Enhanced depletion of MLL-fusion proteins in acute leukemia: potential for improved therapeutic outcomes.

Rearrangements of the MLL (KMT2A) locus are associated with aggressive leukaemia of both myeloid and lymphoid lineages, that present profound therapeutic challenges in pediatric and adult patient populations. MLL-fusion genes resulting from these rearrangements function as driving oncogenes and have been the focus of research aimed at understanding mechanisms underlying their leukemogenic activity and revealing novel therapeutic opportunities. Inspired by the paradigm of depleting the PML-RARA fusion protein in acute promyelocytic leukemia using all-trans retinoic acid and arsenic trioxide, we conducted a screen to identify FDA-approved drugs capable of depleting MLL-fusion protein expression in leukemia cells. Previously, we reported potent anti-leukemia effects of disulfiram (DSF), identified through this screen. In the present study, we demonstrate that another hit compound, niclosamide (NSM), is also able to deplete MLL-fusion proteins derived from a range of different MLL-fusion genes in both acute myeloid (AML) and acute lymphoid (ALL) leukemias. Loss of MLL-fusion protein appeared to result from inhibition of global protein translation by NSM. Importantly, combination of DSF with NSM enhanced MLL-fusion protein depletion. This led to more profound inhibition of downstream transcriptional leukemogenic programs regulated by MLL-fusion proteins and more effective killing of both MLL-rearranged AML and ALL cells. In contrast, DSF/NSM drug combination had little impact on normal hematopoietic progenitor cell differentiation. This study demonstrates that two FDA-approved drugs with excellent safety profiles can be combined to increase the efficacy of MLL-fusion protein depletion and elimination of MLL-rearranged leukaemia.

Exploring access to community neurorehabilitation for people with progressive neurological conditions: a qualitative study.

PURPOSE: Community neurorehabilitation enables people with progressive neurological conditions (PNCs) to manage their symptoms to live an active, fulfilling life; however, it is not accessible to all. This study explored the factors influencing access to community neurorehabilitation in Northern Ireland from the perspective of people with PNCs and their carers. METHODS: Eleven people living with a PNC and three carers took part in virtual focus groups. Data was thematically analysed using the framework method. RESULTS: Access to neurorehabilitation was described as a staged journey, driven by people with PNCs, and impacted by interactions with others. Four themes were identified: the person in the driving seat, describing the value of person-centred care and the need for proactivity; the traffic lights, depicting the role and influence of health care professionals (HCPs); the need for direction; and roadworks and roadblocks, identifying additional barriers to access. In addition, six fundamentals of good access were identified. CONCLUSIONS: This study adds depth to our understanding of the complexity, and the roles and needs of people with PNCs and HCPs, in accessing community neurorehabilitation. Further research is needed to determine how best to empower people to access rehabilitation.

Access to community neurorehabilitation is dependent on personal factors including patient activation level and health care professional knowledge.People need to be empowered to access rehabilitation services.A single point of contact for advice and triaging concerns related to progressive neurological conditions is desirable.There is a need to understand the experiences and needs of people with low levels of patient activation to ensure equitable access to community-based neurorehabilitation.

Physical seed dormancy in pea is genetically separable from seed coat thickness and roughness.

Introduction: The seeds of wild pea (Pisum) exhibit marked physical dormancy due to impermeability of the seed coat to water, and the loss of this dormancy is thought to have been critical for domestication. Wild pea seed coats are also notably thick and rough, traits that have also reduced during domestication and are anecdotally linked to increased permeability. However, how these traits specifically interact with permeability is unclear. Methods: To investigate this, we examined the genetic control of differences in seed coat characteristics between wild P. sativum ssp. humile and a non-dormant domesticated P. s. sativum accession in a recombinant inbred population. QTL effects were confirmed and their locations refined in segregating F4/5 populations. Results: In this population we found a moderate correlation between testa thickness and permeability, and identified loci that affect them independently, suggesting no close functional association. However, the major loci affecting both testa thickness and permeability collocated closely with Mendel's pigmentation locus A, suggesting flavonoid compounds under its control might contribute significantly to both traits. We also show that seed coat roughness is oligogenic in this population, with the major locus independent of both testa thickness and permeability, suggesting selection for smooth seed was unlikely to be due to effects on either of these traits. Discussion: Results indicate loss of seed coat dormancy during domestication was not primarily driven by reduced testa thickness or smooth seededness. The close association between major permeability and thickness QTL and Mendel's 'A' warrant further study, particularly regarding the role of flavonoids.

FDA-approved disulfiram as a novel treatment for aggressive leukemia.

Acute leukemia continues to be a major cause of death from disease worldwide and current chemotherapeutic agents are associated with significant morbidity in survivors. While better and safer treatments for acute leukemia are urgently needed, standard drug development pipelines are lengthy and drug repurposing therefore provides a promising approach. Our previous evaluation of FDA-approved drugs for their antileukemic activity identified disulfiram, used for the treatment of alcoholism, as a candidate hit compound. This study assessed the biological effects of disulfiram on leukemia cells and evaluated its potential as a treatment strategy. We found that disulfiram inhibits the viability of a diverse panel of acute lymphoblastic and myeloid leukemia cell lines (n = 16) and patient-derived xenograft cells from patients with poor outcome and treatment-resistant disease (n = 15). The drug induced oxidative stress and apoptosis in leukemia cells within hours of treatment and was able to potentiate the effects of daunorubicin, etoposide, topotecan, cytarabine, and mitoxantrone chemotherapy. Upon combining disulfiram with auranofin, a drug approved for the treatment of rheumatoid arthritis that was previously shown to exert antileukemic effects, strong and consistent synergy was observed across a diverse panel of acute leukemia cell lines, the mechanism of which was based on enhanced ROS induction. Acute leukemia cells were more sensitive to the cytotoxic activity of disulfiram than solid cancer cell lines and non-malignant cells. While disulfiram is currently under investigation in clinical trials for solid cancers, this study provides evidence for the potential of disulfiram for acute leukemia treatment. KEY MESSAGES: Disulfiram induces rapid apoptosis in leukemia cells by boosting oxidative stress. Disulfiram inhibits leukemia cell growth more potently than solid cancer cell growth. Disulfiram can enhance the antileukemic efficacy of chemotherapies. Disulfiram strongly synergises with auranofin in killing acute leukemia cells by ROS induction. We propose testing of disulfiram in clinical trial for patients with acute leukemia.

Susceptibility of pediatric acute lymphoblastic leukemia to STAT3 inhibition depends on p53 induction.

Advances in the clinical management of pediatric B-cell acute lymphoblastic leukemia (B-ALL) have dramatically improved outcomes for this disease. However, relapsed and high-risk disease still contribute to significant numbers of treatment failures. Development of new, broad range therapies is urgently needed for these cases. We previously reported the susceptibility of ETV6-RUNX1+ pediatric B-ALL to inhibition of signal transducer and activator of transcription 3 (STAT3) activity. In the present study, we demonstrate that pharmacological or genetic inhibition of STAT3 results in p53 induction and that CRISPR-mediated TP53 knockout substantially reverses susceptibility to STAT3 inhibition. Furthermore, we demonstrate that sensitivity to STAT3 inhibition in patient-derived xenograft (PDX) B-ALL samples is not restricted to any particular disease subtype, but rather depends on TP53 status, the only resistant samples being TP53 mutant. Induction of p53 following STAT3 inhibition is not directly dependent on MDM2 but correlates with degradation of MDM4. As such, STAT3 inhibition exhibits synergistic in vitro and in vivo anti-leukemia activity when combined with MDM2 inhibition. Taken together with the relatively low frequency of TP53 mutations in this disease, these data support the future development of combined STAT3/ MDM2 inhibition in the therapy of refractory and relapsed pediatric B-ALL.

Long-term psychological outcomes following stroke: the OX-CHRONIC study.

BACKGROUND: Stroke survivors rate longer-term (> 2 years) psychological recovery as their top priority, but data on how frequently psychological consequences occur is lacking. Prevalence of cognitive impairment, depression/anxiety, fatigue, apathy and related psychological outcomes, and whether rates are stable in long-term stroke, is unknown. METHODS: N = 105 long-term stroke survivors (M [SD] age = 72.92 [13.01]; M [SD] acute NIH Stroke Severity Score = 7.39 [6.25]; 59.0% Male; M [SD] years post-stroke = 4.57 [2.12]) were recruited (potential N = 208). Participants completed 3 remote assessments, including a comprehensive set of standardized cognitive neuropsychological tests comprising domains of memory, attention, language, and executive function, and questionnaires on emotional distress, fatigue, apathy and other psychological outcomes. Ninety participants were re-assessed one year later. Stability of outcomes was assessed by Cohen's d effect size estimates and percent Minimal Clinically Important Difference changes between time points. RESULTS: On the Montreal Cognitive Assessment 65.3% scored < 26. On the Oxford Cognitive Screen 45.9% had at least one cognitive impairment. Attention (27.1%) and executive function (40%) were most frequently impaired. 23.5% and 22.5% had elevated depression/anxiety respectively. Fatigue (51.4%) and apathy (40.5%) rates remained high, comparable to estimates in the first-year post-stroke. Attention (d = -0.12; 85.8% stable) and depression (d = 0.09, 77.1% stable) were the most stable outcomes. Following alpha-adjustments, only perceptuomotor abilities (d = 0.69; 40.4% decline) and fatigue (d = -0.33; 45.3% decline) worsened over one year. Cognitive impairment, depression/anxiety, fatigue and apathy all correlated with worse quality of life. CONCLUSION: Nearly half of participants > 2 years post-event exhibited psychological difficulties including domains of cognition, mood, and fatigue, which impact long-term quality of life. Stroke is a chronic condition with highly prevalent psychological needs, which require monitoring and intervention development.

SET-PP2A complex as a new therapeutic target in KMT2A (MLL) rearranged AML.

KMT2A-rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A-R leukemia. In contrast, the contribution and regulation of phosphatases is unknown. In this study we uncover the essential role and underlying mechanisms of SET, the endogenous inhibitor of Ser/Thr phosphatase PP2A, in KMT2A-R-leukemia. Investigation of SET expression in acute myeloid leukemia (AML) samples demonstrated that SET is overexpressed, and elevated expression of SET is correlated with poor prognosis and with the expression of MEIS and HOXA genes in AML patients. Silencing SET specifically abolished the clonogenic ability of KMT2A-R leukemic cells and the transcription of KMT2A targets genes HOXA9 and HOXA10. Subsequent mechanistic investigations showed that SET interacts with both KMT2A wild type and fusion proteins, and it is recruited to the HOXA10 promoter. Pharmacological inhibition of SET by FTY720 disrupted SET-PP2A interaction leading to cell cycle arrest and increased sensitivity to chemotherapy in KMT2A-R-leukemic models. Phospho-proteomic analyses revealed that FTY720 reduced the activity of kinases regulated by PP2A, including ERK1, GSK3ß, AURB and PLK1 and led to suppression of MYC, supporting the hypothesis of a feedback loop among PP2A, AURB, PLK1, MYC, and SET. Our findings illustrate that SET is a novel player in KMT2A-R leukemia and they provide evidence that SET antagonism could serve as a novel strategy to treat this aggressive leukemia.

A human genome editing-based MLL::AF4 ALL model recapitulates key cellular and molecular leukemogenic features.

Cellular ontogeny and MLL breakpoint site influence the capacity of MLL-edited CD34+ hematopoietic cells to initiate and recapitulate infant patients' features in pro-B-cell acute lymphoblastic leukemia (B-ALL). We provide key insights into the leukemogenic determinants of MLL-AF4+ infant B-ALL.

Development and pilot of a community low-vision, service-specific Patient-Reported Experience Measure.

PURPOSE: Patient-Reported Experience Measures (PREMs) act to identify the patient's objective experience while receiving care. PREM data can provide feedback to professionals on patients' personal experience of care processes, quality of care and insight into patient expectations. This can support service improvements and person-centeredness of care. Despite this, PREMs are not currently routinely collected for any primary eye care services in Wales, inclusive of the National Low Vision Service Wales (LVSW). The primary aim of this project was to develop and pilot a community low-vision, service-specific, PREM (LVSWPREM). METHODS: The development of the LVSWPREMs was performed in partnership with LVSW service users. Fourteen people attended three successive, 1.5-h online focus groups, and informed the development of a draft of LVSWPREMs inclusive of item generation and face validity. Following several rounds of iterative improvements based on the feedback gathered during the focus groups, LVSWPREM V4.0 was agreed upon and piloted for a period of 3 months within Hywel Dda University Health Board. Reliability of the final LVSWPREM V4.0 was assessed using Cronbach α. RESULTS: The final LVSWPREMs consisted of two parts: (1) LVSW-specific items and (2) a generic PREM tool approved by the Welsh Government for use across National Health Service Wales. Reliability analyses with item deletion were conducted for each construct separately using Cronbach α and were 0.94 and 0.63 for parts 1 and 2, respectively. CONCLUSION: The LVSWPREM is a validated, reliable tool, which can be used to provide information regarding patients' experience of accessing a community-based, low-vision service. Developed in partnership with people with vision impairment, it has the potential to be useful as a means of patient engagement and improvement in the delivery of high-quality healthcare.

An Automated, Home-Cage, Video Monitoring-based Mouse Frailty Index Detects Age-associated Morbidity in C57BL/6 and Diversity Outbred Mice.

Frailty indexes (FIs) provide quantitative measurements of nonspecific health decline and are particularly useful as longitudinal monitors of morbidity in aging studies. For mouse studies, frailty assessments can be taken noninvasively, but they require handling and direct observation that is labor-intensive to the scientist and stress inducing to the animal. Here, we implement, evaluate, and provide a refined digital FI composed entirely of computational analyses of home-cage video and compare it to manually obtained frailty scores in both C57BL/6 and genetically heterogeneous Diversity Outbred mice. We show that the frailty scores assigned by our digital index correlate with both manually obtained frailty scores and chronological age. Thus, we provide an automated tool for frailty assessment that can be collected reproducibly, at scale, without substantial labor cost.

Unravelling the complex interactions between self-awareness, cognitive change, and mood at 6-months post-stroke using the Y-shaped model.

We investigated the relationships between cognitive change following stroke, awareness of cognitive impairments, and mood to further understanding of change processes influencing psychological outcomes post-stroke in line with the "Y-shaped" process model. Patients (n = 143; Mage = 73 years, SD = 13.73; 74 males) were assessed at 3-weeks (T1) and 6-months (T2) post-stroke and had completed the Oxford Cognitive Screen (T1 and T2), the Cognitive Failures Questionnaire (CFQ; T2), and the Hospital Anxiety and Depression Scale (HADS; T2). An ANCOVA controlling for disability relating to activities of daily living (ADL) revealed that awareness of cognitive impairment was significantly lower in participants with moderate-severe cognitive impairment. Regression analysis indicated that greater awareness of cognitive impairment and reduced independence in ADL were associated with greater emotional distress at T2. Cognitive improvement was associated with lower emotional distressat T2. Contrary to the awareness hypothesis, moderation analyses suggest that this effect was largest for those most cognitively impaired at T1. Findings emphasize the importance of monitoring stroke patients' capacity to be self-aware when assessing and formulating long-term post-stroke distress and have potential implications for improving long-term emotional status in those most cognitively impaired post-stroke, e.g., through psychoeducation, cognitive rehabilitation, and emotional support.

Direct targeted therapy for MLL-fusion-driven high-risk acute leukaemias.

BACKGROUND: Improving the poor prognosis of infant leukaemias remains an unmet clinical need. This disease is a prototypical fusion oncoprotein-driven paediatric cancer, with MLL (KMT2A)-fusions present in most cases. Direct targeting of these driving oncoproteins represents a unique therapeutic opportunity. This rationale led us to initiate a drug screening with the aim of discovering drugs that can block MLL-fusion oncoproteins. METHODS: A screen for inhibition of MLL-fusion proteins was developed that overcomes the traditional limitations of targeting transcription factors. This luciferase reporter-based screen, together with a secondary western blot screen, was used to prioritize compounds. We characterized the lead compound, disulfiram (DSF), based on its efficient ablation of MLL-fusion proteins. The consequences of drug-induced MLL-fusion inhibition were confirmed by cell proliferation, colony formation, apoptosis assays, RT-qPCR, in vivo assays, RNA-seq and ChIP-qPCR and ChIP-seq analysis. All statistical tests were two-sided. RESULTS: Drug-induced inhibition of MLL-fusion proteins by DSF resulted in a specific block of colony formation in MLL-rearranged cells in vitro, induced differentiation and impeded leukaemia progression in vivo. Mechanistically, DSF abrogates MLL-fusion protein binding to DNA, resulting in epigenetic changes and down-regulation of leukaemic programmes setup by the MLL-fusion protein. CONCLUSION: DSF can directly inhibit MLL-fusion proteins and demonstrate antitumour activity both in vitro and in vivo, providing, to our knowledge, the first evidence for a therapy that directly targets the initiating oncogenic MLL-fusion protein.

Anti-CCR9 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature T lymphocytes, associated with higher rates of induction failure compared with those in B cell acute lymphoblastic leukemia. The potent immunotherapeutic approaches applied in B cell acute lymphoblastic leukemia, which have revolutionized the treatment paradigm, have proven more challenging in T-ALL, largely due to a lack of target antigens expressed on malignant but not healthy T cells. Unlike B cell depletion, T-cell aplasia is highly toxic. Here, we show that the chemokine receptor CCR9 is expressed in >70% of cases of T-ALL, including >85% of relapsed/refractory disease, and only on a small fraction (<5%) of normal T cells. Using cell line models and patient-derived xenografts, we found that chimeric antigen receptor (CAR) T-cells targeting CCR9 are resistant to fratricide and have potent antileukemic activity both in vitro and in vivo, even at low target antigen density. We propose that anti-CCR9 CAR-T cells could be a highly effective treatment strategy for T-ALL, avoiding T cell aplasia and the need for genome engineering that complicate other approaches.

Identification of a c-MYB-directed therapeutic for acute myeloid leukemia.

A significant proportion of patients suffering from acute myeloid leukemia (AML) cannot be cured by conventional chemotherapy, relapsed disease being a common problem. Molecular targeting of essential oncogenic mediators is an attractive approach to improving outcomes for this disease. The hematopoietic transcription factor c-MYB has been revealed as a central component of complexes maintaining aberrant gene expression programs in AML. We have previously screened the Connectivity Map database to identify mebendazole as an anti-AML therapeutic targeting c-MYB. In the present study we demonstrate that another hit from this screen, the steroidal lactone withaferin A (WFA), induces rapid ablation of c-MYB protein and consequent inhibition of c-MYB target gene expression, loss of leukemia cell viability, reduced colony formation and impaired disease progression. Although WFA has been reported to have pleiotropic anti-cancer effects, we demonstrate that its anti-AML activity depends on c-MYB modulation and can be partially reversed by a stabilized c-MYB mutant. c-MYB ablation results from disrupted HSP/HSC70 chaperone protein homeostasis in leukemia cells following induction of proteotoxicity and the unfolded protein response by WFA. The widespread use of WFA in traditional medicines throughout the world indicates that it represents a promising candidate for repurposing into AML therapy.

The genetic architecture of flowering time changes in pea from wild to crop.

Change in phenology has been an important component in crop evolution, and selection for earlier flowering through a reduction in environmental sensitivity has helped broaden adaptation in many species. Natural variation for flowering in domesticated pea (Pisum sativum L.) has been noted and studied for decades, but there has been no clear account of change relative to its wild progenitor. Here we examined the genetic control of differences in flowering time between wild P. sativum ssp. humile and a typical late-flowering photoperiodic P. s. sativum accession in a recombinant inbred population under long and short photoperiods. Our results confirm the importance of the major photoperiod sensitivity locus Hr/PsELF3a and identify two other loci on chromosomes 1 (DTF1) and 3 (DTF3) that contribute to earlier flowering in the domesticated line under both photoperiods. The domesticated allele at a fourth locus on chromosome 6 (DTF6) delays flowering under long days only. Map positions, inheritance patterns, and expression analyses in near-isogenic comparisons imply that DTF1, DTF3, and DTF6 represent gain-of-function alleles of the florigen/antiflorigen genes FTa3, FTa1, and TFL1c/LF, respectively. This echoes similar variation in chickpea and lentil, and suggests a conserved route to reduced photoperiod sensitivity and early phenology in temperate pulses.

Accelerated decline in white matter microstructure in subsequently impaired older adults and its relationship with cognitive decline.

Little is known about a longitudinal decline in white matter microstructure and its associations with cognition in preclinical dementia. Longitudinal diffusion tensor imaging and neuropsychological testing were performed in 50 older adults who subsequently developed mild cognitive impairment or dementia (subsequently impaired) and 200 cognitively normal controls. Rates of white matter microstructural decline were compared between groups using voxel-wise linear mixed-effects models. Associations between change in white matter microstructure and cognition were examined. Subsequently impaired individuals had a faster decline in fractional anisotropy in the right inferior fronto-occipital fasciculus and bilateral splenium of the corpus callosum. A decline in right inferior fronto-occipital fasciculus fractional anisotropy was related to a decline in verbal memory, visuospatial ability, processing speed and mini-mental state examination. A decline in bilateral splenium fractional anisotropy was related to a decline in verbal fluency, processing speed and mini-mental state examination. Accelerated regional white matter microstructural decline is evident during the preclinical phase of mild cognitive impairment/dementia and is related to domain-specific cognitive decline.

Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia.

KMT2A-rearranged infant ALL is an aggressive childhood leukemia with poor prognosis. Here, we investigated the developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia (B-ALL) using bulk messenger RNA (mRNA) meta-analysis and examination of single lymphoblast transcriptomes against a developing bone marrow reference. KMT2A-rearranged infant B-ALL was uniquely dominated by an early lymphocyte precursor (ELP) state, whereas less adverse NUTM1-rearranged infant ALL demonstrated signals of later developing B cells, in line with most other childhood B-ALLs. We compared infant lymphoblasts with ELP cells and revealed that the cancer harbored hybrid myeloid-lymphoid features, including nonphysiological antigen combinations potentially targetable to achieve cancer specificity. We validated surface coexpression of exemplar combinations by flow cytometry. Through analysis of shared mutations in separate leukemias from a child with infant KMT2A-rearranged B-ALL relapsing as AML, we established that KMT2A rearrangement occurred in very early development, before hematopoietic specification, emphasizing that cell of origin cannot be inferred from the transcriptional state.

Total Hip Replacement in Patients with Rheumatoid Arthritis: Trends in Incidence and Complication Rates Over 35 Years.

INTRODUCTION: Advances in rheumatoid arthritis (RA) management have made disease remission achievable. We evaluated trends in total hip replacement (THR) and postoperative outcomes in patients with RA in Western Australia (WA) over more than three decades. METHODS: This was a retrospective analysis of routinely collected prospective data from a state-wide registry containing longitudinally linked administrative health data based on International Classification of Diseases (ICD) diagnostic and procedural codes. We included patients with two or more diagnostic codes for RA (between 1980 and 2015) and studied THR incidence rates (THR IR) and complication rates (revision, peri-prosthetic fracture, infection, venous thrombosis, and mechanical loosening). Survival rates were estimated by Kaplan-Meier method and predictors analyzed by Cox regression. RESULTS: We followed 9201 RA patients over 111,625 person-years, during which 1560 patients (16.9%) underwent THR. From 1985 to 2015, THR IR (per 1000 RA patient-years) decreased from 20.8 (95% CI 20.1-21.5) to 7.3 (95% CI 7.2-7.5), and 5-year THR-free survival increased from 84.3 to 95.3% (1980-2015). Ten-year prosthetic survival was 91.2%. Complication rates in the first 5 years post-THR decreased significantly from 13.1 to 3.7% (p < 0.001). Mechanical complications such as loosening and periprosthetic fracture rates decreased significantly (> 35%, P < 0.05), while infection and revision did not change over the observation period (p > 0.05). CONCLUSIONS: Over the last 30 years in RA patients, THR IR and mechanical complication rates decreased significantly, but the medical complication of infection has not changed significantly.

Learning white matter subject-specific segmentation from structural MRI.

PURPOSE: Mapping brain white matter (WM) is essential for building an understanding of brain anatomy and function. Tractography-based methods derived from diffusion-weighted MRI (dMRI) are the principal tools for investigating WM. These procedures rely on time-consuming dMRI acquisitions that may not always be available, especially for legacy or time-constrained studies. To address this problem, we aim to generate WM tracts from structural magnetic resonance imaging (MRI) image by deep learning. METHODS: Following recently proposed innovations in structural anatomical segmentation, we evaluate the feasibility of training multiply spatial localized convolution neural networks to learn context from fixed spatial patches from structural MRI on standard template. We focus on six widely used dMRI tractography algorithms (TractSeg, RecoBundles, XTRACT, Tracula, automated fiber quantification (AFQ), and AFQclipped) and train 125 U-Net models to learn these techniques from 3870 T1-weighted images from the Baltimore Longitudinal Study of Aging, the Human Connectome Project S1200 release, and scans acquired at Vanderbilt University. RESULTS: The proposed framework identifies fiber bundles with high agreement against tractography-based pathways with a median Dice coefficient from 0.62 to 0.87 on a test cohort, achieving improved subject-specific accuracy when compared to population atlas-based methods. We demonstrate the generalizability of the proposed framework on three externally available datasets. CONCLUSIONS: We show that patch-wise convolutional neural network can achieve robust bundle segmentation from T1w. We envision the use of this framework for visualizing the expected course of WM pathways when dMRI is not available.

TractEM: Evaluation of protocols for deterministic tractography white matter atlas.

Reproducible identification of white matter pathways across subjects is essential for the study of structural connectivity of the human brain. One of the key challenges is anatomical differences between subjects and human rater subjectivity in labeling. Labeling white matter regions of interest presents many challenges due to the need to integrate both local and global information. Clearly communicating the manual processes to capture this information is cumbersome, yet essential to lay a solid foundation for comprehensive atlases. Segmentation protocols must be designed so the interpretation of the requested tasks as well as locating structural landmarks is anatomically accurate, intuitive and reproducible. In this work, we quantified the reproducibility of a first iteration of an open/public multi-bundle segmentation protocol. This allowed us to establish a baseline for its reproducibility as well as to identify the limitations for future iterations. The protocol was tested/evaluated on both typical 3 T research acquisition Baltimore Longitudinal Study of Aging (BLSA) and high-acquisition quality Human Connectome Project (HCP) datasets. The results show that a rudimentary protocol can produce acceptable intra-rater and inter-rater reproducibility. However, this work highlights the difficulty in generalizing reproducible results and the importance of reaching consensus on anatomical description of white matter pathways. The protocol has been made available in open source to improve generalizability and reliability in collaboration. The goal is to improve upon the first iteration and initiate a discussion on the anatomical validity (or lack thereof) of some bundle definitions and the importance of reproducibility of tractography segmentation.