Accuracy of TrUE-Net in comparison to established white matter hyperintensity segmentation methods: An independent validation study.

White matter hyperintensities (WMH) are nearly ubiquitous in the aging brain, and their topography and overall burden are associated with cognitive decline. Given their numerosity, accurate methods to automatically segment WMH are needed. Recent developments, including the availability of challenge data sets and improved deep learning algorithms, have led to a new promising deep-learning based automated segmentation model called TrUE-Net, which has yet to undergo rigorous independent validation. Here, we compare TrUE-Net to six established automated WMH segmentation tools, including a semi-manual method. We evaluated the techniques at both global and regional level to compare their ability to detect the established relationship between WMH burden and age. We found that TrUE-Net was highly reliable at identifying WMH regions with low false positive rates, when compared to semi-manual segmentation as the reference standard. TrUE-Net performed similarly or favorably when compared to the other automated techniques. Moreover, TrUE-Net was able to detect relationships between WMH and age to a similar degree as the reference standard semi-manual segmentation at both the global and regional level. These results support the use of TrUE-Net for identifying WMH at the global or regional level, including in large, combined datasets.

Cross-sectional associations between 24-hour time-use composition, grey matter volume and cognitive function in healthy older adults.

BACKGROUND: Increasing physical activity (PA) is an effective strategy to slow reductions in cortical volume and maintain cognitive function in older adulthood. However, PA does not exist in isolation, but coexists with sleep and sedentary behaviour to make up the 24-hour day. We investigated how the balance of all three behaviours (24-hour time-use composition) is associated with grey matter volume in healthy older adults, and whether grey matter volume influences the relationship between 24-hour time-use composition and cognitive function. METHODS: This cross-sectional study included 378 older adults (65.6 ± 3.0 years old, 123 male) from the ACTIVate study across two Australian sites (Adelaide and Newcastle). Time-use composition was captured using 7-day accelerometry, and T1-weighted magnetic resonance imaging was used to measure grey matter volume both globally and across regions of interest (ROI: frontal lobe, temporal lobe, hippocampi, and lateral ventricles). Pairwise correlations were used to explore univariate associations between time-use variables, grey matter volumes and cognitive outcomes. Compositional data analysis linear regression models were used to quantify associations between ROI volumes and time-use composition, and explore potential associations between the interaction between ROI volumes and time-use composition with cognitive outcomes. RESULTS: After adjusting for covariates (age, sex, education), there were no significant associations between time-use composition and any volumetric outcomes. There were significant interactions between time-use composition and frontal lobe volume for long-term memory (p = 0.018) and executive function (p = 0.018), and between time-use composition and total grey matter volume for executive function (p = 0.028). Spending more time in moderate-vigorous PA was associated with better long-term memory scores, but only for those with smaller frontal lobe volume (below the sample mean). Conversely, spending more time in sleep and less time in sedentary behaviour was associated with better executive function in those with smaller total grey matter volume. CONCLUSIONS: Although 24-hour time use was not associated with total or regional grey matter independently, total grey matter and frontal lobe grey matter volume moderated the relationship between time-use composition and several cognitive outcomes. Future studies should investigate these relationships longitudinally to assess whether changes in time-use composition correspond to changes in grey matter volume and cognition.

Disease progression modelling of Alzheimer's disease using probabilistic principal components analysis.

The recent biological redefinition of Alzheimer's Disease (AD) has spurred the development of statistical models that relate changes in biomarkers with neurodegeneration and worsening condition linked to AD. The ability to measure such changes may facilitate earlier diagnoses for affected individuals and help in monitoring the evolution of their condition. Amongst such statistical tools, disease progression models (DPMs) are quantitative, data-driven methods that specifically attempt to describe the temporal dynamics of biomarkers relevant to AD. Due to the heterogeneous nature of this disease, with patients of similar age experiencing different AD-related changes, a challenge facing longitudinal mixed-effects-based DPMs is the estimation of patient-realigning time-shifts. These time-shifts are indispensable for meaningful biomarker modelling, but may impact fitting time or vary with missing data in jointly estimated models. In this work, we estimate an individual's progression through Alzheimer's disease by combining multiple biomarkers into a single value using a probabilistic formulation of principal components analysis. Our results show that this variable, which summarises AD through observable biomarkers, is remarkably similar to jointly estimated time-shifts when we compute our scores for the baseline visit, on cross-sectional data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Reproducing the expected properties of clinical datasets, we confirm that estimated scores are robust to missing data or unavailable biomarkers. In addition to cross-sectional insights, we can model the latent variable as an individual progression score by repeating estimations at follow-up examinations and refining long-term estimates as more data is gathered, which would be ideal in a clinical setting. Finally, we verify that our score can be used as a pseudo-temporal scale instead of age to ignore some patient heterogeneity in cohort data and highlight the general trend in expected biomarker evolution in affected individuals.

Early brain morphometrics from neonatal MRI predict motor and cognitive outcomes at 2-years corrected age in very preterm infants.

Infants born very preterm face a range of neurodevelopmental challenges in cognitive, language, behavioural and/or motor domains. Early accurate identification of those at risk of adverse neurodevelopmental outcomes, through clinical assessment and Magnetic Resonance Imaging (MRI), enables prognostication of outcomes and the initiation of targeted early interventions. This study utilises a prospective cohort of 181 infants born <31 weeks gestation, who had 3T MRIs acquired at 29-35 weeks postmenstrual age and a comprehensive neurodevelopmental evaluation at 2 years corrected age (CA). Cognitive, language and motor outcomes were assessed using the Bayley Scales of Infant and Toddler Development - Third Edition and functional motor outcomes using the Neuro-sensory Motor Developmental Assessment. By leveraging advanced structural MRI pre-processing steps to standardise the data, and the state-of-the-art developing Human Connectome Pipeline, early MRI biomarkers of neurodevelopmental outcomes were identified. Using Least Absolute Shrinkage and Selection Operator (LASSO) regression, significant associations between brain structure on early MRIs with 2-year outcomes were obtained (r = 0.51 and 0.48 for motor and cognitive outcomes respectively) on an independent 25% of the data. Additionally, important brain biomarkers from early MRIs were identified, including cortical grey matter volumes, as well as cortical thickness and sulcal depth across the entire cortex. Adverse outcome on the Bayley-III motor and cognitive composite scores were accurately predicted, with an Area Under the Curve of 0.86 for both scores. These associations between 2-year outcomes and patient prognosis and early neonatal MRI measures demonstrate the utility of imaging prior to term equivalent age for providing earlier commencement of targeted interventions for infants born preterm.

Functional re-organization of hippocampal-cortical gradients during naturalistic memory processes.

The functional organization of the hippocampus mirrors that of the cortex, changing smoothly along connectivity gradients and abruptly at inter-areal boundaries. Hippocampal-dependent cognitive processes require flexible integration of these hippocampal gradients into functionally related cortical networks. To understand the cognitive relevance of this functional embedding, we acquired fMRI data while participants viewed brief news clips, either containing or lacking recently familiarized cues. Participants were 188 healthy mid-life adults and 31 adults with mild cognitive impairment (MCI) or Alzheimer's disease (AD). We employed a recently developed technique - connectivity gradientography - to study gradually changing patterns of voxel to whole brain functional connectivity and their sudden transitions. We observed that functional connectivity gradients of the anterior hippocampus map onto connectivity gradients across the default mode network during these naturalistic stimuli. The presence of familiar cues in the news clips accentuates a stepwise transition across the boundary from the anterior to the posterior hippocampus. This functional transition is shifted in the posterior direction in the left hippocampus of individuals with MCI or AD. These findings shed new light on the functional integration of hippocampal connectivity gradients into large-scale cortical networks, how these adapt with memory context and how these change in the presence of neurodegenerative disease.

Lower hypothalamic volume with lower body mass index is associated with shorter survival in patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Weight loss in patients with amyotrophic lateral sclerosis (ALS) is associated with faster disease progression and shorter survival. Decreased hypothalamic volume is proposed to contribute to weight loss due to loss of appetite and/or hypermetabolism. We aimed to investigate the relationship between hypothalamic volume and body mass index (BMI) in ALS and Alzheimer's disease (AD), and the associations of hypothalamic volume with weight loss, appetite, metabolism and survival in patients with ALS. METHODS: We compared hypothalamic volumes from magnetic resonance imaging scans with BMI for patients with ALS (n = 42), patients with AD (n = 167) and non-neurodegenerative disease controls (n = 527). Hypothalamic volumes from patients with ALS were correlated with measures of appetite and metabolism, and change in anthropomorphic measures and disease outcomes. RESULTS: Lower hypothalamic volume was associated with lower and higher BMI in ALS (quadratic association; probability of direction = 0.96). This was not observed in AD patients or controls. Hypothalamic volume was not associated with loss of appetite (p = 0.58) or hypermetabolism (p = 0.49). Patients with lower BMI and lower hypothalamic volume tended to lose weight (p = 0.08) and fat mass (p = 0.06) over the course of their disease, and presented with an increased risk of earlier death (hazard ratio [HR] 3.16, p = 0.03). Lower hypothalamic volume alone trended for greater risk of earlier death (HR 2.61, p = 0.07). CONCLUSION: These observations suggest that lower hypothalamic volume in ALS contributes to positive and negative energy balance, and  is not universally associated with loss of appetite or hypermetabolism. Critically, lower hypothalamic volume with lower BMI was associated with weight loss and earlier death.

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.

Leukocyte surface biomarkers implicate deficits of innate immunity in sporadic Alzheimer's disease.

INTRODUCTION: Blood-based diagnostics and prognostics in sporadic Alzheimer's disease (AD) are important for identifying at-risk individuals for therapeutic interventions. METHODS: In three stages, a total of 34 leukocyte antigens were examined by flow cytometry immunophenotyping. Data were analyzed by logistic regression and receiver operating characteristic (ROC) analyses. RESULTS: We identified leukocyte markers differentially expressed in the patients with AD. Pathway analysis revealed a complex network involving upregulation of complement inhibition and downregulation of cargo receptor activity and Aß clearance. A proposed panel including four leukocyte markers - CD11c, CD59, CD91, and CD163 - predicts patients' PET Aß status with an area under the curve (AUC) of 0.93 (0.88 to 0.97). CD163 was the top performer in preclinical models. These findings have been validated in two independent cohorts. CONCLUSION: Our finding of changes on peripheral leukocyte surface antigens in AD implicates the deficit in innate immunity. Leukocyte-based biomarkers prove to be both sensitive and practical for AD screening and diagnosis.

Assessment of a polygenic hazard score for the onset of pre-clinical Alzheimer's disease.

BACKGROUND: With a growing number of loci associated with late-onset (sporadic) Alzheimer's disease (AD), the polygenic contribution to AD is now well established. The development of polygenic risk score approaches have shown promising results for identifying individuals at higher risk of developing AD, thereby facilitating the development of preventative and therapeutic strategies. A polygenic hazard score (PHS) has been proposed to quantify age-specific genetic risk for AD. In this study, we assessed the predictive power and transferability of this PHS in an independent cohort, to support its clinical utility. RESULTS: Using genotype and imaging data from 780 individuals enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we investigated associations between the PHS and several AD-related traits, including 1) cross-sectional Aß-amyloid (Aß) deposition, 2) longitudinal brain atrophy, 3) longitudinal cognitive decline, 4) age of onset. Except in the cognitive domain, we obtained results that were consistent with previously published findings. The PHS was associated with increased Aß burden, faster regional brain atrophy and an earlier age of onset. CONCLUSION: Overall, the results support the predictive power of a PHS, however, with only marginal improvement compared to apolipoprotein E alone.

ß-amyloid PET harmonisation across longitudinal studies: Application to AIBL, ADNI and OASIS3.

INTRODUCTION: The Centiloid scale was developed to harmonise the quantification of ß-amyloid (Aß) PET images across tracers, scanners, and processing pipelines. However, several groups have reported differences across tracers and scanners even after centiloid conversion. In this study, we aim to evaluate the impact of different pre and post-processing harmonisation steps on the robustness of longitudinal Centiloid data across three large international cohort studies. METHODS: All Aß PET data in AIBL (N = 3315), ADNI (N = 3442) and OASIS3 (N = 1398) were quantified using the MRI-based Centiloid standard SPM pipeline and the PET-only pipeline CapAIBL. SUVR were converted into Centiloids using each tracer's respective transform. Global Aß burden from pre-defined target cortical regions in Centiloid units were quantified for both raw PET scans and PET scans smoothed to a uniform 8 mm full width half maximum (FWHM) effective smoothness. For Florbetapir, we assessed the performance of using both the standard Whole Cerebellum (WCb) and a composite white matter (WM)+WCb reference region. Additionally, our recently proposed quantification based on Non-negative Matrix Factorisation (NMF) was applied to all spatially and SUVR normalised images. Correlation with clinical severity measured by the Mini-Mental State Examination (MMSE) and effect size, as well as tracer agreement in 11C-PiB-18F-Florbetapir pairs and longitudinal consistency were evaluated. RESULTS: The smoothing to a uniform resolution partially reduced longitudinal variability, but did not improve inter-tracer agreement, effect size or correlation with MMSE. Using a Composite reference region for 18F-Florbetapir improved inter-tracer agreement, effect size, correlation with MMSE, and longitudinal consistency. The best results were however obtained when using the NMF method which outperformed all other quantification approaches in all metrics used. CONCLUSIONS: FWHM smoothing has limited impact on longitudinal consistency or outliers. A Composite reference region including subcortical WM should be used for computing both cross-sectional and longitudinal Florbetapir Centiloid. NMF improves Centiloid quantification on all metrics examined.

Deep Generative Medical Image Harmonization for Improving Cross-Site Generalization in Deep Learning Predictors.

BACKGROUND: In the medical imaging domain, deep learning-based methods have yet to see widespread clinical adoption, in part due to limited generalization performance across different imaging devices and acquisition protocols. The deviation between estimated brain age and biological age is an established biomarker of brain health and such models may benefit from increased cross-site generalizability. PURPOSE: To develop and evaluate a deep learning-based image harmonization method to improve cross-site generalizability of deep learning age prediction. STUDY TYPE: Retrospective. POPULATION: Eight thousand eight hundred and seventy-six subjects from six sites. Harmonization models were trained using all subjects. Age prediction models were trained using 2739 subjects from a single site and tested using the remaining 6137 subjects from various other sites. FIELD STRENGTH/SEQUENCE: Brain imaging with magnetization prepared rapid acquisition with gradient echo or spoiled gradient echo sequences at 1.5 T and 3 T. ASSESSMENT: StarGAN v2, was used to perform a canonical mapping from diverse datasets to a reference domain to reduce site-based variation while preserving semantic information. Generalization performance of deep learning age prediction was evaluated using harmonized, histogram matched, and unharmonized data. STATISTICAL TESTS: Mean absolute error (MAE) and Pearson correlation between estimated age and biological age quantified the performance of the age prediction model. RESULTS: Our results indicated a substantial improvement in age prediction in out-of-sample data, with the overall MAE improving from 15.81 (±0.21) years to 11.86 (±0.11) with histogram matching to 7.21 (±0.22) years with generative adversarial network (GAN)-based harmonization. In the multisite case, across the 5 out-of-sample sites, MAE improved from 9.78 (±6.69) years to 7.74 (±3.03) years with histogram normalization to 5.32 (±4.07) years with GAN-based harmonization. DATA CONCLUSION: While further research is needed, GAN-based medical image harmonization appears to be a promising tool for improving cross-site deep learning generalization. LEVEL OF EVIDENCE: 4 TECHNICAL EFFICACY: Stage 1.

APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies.

INTRODUCTION: The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. METHODS: We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. RESULTS: A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. DISCUSSION: Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.

Non-negative matrix factorisation improves Centiloid robustness in longitudinal studies.

BACKGROUND: Centiloid was introduced to harmonise ß-Amyloid (Aß) PET quantification across different tracers, scanners and analysis techniques. Unfortunately, Centiloid still suffers from some quantification disparities in longitudinal analysis when normalising data from different tracers or scanners. In this work, we aim to reduce this variability using a different analysis technique applied to the existing calibration data. METHOD: All PET images from the Centiloid calibration dataset, along with 3762 PET images from the AIBL study were analysed using the recommended SPM pipeline. The PET images were SUVR normalised using the whole cerebellum. All SUVR normalised PiB images from the calibration dataset were decomposed using non-negative matrix factorisation (NMF). The NMF coefficients related to the first component were strongly correlated with global SUVR and were subsequently used as a surrogate for Aß retention. For each tracer of the calibration dataset, the components of the NMF were computed in a way such that the coefficients of the first component would match those of the corresponding PiB. Given the strong correlations between the SUVR and the NMF coefficients on the calibration dataset, all PET images from AIBL were subsequently decomposed using the computed NMF, and their coefficients transformed into Centiloids. RESULTS: Using the AIBL data, the correlation between the standard Centiloid and the novel NMF-based Centiloid was high in each tracer. The NMF-based Centiloids showed a reduction of outliers, and improved longitudinal consistency. Furthermore, it removed the effects of switching tracers from the longitudinal variance of the Centiloid measure, when assessed using a linear mixed effects model. CONCLUSION: We here propose a novel image driven method to perform the Centiloid quantification. The methods is highly correlated with standard Centiloids while improving the longitudinal reliability when switching tracers. Implementation of this method across multiple studies may lend to more robust and comparable data for future research.

Fully automated delineation of the optic radiation for surgical planning using clinically feasible sequences.

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.

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.

Relationship between amyloid and tau levels and its impact on tau spreading.

PURPOSE: Previous studies have shown that Aß-amyloid (Aß) likely promotes tau to spread beyond the medial temporal lobe. However, the Aß levels necessary for tau to spread in the neocortex is still unclear. METHODS: Four hundred sixty-six participants underwent tau imaging with [18F]MK6420 and Aß imaging with [18F]NAV4694. Aß scans were quantified on the Centiloid (CL) scale with a cut-off of 25 CL for abnormal levels of Aß (A+). Tau scans were quantified in three regions of interest (ROI) (mesial temporal (Me); temporoparietal neocortex (Te); and rest of neocortex (R)) and four mesial temporal region (entorhinal cortex, amygdala, hippocampus, and parahippocampus). Regional tau thresholds were established as the 95%ile of the cognitively unimpaired A- subjects. The prevalence of abnormal tau levels (T+) along the Centiloid continuum was determined. RESULTS: The plots of prevalence of T+ show earlier and greater increase along the Centiloid continuum in the medial temporal area compared to neocortex. Prevalence of T+ was low but associated with Aß level between 10 and 40 CL reaching 23% in Me, 15% in Te, and 11% in R. Between 40 and 70 CL, the prevalence of T+ subjects per CL increased fourfold faster and at 70 CL was 64% in Me, 51% in Te, and 37% in R. In cognitively unimpaired, there were no T+ in R below 50 CL. The highest prevalence of T+ were found in the entorhinal cortex, reaching 40% at 40 CL and 80% at 60 CL. CONCLUSION: Outside the entorhinal cortex, abnormal levels of cortical tau on PET are rarely found with Aß below 40 CL. Above 40 CL prevalence of T+ accelerates in all areas. Moderate Aß levels are required before abnormal neocortical tau becomes detectable.

Early clinical and MRI biomarkers of cognitive and motor outcomes in very preterm born infants.

BACKGROUND: 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 born <31 weeks gestation. METHODS: 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. RESULTS: The best combined motor outcome model included 3-month GMs (ß = -11.41; 95% CI = -17.34, -5.49), TEA MRI deep grey matter score (ß = -6.23; 95% CI = -9.47, -2.99) and early HNNE reflexes (ß = 3.51; 95% CI = 0.86, 6.16). Combined cognitive model included 3-month GMs (ß = -10.01; 95% CI = -15.90, -4.12) and TEA HNNE score (ß = 1.33; 95% CI = 0.57, 2.08). CONCLUSION: 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. IMPACT: We present associations between 32- and 40-week MRI, comprehensive clinical assessments and later 2-year motor and cognitive outcomes for children born <31 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.

MRI signatures of brain age and disease over the lifespan based on a deep brain network and 14 468 individuals worldwide.

Deep learning has emerged as a powerful approach to constructing imaging signatures of normal brain ageing as well as of various neuropathological processes associated with brain diseases. In particular, MRI-derived brain age has been used as a comprehensive biomarker of brain health that can identify both advanced and resilient ageing individuals via deviations from typical brain ageing. Imaging signatures of various brain diseases, including schizophrenia and Alzheimer's disease, have also been identified using machine learning. Prior efforts to derive these indices have been hampered by the need for sophisticated and not easily reproducible processing steps, by insufficiently powered or diversified samples from which typical brain ageing trajectories were derived, and by limited reproducibility across populations and MRI scanners. Herein, we develop and test a sophisticated deep brain network (DeepBrainNet) using a large (n = 11 729) set of MRI scans from a highly diversified cohort spanning different studies, scanners, ages and geographic locations around the world. Tests using both cross-validation and a separate replication cohort of 2739 individuals indicate that DeepBrainNet obtains robust brain-age estimates from these diverse datasets without the need for specialized image data preparation and processing. Furthermore, we show evidence that moderately fit brain ageing models may provide brain age estimates that are most discriminant of individuals with pathologies. This is not unexpected as tightly-fitting brain age models naturally produce brain-age estimates that offer little information beyond age, and loosely fitting models may contain a lot of noise. Our results offer some experimental evidence against commonly pursued tightly-fitting models. We show that the moderately fitting brain age models obtain significantly higher differentiation compared to tightly-fitting models in two of the four disease groups tested. Critically, we demonstrate that leveraging DeepBrainNet, along with transfer learning, allows us to construct more accurate classifiers of several brain diseases, compared to directly training classifiers on patient versus healthy control datasets or using common imaging databases such as ImageNet. We, therefore, derive a domain-specific deep network likely to reduce the need for application-specific adaptation and tuning of generic deep learning networks. We made the DeepBrainNet model freely available to the community for MRI-based evaluation of brain health in the general population and over the lifespan.

Effectiveness of Curcuma longa Extract for the Treatment of Symptoms and Effusion-Synovitis of Knee Osteoarthritis : A Randomized Trial.

BACKGROUND: Current pharmacologic therapies for patients with osteoarthritis are suboptimal. OBJECTIVE: To determine the efficacy of Curcuma longa extract (CL) for reducing knee symptoms and effusion-synovitis in patients with symptomatic knee osteoarthritis and knee effusion-synovitis. DESIGN: Randomized, double-blind, placebo-controlled trial. (Australian New Zealand Clinical Trials Registry: ACTRN12618000080224). SETTING: Single-center study with patients from southern Tasmania, Australia. PARTICIPANTS: 70 participants with symptomatic knee osteoarthritis and ultrasonography-defined effusion-synovitis. INTERVENTION: 2 capsules of CL (n = 36) or matched placebo (n = 34) per day for 12 weeks. MEASUREMENTS: The 2 primary outcomes were changes in knee pain on a visual analogue scale (VAS) and effusion-synovitis volume on magnetic resonance imaging (MRI). The key secondary outcomes were change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and cartilage composition values. Outcomes were assessed over 12 weeks. RESULTS: CL improved VAS pain compared with placebo by -9.1 mm (95% CI, -17.8 to -0.4 mm [P = 0.039]) but did not change effusion-synovitis volume (3.2 mL [CI, -0.3 to 6.8 mL]). CL also improved WOMAC knee pain (-47.2 mm [CI, -81.2 to -13.2 mm]; P = 0.006) but not lateral femoral cartilage T2 relaxation time (-0.4 ms [CI, -1.1 to 0.3 ms]). The incidence of adverse events was similar in the CL (n = 14 [39%]) and placebo (n = 18 [53%]) groups (P = 0.16); 2 events in the CL group and 5 in the placebo group may have been treatment related. LIMITATION: Modest sample size and short duration. CONCLUSION: CL was more effective than placebo for knee pain but did not affect knee effusion-synovitis or cartilage composition. Multicenter trials with larger sample sizes are needed to assess the clinical significance of these findings. PRIMARY FUNDING SOURCE: University of Tasmania and Natural Remedies Private Limited.

Multi-centre randomised controlled trial comparing arthroscopic hip surgery to physiotherapist-led care for femoroacetabular impingement (FAI) syndrome on hip cartilage metabolism: the Australian FASHIoN trial.

BACKGROUND: Arthroscopic surgery for femoroacetabular impingement syndrome (FAI) is known to lead to self-reported symptom improvement. In the context of surgical interventions with known contextual effects and no true sham comparator trials, it is important to ascertain outcomes that are less susceptible to placebo effects. The primary aim of this trial was to determine if study participants with FAI who have hip arthroscopy demonstrate greater improvements in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to participants who undergo physiotherapist-led management. METHODS: Multi-centre, pragmatic, two-arm superiority randomised controlled trial comparing physiotherapist-led management to hip arthroscopy for FAI. FAI participants were recruited from participating orthopaedic surgeons clinics, and randomly allocated to receive either physiotherapist-led conservative care or surgery. The surgical intervention was arthroscopic FAI surgery. The physiotherapist-led conservative management was an individualised physiotherapy program, named Personalised Hip Therapy (PHT). The primary outcome measure was change in dGEMRIC score between baseline and 12 months. Secondary outcomes included a range of patient-reported outcomes and structural measures relevant to FAI pathoanatomy and hip osteoarthritis development. Interventions were compared by intention-to-treat analysis. RESULTS: Ninety-nine participants were recruited, of mean age 33 years and 58% male. Primary outcome data were available for 53 participants (27 in surgical group, 26 in PHT). The adjusted group difference in change at 12 months in dGEMRIC was -59 ms (95%CI - 137.9 to - 19.6) (p = 0.14) favouring PHT. Hip-related quality of life (iHOT-33) showed improvements in both groups with the adjusted between-group difference at 12 months showing a statistically and clinically important improvement in arthroscopy of 14 units (95% CI 5.6 to 23.9) (p = 0.003). CONCLUSION: The primary outcome of dGEMRIC showed no statistically significant difference between PHT and arthroscopic hip surgery at 12 months of follow-up. Patients treated with surgery reported greater benefits in symptoms at 12 months compared to PHT, but these benefits are not explained by better hip cartilage metabolism. TRIAL REGISTRATION DETAILS: Australia New Zealand Clinical Trials Registry reference: ACTRN12615001177549 . Trial registered 2/11/2015.