Imbalance of Regulatory and Cytotoxic SARS-CoV-2-Reactive CD4+ T Cells in COVID-19.

The contribution of CD4+ T cells to protective or pathogenic immune responses to SARS-CoV-2 infection remains unknown. Here, we present single-cell transcriptomic analysis of >100,000 viral antigen-reactive CD4+ T cells from 40 COVID-19 patients. In hospitalized patients compared to non-hospitalized patients, we found increased proportions of cytotoxic follicular helper cells and cytotoxic T helper (TH) cells (CD4-CTLs) responding to SARS-CoV-2 and reduced proportion of SARS-CoV-2-reactive regulatory T cells (TREG). Importantly, in hospitalized COVID-19 patients, a strong cytotoxic TFH response was observed early in the illness, which correlated negatively with antibody levels to SARS-CoV-2 spike protein. Polyfunctional TH1 and TH17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4+ T cells compared to influenza-reactive CD4+ T cells. Together, our analyses provide insights into the gene expression patterns of SARS-CoV-2-reactive CD4+ T cells in distinct disease severities.

Intratumoral follicular regulatory T cells curtail anti-PD-1 treatment efficacy.

Immune-checkpoint blockade (ICB) has shown remarkable clinical success in boosting antitumor immunity. However, the breadth of its cellular targets and specific mode of action remain elusive. We find that tumor-infiltrating follicular regulatory T (TFR) cells are prevalent in tumor tissues of several cancer types. They are primarily located within tertiary lymphoid structures and exhibit superior suppressive capacity and in vivo persistence as compared with regulatory T cells, with which they share a clonal and developmental relationship. In syngeneic tumor models, anti-PD-1 treatment increases the number of tumor-infiltrating TFR cells. Both TFR cell deficiency and the depletion of TFR cells with anti-CTLA-4 before anti-PD-1 treatment improve tumor control in mice. Notably, in a cohort of 271 patients with melanoma, treatment with anti-CTLA-4 followed by anti-PD-1 at progression was associated with better a survival outcome than monotherapy with anti-PD-1 or anti-CTLA-4, anti-PD-1 followed by anti-CTLA-4 at progression or concomitant combination therapy.

Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening.

Elucidation of the mutational landscape of human cancer has progressed rapidly and been accompanied by the development of therapeutics targeting mutant oncogenes. However, a comprehensive mapping of cancer dependencies has lagged behind and the discovery of therapeutic targets for counteracting tumor suppressor gene loss is needed. To identify vulnerabilities relevant to specific cancer subtypes, we conducted a large-scale RNAi screen in which viability effects of mRNA knockdown were assessed for 7,837 genes using an average of 20 shRNAs per gene in 398 cancer cell lines. We describe findings of this screen, outlining the classes of cancer dependency genes and their relationships to genetic, expression, and lineage features. In addition, we describe robust gene-interaction networks recapitulating both protein complexes and functional cooperation among complexes and pathways. This dataset along with a web portal is provided to the community to assist in the discovery and translation of new therapeutic approaches for cancer.

Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer.

Therapies that boost the anti-tumor responses of cytotoxic T lymphocytes (CTLs) have shown promise; however, clinical responses to the immunotherapeutic agents currently available vary considerably, and the molecular basis of this is unclear. We performed transcriptomic profiling of tumor-infiltrating CTLs from treatment-naive patients with lung cancer to define the molecular features associated with the robustness of anti-tumor immune responses. We observed considerable heterogeneity in the expression of molecules associated with activation of the T cell antigen receptor (TCR) and of immunological-checkpoint molecules such as 4-1BB, PD-1 and TIM-3. Tumors with a high density of CTLs showed enrichment for transcripts linked to tissue-resident memory cells (TRM cells), such as CD103, and CTLs from CD103hi tumors displayed features of enhanced cytotoxicity. A greater density of TRM cells in tumors was predictive of a better survival outcome in lung cancer, and this effect was independent of that conferred by CTL density. Here we define the 'molecular fingerprint' of tumor-infiltrating CTLs and identify potentially new targets for immunotherapy.

Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL.

The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.

FOXO inhibition rescues α-defensin expression in human intestinal organoids.

To mediate critical host-microbe interactions in the human small intestine, Paneth cells constitutively produce abundant levels of α-defensins and other antimicrobials. We report that the expression profile of these antimicrobials is dramatically askew in human small intestinal organoids (enteroids) as compared to that in paired tissue from which they are derived, with a reduction of α-defensins to nearly undetectable levels. Murine enteroids, however, recapitulate the expression profile of Paneth cell α-defensins seen in tissue. WNT/TCF signaling has been found to be instrumental in the regulation of α-defensins, yet in human enteroids exogenous stimulation of WNT signaling appears insufficient to rescue α-defensin expression. By stark contrast, forkhead box O (FOXO) inhibitor AS1842856 induced the expression of α-defensin mRNA in enteroids by >100,000-fold, restoring DEFA5 and DEFA6 to levels comparable to those found in primary human tissue. These results newly identify FOXO signaling as a pathway of biological and potentially therapeutic relevance for the regulation of human Paneth cell α-defensins in health and disease.

Exposure to urban particulate matter (UPM) impairs mitochondrial dynamics in BV2 cells, triggering a mitochondrial biogenesis response.

World Health Organisation data suggest that up to 99% of the global population are exposed to air pollutants above recommended levels. Impacts to health range from increased risk of stroke and cardiovascular disease to chronic respiratory conditions, and air pollution may contribute to over 7 million premature deaths a year. Additionally, mounting evidence suggests that in utero or early life exposure to particulate matter (PM) in ambient air pollution increases the risk of neurodevelopmental impairment with obvious lifelong consequences. Identifying brain-specific cellular targets of PM is vital for determining its long-term consequences. We previously established that microglial-like BV2 cells were particularly sensitive to urban (U)PM-induced damage including reactive oxygen species production, which was abrogated by a mitochondrially targeted antioxidant. Here we extend those studies to find that UPM treatment causes a rapid impairment of mitochondrial function and increased mitochondrial fragmentation. However, there is a subsequent restoration of mitochondrial and therefore cell health occurring concomitantly with upregulated measures of mitochondrial biogenesis and mitochondrial load. Our data highlight that protecting mitochondrial function may represent a valuable mechanism to offset the effects of UPM exposure in the neonatal brain. KEY POINTS: Air pollution represents a growing risk to long-term health especially in early life, and the CNS is emerging a target for airborne particulate matter (PM). We previously showed that microglial-like BV2 cells were vulnerable to urban (U)PM exposure, which impaired cell survival and promoted reactive oxygen species production. Here we find that, following UPM exposure, BV2 mitochondrial membrane potential is rapidly reduced, concomitant with decreased cellular bioenergetics and increased mitochondrial fission. However, markers of mitochondrial biogenesis and mitochondrial mass are subsequently induced, which may represent a cellular mitigation strategy. As mitochondria are more vulnerable in the developing brain, exposure to air pollution may represent a greater risk to lifelong health in this cohort; conversely, promoting mitochondrial integrity may offset these risks.

Executive Function in Preschool Children with Congenital Heart Disease and Controls: The Role of a Cognitively Stimulating Home Environment.

OBJECTIVE: To assess the relationships between (1) environmental and demographic factors and executive function (EF) in preschool children with congenital heart disease (CHD) and controls and (2) clinical and surgical risk factors and EF in preschool children with CHD. STUDY DESIGN: At 4-6 years of age, parents of children with CHD (n = 51) and controls (n = 124) completed the Behavior Rating Inventory of Executive Function, Preschool Version questionnaire and the Cognitively Stimulating Parenting Scale (CSPS). Multivariable general linear modeling assessed the relationship between Behavior Rating Inventory of Executive Function, Preschool Version composite scores (Inhibitory Self-Control Index [ISCI], Flexibility Index [FI], and Emergent Metacognition Index [EMI]) and group (CHD/control), sex, age at assessment, gestational age, Index of Multiple Deprivation, and CSPS scores. The relationships between CHD type, surgical factors, and brain magnetic resonance imaging injury rating and ISCI, FI, and EMI scores were assessed. RESULTS: The presence of CHD, age at assessment, sex, and Index of Multiple Deprivation were not associated with EF scores. Lower gestational age was associated with greater ISCI and FI scores, and age at assessment was associated with lower FI scores. Group significantly moderated the relationship between CSPS and EF, such that CSPS significantly predicted EF in children with CHD (ISCI: P = .0004; FI: P = .0015; EMI: P = .0004) but not controls (ISCI: P = .2727; FI: P = .6185; EMI: P = .3332). There were no significant relationships between EF scores and surgical factors, CHD type, or brain magnetic resonance imaging injury rating. CONCLUSIONS: Supporting parents to provide a cognitively stimulating home environment may improve EF in children with CHD. The home and parenting environment should be considered when designing intervention studies aimed at improving EF in this patient group.

Perioperative Brain Injury in Relation to Early Neurodevelopment Among Children with Severe Congenital Heart Disease: Results from a European Collaboration.

OBJECTIVE: To examine the relationship between perioperative brain injury and neurodevelopment during early childhood in patients with severe congenital heart disease (CHD). STUDY DESIGN: One hundred and seventy children with CHD and born at term who required cardiopulmonary bypass surgery in the first 6 weeks after birth were recruited from 3 European centers and underwent preoperative and postoperative brain MRIs. Uniform description of imaging findings was performed and an overall brain injury score was created, based on the sum of the worst preoperative or postoperative brain injury subscores. Motor and cognitive outcomes were assessed with the Bayley Scales of Infant and Toddler Development Third Edition at 12 to 30 months of age. The relationship between brain injury score and clinical outcome was assessed using multiple linear regression analysis, adjusting for CHD severity, length of hospital stay (LOS), socioeconomic status (SES), and age at follow-up. RESULTS: Neither the overall brain injury score nor any of the brain injury subscores correlated with motor or cognitive outcome. The number of preoperative white matter lesions was significantly associated with gross motor outcome after correction for multiple testing (P = .013, ß = -0.50). SES was independently associated with cognitive outcome (P < .001, ß = 0.26), and LOS with motor outcome (P < .001, ß = -0.35). CONCLUSION: Preoperative white matter lesions appear to be the most predictive MRI marker for adverse early childhood gross motor outcome in this large European cohort of infants with severe CHD. LOS as a marker of disease severity, and SES influence outcome and future intervention trials need to address these risk factors.

T2*-Relaxometry MRI to Assess Third Trimester Placental and Fetal Brain Oxygenation and Placental Characteristics in Healthy Fetuses and Fetuses With Congenital Heart Disease.

BACKGROUND: Congenital heart disease (CHD) has been linked to impaired placental and fetal brain development. Assessing the placenta and fetal brain in parallel may help further our understanding of the relationship between development of these organs. HYPOTHESIS: 1) Placental and fetal brain oxygenation are correlated, 2) oxygenation in these organs is reduced in CHD compared to healthy controls, and 3) placental structure is altered in CHD. STUDY TYPE: Retrospective case-control. POPULATION: Fifty-one human fetuses with CHD (32 male; median [IQR] gestational age [GA] = 32.0 [30.9-32.9] weeks) and 30 from uncomplicated pregnancies with normal birth outcomes (18 male; median [IQR] GA = 34.5 [31.9-36.7] weeks). FIELD STRENGTH/SEQUENCE: 1.5 T single-shot multi-echo-gradient-echo echo-planar imaging. ASSESSMENT: Masking was performed using an automated nnUnet model. Mean brain and placental T2* and quantitative measures of placental texture, volume, and morphology were calculated. STATISTICAL TESTS: Spearman's correlation coefficient for determining the association between brain and placental T2*, and between brain and placental characteristics with GA. P-values for comparing brain T2*, placenta T2*, and placental characteristics between groups derived from ANOVA. Significance level P < 0.05. RESULTS: There was a significant positive association between placental and fetal brain T2* (⍴ = 0.46). Placental and fetal brain T2* showed a significant negative correlation with GA (placental T2* ⍴ = -0.65; fetal brain T2* ⍴ = -0.32). Both placental and fetal brain T2* values were significantly reduced in CHD, after adjusting for GA (placental T2*: control = 97 [±24] msec, CHD = 83 [±23] msec; brain T2*: control = 218 [±26] msec, CHD = 202 [±25] msec). Placental texture and morphology were also significantly altered in CHD (Texture: control = 0.84 [0.83-0.87], CHD = 0.80 [0.78-0.84]; Morphology: control = 9.9 [±2.2], CHD = 10.8 [±2.0]). For all fetuses, there was a significant positive association between placental T2* and placental texture (⍴ = 0.46). CONCLUSION: Placental and fetal brain T2* values are associated in healthy fetuses and those with CHD. Placental and fetal brain oxygenation are reduced in CHD. Placental appearance is significantly altered in CHD and shows associations with placental oxygenation, suggesting altered placental development and function may be related. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Advances in fetal and neonatal neuroimaging and everyday exposures.

The complex, tightly regulated process of prenatal brain development may be adversely affected by "everyday exposures" such as stress and environmental pollutants. Researchers are only just beginning to understand the neural sequelae of such exposures, with advances in fetal and neonatal neuroimaging elucidating structural, microstructural, and functional correlates in the developing brain. This narrative review discusses the wide-ranging literature investigating the influence of parental stress on fetal and neonatal brain development as well as emerging literature assessing the impact of exposure to environmental toxicants such as lead and air pollution. These 'everyday exposures' can co-occur with other stressors such as social and financial deprivation, and therefore we include a brief discussion of neuroimaging studies assessing the effect of social disadvantage. Increased exposure to prenatal stressors is associated with alterations in the brain structure, microstructure and function, with some evidence these associations are moderated by factors such as infant sex. However, most studies examine only single exposures and the literature on the relationship between in utero exposure to pollutants and fetal or neonatal brain development is sparse. Large cohort studies are required that include evaluation of multiple co-occurring exposures in order to fully characterize their impact on early brain development. IMPACT: Increased prenatal exposure to parental stress and is associated with altered functional, macro and microstructural fetal and neonatal brain development. Exposure to air pollution and lead may also alter brain development in the fetal and neonatal period. Further research is needed to investigate the effect of multiple co-occurring exposures, including stress, environmental toxicants, and socioeconomic deprivation on early brain development.

Cerebrospinal fluid immunoglobulins in primary progressive multiple sclerosis are pathogenic.

Multiple sclerosis is clinically characterized by relapses and remissions (relapsing-remitting multiple sclerosis) that over time may evolve to a progressive course (secondary progressive multiple sclerosis) or as having a progressive course from disease onset (primary progressive multiple sclerosis). At present, it is not definitively known whether these clinical entities constitute a single pathological disease or whether these manifestations represent two distinct disease entities sharing inflammatory demyelination as a pathological feature. Here we show using a novel mouse model that CSF of primary progressive multiple sclerosis patients is unique in its capacity to induce motor disability and spinal cord pathology including demyelination, impaired remyelination, reactive astrogliosis and axonal damage. Notably, removal of immunoglobulin G from primary progressive multiple sclerosis CSF via filtration or immunodepletion attenuates its pathogenic capacity. Furthermore, injection of recombinant antibodies derived from primary progressive multiple sclerosis CSF recapitulates the pathology. Our findings suggest that the clinical and pathological features of primary progressive multiple sclerosis are antibody-mediated and pathogenically distinct from relapsing-remitting and secondary progressive multiple sclerosis. Our study has potentially important implications for the development of specific therapies for patients with primary progressive multiple sclerosis.

A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection.

During the course of a viral infection, viral proteins interact with an array of host proteins and pathways. Here, we present a systematic strategy to elucidate the dynamic interactions between H1N1 influenza and its human host. A combination of yeast two-hybrid analysis and genome-wide expression profiling implicated hundreds of human factors in mediating viral-host interactions. These factors were then examined functionally through depletion analyses in primary lung cells. The resulting data point to potential roles for some unanticipated host and viral proteins in viral infection and the host response, including a network of RNA-binding proteins, components of WNT signaling, and viral polymerase subunits. This multilayered approach provides a comprehensive and unbiased physical and regulatory model of influenza-host interactions and demonstrates a general strategy for uncovering complex host-pathogen relationships.

Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells.

An alternative to therapeutic targeting of oncogenes is to perform "synthetic lethality" screens for genes that are essential only in the context of specific cancer-causing mutations. We used high-throughput RNA interference (RNAi) to identify synthetic lethal interactions in cancer cells harboring mutant KRAS, the most commonly mutated human oncogene. We find that cells that are dependent on mutant KRAS exhibit sensitivity to suppression of the serine/threonine kinase STK33 irrespective of tissue origin, whereas STK33 is not required by KRAS-independent cells. STK33 promotes cancer cell viability in a kinase activity-dependent manner by regulating the suppression of mitochondrial apoptosis mediated through S6K1-induced inactivation of the death agonist BAD selectively in mutant KRAS-dependent cells. These observations identify STK33 as a target for treatment of mutant KRAS-driven cancers and demonstrate the potential of RNAi screens for discovering functional dependencies created by oncogenic mutations that may enable therapeutic intervention for cancers with "undruggable" genetic alterations.

Myelodysplasia cutis and VEXAS syndrome initially diagnosed as histiocytoid Sweet syndrome: A diagnostic pitfall.

Histiocytoid Sweet syndrome (H-SS) is a histopathological variant of Sweet syndrome (SS) defined by cutaneous infiltration of immature myeloid cells morphologically resembling histiocytes. The association of H-SS with underlying malignancy, particularly myelodysplastic syndromes, is well-established. Myelodysplasia cutis (MDS-cutis) has been proposed to describe cases historically diagnosed as H-SS but characterized by shared clonality of the myeloid infiltrate in skin and bone marrow. Therefore, identifying patients who might have MDS-cutis is critical for the management of the associated hematologic malignancy. VEXAS syndrome, an adult-onset autoinflammatory disease, should also be included in the histopathologic differential diagnosis of H-SS, as it shares clinical and pathologic features with MDS-cutis. Through the presentation of two cases, we aim to highlight the defining features and key clinical implications of MDS-cutis and VEXAS syndrome.

Comprehensive volumetric phenotyping of the neonatal brain in Down syndrome.

Down syndrome (DS) is the most common genetic cause of intellectual disability with a wide range of neurodevelopmental outcomes. To date, there have been very few in vivo neuroimaging studies of the neonatal brain in DS. In this study we used a cross-sectional sample of 493 preterm- to term-born control neonates from the developing Human Connectome Project to perform normative modeling of regional brain tissue volumes from 32 to 46 weeks postmenstrual age, accounting for sex and age variables. Deviation from the normative mean was quantified in 25 neonates with DS with postnatally confirmed karyotypes from the Early Brain Imaging in DS study. Here, we provide the first comprehensive volumetric phenotyping of the neonatal brain in DS, which is characterized by significantly reduced whole brain, cerebral white matter, and cerebellar volumes; reduced relative frontal and occipital lobar volumes, in contrast with enlarged relative temporal and parietal lobar volumes; enlarged relative deep gray matter volume (particularly the lentiform nuclei); and enlargement of the lateral ventricles, amongst other features. In future, the ability to assess phenotypic severity at the neonatal stage may help guide early interventions and, ultimately, help improve neurodevelopmental outcomes in children with DS.

Self-referential processing in anorexia nervosa.

OBJECTIVE: Anorexia nervosa (AN) is a serious psychiatric illness associated with significant medical and psychiatric comorbidity and impairment. Theoretical models of AN and self-report studies suggest that negative self-evaluation (i.e., low self-esteem) is related to the development and maintenance of AN. The goal of this study was to extend findings from self-report methodology using a neurocognitive task that probes self-evaluation implicitly and explicitly. METHOD: We compared female adolescent and adult patients with AN (n = 35) and healthy controls (HC, n = 38) on explicit (i.e., endorsement of words as self-relevant), implicit (recall, recognition, reaction time), and composite (i.e., valence index, bias score, drift rates) indices of self-evaluation. We applied a drift-diffusion model to compute the drift rates, reflecting participants' decision-making process as to whether words were self-relevant. The association between self-evaluation indices and eating disorder severity was examined. RESULTS: There were significant Group × Condition interaction effects for all explicit and implicit measures (all p's ≤ .01), where the AN group endorsed, recalled, and recognized more negative relative to positive words than HC. The AN group had more negative valence index and bias scores, and slower drift rate away from negative words, reflecting more negative self-evaluation. The finding for recall was attenuated when individuals with depression were excluded. Measures of self-evaluation bias were not related to eating disorder severity. DISCUSSION: Using a neurocognitive approach that includes explicit and implicit indices of bias, results suggest that patients with AN have more negative self-evaluation. Due to the cross-sectional design, additional studies are needed to further evaluate directionality. PUBLIC SIGNIFICANCE: Negative self-evaluation/low self-esteem is thought to contribute to eating disorder symptoms. Findings of this study using a neurocognitive task to probe self-evaluation suggested that individuals with anorexia nervosa have more negative self-evaluation, reflected by endorsing and remembering more negative (than positive) words compared to healthy controls, and doing so faster. Targeting the construct of negative self-evaluation in treatment of AN may be warranted.

Development of human white matter pathways in utero over the second and third trimester.

During the second and third trimesters of human gestation, rapid neurodevelopment is underpinned by fundamental processes including neuronal migration, cellular organization, cortical layering, and myelination. In this time, white matter growth and maturation lay the foundation for an efficient network of structural connections. Detailed knowledge about this developmental trajectory in the healthy human fetal brain is limited, in part, due to the inherent challenges of acquiring high-quality MRI data from this population. Here, we use state-of-the-art high-resolution multishell motion-corrected diffusion-weighted MRI (dMRI), collected as part of the developing Human Connectome Project (dHCP), to characterize the in utero maturation of white matter microstructure in 113 fetuses aged 22 to 37 wk gestation. We define five major white matter bundles and characterize their microstructural features using both traditional diffusion tensor and multishell multitissue models. We found unique maturational trends in thalamocortical fibers compared with association tracts and identified different maturational trends within specific sections of the corpus callosum. While linear maturational increases in fractional anisotropy were seen in the splenium of the corpus callosum, complex nonlinear trends were seen in the majority of other white matter tracts, with an initial decrease in fractional anisotropy in early gestation followed by a later increase. The latter is of particular interest as it differs markedly from the trends previously described in ex utero preterm infants, suggesting that this normative fetal data can provide significant insights into the abnormalities in connectivity which underlie the neurodevelopmental impairments associated with preterm birth.

Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations.

OPA1 mutations are the major cause of dominant optic atrophy (DOA) and the syndromic form DOA plus, pathologies for which there is no established cure. We used a 'drug repurposing' approach to identify FDA-approved molecules able to rescue the mitochondrial dysfunctions induced by OPA1 mutations. We screened two different chemical libraries by using two yeast strains carrying the mgm1I322M and the chim3P646L mutations, identifying 26 drugs able to rescue their oxidative growth phenotype. Six of them, able to reduce the mitochondrial DNA instability in yeast, have been then tested in Opa1 deleted mouse embryonic fibroblasts expressing the human OPA1 isoform 1 bearing the R445H and D603H mutations. Some of these molecules were able to ameliorate the energetic functions and/or the mitochondrial network morphology, depending on the type of OPA1 mutation. The final validation has been performed in patients' fibroblasts, allowing to select the most effective molecules. Our current results are instrumental to rapidly translating the findings of this drug repurposing approach into clinical trial for DOA and other neurodegenerations caused by OPA1 mutations.

Assessing within-subject rates of change of placental MRI diffusion metrics in normal pregnancy.

PURPOSE: Studying placental development informs when development is abnormal. Most placental MRI studies are cross-sectional and do not study the extent of individual variability throughout pregnancy. We aimed to explore how diffusion MRI measures of placental function and microstructure vary in individual healthy pregnancies throughout gestation. METHODS: Seventy-nine pregnant, low-risk participants (17 scanned twice and 62 scanned once) were included. T2 -weighted anatomical imaging and a combined multi-echo spin-echo diffusion-weighted sequence were acquired at 3 T. Combined diffusion-relaxometry models were performed using both a T 2 * $$ {\mathrm{T}}_2^{\ast } $$ -ADC and a bicompartmental T 2 * $$ {\mathrm{T}}_2^{\ast } $$ -intravoxel-incoherent-motion ( T 2 * IVIM $$ {\mathrm{T}}_2^{\ast}\;\mathrm{IVIM} $$ ) model fit. RESULTS: There was a significant decline in placental T 2 * $$ {\mathrm{T}}_2^{\ast } $$ and ADC (both P < 0.01) over gestation. These declines are consistent in individuals for T 2 * $$ {\mathrm{T}}_2^{\ast } $$ (covariance = -0.47), but not ADC (covariance = -1.04). The T 2 * IVIM $$ {\mathrm{T}}_2^{\ast}\;\mathrm{IVIM} $$ model identified a consistent decline in individuals over gestation in T 2 * $$ {\mathrm{T}}_2^{\ast } $$ from both the perfusing and diffusing placental compartments, but not in ADC values from either. The placental perfusing compartment fraction increased over gestation (P = 0.0017), but this increase was not consistent in individuals (covariance = 2.57). CONCLUSION: Whole placental T 2 * $$ {\mathrm{T}}_2^{\ast } $$ and ADC values decrease over gestation, although only T 2 * $$ {\mathrm{T}}_2^{\ast } $$ values showed consistent trends within subjects. There was minimal individual variation in rates of change of T 2 * $$ {\mathrm{T}}_2^{\ast } $$ values from perfusing and diffusing placental compartments, whereas trends in ADC values from these compartments were less consistent. These findings probably relate to the increased complexity of the bicompartmental T 2 * IVIM $$ {\mathrm{T}}_2^{\ast}\;\mathrm{IVIM} $$ model, and differences in how different placental regions evolve at a microstructural level. These placental MRI metrics from low-risk pregnancies provide a useful benchmark for clinical cohorts.