Intratumoral Delivery of Chimeric Antigen Receptor T Cells Targeting CD133 Effectively Treats Brain Metastases.

PURPOSE: Brain metastases (BM) are mainly treated palliatively with an expected survival of less than 12 months after diagnosis. In many solid tumors, the human neural stem cell marker glycoprotein CD133 is a marker of a tumor-initiating cell population that contributes to therapy resistance, relapse, and metastasis. EXPERIMENTAL DESIGN: Here, we use a variant of our previously described CD133 binder to generate second-generation CD133-specific chimeric antigen receptor T cells (CAR-T) to demonstrate its specificity and efficacy against multiple patient-derived BM cell lines with variable CD133 antigen expression. RESULTS: Using both lung- and colon-BM patient-derived xenograft models, we show that a CD133-targeting CAR-T cell therapy can evoke significant tumor reduction and survival advantage after a single dose, with complete remission observed in the colon-BM model. CONCLUSIONS: In summary, these data suggest that CD133 plays a critical role in fueling the growth of BM, and immunotherapeutic targeting of this cell population is a feasible strategy to control the outgrowth of BM tumors that are otherwise limited to palliative care. See related commentary by Sloan et al., p. 477.

Functional dissection and assembly of a small, newly evolved, W chromosome-specific genomic region of the African clawed frog Xenopus laevis.

Genetic triggers for sex determination are frequently co-inherited with other linked genes that may also influence one or more sex-specific phenotypes. To better understand how sex-limited regions evolve and function, we studied a small W chromosome-specific region of the frog Xenopus laevis that contains only three genes (dm-w, scan-w, ccdc69-w) and that drives female differentiation. Using gene editing, we found that the sex-determining function of this region requires dm-w but that scan-w and ccdc69-w are not essential for viability, female development, or fertility. Analysis of mesonephros+gonad transcriptomes during sexual differentiation illustrates masculinization of the dm-w knockout transcriptome, and identifies mostly non-overlapping sets of differentially expressed genes in separate knockout lines for each of these three W-specific gene compared to wildtype sisters. Capture sequencing of almost all Xenopus species and PCR surveys indicate that the female-determining function of dm-w is present in only a subset of species that carry this gene. These findings map out a dynamic evolutionary history of a newly evolved W chromosome-specific genomic region, whose components have distinctive functions that frequently degraded during Xenopus diversification, and evidence the evolutionary consequences of recombination suppression.

Combination of an ACLY inhibitor with a GLP-1R agonist exerts additive benefits on nonalcoholic steatohepatitis and hepatic fibrosis in mice.

Increased liver de novo lipogenesis (DNL) is a hallmark of nonalcoholic steatohepatitis (NASH). A key enzyme controlling DNL upregulated in NASH is ATP citrate lyase (ACLY). In mice, inhibition of ACLY reduces liver steatosis, ballooning, and fibrosis and inhibits activation of hepatic stellate cells. Glucagon-like peptide-1 receptor (GLP-1R) agonists lower body mass, insulin resistance, and steatosis without improving fibrosis. Here, we find that combining an inhibitor of liver ACLY, bempedoic acid, and the GLP-1R agonist liraglutide reduces liver steatosis, hepatocellular ballooning, and hepatic fibrosis in a mouse model of NASH. Liver RNA analyses revealed additive downregulation of pathways that are predictive of NASH resolution, reductions in the expression of prognostically significant genes compared with clinical NASH samples, and a predicted gene signature profile that supports fibrosis resolution. These findings support further investigation of this combinatorial therapy to treat obesity, insulin resistance, hypercholesterolemia, steatohepatitis, and fibrosis in people with NASH.

Development of a new surgical technique to infuse kynurenic acid to optic nerves in chickens for studying loss of myelination.

Prolonged infusion of a high dose of kynurenic acid (KYNA) reduces the myelin content in the rat spinal cord with preservation of the axonal integrity and without inducing an inflammatory response. We hypothesized that subdural infusion of a high concentration of KYNA can induce myelin loss in the optic nerves (ONs) of chickens. However, existing methods to deliver agents to the ON are inefficient, unlocalized and provide only acute exposure. Thus, we developed a surgical approach for sustained delivery of KYNA to the chicken ON. In brief, the novel surgical technique, which does not include excision of the extraocular muscles, involves incision of the skin and underlying fascial sheath to access the optic nerve within the muscle cone, implantation of a catheter in the dura of the optic nerve, the other end of which exits the orbit under the skin. The catheter runs under the skin near the lateral canthus, over the ears to the back of the neck, where a second incision is made to both implant the osmotic pump and to attach the catheter to the osmotic pump. India ink was used to confirm prolonged sustained administration to the optic nerves and across the chiasm. This surgical model was used to investigate KYNA's effect(s) on myelin loss in the ON. ONs of 7-day old chickens were infused with 50 mM KYNA or phosphate buffered saline (PBS) for seven days. Analysis of KYNA-infused contralateral ON g-ratios and protein levels indicated a reduction in myelin. These findings demonstrate the utility of our surgical approach for sustained delivery of KYNA into the ON and suggest a role for KYNA in modulating CNS myelination.

Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia.

Elevated liver de novo lipogenesis contributes to non-alcoholic steatohepatitis (NASH) and can be inhibited by targeting acetyl-CoA carboxylase (ACC). However, hypertriglyceridemia limits the use of pharmacological ACC inhibitors as a monotherapy. ATP-citrate lyase (ACLY) generates acetyl-CoA and oxaloacetate from citrate, but whether inhibition is effective for treating NASH is unknown. Here, we characterize a new mouse model that replicates many of the pathological and molecular drivers of NASH and find that genetically inhibiting ACLY in hepatocytes reduces liver malonyl-CoA, oxaloacetate, steatosis, and ballooning as well as blood glucose, triglycerides, and cholesterol. Pharmacological inhibition of ACLY mirrors genetic inhibition but has additional positive effects on hepatic stellate cells, liver inflammation, and fibrosis. Mendelian randomization of human variants that mimic reductions in ACLY also associate with lower circulating triglycerides and biomarkers of NASH. These data indicate that inhibiting liver ACLY may be an effective approach for treatment of NASH and dyslipidemia.

Exercise Improves Cancer-free Survival and Health Span in a Model of Radiation-induced Cancer.

INTRODUCTION: Radiation therapy increases the risk of secondary malignancy and morbidity in cancer survivors. The role of obesity and exercise training in modulating this risk is not well understood. As such, we used a preclinical model of radiation-induced malignancy to investigate whether diet-induced obesity and/or endurance exercise training altered lifelong survival, cancer incidence, and morbidity. METHODS: Male CBA mice were randomly divided into control diet/sedentary group (CTRL/SED), high-fat diet (45% fat)/sedentary group (HFD/SED), control diet/exercise group (2-3 d·wk-1; CTRL/EX), or high-fat diet/exercise group (HFD/EX) groups then exposed to whole-body radiation (3 Gy). End point monitoring and pathology determined mortality and cancer incidence, respectively. Health span index, a measure of morbidity, was determined by a composite measure of 10 anthropometric, metabolic, performance, and behavioral measures. RESULTS: Overall survival was higher in HFD/SED compared with CTRL/SED (P < 0.05). The risk of cancer-related mortality by 18 months postradiation was 1.99 and 1.63 in HFD/SED compared with CTRL/EX (RR = 1.99, 95% confidence interval = 1.20-3.31, P = 0.0081) and CTRL/SED (RR = 1.63, 95% confidence interval = 1.06-2.49, P = 0.0250), respectively. The number of mice at end point with cancer was higher in HFD/SED compared with CTRL/EX and CTRL/SED (P < 0.05). Health span index was highest in CTRL/EX (score = +2.5), followed by HFD/EX (score = +1), and HFD/SED (score = -1) relative to CTRL/SED. CONCLUSION: This work provides the basis for future preclinical studies investigating the dose-response relationship between exercise training and late effects of radiation therapy as well as the mechanisms responsible for these effects.

Imaging of Neurotrauma in Acute and Chronic Settings.

Traumatic injuries of the brain and spinal cord are a significant source of mortality and long-term disability. A recent systematic study in a rat model of spinal cord injury (SCI) indicates severe, destructive, and very protracted inflammation as the key mechanism initiated by the massive injury involving the white matter. Although the severe inflammation is localized and counteracted by astrogliosis, it has a damaging effect on the blood vessels in the surrounding spinal cord, leading to persistent vasogenic edema. Evaluation of these injuries with imaging of the brain and spinal cord plays a crucial role in the acute trauma work-up, allowing clinicians to quickly identify abnormalities that require immediate medical or surgical intervention or to exclude them from the workup. Recently, anti-inflammatory agents have been shown to inhibit and accelerate the elimination of post-SCI inflammation in preclinical studies, and an exciting potential has arisen for the use of antiinflammatory drugs in clinical studies to achieve neuroprotection (i.e., inhibition of destruction caused by inflammation) and to inhibit vasogenic edema in SCI, traumatic brain injury, and stroke. In both subacute and chronic settings, imaging can guide therapy and provide important prognostic information. In this review, we discuss the imaging workup and evolving imaging findings of neurotrauma in the acute and chronic setting, including conventional and advanced imaging techniques. As neuroimaging is the primary mode of diagnostic analysis in neurotrauma, it is a critical component in future clinical trials evaluating neuroprotective therapies.

The Pathogenesis of Neurotrauma Indicates Targets for Neuroprotective Therapies.

The spinal cord injury (SCI) initiates an extraordinarily protracted disease with 3 phases; acute, inflammatory, and resolution that are restricted to the cavity of injury (COI) or arachnoiditis by a unique CNS reaction against the severity of destructive inflammation. While the severity of inflammation involving the white matter is fueled by a potently immunogenic activity of damaged myelin, its sequestration in the COI and its continuity with the cerebrospinal fluid of the subdural space allow anti-inflammatory therapeutics infused subdurally to inhibit phagocytic macrophage infiltration and thus provide neuroprotection. The role of astrogliosis in containing and ultimately in eliminating severe destructive inflammation post-trauma appears obvious but is not yet sufficiently understood to use in therapeutic neuroprotective and neuroregenerative strategies. An apparent antiinflammatory activity of reactive astrocytes is paralleled by their active role in removing excess edema fluid in blood-brain barrier damaged by inflammation. Recently elucidated pathogenesis of neurotrauma, including SCI, traumatic brain injury (TBI), and stroke, calls for the following principal therapeutic steps in its treatment leading to the recovery of neurologic function: (1) inhibition and elimination of destructive inflammation from the COI with accompanying reduction of vasogenic edema, (2) insertion into the COI of a functional bridge supporting the crossing of regenerating axons, (3) enabling regeneration of axons to their original synaptic targets by temporary safe removal of myelin in targeted areas of white matter, (4) in vivo, systematic monitoring of the consecutive therapeutic steps. The focus of this paper is on therapeutic step 1.

The Role of Astrogliosis in Formation of the Syrinx in Spinal Cord Injury.

A massive localized trauma to the spinal cord results in complex pathologic events driven by necrosis and vascular damage which in turn leads to hemorrhage and edema. Severe, destructive and very protracted inflammatory response is characterized by infiltration by phagocytic macrophages of a site of injury which is converted into a cavity of injury (COI) surrounded by astroglial reaction mounted by the spinal cord. The tissue response to the spinal cord injury (SCI) has been poorly understood but the final outcome appears to be a mature syrinx filled with the cerebrospinal fluid with related neural tissue loss and permanent neurologic deficits. This paper reviews known pathologic mechanisms involved in the formation of the COI after SCI and discusses the integrative role of reactive astrogliosis in mechanisms involved in the removal of edema after the injury. A large proportion of edema fluid originating from the trauma and then from vasogenic edema related to persistent severe inflammation, may be moved into the COI in an active process involving astrogliosis and specifically over-expressed aquaporins.

Neurologic and Histologic Tests Used to Measure Neuroprotective Effectiveness of Virus-Derived Immune-Modulating Proteins.

Severe inflammatory disease initiated by neurotrauma and stroke is of primary concern in these intractable pathologies as noted in recent studies and understanding of the pathogenesis of spinal cord injury (SCI) in the rat model. Successful anti-inflammatory treatments should result in neuroprotection and limit the loss of neurological function to injury caused by the initial damage. Continuous subdural infusion offers direct access to the cavity of injury (COI) that forms after balloon crush SCI deep in the spinal cord. Some anti-inflammatory compounds are not likely capable of crossing the blood-spinal cord barrier. Subdural infusion of myxoma virus-derived Serp-1, an anti-thrombotic/anti-thrombolytic, and also of M-T7, a chemokine inhibitor, improved the locomotor scores and pain sensation scores as well as reduced the numbers of macrophages in the COI by 50 and 80%, respectively, while intraperitoneal infusion of either protein had little effect. Injection of a chitosan hydrogel loaded with Serp-1 into the dorsal spinal column crush also resulted in improved neurological deficits and in reduction of the size of the crush lesion 4 weeks after injury. While neurological scores in a simplified hind-end (HE) locomotor test together with a toe-pinch withdrawal test demonstrated improvement in all balloon crush injury and dorsal spinal crush injury rats, a severe inflammation is induced by the injury indicating additional damage to the spinal cord. Thus neurological function testing can be contradictory, rather than corresponding, to the pathogenesis of SCI. The count of macrophages in the COI offers a precise, reliable method of measuring the effectiveness of a neuroprotective treatment of SCI in preclinical studies.

Neuroprotective Effect of Subdural Infusion of Serp-1 in Spinal Cord Trauma.

Spinal cord injury (SCI) initiates a severe, destructive inflammation with pro-inflammatory, CD68+/CD163-, phagocytic macrophages infiltrating the area of necrosis and hemorrhage by day 3 and persisting for the next 16 weeks. Inhibition of macrophage infiltration of the site of necrosis that is converted into a cavity of injury (COI) during the first week post-SCI, should limit inflammatory damage, shorten its duration and result in neuroprotection. By sustained subdural infusion we administered Serp-1, a Myxoma virus-derived immunomodulatory protein previously shown to improve neurologic deficits and inhibit macrophage infiltration in the COI in rats with the balloon crush SCI. Firstly, in a 7 day long study, we determined that the optimal dose for macrophage inhibition was 0.2 mg/week. Then, we demonstrated that a continuous subdural infusion of Serp-1 for 8 weeks resulted in consistently accelerated lowering of pro-inflammatory macrophages in the COI and in their almost complete elimination similar to that previously observed at 16 weeks in untreated SCI rats. The macrophage count in the COI is a quantitative test directly related to the severity of destructive inflammation initiated by the SCI. This test has consistently demonstrated anti-inflammatory effect of Serp-1 interpreted as neuroprotection, the first and necessary step in a therapeutic strategy in neurotrauma.

A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity.

Tumor-targeted chimeric antigen receptor (CAR)-engineered T lymphocytes (CAR-T cells) have demonstrated striking clinical success, but their use has been associated with a constellation of toxicities. A better understanding of the pathogenesis of these toxicities is required to improve the safety profile of CAR-T cells. Herein, we describe a xenograft model of off-tumor CAR-T cell-associated toxicity. Human CAR-T cells targeted against HER2 using a small-protein binding domain induced acute, dose-dependent toxicities in mice. The inclusion of a CD28 or 4-1BB co-stimulatory domain in the CAR was required to produce toxicity; however, co-stimulation through CD28 was most toxic on a per-cell basis. CAR-T cell activation in the lungs and heart was associated with a systemic cytokine storm. The severity of observed toxicities was dependent upon the peripheral blood mononuclear cell (PBMC) donor used as a T cell source and paralleled the CD4+-to-CD8+ T cell ratio in the adoptive transfer product. CD4+ CAR-T cells were determined to be the primary contributors to CAR-T cell-associated toxicity. However, donor-specific differences persisted after infusion of a purified CD4+ CAR-T cell product, indicating a role for additional variables. This work highlights the contributions of CAR-T cell-intrinsic variables to the pathogenesis of off-tumor toxicity.

Local Serpin Treatment via Chitosan-Collagen Hydrogel after Spinal Cord Injury Reduces Tissue Damage and Improves Neurologic Function.

Spinal cord injury (SCI) results in massive secondary damage characterized by a prolonged inflammation with phagocytic macrophage invasion and tissue destruction. In prior work, sustained subdural infusion of anti-inflammatory compounds reduced neurological deficits and reduced pro-inflammatory cell invasion at the site of injury leading to improved outcomes. We hypothesized that implantation of a hydrogel loaded with an immune modulating biologic drug, Serp-1, for sustained delivery after crush-induced SCI would have an effective anti-inflammatory and neuroprotective effect. Rats with dorsal column SCI crush injury, implanted with physical chitosan-collagen hydrogels (CCH) had severe granulomatous infiltration at the site of the dorsal column injury, which accumulated excess edema at 28 days post-surgery. More pronounced neuroprotective changes were observed with high dose (100 µg/50 µL) Serp-1 CCH implanted rats, but not with low dose (10 µg/50 µL) Serp-1 CCH. Rats treated with Serp-1 CCH implants also had improved motor function up to 20 days with recovery of neurological deficits attributed to inhibition of inflammation-associated tissue damage. In contrast, prolonged low dose Serp-1 infusion with chitosan did not improve recovery. Intralesional implantation of hydrogel for sustained delivery of the Serp-1 immune modulating biologic offers a neuroprotective treatment of acute SCI.

Deriving Immune Modulating Drugs from Viruses-A New Class of Biologics.

Viruses are widely used as a platform for the production of therapeutics. Vaccines containing live, dead and components of viruses, gene therapy vectors and oncolytic viruses are key examples of clinically-approved therapeutic uses for viruses. Despite this, the use of virus-derived proteins as natural sources for immune modulators remains in the early stages of development. Viruses have evolved complex, highly effective approaches for immune evasion. Originally developed for protection against host immune responses, viral immune-modulating proteins are extraordinarily potent, often functioning at picomolar concentrations. These complex viral intracellular parasites have "performed the R&D", developing highly effective immune evasive strategies over millions of years. These proteins provide a new and natural source for immune-modulating therapeutics, similar in many ways to penicillin being developed from mold or streptokinase from bacteria. Virus-derived serine proteinase inhibitors (serpins), chemokine modulating proteins, complement control, inflammasome inhibition, growth factors (e.g., viral vascular endothelial growth factor) and cytokine mimics (e.g., viral interleukin 10) and/or inhibitors (e.g., tumor necrosis factor) have now been identified that target central immunological response pathways. We review here current development of virus-derived immune-modulating biologics with efficacy demonstrated in pre-clinical or clinical studies, focusing on pox and herpesviruses-derived immune-modulating therapeutics.

Prolonged inflammation leads to ongoing damage after spinal cord injury.

The pathogenesis of spinal cord injury (SCI) remains poorly understood and treatment remains limited. Emerging evidence indicates that post-SCI inflammation is severe but the role of reactive astrogliosis not well understood given its implication in ongoing inflammation as damaging or neuroprotective. We have completed an extensive systematic study with MRI, histopathology, proteomics and ELISA analyses designed to further define the severe protracted and damaging inflammation after SCI in a rat model. We have identified 3 distinct phases of SCI: acute (first 2 days), inflammatory (starting day 3) and resolution (>3 months) in 16 weeks follow up. Actively phagocytizing, CD68+/CD163- macrophages infiltrate myelin-rich necrotic areas converting them into cavities of injury (COI) when deep in the spinal cord. Alternatively, superficial SCI areas are infiltrated by granulomatous tissue, or arachnoiditis where glial cells are obliterated. In the COI, CD68+/CD163- macrophage numbers reach a maximum in the first 4 weeks and then decline. Myelin phagocytosis is present at 16 weeks indicating ongoing inflammatory damage. The COI and arachnoiditis are defined by a wall of progressively hypertrophied astrocytes. MR imaging indicates persistent spinal cord edema that is linked to the severity of inflammation. Microhemorrhages in the spinal cord around the lesion are eliminated, presumably by reactive astrocytes within the first week post-injury. Acutely increased levels of TNF-alpha, IL-1beta, IFN-gamma and other pro-inflammatory cytokines, chemokines and proteases decrease and anti-inflammatory cytokines increase in later phases. In this study we elucidated a number of fundamental mechanisms in pathogenesis of SCI and have demonstrated a close association between progressive astrogliosis and reduction in the severity of inflammation.

Myxoma virus derived immune modulating proteins, M-T7 and Serp-1, reduce early inflammation after spinal cord injury in the rat model.

Spinal cord injury (SCI)-initiated inflammation was treated with anti-inflammatory reagents. We compared local spinal cord or intraperitoneal infusion of two Myxoma virus derived immune modulating proteins, Serp-1 and M-T7, with dexamethasone (DEX). Hemorrhage and necrosis after SCI initiate a complex pathogenesis dominated by early, severe and highly destructive inflammatory macrophage infiltration. We examined sustained, 7-day, subdural infusion of either M-T7, a chemokine modulator or Serp-1, a plasminogen activator and factor inhibitor. Mature male rats had epidural balloon crush SCI and sustained subdural infusion of Serp-1, M-T7, DEX or saline for 7 days via the osmotic pump. A separate group of rats with SCI had intra-peritoneal infusion. Clinical evaluation included endpoint monitoring with body weight, hemorrhagic cystitis and bilateral toe pinch response. Sections of the spinal cord were analyzed histologically and macrophage numbers counted by standardized protocol in the cavity of injury (COI). While the rats administered DEX demonstrated substantial body weight loss, dehydration and dermal atrophy consistent with steroid toxicity, rats infused with Serp-1 and M-T7 had no toxicity. Serp-1 improved withdrawal responses. Subdural infusion of Serp-1, M-T7 and DEX significantly reduced numbers of phagocytic, CD68-positive macrophages. With intraperitoneal infusion only M-T7 reduced macrophage counts, Serp-1 showed only a trend. Local infusion of highly active immune modulating proteins; Serp-1 and M-T7, targeting serine protease and chemokine pathways demonstrated excellent potential for neuroprotection after severe SCI in a rat model, without adverse side effects. Sustained subdural infusion offers an alternative route of administration for treatment of SCI.

Modifying the Organ Matrix Pre-engraftment: A New Transplant Paradigm?

The availability of solid organs for transplantation remains low and there is a substantial need for methods to preserve the viability of grafted tissues. Suppression of solid-organ transplant rejection has traditionally focused on highly effective T cell inhibitors that block host immune lymphocyte responses. However, persistent and destructive innate and acquired immune reactions remain difficult to treat, causing late graft loss. Pretreatment of grafts to reduce organ rejection provides an alternate strategy. Approaches using antithrombotics, stem cells, genetic modifications, modulation of infrastructural components (connective tissue, CT; glycocalyx) of donor organs, and engineering of new organs are under investigation. We discuss here new approaches to modify transplanted organs prior to engraftment as a method to reduce rejection, focusing on the CT matrix.

Cross-linked cellulose nanocrystal aerogels as viable bone tissue scaffolds.

Chemically cross-linked cellulose nanocrystal (CNC) aerogels possess many properties beneficial for bone tissue scaffolding applications. CNCs were extracted using sulfuric acid or phosphoric acid, to produce CNCs with sulfate and phosphate half-ester surface groups, respectively. Hydrazone cross-linked aerogels fabricated from the two types of CNCs were investigated using scanning electron microscopy, X-ray micro-computed tomography, X-ray photoelectron spectroscopy, nitrogen sorption isotherms, and compression testing. CNC aerogels were evaluatedin vitrowith osteoblast-like Saos-2 cells and showed an increase in cell metabolism up to 7 days while alkaline phosphatase assays revealed that cells maintained their phenotype. All aerogels demonstrated hydroxyapatite growth over 14 days while submerged in simulated body fluid solution with a 0.1 M CaCl2 pre-treatment. Sulfated CNC aerogels slightly outperformed phosphated CNC aerogels in terms of compressive strength and long-term stability in liquid environments, and were implanted into the calvarian bone of adult male Long Evans rats. Compared to controls at 3 and 12 week time points, sulfated CNC aerogels showed increased bone volume fraction of 33% and 50%, respectively, compared to controls, and evidence of osteoconductivity. These results demonstrate that cross-linked CNC aerogels are flexible, porous and effectively facilitate bone growth after they are implanted in bone defects. STATEMENT OF SIGNIFICANCE: Due to the potential complications associated with autografts, there is a need for synthetic bone tissue scaffolds. Here, we report a new naturally-based aerogel material for bone regeneration made solely from chemically cross-linked cellulose nanocrystals (CNC). These highly porous CNC aerogels were shown to promote the proliferation of bone-like cells and support the growth of hydroxyapatite on their surface in vitro. The first in vivo study on these materials was conducted in rats and showed their osteconductive properties and an increase in bone volume up to 50% compared to sham sites. This study demonstrates the potential of using functionalized cellulose nanocrystals as the basis for aerogel scaffolds for bone tissue engineering.

Age-related deficits in intracortical myelination in young adults with bipolar disorder type I

Background: Previous studies have implicated white-matter-related changes in the pathophysiology of bipolar disorder. However, most of what is known is derived from in vivo subcortical white-matter imaging or postmortem studies. In this study, we investigated whole-brain intracortical myelin (ICM) content in people with bipolar disorder type I and controls. Methods: Between Sept. 1, 2014, and Jan. 31, 2017, we used a 3 T General Electric scanner to collect T1-weighted images in 45 people with bipolar disorder type I and 60 controls aged 17 to 45 years using an optimized sequence that was sensitive to ICM content. We analyzed images using a surfacebased approach. We used general linear models with quadratic age terms to examine the signal trajectory of ICM across the age range. Results: In healthy controls, the T1-weighted signal followed an inverted-U trajectory over age; in people with bipolar disorder type I, the association between ICM and age followed a flat trajectory (p < 0.05, Bonferroni corrected). Exploratory analyses showed that ICM signal intensity was associated with duration of illness, age of onset, and anticonvulsant and antipsychotic use in people with bipolar disorder type I (p < 0.05, uncorrected). Limitations: Because of the cross-sectional nature of the study, we were unable to comment on whether the effects were due to dysmyelination or demyelination in bipolar disorder. Conclusion: This foundational study is, to our knowledge, the first to show global age-related deficits in ICM maturation throughout the cortex in bipolar disorder. Considering the impact of myelination on the maintenance of neural synchrony and the integrity of neural connections, this work may help us better understand the cognitive and behavioural deficits seen in bipolar disorder.