the utility of OCTA that can be widely used in studies of vascular development and regression and preclinical evaluation of new anti-angiogenic drugs.

Glioblastoma is a common and aggressive form of brain cancer affecting up to 20,000 new patients in the US annually. Despite rigorous therapies, current median survival is only 15–20 months. Patients who complete initial treatment undergo follow-up imaging at routine intervals to assess for tumor recurrence. Imaging is a central part of brain tumor management, but MRI findings in patients with brain tumor can be challenging to interpret and are further confounded by interpretation variability. Disease-specific structured reporting attempts to reduce variability in imaging results by implementing well-defined imaging criteria and standardized language. The Brain Tumor Reporting and Data System (BT-RADS) is one such framework streamlined for clinical workflows and includes quantitative criteria for more objective evaluation of follow-up imaging. To facilitate accurate and objective monitoring of patients during the follow-up period, we developed a cloud platform, the Brain Imaging Collaborative Suite's Longitudinal Imaging Tracker (BrICS-LIT). BrICS-LIT uses semiautomated tumor segmentation algorithms of both T2-weighted FLAIR and contrast-enhanced T1-weighted MRI to assist clinicians in quantitative assessment of brain tumors. The LIT platform can ultimately guide clinical decision-making for patients with glioblastoma by providing quantitative metrics for BT-RADS scoring. Further, this platform has the potential to increase objectivity when measuring efficacy of novel therapies for patients with brain tumor during their follow-up. Therefore, LIT will be used to track patients in a dose-escalated clinical trial, where spectroscopic MRI has been used to guide radiation therapy (Clinicaltrials.gov NCT03137888), and compare patients to a control group that received standard of care.

In vivo micro-CT has already been used to monitor microstructural changes of bone in mice of different ages and in models of age-related diseases such as osteoporosis. However, as aging is accompanied by frailty and subsequent increased sensitivity to external stimuli such as handling and anesthesia, the extent to which longitudinal imaging can be applied in aging studies remains unclear. Consequently, the potential of monitoring individual mice during the entire aging process – from healthy to frail status – has not yet been exploited. In this study, we assessed the effects of long-term in vivo micro-CT imaging - consisting of 11 imaging sessions over 20 weeks - on hallmarks of aging both on a local (i.e., static and dynamic bone morphometry) and systemic (i.e., frailty index (FI) and body weight) level at various stages of the aging process. Furthermore, using a premature aging model (PolgA(D257A/D257A)), we assessed whether these effects differ between genotypes.The 6th caudal vertebrae of 4 groups of mice (PolgA(D257A/D257A) and PolgA(+/+)) were monitored by in vivo micro-CT every 2 weeks. One group was subjected to 11 scans between weeks 20 and 40 of age, whereas the other groups were subjected to 5 scans between weeks 26-34, 32-40 and 40-46, respectively. The long-term monitoring approach showed small but significant changes in the static bone morphometric parameters compared to the other groups. However, no interaction effect between groups and genotype was found, suggesting that PolgA mutation does not render bone more or less susceptible to long-term micro-CT imaging. The differences between groups observed in the static morphometric parameters were less pronounced in the dynamic morphometric parameters. Moreover, the body weight and FI were not affected by more frequent imaging sessions. Finally, we observed that longitudinal designs including baseline measurements at young adult age are more powerful at detecting effects of in vivo micro-CT imaging on hallmarks of aging than cross-sectional comparisons between multiple groups of aged mice subjected to fewer imaging sessions.

Accurate quantitation of bone density variation would allow monitoring changes due to aging, disease progression, therapy outcomes or drug response. We present results from our material decomposition method using spectral computed tomography (CT) with a photon counting detector (PCD) for estimating quantitative bone density variations in healthy and arthritic mice. Limited samples of healthy mice and collagen antibody-induced arthritis (CAIA) mice were imaged on our home-built benchtop micro CT system with a wide area photon counting detector with a high resolution 55 micrometer pixel size. A material decomposition algorithm was applied in the image domain to separate and quantify bone and soft tissue variations. The resulting bone densities were quantified globally and locally for both mice. Higher bone densities were seen in the control mice over their arthritis counterparts by about 6-12%. Based on our preliminary results, material decomposition of multi-energy CT images collected with a PCD appears promising for bone density quantification. Our results show that these methods could be successfully applied to arthritis diagnosis and treatment monitoring in a mouse model. We will further investigate the utility of our methods to simultaneously quantify bone density as well as tagged contrast agents. These investigations are expected to help with longitudinal imaging studies to understand disease progression in animal models.

To move Alzheimer Disease (AD) research forward it is essential to collect data from large cohorts, but also make such data available to the global research community. We describe the creation of an open science dataset from the PREVENT-AD (PResymptomatic EValuation of Experimental or Novel Treatments for AD) cohort, composed of cognitively unimpaired older individuals with a parental or multiple-sibling history of AD. From 2011 to 2017, 386 participants were enrolled (mean age 63 years old ± 5) for sustained investigation among whom 349 have retrospectively agreed to share their data openly. Repositories are findable through the unified interface of the Canadian Open Neuroscience Platform (https://portal.conp.ca/) and contain up to five years of longitudinal imaging data, cerebral fluid biochemistry, neurosensory capacities, cognitive, genetic, and medical information. Imaging data can be accessed openly at https://openpreventad.loris.ca while most of the other information, sensitive by nature, is accessible by qualified researchers at https://registeredpreventad.loris.ca. In addition to being a living resource for continued data acquisition, PREVENT-AD offers opportunities to facilitate understanding of AD pathogenesis.

Significance: The blood–brain barrier (BBB) is a major obstacle to detecting and treating brain tumors. Overcoming this challenge will facilitate the early and accurate detection of brain lesions and guide surgical resection of tumors. Aim: We generated an orthotopic brain tumor model that simulates the pathophysiology of gliomas at early stages; determine the BBB integrity and breakdown over the time course of tumor progression using generic and cancer-targeted near-infrared (NIR) fluorescent molecular probes. Approach: We developed an intracranial tumor xenograft model that rapidly reestablished BBB integrity and monitored tumor progression by bioluminescence imaging. Sham control mice were injected with phosphate-buffered saline only. Fluorescence molecular tomography (FMT) was used to quantify the uptake of tumor-targeted and passive NIR fluorescent imaging agents in orthotopic glioma (U87-GL-GFP PDE7B H217Q cells) tumor model. Cancer-induced and transient (with focused ultrasound, FUS) disruption of BBB integrity was monitored with NIR fluorescent dyes. Results: Stereotactic injection of 50,000 cells into mouse brain allowed rapid reestablishment of BBB integrity within a week, as determined by the inability of both tumor-targeted and generic NIR imaging agents to extravasate into the brain. Tumor-induced BBB disruption was observed 7 weeks after tumor implantation. FUS achieved a similar effect at any time point after reestablishing BBB integrity. While tumor uptake and retention of the passive NIR dye, indocyanine green, was negligible, both actively tumor-targeting agents exhibited selective accumulation in the tumor region. The tumor-targeting molecular probe that clears rapidly from nontumor brain tissue exhibits higher contrast than the analogous vascular-targeting agent and helps delineate tumors from sham control. Conclusions: We highlight the utility of FMT imaging for longitudinal assessment of brain tumors and the interplay between the stages of BBB disruption and molecular probe retention in tumors, with potential application to other neurological diseases.

The differentiation between radiation-induced changes and tumor recurrence is a major pitfall of magnetic resonance imaging, which can be overcome by the use of PET. Although amino-acid PET tracers showed several advantages over F-fluorodeoxyglucose in neurooncology, studies comparing these 2 types of radiopharmaceuticals in previously irradiated brain metastases are lacking. Here, we demonstrated a mismatch between 3,4-dihydroxy-6-[F]-fluoro-L-phenylalanine (F-DOPA) and FDG in the first report of a previously irradiated brain metastasis undergoing a longitudinal evaluation by sequential double tracer PET imaging.

In the past decades, considerable progress has been made in our understanding and treatment of multiple myeloma. Several challenges remain including our abilities to longitudinally image tumor responses to treatment, to combine various therapeutic agents with different mechanisms of action but with overlapping toxicities, and to efficiently harness the power of the immune system to augment remission and/or to induce permanent cures. Nanomedicine may help to address many of these outstanding issues, affording novel diagnostic capabilities and offering disruptive technologies that promise to revolutionize treatment. Here, we review recent developments and the future of nanomedicine for multiple myeloma, highlighting new considerations in nanoparticle designs that may help to augment active targeting, to facilitate longitudinal imaging, and to improve drug delivery.

We present longitudinal imaging data of a child with Sturge–Weber syndrome (SWS). At age 8 months, 3 weeks after initial seizures and prolonged motor deficit, MRI showed extensive right hemispheric SWS involvement with severe glucose hypometabolism on PET. She was treated with levetiracetam and aspirin. Follow‐up imaging at age 29 months showed a robust interval expansion of enlarged deep medullary veins throughout the affected hemisphere along with a dramatic recovery of hemispheric metabolism and normalized neurocognitive functioning. These findings demonstrate a robust, multilobar hemispheric remodeling of deep venous collaterals that likely contributed to reversal of initial metabolic and neurocognitive deficits.

A high-resolution, three-dimensional, optical imaging technique for the murine brain was developed to identify the effects of different therapeutic windows for preclinical brain research. This technique tracks the same cells over several weeks. We conducted a pilot study of a promising drug to treat diffuse axonal injury (DAI) caused by traumatic brain injury, using two different therapeutic windows, as a means to demonstrate the utility of this novel longitudinal imaging technique. DAI causes immediate, sporadic axon damage followed by progressive secondary axon damage. We administered minocycline for three days commencing one hour after injury in one treatment group and beginning 72 hours after injury in another group to demonstrate the method’s ability to show how and when the therapeutic drug exerts protective and/or healing effects. Fewer varicosities developed in acutely treated mice while more varicosities resolved in mice with delayed treatment. For both treatments, the drug arrested development of new axonal damage by 30 days. In addition to evaluation of therapeutics for traumatic brain injury, this hybrid microlens imaging method should be useful to study other types of brain injury and neurodegeneration and cellular responses to treatment.

Radiographic medical images contain a vast wealth of information allowing for accurate non-invasive tumor characterization and ultimately improving cancer care. Radiomics enables the extraction of mineable high-dimensional features from images, quantification of tumor phenotypes for survival, recurrence, and treatment response prediction, and ultimately better patient stratification. Recent advances in AI, deep learning in particular, has allowed for the automated extraction of imaging features without the need for pre-definition. In this talk, we will be exploring deep learning radiomics applications in cancer patients from both single time point and longitudinal imaging data. We will also be identifying challenges regarding the stability, reproducibility, and transparency of such approaches. Citation Format: Ahmed Hosny. Deep learning radiomics in cancer imaging [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr IA-05.

Introduction: Micro-computed tomography with nanoparticle contrast agents may be a suitable tool for monitoring the time course of the development and progression of tumors. Here, we suggest a practical and convenient experimental method for generating and longitudinally imaging murine liver cancer models. Methods: Liver cancer was induced in 6 experimental mice by injecting clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated protein 9 plasmids causing mutations in genes expressed by hepatocytes. Nanoparticle agents are captured by Kupffer cells and detected by micro-computed tomography, thereby enabling longitudinal imaging. A total of 9 mice were used for the experiment. Six mice were injected with both plasmids and contrast, 2 injected with contrast alone, and one not injected with either agent. Micro-computed tomography images were acquired every 2- up to 14-weeks after cancer induction. Results: Liver cancer was first detected by micro-computed tomography at 8 weeks. The mean value of hepatic parenchymal attenuation remained almost unchanged over time, although the standard deviation of attenuation, reflecting heterogeneous contrast enhancement of the hepatic parenchyma, increased slowly over time in all mice. Histopathologically, heterogeneous distribution and aggregation of Kupffer cells was more prominent in the experimental group than in the control group. Heterogeneous enhancement of hepatic parenchyma, which could cause image quality deterioration and image misinterpretation, was observed and could be due to variation in Kupffer cells distribution. Conclusion: Micro-computed tomography with nanoparticle contrast is useful in evaluating the induction and characteristics of liver cancer, determining appropriate size of liver cancer for testing, and confirming therapeutic response.

Highlights • We introduce a novel method, based on a neural network (DeepSCAN), for detecting lesion change in longitudinal MRI imaging in multiple sclerosis. • The method had a sensitivity of 1.00 and a positive predictive value of 0.59 for detecting lesion load change, and an AUC of 0.999, when assessed on twenty-six MS patients with longitudinal imaging. • This compares to a sensitivity of 0.69 and a PPV of 0.18 when lesion volume, as measured by our classifier, was used to assess lesion load change (AUC = 0.71) • Change in lesion count (another commonly used metric) had a sensitivity of 0.57 and a PPV of 0.38 (AUC = 0.51)., The detection of new or enlarged white-matter lesions is a vital task in the monitoring of patients undergoing disease-modifying treatment for multiple sclerosis. However, the definition of ‘new or enlarged’ is not fixed, and it is known that lesion-counting is highly subjective, with high degree of inter- and intra-rater variability. Automated methods for lesion quantification, if accurate enough, hold the potential to make the detection of new and enlarged lesions consistent and repeatable. However, the majority of lesion segmentation algorithms are not evaluated for their ability to separate radiologically progressive from radiologically stable patients, despite this being a pressing clinical use-case. In this paper, we explore the ability of a deep learning segmentation classifier to separate stable from progressive patients by lesion volume and lesion count, and find that neither measure provides a good separation. Instead, we propose a method for identifying lesion changes of high certainty, and establish on an internal dataset of longitudinal multiple sclerosis cases that this method is able to separate progressive from stable time-points with a very high level of discrimination (AUC = 0.999), while changes in lesion volume are much less able to perform this separation (AUC = 0.71). Validation of the method on two external datasets confirms that the method is able to generalize beyond the setting in which it was trained, achieving an accuracies of 75 % and 85 % in separating stable and progressive time-points.

Objective To describe longitudinal image changes in supratentorial hemispheric meningiomas based on magnetic resonance imaging after preoperative embolization using calibrated microspheres. Methods A total of 14 patients with symptomatic supratentorial meningiomas were included in a prospective, mono-centric, mono-arm study. Magnetic resonance imaging changes on diffusion-weighted imaging, dynamic contrast susceptibility–perfusion-weighted imaging, susceptibility-weighted imaging, and magnetization-prepared rapid acquisition gradient-echo sequence T1-weighted postcontrast sequences 6 and 48 hours after embolization were evaluated and correlated with angiographic and clinical data. Results The mean age of the patients was 63 ± 12.7 years with an equal female/male ratio. Twelve meningiomas were World Health Organization grade I and II tumors. After embolization, baseline apparent diffusion coefficient (901 ± 166 mm2/s) decreased significantly within 6 hours (696 ± 115 mm2/s, P = 0.0008) as well within 48 hours (752 ± 134 mm2/s; P = 0.0147). Baseline mean ratio of relative cerebral blood volume (rCBV)tumor/rCBVwhite matter (3.67 ± 1.83) and relative cerebral blood flow (rCBF)tumor/rCBFwhite matter (2.89 ± 1.57) significantly decreased after embolization within 6 hours (rCBVtumor/rCBVwhite matter of 1.45 ± 0.9; P = 0.0007, rCBF of 1.16 ± 0.68; P = 0.0029) and 48 hours (rCBV of 1.50 ± 1.07; P = 0.0009, rCBFtumor/rCBFwhite matter of 1.19 ± 0.8; P = 0.003). The viable enhanced baseline mean tumor volume (54.3 ± 34.9 mm3) was sustainably and significantly diminished within 6 hours (26.6 ± 20.8 mm3; P = 0.02) and 48 hours (29.7 ± 22.5 mm3; P = 0.035) after embolization. There was a good correlation between angiographic devascularization rate and the embolized tumor volume at 6 hours (r = 0.7; P = 0.03) and 48 hours (r = 0.78; P = 0.041). Conclusions Preoperative meningioma embolization with calibrated microspheres is safe and effectively induces a significant and sustainable tissue transformation over 48 hours.

Rehabilitation is the most effective treatment for promoting the recovery of motor deficits after stroke. Despite its importance, the processes associated with rehabilitative intervention are poorly understood. One of the most challenging experimental goals is to unambiguously link specific circuit changes induced by rehabilitation to improved behavior. Here, we investigate which facets of cortical remodeling are induced by rehabilitation by combining optical imaging and manipulation tools in a mouse model of stroke. We demonstrate the progressive restoration of cortical motor maps and of cortical activity in parallel with the reinforcement of inter-hemispheric connectivity after rehabilitation. Furthermore, we reveal that the increase in vascular density goes along with the stabilization of peri-infarct neural circuitry at synaptic level. The present work provides the first evidences that rehabilitation is sufficient to promote the combined recovery of distinct structural and functional features distinctive of healthy neuronal networks.

Rodents including rats and mice are important models to study obesity, diabetes, and metabolic syndrome in a preclinical setting. Translational and longitudinal imaging of these rodents permit investigation of metabolic diseases and identification of imaging biomarkers suitable for clinical translation. Here we describe the imaging protocols for achieving quantitative abdominal imaging in small animals followed by segmentation and quantification of fat volumes.

Mucositis is the limiting toxicity of radio(chemo)therapy of head and neck cancer. Diagnostics, prophylaxis and correction of this condition demand new accurate and objective approaches. Here we report on an in vivo longitudinal monitoring of the oral mucosa dynamics in 25 patients during the course of radiotherapy of oropharyngeal and nasopharyngeal cancer using multifunctional optical coherence tomography (OCT). A spectral domain OCT system with a specially-designed oral imaging probe was used. Microvasculature visualization was based on temporal speckle variations of the full complex signal evaluated by high-pass filtering of 3D data along the slow scan axis. Angiographic image quantification demonstrated an increase of the vascular density and total length of capillary-like-vessels before visual signs or clinical symptoms of mucositis occur. Especially significant microvascular changes compared to their initial levels occurred when grade two and three mucositis developed. Further, microvascular reaction was seen to be dose-level dependent. OCT monitoring in radiotherapy offers a non-invasive, convenient, label-free quantifiable structural and functional volumetric imaging method suitable for longitudinal human patient studies, furnishing fundamental radiobiological insights and potentially providing useful feedback data to enable adaptive radiotherapy (ART).

Osteoporosis-related vertebral compression fractures (OVCFs) are a common and clinically unmet need with increasing prevalence as the world population ages. Animal OVCF models are essential to the preclinical development of translational tissue engineering strategies. While a number of models currently exist, this protocol describes an optimized method for inducing multiple highly reproducible vertebral defects in a single nude rat. A novel longitudinal semiautomated microcomputed tomography (µCT)-based quantitative structural analysis of the vertebral defects is also detailed. Briefly, rats were imaged at multiple time points post-op. The day 1 scan was reoriented to a standard position, and a standard volume of interest was defined. Subsequent µCT scans of each rat were automatically registered to the day 1 scan so the same volume of interest was then analyzed to assess for new bone formation. This versatile approach can be adapted to a variety of other models where longitudinal imaging-based analysis could benefit from precise 3D semiautomated alignment. Taken together, this protocol describes a readily quantifiable and easily reproducible system for osteoporosis and bone research. The suggested protocol takes 4 months to induce osteoporosis in nude ovariectomized rats and between 2.7 and 4 h to generate, image, and analyze two vertebral defects, depending on tissue size and equipment.

Bone marrow transplantation became the standard choice for treatment of many leukemias, tumors and metabolic diseases. Understanding the dynamic behavior of bone marrow niches, especially in case of bone marrow transplantation is critical to improve the efficiency of the treatment. Intravital microscopy was demonstrated to be a powerful tool to study physiological structure of bone marrow niche. However, current method of intravital microscopy has difficulty in longitudinal monitoring the same bone marrow niche site due to the invasion of the prior-imaging surgery. In this study, we introduce a method to improve the bone marrow niche imaging process and enable the longitudinal imaging of murine calvarium bone marrow. Mouse model for calvarium bone marrow imaging was made by attaching cover glass window to the calvarium bone. Longitudinal imaging of whole bone marrow engraftment process was carried out to demonstrate the advantage of our mouse model. Qualitative and quantitative analysis were also executed on the image data. The result provided a dynamic and full visualization of the bone marrow engraftment process. The study was expected to provide helpful tool for bone marrow studies and useful information for bone marrow transplantation in future.

A recurrent question within oncology drug development is predicting phase III outcome for a new treatment using early clinical data. One approach to tackle this problem has been to derive metrics from mathematical models that describe tumour size dynamics termed re-growth rate and time to tumour re-growth. They have shown to be strong predictors of overall survival in numerous studies but there is debate about how these metrics are derived and if they are more predictive than empirical end-points. This work explores the issues raised in using model-derived metric as predictors for survival analyses. Re-growth rate and time to tumour re-growth were calculated for three large clinical studies by forward and reverse alignment. The latter involves re-aligning patients to their time of progression. Hence it accounts for the time taken to estimate re-growth rate and time to tumour re-growth but also assesses if these predictors correlate to survival from the time of progression. We found that neither re-growth rate nor time to tumour re-growth correlated to survival using reverse alignment. This suggests that the dynamics of tumours up until disease progression has no relationship to survival post progression. For prediction of a phase III trial we found the metrics performed no better than empirical end-points. These results highlight that care must be taken when relating dynamics of tumour imaging to survival and that bench-marking new approaches to existing ones is essential.

There is evidence that cortico-striato-thalamo-cortical pathways are involved in Tourette syndrome. We performed a longitudinal imaging study in 22 patients and 21 healthy controls in order to examine the development of tics and its correlation with magnetic resonance imaging (MRI) findings. Patients were divided in a group with persisting and a group with remission of tics. We found a decrease in volume of left putamen in controls, but not in patients. We found changes in mean diffusivity between patients and controls in right caudate nucleus, thalamus, and frontal lobe. In contrast to controls, parallel and perpendicular diffusivity decreased in patients and were most pronounced in the patients with persisting tics compared to those with remission. The findings suggest that the development of the brain in patients with remission resembles the normal development more than in patients with persistent tics. This could reflect a change in brain structure or compensatory mechanisms in the brain.

Brain imaging studies in schizophrenia have typically involved single assessment and cross-sectional designs, while longitudinal studies rarely incorporate more than two time points. While informative, these studies do not adequately capture potential trajectories of neurobiological change, particularly in the context of a changing clinical picture. We propose that the analysis of brain trajectories using multiple time points may inform our understanding of the illness and the effect of treatment. This paper makes the case for frequent serial neuroimaging across the course of schizophrenia psychoses and its application to active illness epsiodes to provide a detailed examination of psychosis relapse and remission.

Metastasis is a highly dynamic process during which cancer and microenvironmental cells undergo a cascade of events required for efficient dissemination throughout the body. During the metastatic cascade, tumor cells can change their state and behavior, a phenomenon commonly defined as cellular plasticity. To monitor cellular plasticity during metastasis, high-resolution intravital microscopy (IVM) techniques have been developed and allow us to visualize individual cells by repeated imaging in animal models. In this review, we summarize the latest technological advancements in the field of IVM and how they have been applied to monitor metastatic events. In particular, we highlight how longitudinal imaging in native tissues can provide new insights into the plastic physiological and developmental processes that are hijacked by cancer cells during metastasis.

Myelin plays an essential role in the nervous system and its disruption in diseases such as multiple sclerosis may lead to neuronal death, thus causing irreversible functional impairments. Understanding myelin biology is therefore of fundamental and clinical importance, but no tools currently exist to describe the fine spatial organization of myelin sheaths in vivo. Here we demonstrate intravital quantification of the myelin molecular structure using a microscopy method based on polarization-resolved coherent Raman scattering. Developmental myelination was imaged noninvasively in live zebrafish. Longitudinal imaging of individual axons revealed changes in myelin organization beyond the diffraction limit. Applied to promyelination drug screening, the method uniquely enabled the identification of focal myelin regions with differential architectures. These observations indicate that the study of myelin biology and the identification of therapeutic compounds will largely benefit from a method to quantify the myelin molecular organization in vivo.

Purpose of review Neurologists are frequently asked to consult on patients with incidentally observed anomalies on brain MRI that may be suggestive of multiple sclerosis (MS). The identification of such findings has important clinical management implications. This review provides an overview and practical clinical approach options for clinicians. Recent findings An increase in the number of brain MRI studies performed annually is expected to result in detection of a corresponding greater number of unanticipated anomalies. A disproportionate number of patients referred to neurologists for this reason have punctate subcortical T2 hyperintensities that appear nonspecific in origin rather than having imaging features concerning for MS. However, in some instances, the MRI characteristics appear to be typical for demyelination. When these features are observed, efforts should be pursued to identify an accurate explanation for the preclinical findings through rigorous clinical evaluation, paraclinical testing, and utilization of longitudinal imaging. Summary The identification of subjects with incidental T2 hyperintensities highly suggestive of MS is important for patient counseling and management. Continued neurologic evaluations and reassessment of the original clinical impression are recommended to ensure accurate interpretation of the available data.

Success of personalized medicine in cancer therapy depends on the ability to identify and molecularly phenotype tumors. Current clinical imaging techniques cannot be integrated with precision molecular medicine at the level of single cells or microlesions due to limited resolution. In this work we use molecularly targeted infrared emitting optical probes to identify and characterize metastatic microlesions prior to their detection with clinically relevant imaging modalities. These contrast agents form the basis of an in vivo optical imaging system capable of resolving internal microlesions, filling a critical unmet need in cancer imaging.

Aim To determine the patterns of metastasis and recurrence in thymic epithelial tumours based on longitudinal imaging studies, and to correlate the patterns with World Health Organization (WHO) histological classifications. Materials and methods Seventy-seven patients with histopathologically confirmed thymomas ( n =62) and thymic carcinomas ( n =15) who were followed with cross-sectional follow-up imaging after surgery were retrospectively studied. All cross-sectional imaging studies during the disease course were reviewed to identify metastasis or recurrence. The sites of involvement and the time of involvement measured from surgery were recorded. Results Metastasis or recurrence was noted in 24 (31%) of the 77 patients. Patients with metastasis or recurrence were significantly younger than those without (median age: 46 versus 60, respectively; p =0.0005), and more commonly had thymic carcinomas than thymomas ( p =0.002). The most common site of involvement was the pleura (17/24), followed by the lung (9/24), and thoracic nodes (9/24). Abdominopelvic involvement was noted in 12 patients, most frequently in the liver ( n =8). Lung metastasis was more common in thymic carcinomas than thymomas ( p =0.0005). Time from surgery to the development of metastasis or recurrence was shortest in thymic carcinoma, followed by high-risk thymomas, and was longest in low-risk thymoma (median time in months: 25.1, 68.8, and not reached, respectively; p =0.0015). Conclusions The patterns of metastasis and recurrence of thymic epithelial tumours differ significantly across histological subgroups, with thymic carcinomas more commonly having metastasis with shorter length of time after surgery. The knowledge of different patterns of tumour spread may contribute to further understanding of the biological and clinical behaviours of these tumours.

Neurofibrillary tangles are intracellular accumulations of hyperphosphorylated and misfolded tau protein characteristic of Alzheimer's disease and other tauopathies. Classic cross-sectional studies of Alzheimer patient brains showed associations of tangle accumulation with neuronal loss, synapse loss, and dementia, which led to the supposition that tangles are toxic to neurons. More recent advances in imaging techniques and mouse models have allowed the direct exploration of the question of toxicity of aggregated versus soluble tau and have surprisingly challenged the view of tangles as toxic species in the brain. Here, we review these recent experiments on the nature of the toxicity of tau with particular emphasis on our experiments imaging tangles in the intact brain through a cranial window, which allows observation of tangle formation and longitudinal imaging of the fate of tangle-bearing neurons. Neurofibrillary tangles (NFT) were first described in 1906 by Alois Alzheimer based on Bielschowsky silver staining of the brain of his demented patient Auguste D (Alzheimer 1907; Goedert and Spillantini 2006). These intraneuronal aggregates have subsequently been found to be composed primarily of hyperphosphorylated tau protein and are definitive pathological lesions not only in Alzheimer's disease but also in a class of neurodegenerative tauopathies (Goedert et al. 1988; Spires-Jones et al. 2009). NFT pathology in Alzheimer's disease (AD) correlates closely with cognitive decline and synapse and neuronal loss (Braak and Braak 1997; Bretteville and Planel 2008; Congdon and Duff 2008; Mocanu et al. 2008b; Spires-Jones et al. 2009). As a result, NFT have long been considered indicative of impending neuronal cell death. More recent evidence, however, opposes this classical view. Here we review evidence addressing the question of whether NFT cause structural or functional neuronal damage.