An Informatics Platform for the Management of Data for Australian Dementia Network (ADNeT) Initiative.

Alzheimer's disease and other dementias are becoming more prevalent and placing increasing burdens on the community. The ADNeT Screening and Trials initiative aims to improve research outcomes by identifying people with an increased risk of developing these diseases and directing them to suitable clinical trials. To support the initiative, we have developed a modular informatics platform utilizing private cloud deployment to securely manage operational and research data across six clinical sites.

A FHIR Native Radiology Informatics Platform.

FHIR is a new standard that is rapidly being adopted in healthcare. We describe and implement a Radiology informatics platform (RIS) that is FHIR native and incorporates the ability to execute AI algorithms to aid with the interpretation of scans. Our design utilises the FHIR workflow pattern as an application programming interface with functionality provided by independent micro services thus granting flexibility and expandability.

An Approach for Generating Realistic Australian Synthetic Healthcare Data.

Healthcare data is a scarce resource and access is often cumbersome. While medical software development would benefit from real datasets, the privacy of the patients is held at a higher priority. Realistic synthetic healthcare data can fill this gap by providing a dataset for quality control while at the same time preserving the patient's anonymity and privacy. Existing methods focus on American or European patient healthcare data but none is exclusively focused on the Australian population. Australia is a highly diverse country that has a unique healthcare system. To overcome this problem, we used a popular publicly available tool, Synthea, to generate disease progressions based on the Australian population. With this approach, we were able to generate 100,000 patients following Queensland (Australia) demographics.

Multi T1-weighted contrast imaging and T1 mapping with compressed sensing FLAWS at 3 T.

OBJECTIVE: The Fluid And White matter Suppression (FLAWS) MRI sequence provides multiple T1-weighted contrasts of the brain in a single acquisition. However, the FLAWS acquisition time is approximately 8 min with a standard GRAPPA 3 acceleration factor at 3 T. This study aims at reducing the FLAWS acquisition time by providing a new sequence optimization based on a Cartesian phyllotaxis k-space undersampling and a compressed sensing (CS) reconstruction. This study also aims at showing that T1 mapping can be performed with FLAWS at 3 T. MATERIALS AND METHODS: The CS FLAWS parameters were determined using a method based on a profit function maximization under constraints. The FLAWS optimization and T1 mapping were assessed with in-silico, in-vitro and in-vivo (10 healthy volunteers) experiments conducted at 3 T. RESULTS: In-silico, in-vitro and in-vivo experiments showed that the proposed CS FLAWS optimization allows the acquisition time of a 1 mm-isotropic full-brain scan to be reduced from [Formula: see text] to [Formula: see text] without decreasing image quality. In addition, these experiments demonstrate that T1 mapping can be performed with FLAWS at 3 T. DISCUSSION: The results obtained in this study suggest that the recent advances in FLAWS imaging allow to perform multiple T1-weighted contrast imaging and T1 mapping in a single [Formula: see text] sequence acquisition.

A prospective cohort study of prodromal Alzheimer's disease: Prospective Imaging Study of Ageing: Genes, Brain and Behaviour (PISA).

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.

High-resolution multi-T1 -weighted contrast and T1 mapping with low B1>+ sensitivity using the fluid and white matter suppression (FLAWS) sequence at 7T.

PURPOSE: To demonstrate that fluid and white matter suppression (FLAWS) imaging can be used for high-resolution T1 mapping with low transmitted bias field ( B1+ ) sensitivity at 7T. METHODS: The FLAWS sequence was optimized for 0.8-mm isotropic resolution imaging. The theoretical accuracy and precision of the FLAWS T1 mapping was compared with the one of the magnetization-prepared two rapid gradient echoes (MP2RAGE) sequence optimized for low B1+ sensitivity. FLAWS images were acquired at 7T on six healthy volunteers (21 to 48 years old; two women). MP2RAGE and saturation-prepared with two rapid gradient echoes (SA2RAGE) datasets were also acquired to obtain T1 mapping references and B1+ maps. The contrast-to-noise ratio (CNR) between brain tissues was measured in the FLAWS-hco and MP2RAGE-uni images. The Pearson correlation was measured between the MP2RAGE and FLAWS T1 maps. The effect of B1+ on FLAWS T1 mapping was assessed using the Pearson correlation. RESULTS: The FLAWS-hco images were characterized by a higher brain tissue CNR ( CNRWM/GM=5.5 , CNRWM/CSF=14.7 , CNRGM/CSF=10.3 ) than the MP2RAGE-uni images ( CNRWM/GM=4.9 , CNRWM/CSF=6.6 , CNRGM/CSF=3.7 ). The theoretical accuracy and precision of the FLAWS T1 mapping ( acc=91.9%;prec=90.2% ) were in agreement with those provided by the MP2RAGE T1 mapping ( acc=90.0%;prec=86.8% ). A good agreement was found between in vivo T1 values measured with the MP2RAGE and FLAWS sequences (r = 0.91). A weak correlation was found between the FLAWS T1 map and the B1+ map within cortical gray matter and white matter segmentations ( rWM=-0.026 ; rGM=0.081 ). CONCLUSION: The results from this study suggest that FLAWS is a good candidate for high-resolution T1 -weighted imaging and T1 mapping at the field strength of 7T.

Comorbidity of Cerebrovascular and Alzheimer's Disease in Aging.

BACKGROUND: Cerebrovascular disease often coexists with Alzheimer's disease (AD). While both diseases share common risk factors, their interrelationship remains unclear. Increasing the understanding of how cerebrovascular changes interact with AD is essential to develop therapeutic strategies and refine biomarkers for early diagnosis. OBJECTIVE: We investigate the prevalence and risk factors for the comorbidity of amyloid-ß (Aß) and cerebrovascular disease in the Australian Imaging, Biomarkers and Lifestyle Study of Ageing, and further examine their cross-sectional association. METHODS: A total of 598 participants (422 cognitively normal, 89 with mild cognitive impairment, 87 with AD) underwent positron emission tomography and structural magnetic resonance imaging for assessment of Aß deposition and cerebrovascular disease. Individuals were categorized based on the comorbidity status of Aß and cerebrovascular disease (V) as Aß-V-, Aß-V+, Aß+V-, or Aß+V+. RESULTS: Advancing age was associated with greater likelihood of cerebrovascular disease, high Aß load and their comorbidity. Apolipoprotein E ɛ4 carriage was only associated with Aß positivity. Greater total and regional WMH burden were observed in participants with AD. However, no association were observed between Aß and WMH measures after stratification by clinical classification, suggesting that the observed association between AD and cerebrovascular disease was driven by the common risk factor of age. CONCLUSION: Our observations demonstrate common comorbid condition of Aß and cerebrovascular disease in later life. While our study did not demonstrate a convincing cross-sectional association between Aß and WMH burden, future longitudinal studies are required to further confirm this.

Restricted Effect of Cerebral Microbleeds on Regional Magnetic Susceptibility.

BACKGROUND: Cortical iron accumulation has been reported as a pathological feature of Alzheimer's disease (AD). The cause of cortical iron elevation in AD is unknown but may be contributed by hemosiderin deposits in cerebral microbleeds that frequently occur in this disease. OBJECTIVE: To investigate the impact of cerebral microbleeds (which are more frequent in AD) on the magnetic susceptibility of the surrounding brain tissue. METHODS: 32 MRI scans from the Australian Imaging, Biomarker and Lifestyle (AIBL) study were found to have cerebral microbleeds by manual assessment of susceptibility weighted images. Quantitative susceptibility mapping (QSM; an MRI technique that is sensitive to iron) was used to estimate iron content in the tissue surrounding the microbleed in four concentric radii. Furthermore, the mirror regions on the contralateral hemisphere were also demarcated. A simulation analysis was conducted to investigate the effect of QSM imaging on cerebral microbleeds with varying sizes. RESULTS: 77 microbleeds were identified from the available scans. The immediate proximal region to the cerebral microbleeds had enhanced tissue susceptibility (∼0.02 PPM), but importantly, this did not extend beyond one voxel radius. This finding with in vivo data was also replicated in a simulation study. However, the presence of microbleeds could lead to over-estimation of tissue QSM in unsupervised quantification, therefore processing methods to avoid this artefact without the need for their manual identification are proposed. CONCLUSION: The local changes in susceptibility due to microbleeds outside the focal lesion are restricted to 1 voxel and may be explained by partial voluming artefacts caused by limited imaging resolution. The susceptibly change induced by the microbleed is a relatively small proportion of tissue and could not account for regional iron changes observed in AD cortex.

Increased cerebral blood flow with increased amyloid burden in the preclinical phase of alzheimer's disease.

BACKGROUND: Arterial spin labeling (ASL) is an emerging MRI technique for noninvasive measurement of cerebral blood flow (CBF) that has been used to show hemodynamic changes in the brains of people with Alzheimer's disease (AD). CBF changes have been measured using positron emission tomography (PET) across the AD spectrum, but ASL showed limited success in measuring CBF variations in the preclinical phase of AD, where amyloid ß (Aß) plaques accumulate in the decades prior to symptom onset. PURPOSE: To investigate the relationship between CBF measured by multiphase-pseudocontinuous-ASL (MP-PCASL) and Aß burden as measured by 11 C-PiB PET imaging in a study of cognitively normal (CN) subjects age over 65. STUDY TYPE: Cross-sectional. POPULATION: Forty-six CN subjects including 33 with low levels of Aß burden and 13 with high levels of Aß. FIELD STRENGTH/SEQUENCE: 3T/3D MP-PCASL. ASSESSMENT: The MP-PCASL method was chosen because it has a high signal-to-noise ratio. Furthermore, the data were analyzed using an efficient processing pipeline consisting of motion correction, ASL motion correction imprecision removal, temporal and spatial filtering, and partial volume effect correction. STATISTICAL TESTS: General Linear Model. RESULTS: In CN subjects positive for Aß burden (n = 13), we observed a positive correlation between CBF and Aß burden in the hippocampus, amygdala, caudate (P < 0.01), frontal, temporal, and insula (P < 0.05). DATA CONCLUSION: To the best of our knowledge, this is the first study using MP-PCASL in the study of AD, and the results suggest a potential compensatory hemodynamic mechanism that protects against pathology in the early stages of AD. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2020;51:505-513.

A Multi-center Prospective Study for Implementation of an MRI-Only Prostate Treatment Planning Workflow.

Purpose: This project investigates the feasibility of implementation of MRI-only prostate planning in a prospective multi-center study. Method and Materials: A two-phase implementation model was utilized where centers performed retrospective analysis of MRI-only plans for five patients followed by prospective MRI-only planning for subsequent patients. Feasibility was assessed if at least 23/25 patients recruited to phase 2 received MRI-only treatment workflow. Whole-pelvic MRI scans (T2 weighted, isotropic 1.6 mm voxel 3D sequence) were converted to pseudo-CT using an established atlas-based method. Dose plans were generated using MRI contoured anatomy with pseudo-CT for dose calculation. A conventional CT scan was acquired subsequent to MRI-only plan approval for quality assurance purposes (QA-CT). 3D Gamma evaluation was performed between pseudo-CT calculated plan dose and recalculation on QA-CT. Criteria was 2%, 2 mm criteria with 20% low dose threshold. Gold fiducial marker positions for image guidance were compared between pseudo-CT and QA-CT scan prior to treatment. Results: All 25 patients recruited to phase 2 were treated using the MRI-only workflow. Isocenter dose differences between pseudo-CT and QA-CT were -0.04 ± 0.93% (mean ± SD). 3D Gamma dose comparison pass-rates were 99.7% ± 0.5% with mean gamma 0.22 ± 0.07. Results were similar for the two centers using two different scanners. All gamma comparisons exceeded the 90% pass-rate tolerance with a minimum gamma pass-rate of 98.0%. In all cases the gold fiducial markers were correctly identified on MRI and the distances of all seeds to centroid were within the tolerance of 1.0 mm of the distances on QA-CT (0.07 ± 0.41 mm), with a root-mean-square difference of 0.42 mm. Conclusion: The results support the hypothesis that an MRI-only prostate workflow can be implemented safely and accurately with appropriate quality assurance methods.

Sexual Dimorphism of Resting-State Network Connectivity in Healthy Ageing.

OBJECTIVES: The onset of many illnesses is confounded with age and sex. Increasing age is a risk factor for the development of many illnesses, and sexual dimorphism influences brain anatomy, function, and cognition. Here, we examine frequency-specific connectivity in resting-state networks in a large sample (n = 406) of healthy aged adults. METHOD: We quantify frequency-specific connectivity in three resting-state networks known to be implicated in age-related decline: the default mode, dorsal attention, and salience networks, using multiband functional magnetic resonance imaging. Frequency-specific connectivity was quantified in four bands: low (0.015-0.027 Hz), moderately low (0.027-0.073 Hz), moderately high (0.073-0.198 Hz), and high (0.198-0.5 Hz) frequency bands, using mean intensity and spatial extent. Differences in connectivity between the sexes in each of the three networks were examined. RESULTS: Each network showed the largest intensity and spatial extent at low frequencies and smallest extent at high frequencies. Males showed greater connectivity than females in the salience network. Females showed greater connectivity than males in the default mode network. DISCUSSION: Results in this healthy aged cohort are compatible with those obtained in young samples, suggesting that frequency-specific connectivity, and differences between the sexes, are maintained into older age. Our results indicate that sex should be considered as an influencing factor in studies of resting-state connectivity.

MRI white matter lesion segmentation using an ensemble of neural networks and overcomplete patch-based voting.

Accurate quantification of white matter hyperintensities (WMH) from Magnetic Resonance Imaging (MRI) is a valuable tool for the analysis of normal brain ageing or neurodegeneration. Reliable automatic extraction of WMH lesions is challenging due to their heterogeneous spatial occurrence, their small size and their diffuse nature. In this paper, we present an automatic method to segment these lesions based on an ensemble of overcomplete patch-based neural networks. The proposed method successfully provides accurate and regular segmentations due to its overcomplete nature while minimizing the segmentation error by using a boosted ensemble of neural networks. The proposed method compared favourably to state of the art techniques using two different neurodegenerative datasets.

Combining images and anatomical knowledge to improve automated vein segmentation in MRI.

PURPOSE: To improve the accuracy of automated vein segmentation by combining susceptibility-weighted images (SWI), quantitative susceptibility maps (QSM), and a vein atlas to produce a resultant image called a composite vein image (CV image). METHOD: An atlas was constructed in common space from manually traced MRI images from ten volunteers. The composite vein image was derived for each subject as a weighted sum of three inputs; an SWI image, a QSM image and the vein atlas. The weights for each input and each anatomical location, called template priors, were derived by assessing the accuracy of each input over an independent data set. The accuracy of vein segmentations derived automatically from each of the CV image, SWI, and QSM image sets was assessed by comparison with manual tracings. Three different automated vein segmentation techniques were used, and ten performance metrics evaluated. RESULTS: Vein segmentations using the CV image were comprehensively better than those derived from SWI or QSM images (mean Cohen's d = 1.1). Sixty permutations of performance metric, benchmark image, and automated segmentation technique were evaluated. Vein identification improvements that were both large and significant (Cohen's d > 0.80, p < 0.05) were found in 77% of the permutations, compared to no improvement in 5%. CONCLUSION: The accuracy of automated vein segmentations derived from the composite vein image was overwhelmingly superior to segmentations derived from SWI or QSM alone.

Cerebral quantitative susceptibility mapping predicts amyloid-ß-related cognitive decline.

See Derry and Kent (doi:10.1093/awx167) for a scientific commentary on this article.The large variance in cognitive deterioration in subjects who test positive for amyloid-ß by positron emission tomography indicates that convergent pathologies, such as iron accumulation, might combine with amyloid-ß to accelerate Alzheimer's disease progression. Here, we applied quantitative susceptibility mapping, a relatively new magnetic resonance imaging method sensitive to tissue iron, to assess the relationship between iron, amyloid-ß load, and cognitive decline in 117 subjects who underwent baseline magnetic resonance imaging and amyloid-ß positron emission tomography from the Australian Imaging, Biomarkers and Lifestyle study (AIBL). Cognitive function data were collected every 18 months for up to 6 years from 100 volunteers who were either cognitively normal (n = 64) or diagnosed with mild cognitive impairment (n = 17) or Alzheimer's disease (n = 19). Among participants with amyloid pathology (n = 45), higher hippocampal quantitative susceptibility mapping levels predicted accelerated deterioration in composite cognition tests for episodic memory [ß(standard error) = -0.169 (0.034), P = 9.2 × 10-7], executive function [ß(standard error) = -0.139 (0.048), P = 0.004), and attention [ß(standard error) = -0.074 (0.029), P = 0.012]. Deteriorating performance in a composite of language tests was predicted by higher quantitative susceptibility mapping levels in temporal lobe [ß(standard error) = -0.104 (0.05), P = 0.036] and frontal lobe [ß(standard error) = -0.154 (0.055), P = 0.006]. These findings indicate that brain iron might combine with amyloid-ß to accelerate clinical progression and that quantitative susceptibility mapping could be used in combination with amyloid-ß positron emission tomography to stratify individuals at risk of decline.

Partial volume model for brain MRI scan using MP2RAGE.

MP2RAGE is a T1 weighted MRI sequence that estimates a composite image providing much reduction of the receiver bias, has a high intensity dynamic range, and provides an estimate of T1 mapping. It is, therefore, an appealing option for brain morphometry studies. However, previous studies have reported a difference in cortical thickness computed from MP2RAGE compared with widely used Multi-Echo MPRAGE. In this article, we demonstrated that using standard segmentation and partial volume estimation techniques on MP2RAGE introduces systematic errors, and we proposed a new model to estimate partial volume of the cortical gray matter. We also included in their model a local estimate of tissue intensity to take into account the natural variation of tissue intensity across the brain. A theoretical framework is provided and validated using synthetic and physical phantoms. A repeatability experiment comparing MPRAGE and MP2RAGE confirmed that MP2RAGE using our model could be considered for structural imaging in brain morphology study, with similar cortical thickness estimate than that computed with MPRAGE. Hum Brain Mapp 38:5115-5127, 2017. © 2017 Wiley Periodicals, Inc.

Improved Quantification of Cerebral Vein Oxygenation Using Partial Volume Correction.

Purpose: Quantitative susceptibility mapping (QSM) enables cerebral venous characterization and physiological measurements, such as oxygen extraction fraction (OEF). The exquisite sensitivity of QSM to deoxygenated blood makes it possible to image small veins; however partial volume effects must be addressed for accurate quantification. We present a new method, Iterative Cylindrical Fitting (ICF), to estimate voxel-based partial volume effects for susceptibility maps and use it to improve OEF quantification of small veins with diameters between 1.5 and 4 voxels. Materials and Methods: Simulated QSM maps were generated to assess the performance of the ICF method over a range of vein geometries with varying echo times and noise levels. The ICF method was also applied to in vivo human brain data to assess the feasibility and behavior of OEF measurements compared to the maximum intensity voxel (MIV) method. Results: Improved quantification of OEF measurements was achieved for vessels with contrast to noise greater than 3.0 and vein radii greater than 0.75 voxels. The ICF method produced improved quantitative accuracy of OEF measurement compared to the MIV approach (mean OEF error 7.7 vs. 12.4%). The ICF method provided estimates of vein radius (mean error <27%) and partial volume maps (root mean-squared error <13%). In vivo results demonstrated consistent estimates of OEF along vein segments. Conclusion: OEF quantification in small veins (1.5-4 voxels in diameter) had lower error when using partial volume estimates from the ICF method.

ASPREE-NEURO study protocol: A randomized controlled trial to determine the effect of low-dose aspirin on cerebral microbleeds, white matter hyperintensities, cognition, and stroke in the healthy elderly.

Rationale Cerebral microbleeds seen on brain magnetic resonance imaging are markers of small vessel disease, linked to cognitive dysfunction and increased ischemic and hemorrhagic stroke risk. Observational studies suggest that aspirin use may induce cerebral microbleeds, and associated overt intracranial hemorrhage, but this has not been definitively resolved. Aims ASPREE-NEURO will determine the effect of aspirin on cerebral microbleed development over three years in healthy adults aged 70 years and over, participating in the larger 'ASPirin in Reducing Events in the Elderly (ASPREE)' primary prevention study of aspirin. Sample size Five hundred and fifty-nine participants provide 75% power (two-sided p value of 0.05) to determine an average difference of 0.5 cerebral microbleed per person after three years. Methods and design A multi-center, randomized placebo-controlled trial of 100 mg daily aspirin in participants who have brain magnetic resonance imaging at study entry, one and three years after randomization and who undergo cognitive testing at the same time points. Study outcomes The primary outcome is the number of new cerebral microbleeds on magnetic resonance imaging after three years. Secondary outcomes are the number of new cerebral microbleeds after one year, change in volume of white matter hyperintensity, cognitive function, and stroke. Discussion ASPREE-NEURO will resolve whether aspirin affects the presence and number of cerebral microbleeds, their relationship with cognitive performance, and indicate whether consideration of cerebral microbleeds alters the risk-benefit profile of aspirin in primary prevention for older people. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12613001313729.

Design, implementation and operation of a multimodality research imaging informatics repository.

BACKGROUND: Biomedical imaging research increasingly involves acquiring, managing and processing large amounts of distributed imaging data. Integrated systems that combine data, meta-data and workflows are crucial for realising the opportunities presented by advances in imaging facilities. METHODS: This paper describes the design, implementation and operation of a multi-modality research imaging data management system that manages imaging data obtained from biomedical imaging scanners operated at Monash Biomedical Imaging (MBI), Monash University in Melbourne, Australia. In addition to Digital Imaging and Communications in Medicine (DICOM) images, raw data and non-DICOM biomedical data can be archived and distributed by the system. Imaging data are annotated with meta-data according to a study-centric data model and, therefore, scientific users can find, download and process data easily. RESULTS: The research imaging data management system ensures long-term usability, integrity inter-operability and integration of large imaging data. Research users can securely browse and download stored images and data, and upload processed data via subject-oriented informatics frameworks including the Distributed and Reflective Informatics System (DaRIS), and the Extensible Neuroimaging Archive Toolkit (XNAT).

New partial volume estimation methods for MRI MP2RAGE.

Magnetic resonance imaging (MRI) is commonly used as a medical iagnosis tool, especially for brain applications. Some limitations affecting image quality include receive field (RF) inhomogeneity and partial volume (PV) effects which arise when a voxel contains two different tissues, introducing blurring. The novel Magnetization-Prepared 2 Rapid Acquisition Gradient Echoes (MP2RAGE) provides an image robust to RF inhomogeneity. However, PV effects are still an issue for automated brain quantification. PV estimation methods have been proposed based on computing the proportion of one tissue with respect to the other using linear interpolation of pure tissue intensity means. We demonstrated that this linear model introduces bias when used with MP2RAGE and we propose two novel solutions. The PV estimation methods were tested on 4 MP2RAGE data sets.