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Background: The metabolomic and proteomic basis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is poorly understood and the relationships between systemic abnormalities in metabolism and AD/AMCI pathogenesis are unclear. Objective: The aim of the study was to compare the metabolomic and proteomic signature of saliva from cognitively normal and patients diagnosed with MCI or AD, to identify specific cellular pathways altered with the progression of the disease. Methods: We analyzed 80 saliva samples from individuals with MCI or AD as well as age- and gender-matched healthy controls. Saliva proteomic and metabolomic analyses were conducted utilizing mass spectrometry methods and data combined using pathway analysis. Results: We found significant alterations in multiple cellular pathways, demonstrating that at the omics level, disease progression impacts numerous cellular processes. Multivariate statistics using SIMCA showed that partial least squares-data analysis could be used to provide separation of the three groups. Conclusion: This study found significant changes in metabolites and proteins from multiple cellular pathways in saliva. These changes were associated with AD, demonstrating that this approach might prove useful to identify new biomarkers based upon integration of multi-omics parameters.

The implementation of accurate and sensitive molecular detection for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is paramount to effectively control the ongoing coronavirus disease 2019 (COVID-19) pandemic. In this regard, we herein propose the specific and highly sensitive SARS-CoV-2 detection based on nanoyeast single-chain-variable fragment (scFv) and ultrasensitive plasmonic nanobox-integrated nanomixing microassay. Importantly, this designed platform showcases the utility of nanoyeast-scFvs as specific capture reagents targeting the receptor-binding domain (RBD) of the virus and as monoclonal antibody alternatives suitable for cost-effective mass production and frequent testing. By capitalizing on single-particle active nanoboxes as plasmonic nanostructures for surface-enhanced Raman scattering (SERS), the microassay utilizes highly sensitive Raman signals to indicate virus infection. The developed microassay further integrated nanomixing for accelerating molecular collisions. Through the synergistic working of nanoyeast-scFv, plasmonic nanoboxes, and nanomixing, the highly specific and sensitive SARS-CoV-2 detection is achieved as low as 17 virus/μL without any molecular amplification. We successfully demonstrate SARS-CoV-2 detection in saliva samples of simulated patients at clinically relevant viral loads, suggesting the possibility of this platform for accurate and noninvasive patient screening.

Objective: White matter (WM) changes detected using diffusion tensor imaging (DTI) are reportedly related to cognitive outcomes following traumatic brain injury (TBI), but much existing research is underpowered or has only examined general outcomes, rather than cognitive functioning. Method: A large sample of adults who had sustained mild, moderate or severe TBIs seven months prior (N = 165) and a control group (N = 106) underwent DTI and cognitive testing. Fractional anisotropy and mean diffusivity were calculated for 5 regions (corpus callosum: genu, body, splenium; fornix; superior longitudinal fasciculus) that recent meta-analyses identified as being affected by TBI and related to cognition following TBI. Memory, attention and executive functioning, which are often affected by TBI, were assessed. Results: Overall, mild TBI did not show significant WM or cognitive changes, relative to controls, but moderate to severe TBI was associated with large WM alterations (all regions) and poorer cognitive performance. No significant correlations were found between DTI findings and cognition in the moderate to severe group. Conclusions: The findings have shown that moderate to severe TBI leads to considerable WM and cognitive changes. Early and ongoing examination of mild TBI is needed to determine whether WM and cognitive changes are initially present and, if so, when they resolve. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

At diagnosis, 22% of colorectal cancer (CRC) patients have metastases, and 50% later develop metastasis. Peptide receptor radionuclide therapy (PRRT), such as 177Lu-PSMA-617, is used to treat metastatic prostate cancer. 177Lu-PSMA-617 targets prostate-specific membrane antigen (PSMA), a cell-surface protein enriched in prostate cancer and the neovasculature of other solid tumors, including CRC. We performed 68Ga-PSMA-11 PET/CT imaging of 10 patients with metastatic CRC to assess metastasis avidity. Eight patients had lesions lacking avidity, and 2 had solitary metastases exhibiting very low avidity. Despite expression of PSMA in CRC neovasculature, none of the patients exhibited tumor avidity sufficient to be considered for 177Lu-PSMA-617 PRRT.

The clinical translation of new nanoparticle-based therapies for high-grade glioma (HGG) remains extremely poor. This has partly been due to the lack of suitable preclinical mouse models capable of replicating the complex characteristics of recurrent HGG (rHGG), namely the heterogeneous structural and functional characteristics of the blood-brain barrier (BBB). The goal of this study is to compare the characteristics of the tumor BBB of rHGG with two different mouse models of HGG, the ubiquitously used U87 cell line xenograft model and a patient-derived cell line WK1 xenograft model, in order to assess their suitability for nanomedicine research. Method: Structural MRI was used to assess the extent of BBB opening in mouse models with a fully developed tumor, and dynamic contrast enhanced MRI was used to obtain values of BBB permeability in contrast enhancing tumor. H&E and immunofluorescence staining were used to validate results obtained from the in vivo imaging studies. Results: The extent of BBB disruption and permeability in the contrast enhancing tumor was significantly higher in the U87 model than in rHGG. These values in the WK1 model are similar to those of rHGG. The U87 model is not infiltrative, has an entirely abnormal and leaky vasculature and it is not of glial origin. The WK1 model infiltrates into the non-neoplastic brain parenchyma, it has both regions with intact BBB and regions with leaky BBB and remains of glial origin. Conclusion: The WK1 mouse model more accurately reproduces the extent of BBB disruption, the level of BBB permeability and the histopathological characteristics found in rHGG patients than the U87 mouse model, and is therefore a more clinically relevant model for preclinical evaluations of emerging nanoparticle-based therapies for HGG.

The presence of bilateral brain injury in patients with unilateral cerebral palsy (CP) may impact neuroplasticity in the ipsilateral hemisphere; however, this pattern of injury is typically under‐analyzed due to the lack of methods robust to severe injury. In this study, injury‐robust methods have been applied to structural brain magnetic resonance imaging (MRI) data of a cohort of 91 children with unilateral CP (37 with unilateral and 54 with bilateral brain injury, 4–17 years) and 44 typically developing controls (5–17 years), to determine how brain structure is associated with concurrent motor function, and if these associations differ between patients with unilateral or bilateral injury. Regression models were used to associate these measures with two clinical scores of hand function, with patient age, gender, brain injury laterality, and interaction effects included. Significant associations with brain structure and motor function were observed (Pearson's r = .494–.716), implicating several regions of the motor pathway, and demonstrating an accurate prediction of hand function from MRI, regardless of the extent of brain injury. Reduced brain volumes were observed in patients with bilateral injury, including volumes of the thalamus and corpus callosum splenium, compared to those with unilateral injury, and the healthy controls. Increases in cortical thickness in several cortical regions were observed in cohorts with unilateral and bilateral injury compared to controls, potentially suggesting neuroplasticity might be occurring in the inferior frontal gyrus and the precuneus. These findings identify prospective useful target regions for transcranial magnetic stimulation intervention.

Background: CUB domain-containing protein 1 (CDCP1) is a cell surface receptor regulating key signalling pathways in malignant cells. CDCP1 has been proposed as a molecular target to abrogate oncogenic signalling pathways and specifically deliver anti-cancer agents to tumors. However, the development of CDCP1-targeting agents has been questioned by its frequent proteolytic processing which was thought to result in shedding of the CDCP1 extracellular domain limiting its targetability. In this study, we investigated the relevance of targeting CDCP1 in the context of pancreatic ductal adenocarcinoma (PDAC) and assess the impact of CDCP1 proteolysis on the effectiveness of CDCP1 targeting agents. Methods: The involvement of CDCP1 in PDAC progression was assessed by association analysis in several PDAC cohorts and the proteolytic processing of CDCP1 was evaluated in PDAC cell lines and patient-derived cells. The consequences of CDCP1 proteolysis on its targetability in PDAC cells was assessed using immunoprecipitation, immunostaining and biochemical assays. The involvement of CDCP1 in PDAC progression was examined by loss-of-function in vitro and in vivo experiments employing PDAC cells expressing intact or cleaved CDCP1. Finally, we generated antibody-based imaging and therapeutic agents targeting CDCP1 to demonstrate the feasibility of targeting this receptor for detection and treatment of PDAC tumors. Results: High CDCP1 expression in PDAC is significantly associated with poorer patient survival. In PDAC cells proteolysis of CDCP1 does not always result in the shedding of CDCP1-extracellular domain which can interact with membrane-bound CDCP1 allowing signal transduction between the different CDCP1-fragments. Targeting CDCP1 impairs PDAC cell functions and PDAC tumor growth independently of CDCP1 cleavage status. A CDCP1-targeting antibody is highly effective at delivering imaging radionuclides and cytotoxins to PDAC cells allowing specific detection of tumors by PET/CT imaging and superior anti-tumor effects compared to gemcitabine in in vivo models. Conclusion: Independent of its cleavage status, CDCP1 exerts oncogenic functions in PDAC and has significant potential to be targeted for improved radiological staging and treatment of this cancer. Its elevated expression by most PDAC tumors and lack of expression by normal pancreas and other major organs, suggest that targeting CDCP1 could benefit a significant proportion of PDAC patients. These data support the further development of CDCP1-targeting agents as personalizable tools for effective imaging and treatment of PDAC.

Diffusion tensor imaging is often used to assess white matter (WM) changes following traumatic brain injury (TBI), but is limited in voxels that contain multiple fibre tracts. Fixel‐based analysis (FBA) addresses this limitation by using a novel method of analysing high angular resolution diffusion‐weighted imaging (HARDI) data. FBA examines three aspects of each fibre tract within a voxel: tissue micro‐structure (fibre density [FD]), tissue macro‐structure (fibre‐bundle cross section [FC]) and a combined measure of both (FD and fibre‐bundle cross section [FDC]). This study used FBA to identify the location and extent of micro‐ and macro‐structural changes in WM following TBI. A large TBI sample (N mild = 133, N moderate–severe = 29) and control group (healthy and orthopaedic; N = 107) underwent magnetic resonance imaging with HARDI and completed reaction time tasks approximately 7 months after their injury (range: 98–338 days). The TBI group showed micro‐structural differences (lower FD) in the corpus callosum and forceps minor, compared to controls. Subgroup analyses revealed that the mild TBI group did not differ from controls on any fixel metric, but the moderate to severe TBI group had significantly lower FD, FC and FDC in multiple WM tracts, including the corpus callosum, cerebral peduncle, internal and external capsule. The moderate to severe TBI group also had significantly slower reaction times than controls, but the mild TBI group did not. Reaction time was not related to fixel findings. Thus, the WM damage caused by moderate to severe TBI manifested as fewer axons and a reduction in the cross‐sectional area of key WM tracts.

Colorectal cancer (CRC) is the third most common malignancy in the world, with 22% of patients presenting with metastatic disease and a further 50% destined to develop metastasis. Molecular imaging uses antigen-specific ligands conjugated to radionuclides to detect and characterise primary cancer and metastases. Expression of the cell surface protein CDCP1 is increased in CRC, and here we sought to assess whether it is a suitable molecular imaging target for the detection of this cancer. CDCP1 expression was assessed in CRC cell lines and a patient-derived xenograft to identify models suitable for evaluation of radio-labelled 10D7, a CDCP1-targeted, high-affinity monoclonal antibody, for preclinical molecular imaging. Positron emission tomography-computed tomography was used to compare zirconium-89 (89Zr)-10D7 avidity to a nonspecific, isotype control 89Zr-labelled IgGκ1 antibody. The specificity of CDCP1-avidity was further confirmed using CDCP1 silencing and blocking models. Our data indicate high avidity and specificity for of 89Zr-10D7 in CDCP1 expressing tumors at. Significantly higher levels than normal organs and blood, with greatest tumor avidity observed at late imaging time points. Furthermore, relatively high avidity is detected in high CDCP1 expressing tumors, with reduced avidity where CDCP1 expression was knocked down or blocked. The study supports CDCP1 as a molecular imaging target for CRC in preclinical PET-CT models using the radioligand 89Zr-10D7.

Systemic therapies have limited efficacy against brain metastases, largely because passive delivery of naked compounds via the bloodstream does not achieve sufficiently high or evenly dispersed intratumoural concentrations. Heterogeneous tissue architecture, abnormal perfusion, hypoxic zones and high interstitial fluid pressure are key factors limiting drug delivery, compounded by patchy blood-tumour-barrier permeability. Also, brain metastases are usually detected late, once patients become symptomatic. We are investigating whether engineered biopharmaceuticals might improve diagnostic sensitivity for earlier detection, as well as therapeutic efficacy and side-effect profiles of existing agents through active tumour targeting, delayed clearance and microenvironment-mediated activation. This study is proceeding with parallel preclinical and clinical tracks. Preclinical aims: (1) Develop and characterise monoclonal antibody (mAb) fragments (scFvs) that target the brain metastasis markers HER2 and HER3; (2) Functionalise polyethylene glycol (PEG)-based nanocarriers with the scFvs, along with imaging agents to facilitate in vivoand ex vivoanalysis of tissue distribution; (3) Functionalise HER2/3-targeted carriers with doxorubicin via an acid-labile hydrazone bond for release in hypoxic environments, or the endosome compartment after internalization. Results to date. His-tagged HER2- and HER3-targeted scFvs based on ligand-binding sequences of clinically-approved mAbs were expressed and purified from Expi293 suspension cultures. Binding affinities are an order of magnitude stronger than parent mAbs (KD 2-8x10E-11M), determined using surface plasmon resonance analysis. The scFvs are cytostatic and moderately cytotoxic in vitro, with IC50s in order of 0.4-1.0μM. HER2 and HER3 scFvs exhibited dose-dependent, additive growth inhibition when used in combination, and induced internalisation of their receptor ligands within 4 hours in SKBr3 cells. Conclusions.The scFvs are strong carrier-tethering candidates in terms of both extracellular and intracellular payload release. Carrier synthesis is currently underway and preliminary in vivo data will be presented. Clinical aims: (1) Develop and characterise 89Zirconium-labelled HER2-targeted PET tracers based on parent mAb and scFv; (2) Compare uptake and retention of the tracers in breast cancer patients with brain metastases; (3) Computationally relate tumour uptake to the administered dose, perfusion, tumour size and HER2 expression; (4) Determine the uptake range within and between patients, and the minimum size for reliable detection. Results to date. The mAb tracer has been synthesised, characterised and labelling processes scaled for clinical production. It is stable in physiologic conditions, retains HER2-binding activity and has a favourable biodistribution profile in NOD-SCID mice bearing BT474 xenografts. Conclusions. Australian regulatory approvals are in place and recruitment for the mAb imaging trial ("BoNSAI") has begun. Preliminary data will be presented. Citation Format: Saunus JM, Lim M, Puttick S, Kalita-de Croft P, Houston ZH, Jones ML, Latter MJ, Campbell LC, Thomas P, Jeffree RL, Rose SE, Mahler SM, Thurecht KJ, Scott AM, Lakhani SR. Innovation in diagnosis and treatment of brain metastases using multifunctional nanomedicines [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-19-02.

Highlights • Detailed protocol of the Prospective Imaging Study of Ageing (PISA) Study. • Genetic risk prediction to identify those at differing risk of Alzheimer’s disease. • Longitudinal cohort for the study of precursors and lifestyle risk factors. • Use of online surveys and cognitive testing for large scale phenotyping. • Functional, structural and molecular neuroimaging with neurocognitive testing., This prospective cohort study, “Prospective Imaging Study of Ageing: Genes, Brain and Behaviour” (PISA) seeks to characterise the phenotype and natural history of healthy adult Australians at high future risk of Alzheimer’s disease (AD). In particular, we are recruiting midlife and older Australians with high and low genetic risk of dementia to discover biological markers of early neuropathology, identify modifiable risk factors, and establish the very earliest phenotypic and neuronal signs of disease onset. PISA utilises genetic prediction to recruit and enrich a prospective cohort and follow them longitudinally. Online surveys and cognitive testing are used to characterise an Australia-wide sample currently totalling over 3800 participants. Participants from a defined at-risk cohort and positive controls (clinical cohort of patients with mild cognitive impairment or early AD) are invited for onsite visits for detailed functional, structural and molecular neuroimaging, lifestyle monitoring, detailed neurocognitive testing, plus blood sample donation. This paper describes recruitment of the PISA cohort, study methodology and baseline demographics.

Quadrantanopia caused by inadvertent severing of Meyer's Loop of the optic radiation is a well‐recognised complication of temporal lobectomy for conditions such as epilepsy. Dissection studies indicate that the anterior extent of Meyer's Loop varies considerably between individuals. Quantifying this for individual patients is thus an important step to improve the safety profile of temporal lobectomies. Previous attempts to delineate Meyer's Loop using diffusion MRI tractography have had difficulty estimating its full anterior extent, required manual ROI placement, and/or relied on advanced diffusion sequences that cannot be acquired routinely in most clinics. Here we present CONSULT: a pipeline that can delineate the optic radiation from raw DICOM data in a completely automated way via a combination of robust pre‐processing, segmentation, and alignment stages, plus simple improvements that bolster the efficiency and reliability of standard tractography. We tested CONSULT on 696 scans of predominantly healthy participants (539 unique brains), including both advanced acquisitions and simpler acquisitions that could be acquired in clinically acceptable timeframes. Delineations completed without error in 99.4% of the scans. The distance between Meyer's Loop and the temporal pole closely matched both averages and ranges reported in dissection studies for all tested sequences. Median scan‐rescan error of this distance was 1 mm. When tested on two participants with considerable pathology, delineations were successful and realistic. Through this, we demonstrate not only how to identify Meyer's Loop with clinically feasible sequences, but also that this can be achieved without fundamental changes to tractography algorithms or complex post‐processing methods., Quadrantanopia caused by inadvertent severing of Meyer's Loop of the optic radiation is a well‐recognised complication of temporal lobectomy. We demonstrated a fully automated pipeline that could delineate this structure reliably and realistically on more than 500 unique brains, including both advanced and more clinically‐accessible acquisitions. Results were in line with historical dissections studies and median scan‐rescan error was 1 mm.

This study aimed to identify which MRI and clinical assessments, alone or in combination, from (i) early (32 weeks postmenstrual age, PMA), (ii) term equivalent age (TEA) and (iii) 3 months corrected age (CA) are associated with motor or cognitive outcomes at 2 years CA in infants born31 weeks gestation.Prospective cohort study of 98 infants who underwent early and TEA MRI (n = 59 males; median birth gestational age 28 + 5 weeks). Hammersmith Neonatal Neurological Examination (HNNE), NICU Neonatal Neurobehavioural Scale and General Movements Assessment (GMs) were performed early and at TEA. Premie-Neuro was performed early and GMs, Test of Infant Motor Performance and visual assessment were performed at TEA and 3 months CA. Neurodevelopmental outcomes were determined using Bayley Scales of Infant and Toddler Development 3rd edition.The best combined motor outcome model included 3-month GMs (β = -11.41; 95% CI = -17.34, -5.49), TEA MRI deep grey matter score (β = -6.23; 95% CI = -9.47, -2.99) and early HNNE reflexes (β = 3.51; 95% CI = 0.86, 6.16). Combined cognitive model included 3-month GMs (β = -10.01; 95% CI = -15.90, -4.12) and TEA HNNE score (β = 1.33; 95% CI = 0.57, 2.08).Early neonatal neurological assessment improves associations with motor outcomes when combined with term MRI and 3-month GMs. Term neurological assessment combined with 3-month GMs improves associations with cognitive outcomes.We present associations between 32- and 40-week MRI, comprehensive clinical assessments and later 2-year motor and cognitive outcomes for children born31 weeks gestation. MRI and clinical assessment of motor, neurological and neurobehavioural function earlier than term equivalent age in very preterm infants is safe and becoming more available in clinical settings. Most of these children are discharged from hospital before term age and so completing assessments prior to discharge can assist with follow up. MRI and neurological assessment prior to term equivalent age while the child is still in hospital can provide earlier identification of children at highest risk of adverse outcomes and guide follow-up screening and intervention services.

1AbstractQuadrantanopia caused by inadvertent severing of Meyer’s Loop of the optic radiation is a well-recognised complication of temporal lobectomy for conditions such as epilepsy. Dissection studies indicate that the anterior extent of Meyer’s Loop varies considerably between individuals. Quantifying this for individual patients is thus an important step to improve the safety profile of temporal lobectomies. Previous attempts to delineate Meyer’s Loop using diffusion MRI tractography have had difficulty estimating its full anterior extent, required manual ROI placement, and/or relied on advanced diffusion sequences that cannot be acquired routinely in most clinics. Here we present CONSULT – a pipeline that can delineate the optic radiation from raw DICOM data in a completely automated way via a combination of robust preprocessing, segmentation, and alignment stages, plus simple improvements that bolster the efficiency and reliability of standard tractography. We tested CONSULT on 694 scans of predominantly healthy participants (538 unique brains), including both advanced acquisitions and simpler acquisitions that could be acquired in clinically acceptable timeframes. Delineations completed without error in 99.4% of the scans. The distance between Meyer’s Loop and the temporal pole closely matched both averages and ranges reported in dissection studies for all tested sequences. Median scan-rescan error of this distance was 1mm. When tested on two participants with considerable pathology, delineations were successful and realistic. Through this, we demonstrate not only how to identify Meyer’s Loop with clinically accessible sequences, but also that this can be achieved without fundamental changes to tractography algorithms or complex post-processing methods.HighlightsWe propose a fully automated means of delineating the optic radiation using diffusion MRI from DICOM dataAnatomical measurements from tractography of over 500 brains align well with previous dissection studiesThe proposed pipeline works well with clinically accessible and advanced acquisitionsMedian scan-rescan error was 1mmPlausible tractography was generated when pathology was present

IntroductionInfants born very preterm are at risk of adverse neurodevelopmental outcomes, including cognitive deficits, motor impairments and cerebral palsy. Earlier identification enables targeted early interventions to be implemented with the aim of improving outcomes.Methods and analysisProtocol for 6-year follow-up of two cohorts of infants born AimsExamine the ability of early neonatal MRI, EEG and concurrent clinical measures at 32 weeks PMA to predict motor, cognitive, language, academic achievement and mental health outcomes at 6 years CA.Determine if early brain abnormalities persist and are evident on brain MRI at 6 years CA and the relationship to EEG and concurrent motor, cognitive, language, academic achievement and mental health outcomes.Ethics and disseminationEthical approval has been obtained from Human Research Ethics Committees at Children’s Health Queensland (HREC/19/QCHQ/49800) and The University of Queensland (2019000426). Study findings will be presented at national and international conferences and published in peer-reviewed journals.Trial registration numberACTRN12619000155190p.Web address of trialhttp://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12619000155190p

Background High-grade glioma (HGG) remains a recalcitrant clinical problem despite many decades of research. A major challenge in improving prognosis is the inability of current therapeutic strategies to address a clinically significant burden of infiltrating tumor cells that extend beyond the margins of the primary tumor mass. Such cells cannot be surgically excised nor efficiently targeted by radiation therapy. Therapeutic targeting of this tumor cell population is significantly hampered by the presence of an intact blood–brain barrier (BBB). In this study, we performed a preclinical investigation of the efficiency of MR-guided Focused Ultrasound (FUS) to temporarily disrupt the BBB to allow selective delivery of a tumor-targeting antibody to infiltrating tumor. Methods Structural MRI, dynamic-contrast enhancement MRI, and histology were used to fully characterize the MR-enhancing properties of a patient-derived xenograft (PDX) orthotopic mouse model of HGG and to develop a reproducible, robust model of nonenhancing HGG. PET–CT imaging techniques were then used to evaluate the efficacy of FUS to increase 89Zr-radiolabeled antibody concentration in nonenhancing HGG regions and adjacent non-targeted tumor tissue. Results The PDX mouse model of HGG has a significant tumor burden lying behind an intact BBB. Increased antibody uptake in nonenhancing tumor regions is directly proportional to the FUS-targeted volume. FUS locally increased antibody uptake in FUS-targeted regions of the tumor with an intact BBB, while leaving untargeted regions unaffected. Conclusions FUS exposure successfully allowed temporary BBB disruption, localized to specifically targeted, nonenhancing, infiltrating tumor regions and delivery of a systemically administered antibody was significantly increased.

This study aimed to examine associations between structural MRI and concurrent motor, neurological and neurobehavioral measures at 30-32 weeks postmenstrual age (PMA; 'Early'), and at term equivalent age ('Term').In this prospective cohort study, infants underwent Early MRI (n = 119; 73 male; median 32 weeks 1 day PMA) and Term MRI (n = 102; 61 male; median 40 weeks 4 days PMA) at 3 T. Structural images were scored generating white matter (WM), cortical gray matter, deep gray matter, cerebellar and global brain abnormality scores. Clinical measures were General Movements Assessment (GMs), Hammersmith Neonatal Neurological Examination (HNNE) and NICU Neonatal Neurobehavioral Scale (NNNS). The Premie-Neuro was administered Early and the Test of Infant Motor Performance (TIMP) and a visual assessment at Term.Early MRI cerebellar scores were strongly associated with neurological components of HNNE (reflexes), NNNS (Hypertonicity), the Premie-Neuro neurological subscale (regression coefficient β = -0.06; 95% confidence interval CI = -0.09, -0.04; p .001) and cramped-synchronized GMs (β = 1.10; 95%CI = 0.57, 1.63; p .001). Term MRI WM and global scores were strongly associated with the TIMP (WM β = -1.02; 95%CI = -1.67, -0.36; p = .002; global β = -1.59; 95%CI = -2.62, -0.56; p = .001).Brain structure on Early and Term MRI was associated with concurrent motor, neurological and neurobehavioral function in very preterm infants.

There is currently intense interest in new methods for understanding the fate of therapeutically-relevant cells, such as mesenchymal stem cells (MSCs). The absence of a confounding background signal and consequent unequivocal assignment makes 19F MRI one of the most attractive modalities for the tracking of injected cells in vivo. We describe here the synthesis of novel partly-fluorinated polymeric nanoparticles with small size and high fluorine content as MRI agents. The polymers, constructed from perfluoropolyether methacrylate (PFPEMA) and oligo(ethylene glycol) methacrylate (OEGMA) have favourable cell uptake profiles and excellent MRI performance. To facilitate cell studies the polymer was further conjugated with a fluorescent dye creating a dual-modal imaging agent. The efficacy of labelling of MSCs was assessed using 19F NMR, flow cytometry and confocal microscopy. The labelling efficiency of 2.6 ± 0.1 × 1012 19F atoms per cell, and viability of >90% demonstrates high uptake and good tolerance by the cells. This loading translates to a minimum 19F MRI detection sensitivity of ∼7.4 × 103 cells per voxel. Importantly, preliminary in vivo data demonstrate that labelled cells can be readily detected within a short acquisition scan period (12 minutes). Hence, these copolymers show outstanding potential for 19F MRI cellular tracking and for quantification of non-phagocytic and therapeutically-relevant cells in vivo.

Preterm birth causes significant disruption in ongoing brain development, frequently resulting in adverse neurodevelopmental outcomes. Brain imaging using diffusion MRI may provide valuable insight into microstructural properties of the developing brain. The aim of this study was to establish whether the recently introduced fixel-based analysis method, with its associated measures of fibre density (FD), fibre bundle cross-section (FC), and fibre density and bundle cross-section (FDC), is suitable for the investigation of the preterm infant brain at term equivalent age. High-angular resolution diffusion weighted images (HARDI) of 55 preterm-born infants and 20 term-born infants, scanned around term-equivalent age, were included in this study (3 T, 64 directions, b = 2000 s/mm2). Postmenstrual age at the time of MRI, and intracranial volume (FC and FDC only), were identified as confounding variables. Gestational age at birth was correlated with all fixel measures in the splenium of the corpus callosum. Compared to term-born infants, preterm infants showed reduced FD, FC, and FDC in a number of regions, including the corpus callosum, anterior commissure, cortico-spinal tract, optic radiations, and cingulum. Preterm infants with minimal macroscopic brain abnormality showed more extensive reductions than preterm infants without any macroscopic brain abnormality; however, little differences were observed between preterm infants with no and with minimal brain abnormality. FC showed significant reductions in preterm versus term infants outside regions identified with FD and FDC, highlighting the complementary role of these measures. Fixel-based analysis identified both microstructural and macrostructural abnormalities in preterm born infants, providing a more complete picture of early brain development than previous diffusion tensor imaging (DTI) based approaches., Highlights • Gestational age at birth associated with measurements in corpus callosum splenium. • Preterms without macroscopic brain abnormality show differences to term infants. • No differences between preterms with minimal versus without abnormality detected.

Aim: To examine the diagnostic ability of early magnetic resonance imaging (MRI

Patient motion is an important consideration in modern PET image reconstruction. Advances in PET technology mean motion has an increasingly important influence on resulting image quality. Motion-induced artifacts can have adverse effects on clinical outcomes, including missed diagnoses and oversized radiotherapy treatment volumes. This review aims to summarize the wide variety of motion correction techniques available in PET and combined PET/CT and PET/MR, with a focus on the latter. A general framework for the motion correction of PET images is presented, consisting of acquisition, modeling, and correction stages. Methods for measuring, modeling, and correcting motion and associated artifacts, both in literature and commercially available, are presented, and their relative merits are contrasted. Identified limitations of current methods include modeling of aperiodic and/or unpredictable motion, attaining adequate temporal resolution for motion correction in dynamic kinetic modeling acquisitions, and maintaining availability of the MR in PET/MR scans for diagnostic acquisitions. Finally, avenues for future investigation are discussed, with a focus on improvements that could improve PET image quality, and that are practical in the clinical environment.

Background Plasmodium vivax has been proposed to infect and replicate in the human spleen and bone marrow. Compared to Plasmodium falciparum, which is known to undergo microvascular tissue sequestration, little is known about the behavior of P. vivax outside of the circulating compartment. This may be due in part to difficulties in studying parasite location and activity in life. Methods and findings To identify organ-specific changes during the early stages of P. vivax infection, we performed 18-F fluorodeoxyglucose (FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) at baseline and just prior to onset of clinical illness in P. vivax experimentally induced blood-stage malaria (IBSM) and compared findings to P. falciparum IBSM. Seven healthy, malaria-naive participants were enrolled from 3 IBSM trials: NCT02867059, ACTRN12616000174482, and ACTRN12619001085167. Imaging took place between 2016 and 2019 at the Herston Imaging Research Facility, Australia. Postinoculation imaging was performed after a median of 9 days in both species (n = 3 P. vivax; n = 4 P. falciparum). All participants were aged between 19 and 23 years, and 6/7 were male. Splenic volume (P. vivax: +28.8% [confidence interval (CI) +10.3% to +57.3%], P. falciparum: +22.9 [CI −15.3% to +61.1%]) and radiotracer uptake (P. vivax: +15.5% [CI −0.7% to +31.7%], P. falciparum: +5.5% [CI +1.4% to +9.6%]) increased following infection with each species, but more so in P. vivax infection (volume: p = 0.72, radiotracer uptake: p = 0.036). There was no change in FDG uptake in the bone marrow (P. vivax: +4.6% [CI −15.9% to +25.0%], P. falciparum: +3.2% [CI −3.2% to +9.6%]) or liver (P. vivax: +6.2% [CI −8.7% to +21.1%], P. falciparum: −1.4% [CI −4.6% to +1.8%]) following infection with either species. In participants with P. vivax, hemoglobin, hematocrit, and platelet count decreased from baseline at the time of postinoculation imaging. Decrements in hemoglobin and hematocrit were significantly greater in participants with P. vivax infection compared to P. falciparum. The main limitations of this study are the small sample size and the inability of this tracer to differentiate between host and parasite metabolic activity. Conclusions PET/MRI indicated greater splenic tropism and metabolic activity in early P. vivax infection compared to P. falciparum, supporting the hypothesis of splenic accumulation of P. vivax very early in infection. The absence of uptake in the bone marrow and liver suggests that, at least in early infection, these tissues do not harbor a large parasite biomass or do not provoke a prominent metabolic response. PET/MRI is a safe and noninvasive method to evaluate infection-associated organ changes in morphology and glucose metabolism., John Woodford and co-authors use positron emission tomography/magnetic resonance imaging (PET/MRI) to describe unique splenic morphology and metabolism in early P. vivax infection., Author summary Why was this study done? In contrast to Plasmodium falciparum, blood-stage Plasmodium vivax is not traditionally thought to accumulate outside of the circulating blood compartment. Emerging data suggest that a hidden compartment of P. vivax may exist outside of circulation, in reticulocyte (very young red blood cells)-containing organs. The presence of a hidden compartment affects our understanding of the basic biology and pathology of this common parasite and may have implications when developing antimalarial treatments. Studying the accumulation of malaria parasites is extremely challenging in vivo and has historically been limited to late stage disease and postmortem studies. What did the researchers do and find? We performed whole body magnetic resonance imaging (MRI) and positron emission tomography (PET) in individuals undergoing experimental malaria infection to identify changes in organ morphology and glucose metabolism following infection. Splenic uptake of radiolabeled glucose increased following P. vivax and P. falciparum infection and was more pronounced in the P. vivax group. Glucose uptake in the liver and bone marrow was not increased following infection with either P. vivax or P. falciparum. What do these findings mean? Increased splenic glucose metabolism is present in the early stages of infection with both P. vivax and P. falciparum and is more pronounced in P. vivax, consistent with other emerging evidence of a greater predilection for the spleen in P. vivax than P. falciparum. Functional medical imaging may be a useful tool to study biological processes in experimental malaria infection.

We have reported reliable changes in behavior, brain structure, and function in 24 healthy right‐handed adults who practiced a finger‐thumb opposition sequence task with their left hand for 10 min daily, over 4 weeks. Here, we extend these findings by using diffusion MRI to investigate white‐matter changes in the corticospinal tract, basal‐ganglia, and connections of the dorsolateral prefrontal cortex. Twenty‐three participant datasets were available with pre‐training and post‐training scans. Task performance improved in all participants (mean: 52.8%, SD: 20.0%; group P

Although different aspects of neuroplasticity can be quantified with behavioral probes, brain stimulation, and brain imaging assessments, no study to date has combined all these approaches into one comprehensive assessment of brain plasticity. Here, 24 healthy right-handed participants practiced a sequence of finger-thumb opposition movements for 10 min each day with their left hand. After 4 weeks, performance for the practiced sequence improved significantly (P

Advanced connectivity studies in toddlers with Autism Spectrum Disorder (ASD) are increasing and consistently reporting a disruption of brain connectivity. However, most of these studies compare ASD and typically developing subjects, thus providing little information on the specificity of the abnormalities detected in comparison with other developmental disorders (other-DD). We recruited subjects aged below 36 months who received a clinical diagnosis of Neurodevelopmental Disorder (32 ASD and 16 other-DD including intellectual disability and language disorder) according to DSM-IV TR. Structural and diffusion MRI were acquired to perform whole brain probabilistic and anatomically constrained tractography. Network connectivity matrices were built encoding the number of streamlines (DNUM ) and the tract-averaged fractional anisotropy (DFA ) values connecting each pair of cortical and subcortical regions. Network Based Statistics (NBS) was finally applied on the connectivity matrices to evaluate the network differences between the ASD and other-DD groups. The network differences resulted in an over-connectivity pattern (i.e., higher DNUM and DFA values) in the ASD group with a significance of P

Understanding the relationships between the structure and function of the brain largely relies on the qualitative assessment of Magnetic Resonance Images (MRIs) by expert clinicians. Automated analysis systems can support these assessments by providing quantitative measures of brain injury. However, the assessment of deep gray matter structures, which are critical to motor and executive function, remains difficult as a result of large anatomical injuries commonly observed in children with Cerebral Palsy (CP). Hence, this article proposes a robust surrogate marker of the extent of deep gray matter injury based on impingement due to local ventricular enlargement on surrounding anatomy. Local enlargement was computed using a statistical shape model of the lateral ventricles constructed from 44 healthy subjects. Measures of injury on 95 age-matched CP patients were used to train a regression model to predict six clinical measures of function. The robustness of identifying ventricular enlargement was demonstrated by an area under the curve of 0.91 when tested against a dichotomised expert clinical assessment. The measures also showed strong and significant relationships for multiple clinical scores, including: motor function (r = 0.62, P < 0.005), executive function (r = 0.55, P < 0.005), and communication (r = 0.50, P < 0.005), especially compared to using volumes obtained from standard anatomical segmentation approaches. The lack of reliance on accurate anatomical segmentations and its resulting robustness to large anatomical variations is a key feature of the proposed automated approach. This coupled with its strong correlation with clinically meaningful scores, signifies the potential utility to repeatedly assess MRIs for clinicians diagnosing children with CP. Hum Brain Mapp 37:3795–3809, 2016.

Very preterm-born infants are at risk of adverse neurodevelopmental outcomes. Brain magnetic resonance imaging (MRI) at term equivalent age (TEA) can probe tissue microstructure and morphology, and demonstrates potential in the early prediction of outcomes. In this study, we use the recently introduced fixel-based analysis method for diffusion MRI to investigate the association between microstructure and morphology at TEA, and motor and cognitive development at 1 and 2 years corrected age (CA). Eighty infants born

The deep grey matter (DGM) nuclei of the brain play a crucial role in learning, behaviour, cognition, movement and memory. Although automated segmentation strategies can provide insight into the impact of multiple neurological conditions affecting these structures, such as Multiple Sclerosis (MS), Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD) and Cerebral Palsy (CP), there are a number of technical challenges limiting an accurate automated segmentation of the DGM. Namely, the insufficient contrast of T1 sequences to completely identify the boundaries of these structures, as well as the presence of iso-intense white matter lesions or extensive tissue loss caused by brain injury. Therefore in this systematic review, 269 eligible studies were analysed and compared to determine the optimal approaches for addressing these technical challenges. The automated approaches used among the reviewed studies fall into three broad categories, atlas-based approaches focusing on the accurate alignment of atlas priors, algorithmic approaches which utilise intensity information to a greater extent, and learning-based approaches that require an annotated training set. Studies that utilise freely available software packages such as FIRST, FreeSurfer and LesionTOADS were also eligible, and their performance compared. Overall, deep learning approaches achieved the best overall performance, however these strategies are currently hampered by the lack of large-scale annotated data. Improving model generalisability to new datasets could be achieved in future studies with data augmentation and transfer learning. Multi-atlas approaches provided the second-best performance overall, and may be utilised to construct a "silver standard" annotated training set for deep learning. To address the technical challenges, providing robustness to injury can be improved by using multiple channels, highly elastic diffeomorphic transformations such as LDDMM, and by following atlas-based approaches with an intensity driven refinement of the segmentation, which has been done with the Expectation Maximisation (EM) and level sets methods. Accounting for potential lesions should be achieved with a separate lesion segmentation approach, as in LesionTOADS. Finally, to address the issue of limited contrast, R2*, T2* and QSM sequences could be used to better highlight the DGM due to its higher iron content. Future studies could look to additionally acquire these sequences by retaining the phase information from standard structural scans, or alternatively acquiring these sequences for only a training set, allowing models to learn the "improved" segmentation from T1-sequences alone.

Background.One in three survivors of stroke experience poststroke depression (PSD). PSD has been linked with poorer recovery of function and cognition, yet our understanding of potential mechanisms is currently limited. Alterations in resting-state functional MRI have been investigated to a limited extent. Fluctuations in low frequency signal are reported, but it is unknown if interactions are present between the level of depressive symptom score and intrinsic brain activity in varying brain regions.Objective.To investigate potential interaction effects between whole-brain resting-state activity and depressive symptoms in stroke survivors with low and high levels of depressive symptoms.Methods.A cross-sectional analysis of 63 stroke survivors who were assessed at 3 months poststroke for depression, using the Montgomery–Åsberg Depression Rating Scale (MÅDRS-SIGMA), and for brain activity using fMRI. A MÅDRS-SIGMA score of >8 was classified as high depressive symptoms. Fractional amplitude of frequency fluctuations (fALFF) data across three frequency bands (broadband, i.e., ~0.01–0.08; subbands, i.e., slow-5: ~0.01–0.027 Hz, slow-4: 0.027–0.07) was examined.Results.Of the 63 stroke survivors, 38 were classified as “low-depressive symptoms” and 25 as “high depressive symptoms.” Six had a past history of depression. We found interaction effects across frequency bands in several brain regions that differentiated the two groups. The broadband analysis revealed interaction effects in the left insula and the left superior temporal lobe. The subband analysis showed contrasting fALFF response between the two groups in the left thalamus, right caudate, and left cerebellum. Across the three frequency bands, we found contrasting fALFF response in areas within the fronto-limbic-thalamic network and cerebellum.Conclusions.We provide evidence that fALFF is sensitive to changes in poststroke depressive symptom severity and implicates frontostriatal and cerebellar regions, consistent with previous studies. The use of multiband analysis could be an effective method to examine neural correlates of depression after stroke. The START-PrePARE trial is registered with the Australian New Zealand Clinical Trial Registry, numberACTRN12610000987066.

The EphA3 receptor has recently emerged as a functional tumour-specific therapeutic target in glioblastoma (GBM). EphA3 is significantly elevated in recurrent disease, is most highly expressed on glioma stem cells (GSCs), and has a functional role in maintaining self-renewal and tumourigenesis. An unlabelled EphA3-targeting therapeutic antibody is currently under clinical assessment in recurrent GBM patients. In this study, we assessed the efficacy of EphA3 antibody drug conjugate (ADC) and radioimmunotherapy (RIT) approaches using orthotopic animal xenograft models. Brain uptake studies, using positron emission tomography/computed tomography (PET/CT) imaging, show EphA3 antibodies are effectively delivered across the blood-tumour barrier and accumulate at the tumour site with no observed normal brain reactivity. A robust anti-tumour response, with no toxicity, was observed using EphA3, ADC, and RIT approaches, leading to a significant increase in overall survival. Our current research provides evidence that GBM patients may benefit from pay-loaded EphA3 antibody therapies.

Aims To investigate the extent of white matter damage in children with unilateral cerebral palsy (UCP) caused by periventricular white matter lesions comparing between unilateral and bilateral lesions; and to investigate a relationship between white matter microstructure and hand function. Methods and procedures Diffusion MRI images from 46 children with UCP and 18 children with typical development (CTD) were included. Subjects were grouped by side of hemiparesis and unilateral or bilateral lesions. A voxel-wise white matter analysis was performed to identify regions where fractional anisotropy (FA) was significantly different between UCP groups and CTD; and where FA correlated with either dominant or impaired hand function (using Jebsen Taylor Hand Function Test). Outcomes and results Children with unilateral lesions had reduced FA in the corticospinal tract of the affected hemisphere. Children with bilateral lesions had widespread reduced FA extending into all lobes. In children with left hemiparesis, impaired hand function correlated with FA in the contralateral corticospinal tract. Dominant hand function correlated with FA in the posterior thalamic radiations as well as multiple other regions in both left and right hemiparesis groups. Conclusions and implications Periventricular white matter lesions consist of focal and diffuse components. Focal lesions may cause direct motor fibre insult resulting in motor impairment. Diffuse white matter injury is heterogeneous, and may contribute to more global dysfunction. What this paper adds ⿢ Focal white matter alterations are observed in the corticospinal tract in UCP with unilateral white matter lesions ⿢ Diffuse white matter alterations throughout all cerebral lobes are observed in UCP with bilateral white matter lesions ⿢ Fractional anisotropy in the posterior thalamic radiations correlates with dominant hand function

Congenital brain lesions result in a wide range of cerebral tissue alterations observed in children with cerebral palsy (CP) that are associated with a range of functional impairments. The relationship between injury severity and functional outcomes, however, remains poorly understood. This research investigates the differences in cortical shape between children with congenital brain lesions and typically developing children (TDC) and investigates the correlations between cortical shape and functional outcome in a large cohort of patients diagnosed with unilateral CP. Using 139 structural magnetic resonance images, including 95 patients with clinically diagnosed CP and 44 TDC, cortical segmentations were obtained using a modified expectation maximization algorithm. Three shape characteristics (cortical thickness, curvature, and sulcal depth) were computed within a number of cortical regions. Significant differences in these shape measures compared to the TDC were observed on both the injured hemisphere of children with CP (P

This study meta-analyzed research examining relationships between diffusion tensor imaging and cognition following pediatric traumatic brain injury (TBI). Data from 14 studies that correlated fractional anisotropy (FA) or apparent diffusion coefficient/mean diffusivity with cognition were analyzed. Short-term (

The aim of this study is to investigate the genetic influence on the cerebral cortex, based on the analyses of heritability and genetic correlation between grey matter (GM) thickness, derived from structural MR images (sMRI), and associated white matter (WM) connections obtained from diffusion MRI (dMRI). We measured on sMRI the cortical thickness (CT) from a large twin imaging cohort using a surface-based approach (N = 308, average age 22.8 ± 2.3 SD). An ACE model was employed to compute the heritability of CT. WM connections were estimated based on probabilistic tractography using fiber orientation distributions (FOD) from dMRI. We then fitted the ACE model to estimate the heritability of CT and FOD peak measures along WM fiber tracts. The WM fiber tracts where genetic influence was detected were mapped onto the cortical surface. Bivariate genetic modeling was performed to estimate the cross-trait genetic correlation between the CT and the FOD-based connectivity of the tracts associated with the cortical regions. We found some cortical regions displaying heritable and genetically correlated GM thickness and WM connectivity, forming networks under stronger genetic influence. Significant heritability and genetic correlations between the CT and WM connectivity were found in regions including the right postcentral gyrus, left posterior cingulate gyrus, right middle temporal gyri, suggesting common genetic factors influencing both GM and WM. Hum Brain Mapp 37:2331-2347, 2016. © 2016 Wiley Periodicals, Inc.

Direct measurement of recovery from brain injury is an important goal in neurorehabilitation, and requires reliable, objective, and interpretable measures of changes in brain function, referred to generally as “neuroplasticity.” One popular imaging modality for measuring neuroplasticity is task-based functional magnetic resonance imaging (t-fMRI). In the field of neurorehabilitation, however, assessing neuroplasticity using t-fMRI presents a significant challenge. This commentary reviews t-fMRI changes commonly reported in patients with cerebral palsy or acquired brain injuries, with a focus on studies of motor rehabilitation, and discusses complexities surrounding their interpretations. Specifically, we discuss the difficulties in interpreting t-fMRI changes in terms of their underlying causes, that is, differentiating whether they reflect genuine reorganisation, neurological restoration, compensation, use of preexisting redundancies, changes in strategy, or maladaptive processes. Furthermore, we discuss the impact of heterogeneous disease states and essential t-fMRI processing steps on the interpretability of activation patterns. To better understand therapy-induced neuroplastic changes, we suggest that researchers utilising t-fMRI consider concurrently acquiring information from an additional modality, to quantify, for example, haemodynamic differences or microstructural changes. We outline a variety of such supplementary measures for investigating brain reorganisation and discuss situations in which they may prove beneficial to the interpretation of t-fMRI data.

White and grey matter lesions are the most prevalent type of injury observable in the Magnetic Resonance Images (MRIs) of children with cerebral palsy (CP). Previous studies investigating the impact of lesions in children with CP have been qualitative, limited by the lack of automated segmentation approaches in this setting. As a result, the quantitative relationship between lesion burden has yet to be established. In this study, we perform automatic lesion segmentation on a large cohort of data (107 children with unilateral CP and 18 healthy children) with a new, validated method for segmenting both white matter (WM) and grey matter (GM) lesions. The method has better accuracy (94%) than the best current methods (73%), and only requires standard structural MRI sequences. Anatomical lesion burdens most predictive of clinical scores of motor, cognitive, visual and communicative function were identified using the Least Absolute Shrinkage and Selection operator (LASSO). The improved segmentations enabled identification of significant correlations between regional lesion burden and clinical performance, which conform to known structure-function relationships. Model performance was validated in an independent test set, with significant correlations observed for both WM and GM regional lesion burden with motor function (p, Graphical abstract Image 1, Highlights • Presents an automated lesion segmentation approach tailored to cerebral palsy • Demonstrates the utility of quantifying lesions from MRI • Illustrates the influence that grey matter lesions have on functional impairments

Background and aims: Preterm birth imposes a high risk for developing neuromotor delay. Earlier prediction of adverse outcome in preterm infants is crucial for referral to earlier intervention. This study aimed to predict abnormal motor outcome at 2 years from early brain diffusion magnetic resonance imaging (MRI) acquired between 29 and 35 weeks postmenstrual age (PMA) using a deep learning convolutional neural network (CNN) model. Methods: Seventy-seven very preterm infants (born

4609 Background: Peptide receptor radionuclide therapy (PRRT) is an effective treatment option in patients with advanced neuroendocrine tumours (NETs). Patients are pre-selected based on 68Gallium-DOTA-(0-Tyr3)-octreotate Positron Emission Tomography (68Ga-DOTATATE PET) uptake. The level of uptake in tumour on the baseline 68Ga-DOTATATE PET scan has been explored as a predictor of response in NETs with inconclusive evidence. The aim of this study is to determine the correlation between 68Ga-DOTATATE PET SUV parameters to survival outcomes. Methods: We retrospectively analysed 142 lesions (up to five lesions per patient) in 73 patients with NET undergoing PRRT with 177Lutetium octreotate (8.0-8.3GBq) and pretherapeutic 68Ga-DOTATATE PET/CT in a single institution. Standardised uptake values (SUVs) max and mean were correlated with progression-free survival (PFS) and overall survival (OS). Results: A total of 73 patients were included in the analysis. The median age was 63 (28-89) years. NET origin was gastroenteric (49%), pancreatic [pNET] (38%), bronchial (10%) and other (3%). Ki-67 proliferation index ( < 3%: 36%, 3-20%: 36%, > 20%- < 50%: 8%, unknown: 21%) was seen. Pretherapeutic SUV max but not SUV mean was higher in pNETs (P = 0.04). No difference was seen with Ki-67 index. The median PFS was 32 (95%CI: 26-38) months. Median PFS was reduced with increasing ECOG performance status [PS] (P= 0.029), increasing tumour grade (P = 0.003), increasing Ki-67 proliferation index (P = 0.013), reduced SUV max (P= 0.003), reduced SUV mean (P= 0.001). Multivariate analysis confirmed SUV mean (HR =-1.71 [95%CI: -2.66- -0.80]; P 30: 48 [44-51]; P 20: 47 [43-51]; P68Ga-DOTATATE PET SUV measures correlated with an improved PFS on multivariate analysis as well as improved OS in this select group of patients suitable for PRRT. Those patients with lower SUV mean may benefit from escalation of therapy such as increasing administered therapeutic activity.

Despite significant improvements in the clinical management of glioblastoma, poor delivery of systemic therapies to the entire population of tumour cells remains one of the biggest challenges in the achievement of more effective treatments. On the one hand, the abnormal and dysfunctional tumour vascular network largely limits blood perfusion, resulting in an inhomogeneous delivery of drugs to the tumour. On the other hand, the presence of an intact blood-brain barrier (BBB) in certain regions of the tumour prevents chemotherapeutic drugs from permeating through the tumour vessels and reaching the diseased cells. In this review we analyse in detail the implications of the presence of a dysfunctional vascular network and the impenetrable BBB on drug transport. We discuss advantages and limitations of the currently available strategies for remodelling the tumour vasculature aiming to ameliorate the above mentioned limitations. Finally we review research methods for visualising vascular dysfunction and highlight the power of DCE- and DSC-MRI imaging to assess changes in blood perfusion and BBB permeability.

Background Of children with hemiplegic cerebral palsy, 75% have impaired somatosensory function, which contributes to learned non-use of the affected upper limb. Currently, motor learning approaches are used to improve upper-limb motor skills in these children, but few studies have examined the effect of any intervention to ameliorate somatosensory impairments. Recently, Sense© training was piloted with a paediatric sample, seven children with hemiplegic cerebral palsy, demonstrating statistically and clinically significant change in limb position sense, goal performance and bimanual hand-use. This paper describes a protocol for a Randomised Controlled Trial of Sense© for Kids training, hypothesising that its receipt will improve somatosensory discrimination ability more than placebo (dose-matched Goal Directed Therapy via Home Program). Secondary hypotheses include that it will alter brain activation in somatosensory processing regions, white-matter characteristics of the thalamocortical tracts and improve bimanual function, activity and participation more than Goal Directed Training via Home Program. Methods and design This is a single blind, randomised matched-pair, placebo-controlled trial. Participants will be aged 6–15 years with a confirmed description of hemiplegic cerebral palsy and somatosensory discrimination impairment, as measured by the sense©_assess Kids. Participants will be randomly allocated to receive 3h a week for 6 weeks of either Sense© for Kids or Goal Directed Therapy via Home Program. Children will be matched on age and severity of somatosensory discrimination impairment. The primary outcome will be somatosensory discrimination ability, measured by sense©_assess Kids score. Secondary outcomes will include degree of brain activation in response to a somatosensory task measured by functional MRI, changes in the white matter of the thalamocortical tract measured by diffusion MRI, bimanual motor function, activity and participation. Discussion This study will assess the efficacy of an intervention to increase somatosensory discrimination ability in children with cerebral palsy. It will explore clinically important questions about the efficacy of intervening in somatosensation impairment to improve bimanual motor function, compared with focusing on motor impairment directly, and whether focusing on motor impairment alone can affect somatosensory ability. Trial registration This trial is registered with the Australian New Zealand Clinical Trials Registry, registration number: ACTRN12618000348257. World Health Organisation universal trial number: U1111–1210-1726. Electronic supplementary material The online version of this article (10.1186/s12887-018-1217-5) contains supplementary material, which is available to authorized users.

Background Peptide receptor radionuclide therapy (PRRT) with 177Lutetium (177Lu) -DOTATATE is effective treatment for neuroendocrine tumors (NETs). Dosimetry assessment can be used to maximize the tumour dose, while keeping the dose delivered to critical organs to acceptable levels. The association between tumour absorbed dosimetry (TAD) and progression-free (PFS) and overall survival (OS) is not well understood. Methods Single institution retrospective analysis of patients with metastatic NET whom underwent up to 4 cycles of 7.45GBq 177Lu octreotate PRRT. Intra-therapeutic tumour dosimetry was performed with non-gated single photon emission computed tomography (SPECT) to quantify activity at 5 time points after administration of 177 Lu during cycle 1. TAD per injected activity (A0) and estimated total TAD (multiplied by total administered activity of 177Lu) was correlated with OS and PFS using the Kaplan–Meier method and Cox proportional-hazards model. Results 79 patients were included, primary site: gastroenteric (48%), pancreatic (39%), bronchial (9%), other (4%), ECOG Performance status (PS) 0/1 (94%), Grade: G1 (47%), G2 (42%), G3 (11%), Ki-67≤20% (89%), concurrent chemotherapy use (29%). Mean TAD/A0 was 9(7-11) Gy/GBq. Progressive disease (54%) and death (29%) was seen. Median follow-up of 35 months. Median PFS was 32 [26-38] months. PFS was shorter with increasing ECOG PS (P = 0.02), tumour grade (P Conclusions TAD was independently associated with OS and PFS validating dosimetry assessment in NET patients undergoing PRRT. Prospective refinement of the association on larger, more homogenous cohorts of NET patients is needed. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Autism Spectrum Disorder (ASD) affects approximately 1% of the population and leads to impairments in social interaction, communication and restricted, repetitive behaviours. Establishing robust neuroimaging biomarkers of ASD using structural magnetic resonance imaging (MRI) is an important step for diagnosing and tailoring treatment, particularly early in life when interventions can have the greatest effect. However currently, there is mixed findings on the structural brain changes associated with autism. Therefore in this systematic review, recent (post-2007), high-resolution (3 T) MRI studies investigating brain morphology associated with ASD have been collated to identify robust neuroimaging biomarkers of ASD. A systematic search was conducted on three databases; PubMed, Web of Science and Scopus, resulting in 123 reviewed articles. Patients with ASD were observed to have increased whole brain volume, particularly under 6 years of age. Other consistent changes observed in ASD patients include increased volume in the frontal and temporal lobes, increased cortical thickness in the frontal lobe, increased surface area and cortical gyrification, and increased cerebrospinal fluid volume, as well as reduced cerebellum volume and reduced corpus callosum volume, compared to typically developing controls. Findings were inconsistent regarding the developmental trajectory of brain volume and cortical thinning with age in ASD, as well as potential volume differences in the white matter, hippocampus, amygdala, thalamus and basal ganglia. To elucidate these inconsistencies, future studies should look towards aggregating MRI data from multiple sites or available repositories to avoid underpowered studies, as well as utilising methods which quantify larger-scale image features to reduce the number of statistical tests performed, and hence risk of false positive findings. Additionally, studies should look to perform a thorough validation strategy, to ensure generalisability of study findings, as well as look to leverage the improved image resolution of 3 T scanning to identify subtle brain changes related to ASD.

This study examined postmenstrual age (PMA) estimation (in weeks) from brain diffusion MRI of very preterm born infants (born

Recent diffusion tensor imaging studies in adolescents and children with Autism Spectrum Disorder (ASD) have reported a loss or an inversion of the typical left-right lateralization in fronto-temporal regions crucial for sociocommunicative skills. No studies explored atypical lateralization in toddlers and its correlation with clinical severity of ASD. We recruited a cohort of 20 subjects aged 36 months or younger receiving a first clinical diagnosis of ASD (15 males; age range 20-36 months). Patients underwent diffusion MRI (High-Angular-Resolution Diffusion Imaging protocol). Data from cortical parcellation were combined with tractography to obtain a connection matrix and diffusion indexes (DI ) including mean fractional anisotropy (DFA ), number of tracts (DNUM ), and total tract length (DTTL ). A laterality index was generated for each measure, and then correlated with the Autism Diagnostic Observation Schedule-Generic (ADOS-G) total score. Laterality indexes of DFA were significantly correlated with ADOS-G total scores only in two intrafrontal connected areas (correlation was positive in one case and negative in the other). Laterality indexes of DTTL and DNUM showed significant negative correlations (P < 0.05) in six connected areas, mainly fronto-temporal. This study provides first evidence of a significant correlation between brain lateralization of diffusion indexes and clinical severity in toddlers with a first diagnosis of ASD. Significant correlations mainly involved regions within the fronto-temporal circuits, known to be crucial for sociocommunicative skills. It is of interest that all correlations but one were negative, suggesting an inversion of the typical left-right asymmetry in subjects with most severe clinical impairment.

Introduction: Accurate knowledge of O-6-methylguanine methyltransferase (MGMT) gene promoter subtype in patients with glioblastoma (GBM) is important for treatment. However, this test is not always available. Pre-operative diffusion MRI (dMRI) can be used to probe tumour biology using the apparent diffusion coefficient (ADC); however, its ability to act as a surrogate to predict MGMT status has shown mixed results. We investigated whether this was due to variations in the method used to analyse ADC. Methods: We undertook a retrospective study of 32 patients with GBM who had MGMT status measured. Matching pre-operative MRI data were used to calculate the ADC within contrast enhancing regions of tumour. The relationship between ADC and MGMT was examined using two published ADC methods. Results: A strong trend between a measure of 'minimum ADC' and methylation status was seen. An elevated minimum ADC was more likely in the methylated compared to the unmethylated MGMT group (U = 56, P = 0.0561). In contrast, utilising a two-mixture model histogram approach, a significant reduction in mean measure of the 'low ADC' component within the histogram was associated with an MGMT promoter methylation subtype (P < 0.0246). Conclusion: This study shows that within the same patient cohort, the method selected to analyse ADC measures has a significant bearing on the use of that metric as a surrogate marker of MGMT status. Thus for dMRI data to be clinically useful, consistent methods of data analysis need to be established prior to establishing any relationship with genetic or epigenetic profiling.

Damage to the blood-brain barrier (BBB) is an important secondary mechanism that occurs following traumatic brain injury (TBI) and may provide a potential therapeutic target to improve patient outcome. For such a progress to be realised, an accurate assessment of BBB compromise needs to be established.Fourteen patients with TBI were prospectively recruited. Post-traumatic BBB dysfunction was assessed using dynamic contrast-enhanced MRI (DCE-MRI), single-photon emission computerised tomography (SPECT) and serum S100B levels.A statistically significant correlation between standardised uptake value ratio (SUVR) calculated from 99mTc-DTPA SPECT and K(trans) (a volume transfer constant) from DCE-MRI was found for those eight patients who had concurrent scans. The positive correlation persisted when the data were corrected for patient age, number of days following trauma and both parameters combined. We found no statistically significant correlation between either of the imaging modalities and concurrent serum S100B levels.The correlation of SPECT with DCE-MRI suggests that either scan may be used to assess post-traumatic BBB damage. We could not support serum S100B to be an accurate measure of BBB damage when sampled a number of days following injury but the small number of patients, the heterogeneity in TBI patients and the delay following injury makes any firm conclusions regarding S100B and BBB difficult.

Background. Crossed cerebellar diaschisis is the disruption of functional connectivity between cerebrum and cerebellum after hemispheric unilateral brain lesions. In adults and to a lesser extent in children, crossed cerebellar diaschisis has been largely investigated by functional connectivity and demonstrated to influence paretic hand function. Objective. We aim to demonstrate a disruption in structural corticopontocerebellar (CPC) connectivity in children with congenital brain lesions and examine its correlation with paretic hand motor function. Methods. Thirty-six children (Manual Ability Classification System: I, n = 21; II, n = 15) with unilateral brain lesions and 18 controls were analyzed in a case-control study, and diffusion magnetic resonance imaging data were acquired at 3T. High angular resolution diffusion imaging probabilistic tractography was employed for the region of interest–based reconstruction of CPC tracts. To identify statistical differences in structural cerebrocerebellar connectivity between case and control groups, an asymmetry index based on the number of streamlines of CPC tracts was used. In the case group, the correlation between asymmetry index and hand function measures was also determined. Results. Projections through the middle cerebellar peduncle to the contralateral cerebral cortex showed greater asymmetry in children with congenital unilateral brain lesion compared to controls ( P = .03), thus indicating a disruption of structural cerebrocerebellar connectivity. The degree of asymmetry index showed a correlation ( P < .03; r = −0.31) with impaired hand abilities in bimanual tasks. Conclusions. Disruption of structural cerebrocerebellar connectivity is present in patients with congenital unilateral brain injury and might be related to impaired hand function in bimanual skills, with potential implication in tailoring early intervention strategies.

The brains of patients suffering from Alzheimer's disease (AD) have three classical pathological hallmarks: amyloid-beta (Aβ) plaques, tau tangles, and neurodegeneration, including that of cholinergic neurons of the basal forebrain. However the relationship between Aβ burden and basal forebrain degeneration has not been extensively studied. To investigate this association, basal forebrain volumes were determined from magnetic resonance images of controls, subjects with amnestic mild cognitive impairment (aMCI) and AD patients enrolled in the longitudinal Alzheimer's Disease Neuroimaging Initiative (ADNI) and Australian Imaging, Biomarkers and Lifestyle (AIBL) studies. In the AIBL cohort, these volumes were correlated within groups to neocortical gray matter retention of Pittsburgh compound B (PiB) from positron emission tomography images as a measure of Aβ load. The basal forebrain volumes of AD and aMCI subjects were significantly reduced compared to those of control subjects. Anterior basal forebrain volume was significantly correlated to neocortical PiB retention in AD subjects and aMCI subjects with high Aβ burden, whereas posterior basal forebrain volume was significantly correlated to neocortical PiB retention in control subjects with high Aβ burden. Therefore this study provides new evidence for a correlation between neocortical Aβ accumulation and basal forebrain degeneration. In addition, cluster analysis showed that subjects with a whole basal forebrain volume below a determined cut-off value had a 7 times higher risk of having a worse diagnosis within ~18 months., Highlights • The link between amyloid (Aβ) and basal forebrain degeneration in AD is unclear. • We find that basal forebrain volumes are correlated with neocortical Aβ burden. • Basal forebrain volume correlates with Aβ burden in at-risk control subjects. • Basal forebrain atrophy delineates subjects at increased risk of progressing to AD.

Limb weakness in amyotrophic lateral sclerosis (ALS) is typically asymmetric. Previous studies have identified an effect of limb dominance on onset and spread of weakness, however relative atrophy of dominant and non-dominant brain regions has not been investigated. Our objective was to use voxel-based morphometry (VBM) to explore gray matter (GM) asymmetry in ALS, in the context of limb dominance. 30 ALS subjects were matched with 17 healthy controls. All subjects were right-handed. Each underwent a structural MRI sequence, from which GM segmentations were generated. Patterns of GM atrophy were assessed in ALS subjects with first weakness in a right-sided limb (n = 15) or left-sided limb (n = 15). Within each group, a voxelwise comparison was also performed between native and mirror GM images, to identify regions of hemispheric GM asymmetry. Subjects with ALS showed disproportionate atrophy of the dominant (left) motor cortex hand area, irrespective of the side of first limb weakness (p, Highlights • GM asymmetry was assessed, using VBM, in right-handed ALS and control subjects. • The dominant motor hand area underwent disproportionate atrophy in ALS (p ≤ 0.01). • In subjects with dominant limb onset, there was greater atrophy of language areas. • A VBM asymmetry protocol is more sensitive than standard group comparisons. • Asymmetric vulnerability of cortical GM supports a role for brain development in the pathogenesis of ALS.