Marinescu R, Oxtoby NP, Young AL, Bron EE, Toga AW, Weiner MW, Barkhof F, Fox NC, Golland P, Klein S, Alexander DC. TADPOLE Challenge: Accurate Alzheimer s Disease Prediction Through Crowdsourced Forecasting of Future Data. Predict Intell Med 2019;11843:1-10.

The Alzheimer’s Disease Prediction Of Longitudinal Evolution (TADPOLE) Challenge compares the performance of algorithms at predicting the future evolution of individuals at risk of Alzheimer’s disease. TADPOLE Challenge participants train their models and algorithms on historical data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Participants are then required to make forecasts of three key outcomes for ADNI-3 rollover participants: clinical diagnosis, Alzheimer’s Disease Assessment Scale Cognitive Subdomain (ADAS-Cog 13), and total volume of the ventricles - which are then compared with future measurements. Strong points of the challenge are that the test data did not exist at the time of forecasting (it was acquired afterwards), and that it focuses on the challenging problem of cohort selection for clinical trials by identifying fast progressors. The submission phase of TADPOLE was open until 15 November 2017; since then data has been acquired until April 2019 from 219 subjects with 223 clinical visits and 150 Magnetic Resonance Imaging (MRI) scans, which was used for the evaluation of the participants’ predictions. Thirty-three teams participated with a total of 92 submissions. No single submission was best at predicting all three outcomes. For diagnosis prediction, the best forecast (team Frog), which was based on gradient boosting, obtained a multiclass area under the receiver-operating curve (MAUC) of 0.931, while for ventricle prediction the best forecast (team ), which was based on disease progression modelling and spline regression, obtained mean absolute error of 0.41% of total intracranial volume (ICV). For ADAS-Cog 13, no forecast was considerably better than the benchmark mixed effects model ( ), provided to participants before the submission deadline. Further analysis can help understand which input features and algorithms are most suitable for Alzheimer’s disease prediction and for aiding patient stratification in clinical trials. The submission system remains open via the website:

Marinescu R, Lorenzi M, Blumberg SB, Young AL, Planell-Morell P, Oxtoby NP, Eshaghi A, Yong KX, Crutch SJ, Golland P, Alexander DC. Disease Knowledge Transfer across Neurodegenerative Diseases. Med Image Comput Comput Assist Interv 2019;11765:860-8.

We introduce Disease Knowledge Transfer (DKT), a novel technique for transferring biomarker information between related neurodegenerative diseases. DKT infers robust multimodal biomarker trajectories in rare neurodegenerative diseases even when only limited, unimodal data is available, by transferring information from larger multimodal datasets from common neurodegenerative diseases. DKT is a joint-disease generative model of biomarker progressions, which exploits biomarker relationships that are shared across diseases. Our proposed method allows, for the first time, the estimation of plausible biomarker trajectories in Posterior Cortical Atrophy (PCA), a rare neurodegenerative disease where only unimodal MRI data is available. For this we train DKT on a combined dataset containing subjects with two distinct diseases and sizes of data available: 1) a larger, multimodal typical AD (tAD) dataset from the TADPOLE Challenge, and 2) a smaller unimodal Posterior Cortical Atrophy (PCA) dataset from the Dementia Research Centre (DRC), for which only a limited number of Magnetic Resonance Imaging (MRI) scans are available. Although validation is challenging due to lack of data in PCA, we validate DKT on synthetic data and two patient datasets (TADPOLE and PCA cohorts), showing it can estimate the ground truth parameters in the simulation and predict unseen biomarkers on the two patient datasets. While we demonstrated DKT on Alzheimer’s variants, we note DKT is generalisable to other forms of related neurodegenerative diseases. Source code for DKT is available online:

Lepage C, Muehlmann M, Tripodis Y, Hufschmidt J, Stamm J, Green K, Wrobel P, Schultz V, Weir I, Alosco ML, Baugh CM, Fritts NG, Martin BM, Chaisson C, Coleman MJ, Lin AP, Pasternak O, Makris N, Stern RA, Shenton ME, Koerte IK. Limbic System Structure Volumes and Associated Neurocognitive Functioning in Former NFL Players. Brain Imaging Behav 2019;13(3):725-34.
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts. CTE has been linked to disruptions in cognition, mood, and behavior. Unfortunately, the diagnosis of CTE can only be made post-mortem. Neuropathological evidence suggests limbic structures may provide an opportunity to characterize CTE in the living. Using 3 T magnetic resonance imaging, we compared select limbic brain regional volumes - the amygdala, hippocampus, and cingulate gyrus - between symptomatic former National Football League (NFL) players (n = 86) and controls (n = 22). Moreover, within the group of former NFL players, we examined the relationship between those limbic structures and neurobehavioral functioning (n = 75). The former NFL group comprised eighty-six men (mean age = 55.2 ± 8.0 years) with at least 12 years of organized football experience, at least 2 years of active participation in the NFL, and self-reported declines in cognition, mood, and behavior within the last 6 months. The control group consisted of men (mean age = 57.0 ± 6.6 years) with no history of contact-sport involvement or traumatic brain injury. All control participants provided neurobehavioral data. Compared to controls, former NFL players exhibited reduced volumes of the amygdala, hippocampus, and cingulate gyrus. Within the NFL group, reduced bilateral cingulate gyrus volume was associated with worse attention and psychomotor speed (r = 0.4 (right), r = 0.42 (left); both p < 0.001), while decreased right hippocampal volume was associated with worse visual memory (r = 0.25, p = 0.027). Reduced volumes of limbic system structures in former NFL players are associated with neurocognitive features of CTE. Volume reductions in the amygdala, hippocampus, and cingulate gyrus may be potential biomarkers of neurodegeneration in those at risk for CTE.
Vipin A, Ng KK, Ji F, Shim HY, Lim JKW, Pasternak O, Zhou JH, Initiative A s DN. Amyloid Burden Accelerates White Matter Degradation in Cognitively Normal Elderly Individuals. Hum Brain Mapp 2019;40(7):2065-75.
Alterations in parietal and temporal white matter microstructure derived from diffusion tensor imaging occur in preclinical and clinical Alzheimer’s disease. Amyloid beta (Aβ) deposition and such white matter alterations are two pathological hallmarks of Alzheimer’s disease. However, the relationship between these pathologies is not yet understood, partly since conventional diffusion MRI methods cannot distinguish between cellular and extracellular processes. Thus, we studied Aβ-associated longitudinal diffusion MRI changes in Aβ-positive (N = 21) and Aβ-negative (N = 51) cognitively normal elderly obtained from the Alzheimer’s Disease Neuroimaging Initiative dataset using linear mixed models. Aβ-positivity was based on Alzheimer’s Disease Neuroimaging Initiative amyloid-PET recommendations using a standardized uptake value ratio cut-off of 1.11. We used free-water imaging to distinguish cellular and extracellular changes. We found that Aβ-positive subjects had increased baseline right uncinate fasciculus free-water fraction (FW), associated with worse baseline Alzheimer’s disease assessment scale scores. Furthermore, Aβ-positive subjects showed faster decrease in fractional anisotropy (FW-corrected) in the right uncinate fasciculus and faster age-dependent right inferior longitudinal fasciculus FW increases over time. Right inferior longitudinal fasciculus FW increases were associated with greater memory decline. Importantly, these results remained significant after controlling for gray and white matter volume and hippocampal volume. This is the first study to illustrate the influence of Aβ burden on early longitudinal (in addition to baseline) white matter changes in cognitively normal elderly individuals at-risk of Alzheimer’s disease, thus underscoring the importance of longitudinal studies in assessing microstructural alterations in individuals at risk of Alzheimer’s disease prior to symptoms onset.
Jolley MA, Lasso A, Nam HH, Dinh P, Scanlan AB, Nguyen A, Ilina A, Morray B, Glatz AC, McGowan FX, Whitehead K, Dori Y, Gorman JH, Gorman RC, Fichtinger G, Gillespie MJ. Toward Predictive Modeling of Catheter-based Pulmonary Valve Replacement into Native Right Ventricular Outflow Tracts. Catheter Cardiovasc Interv 2019;93(3):E143-E152.
BACKGROUND: Pulmonary insufficiency is a consequence of transannular patch repair in Tetralogy of Fallot (ToF) leading to late morbidity and mortality. Transcatheter native outflow tract pulmonary valve replacement has become a reality. However, predicting a secure, atraumatic implantation of a catheter-based device remains a significant challenge due to the complex and dynamic nature of the right ventricular outflow tract (RVOT). We sought to quantify the differences in compression and volume for actual implants, and those predicted by pre-implant modeling. METHODS: We used custom software to interactively place virtual transcatheter pulmonary valves (TPVs) into RVOT models created from pre-implant and post Harmony valve implant CT scans of 5 ovine surgical models of TOF to quantify and visualize device volume and compression. RESULTS: Virtual device placement visually mimicked actual device placement and allowed for quantification of device volume and radius. On average, simulated proximal and distal device volumes and compression did not vary statistically throughout the cardiac cycle (P = 0.11) but assessment was limited by small sample size. In comparison to actual implants, there was no significant pairwise difference in the proximal third of the device (P > 0.80), but the simulated distal device volume was significantly underestimated relative to actual device implant volume (P = 0.06). CONCLUSIONS: This study demonstrates that pre-implant modeling which assumes a rigid vessel wall may not accurately predict the degree of distal RVOT expansion following actual device placement. We suggest the potential for virtual modeling of TPVR to be a useful adjunct to procedural planning, but further development is needed.
Nguyen A, Lasso A, Nam HH, Faerber J, Aly AH, Pouch AM, Scanlan AB, McGowan FX, Mercer-Rosa L, Cohen MS, Simpson J, Fichtinger G, Jolley MA. Dynamic Three-Dimensional Geometry of the Tricuspid Valve Annulus in Hypoplastic Left Heart Syndrome with a Fontan Circulation. J Am Soc Echocardiogr 2019;32(5):655-66.
BACKGROUND: Tricuspid regurgitation (TR) is a significant contributor to morbidity and mortality in patients with hypoplastic left heart syndrome. The goal of this study was to characterize the dynamic annular motion of the tricuspid valve in patients with HLHS with a Fontan circulation and assess the relation to tricuspid valve function. METHODS: Tricuspid annuli of 48 patients with HLHS with a Fontan circulation were modeled at end-diastole, mid-systole, end-systole, and mid-diastole using transthoracic three-dimensional echocardiography and custom code in 3D Slicer. The angle of the anterior papillary muscle (APM) relative to the annular plane in each systolic phase was also measured. RESULTS: Imaging was performed 5.0 years (interquartile range, 2-11 years) after Fontan operation. The tricuspid annulus varies in shape significantly throughout the cardiac cycle, changing in sphericity (P < .001) but not in annular height or bending angle. In univariate modeling, patients with significant TR had larger changes in septolateral diameter, lateral quadrant area, and posterior quadrant area (P < .05 for all) as well as lower (more laterally directed) APM angles (P < .001) than patients with mild or less TR. In multivariate modeling, a 1 mm/(body surface area) increase in the maximum change in septolateral diameter was associated with a 1.7-fold increase in having moderate or greater TR, while a 10° decrease in APM angle at mid-systole was associated with an almost 2.5-fold increase in moderate or greater TR (P 
Valera EM, Cao A, Pasternak O, Shenton ME, Kubicki M, Makris N, Adra N. White Matter Correlates of Mild Traumatic Brain Injuries in Women Subjected to Intimate-Partner Violence: A Preliminary Study. J Neurotrauma 2019;36(5):661-8.
A large proportion (range of 44-75%) of women who experience intimate-partner violence (IPV) have been shown to sustain repetitive mild traumatic brain injuries (mTBIs) from their abusers. Further, despite requests for research on TBI-related health outcomes, there are currently only a handful of studies addressing this issue and only one prior imaging study that has investigated the neural correlates of IPV-related TBIs. In response, we examined specific regions of white matter microstructure in 20 women with histories of IPV. Subjects were imaged on a 3-Tesla Siemens Magnetom TrioTim scanner using diffusion magnetic resonance imaging. We investigated the association between a score reflecting number and recency of IPV-related mTBIs and fractional anisotropy (FA) in the posterior and superior corona radiata as well as the posterior thalamic radiation, brain regions shown previously to be involved in mTBI. We also investigated the association between several cognitive measures, namely learning, memory, and cognitive flexibility, and FA in the white matter regions of interest. We report a negative correlation between the brain injury score and FA in regions of the posterior and superior corona radiata. We failed to find an association between our cognitive measures and FA in these regions, but the interpretation of these results remains inconclusive due to possible power issues. Overall, these data build upon the small but growing literature demonstrating potential consequences of mTBIs for women experiencing IPV, and further underscore the urgent need for larger and more comprehensive studies in this area.
Lampinen B, Szczepankiewicz F, Novén M, van Westen D, Hansson O, Englund E, Mårtensson J, Westin C-F, Nilsson M. Searching for the Neurite Density with Diffusion MRI: Challenges for Biophysical Modeling. Hum Brain Mapp 2019;40(8):2529-45.
In vivo mapping of the neurite density with diffusion MRI (dMRI) is a high but challenging aim. First, it is unknown whether all neurites exhibit completely anisotropic ("stick-like") diffusion. Second, the "density" of tissue components may be confounded by non-diffusion properties such as T2 relaxation. Third, the domain of validity for the estimated parameters to serve as indices of neurite density is incompletely explored. We investigated these challenges by acquiring data with "b-tensor encoding" and multiple echo times in brain regions with low orientation coherence and in white matter lesions. Results showed that microscopic anisotropy from b-tensor data is associated with myelinated axons but not with dendrites. Furthermore, b-tensor data together with data acquired for multiple echo times showed that unbiased density estimates in white matter lesions require data-driven estimates of compartment-specific T2 values. Finally, the "stick" fractions of different biophysical models could generally not serve as neurite density indices across the healthy brain and white matter lesions, where outcomes of comparisons depended on the choice of constraints. In particular, constraining compartment-specific T2 values was ambiguous in the healthy brain and had a large impact on estimated values. In summary, estimating neurite density generally requires accounting for different diffusion and/or T2 properties between axons and dendrites. Constrained "index" parameters could be valid within limited domains that should be delineated by future studies.
Jafari-Khouzani K, Paynabar K, Hajighasemi F, Rosen B. Effect of Region of Interest Size on the Repeatability of Quantitative Brain Imaging Biomarkers. IEEE Trans Biomed Eng 2019;66(3):864-72.
In the repeatability analysis, when the measurement is the mean value of a parametric map within a region of interest (ROI), the ROI size becomes important as by increasing the size, the measurement will have a smaller variance. This is important in decision-making in prospective clinical studies of brain when the ROI size is variable, e.g., in monitoring the effect of treatment on lesions by quantitative MRI, and in particular when the ROI is small, e.g., in the case of brain lesions in multiple sclerosis. Thus, methods to estimate repeatability measures for arbitrary sizes of ROI are desired. We propose a statistical model of the values of parametric map within the ROI and a method to approximate the model parameters, based on which we estimate a number of repeatability measures including repeatability coefficient, coefficient of variation, and intraclass correlation coefficient for an ROI with an arbitrary size. We also show how this gives an insight into related problems such as spatial smoothing in voxel-wise analysis. Experiments are conducted on simulated data as well as on scan-rescan brain MRI of healthy subjects. The main application of this study is the adjustment of the decision threshold based on the lesion size in treatment monitoring.
Nitsch J, Klein J, Dammann P, Wrede K, Gembruch O, Moltz JH, Meine H, Sure U, Kikinis R, Miller D. Automatic and Efficient MRI-US Segmentations for Improving Intraoperative Image Fusion in Image-guided Neurosurgery. Neuroimage Clin 2019;22:101766.
Knowledge of the exact tumor location and structures at risk in its vicinity are crucial for neurosurgical interventions. Neuronavigation systems support navigation within the patient’s brain, based on preoperative MRI (preMRI). However, increasing tissue deformation during the course of tumor resection reduces navigation accuracy based on preMRI. Intraoperative ultrasound (iUS) is therefore used as real-time intraoperative imaging. Registration of preMRI and iUS remains a challenge due to different or varying contrasts in iUS and preMRI. Here, we present an automatic and efficient segmentation of B-mode US images to support the registration process. The falx cerebri and the tentorium cerebelli were identified as examples for central cerebral structures and their segmentations can serve as guiding frame for multi-modal image registration. Segmentations of the falx and tentorium were performed with an average Dice coefficient of 0.74 and an average Hausdorff distance of 12.2 mm. The subsequent registration incorporates these segmentations and increases accuracy, robustness and speed of the overall registration process compared to purely intensity-based registration. For validation an expert manually located corresponding landmarks. Our approach reduces the initial mean Target Registration Error from 16.9 mm to 3.8 mm using our intensity-based registration and to 2.2 mm with our combined segmentation and registration approach. The intensity-based registration reduced the maximum initial TRE from 19.4 mm to 5.6 mm, with the approach incorporating segmentations this is reduced to 3.0 mm. Mean volumetric intensity-based registration of preMRI and iUS took 40.5 s, including segmentations 12.0 s.