Longitudinal changes in brain-derived neurotrophic factor (BDNF) but not cytokines contribute to hippocampal recovery in anorexia nervosa above increases in body mass index.

BACKGROUND: Physical sequelae of anorexia nervosa (AN) include a marked reduction in whole brain volume and subcortical structures such as the hippocampus. Previous research has indicated aberrant levels of inflammatory markers and growth factors in AN, which in other populations have been shown to influence hippocampal integrity. METHODS: Here we investigated the influence of concentrations of two pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6]) and brain-derived neurotrophic factor (BDNF) on the whole hippocampal volume, as well as the volumes of three regions (the hippocampal body, head, and tail) and 18 subfields bilaterally. Investigations occurred both cross-sectionally between acutely underweight adolescent/young adult females with AN (acAN; n = 82) and people recovered from AN (recAN; n = 20), each independently pairwise age-matched with healthy controls (HC), and longitudinally in acAN after partial renourishment (n = 58). Hippocampal subfield volumes were quantified using FreeSurfer. Concentrations of molecular factors were analyzed in linear models with hippocampal (subfield) volumes as the dependent variable. RESULTS: Cross-sectionally, there was no evidence for an association between IL-6, TNF-α, or BDNF and between-group differences in hippocampal subfield volumes. Longitudinally, increasing concentrations of BDNF were positively associated with longitudinal increases in bilateral global hippocampal volumes after controlling for age, age2, estimated total intracranial volume, and increases in body mass index (BMI). CONCLUSIONS: These findings suggest that increases in BDNF may contribute to global hippocampal recovery over and above increases in BMI during renourishment. Investigations into treatments targeted toward increasing BDNF in AN may be warranted.

Differential longitudinal changes of hippocampal subfields in patients with anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is a mental disorder characterized by dietary restriction, fear of gaining weight, and distorted body image. Recent studies indicate that the hippocampus, crucial for learning and memory, may be affected in AN, yet subfield-specific effects remain unclear. We investigated hippocampal subfield alterations in acute AN, changes following weight restoration, and their associations with leptin levels. METHODS: T1-weighted magnetic resonance imaging scans were processed using FreeSurfer. We compared 22 left and right hemispheric hippocampal subfield volumes cross-sectionally and longitudinally in females with acute AN (n = 165 at baseline, n = 110 after partial weight restoration), healthy female controls (HCs; n = 271), and females after long-term recovery from AN (n = 79) using linear models. RESULTS: We found that most hippocampal subfield volumes were significantly reduced in patients with AN compared with HCs (~-3.9%). Certain areas such as the subiculum exhibited no significant reduction in the acute state of AN, while other areas, such as the hippocampal tail, showed strong decreases (~-9%). Following short-term weight recovery, most subfields increased in volume. Comparisons between participants after long-term weight-recovery and HC yielded no differences. The hippocampal tail volume was positively associated with leptin levels in AN independent of body mass index. CONCLUSIONS: Our study provides evidence of differential volumetric differences in hippocampal subfields between individuals with AN and HC and almost complete normalization after weight rehabilitation. These alterations are spatially inhomogeneous and more pronounced compared with other major mental disorders (e.g. major depressive disorder and schizophrenia). We provide novel insights linking hypoleptinemia to hippocampal subfield alterations hinting towards clinical relevance of leptin normalization in AN recovery.

A subpopulation of lipogenic brown adipocytes drives thermogenic memory.

Sustained responses to transient environmental stimuli are important for survival. The mechanisms underlying long-term adaptations to temporary shifts in abiotic factors remain incompletely understood. Here, we find that transient cold exposure leads to sustained transcriptional and metabolic adaptations in brown adipose tissue, which improve thermogenic responses to secondary cold encounter. Primary thermogenic challenge triggers the delayed induction of a lipid biosynthesis programme even after cessation of the original stimulus, which protects from subsequent exposures. Single-nucleus RNA sequencing and spatial transcriptomics reveal that this response is driven by a lipogenic subpopulation of brown adipocytes localized along the perimeter of Ucp1hi adipocytes. This lipogenic programme is associated with the production of acylcarnitines, and supplementation of acylcarnitines is sufficient to recapitulate improved secondary cold responses. Overall, our data highlight the importance of heterogenous brown adipocyte populations for 'thermogenic memory', which may have therapeutic implications for leveraging short-term thermogenesis to counteract obesity.

Dynamic Amygdala Nuclei Alterations in Relation to Weight Status in Anorexia Nervosa Are Mediated by Leptin.

OBJECTIVE: The amygdaloid complex is a subcortical limbic group of distinct nuclei. In a previous patient-control study, differential amygdala nuclei alterations were found in acute anorexia nervosa (AN); rostral-medial nuclei involved in fear and reward processing were substantially reduced in volume and associated with hypoleptinemia, a key neuroendocrine characteristic of AN. Here, longitudinal amygdala nuclei alterations in AN were investigated in relation to weight status and their associations with leptin levels. METHOD: T1-weighted structural magnetic resonance imaging scans were longitudinally processed with FreeSurfer. Amygdala nuclei volumes in young female patients with acute AN before and after short-term weight restoration (n = 110, >14% body mass index increase over 3 months) and female participants with a history of AN (n = 79, long-term [mean 5 years] weight recovered) were compared with female healthy control participants (n = 271) using linear mixed effects models. RESULTS: Rostral-medially clustered amygdala nuclei volumes, accessory basal, cortical, medial nuclei, and corticoamygdaloid transition, increased during short-term weight restoration (Cohen's d range 0.18-0.30). However, volumetric normalization across nuclei was heterogeneous. Right cortical, medial nuclei, bilateral corticoamygdaloid transitions, and anterior amygdaloid areas were only partially normalized following short-term weight restoration. Right anterior amygdaloid area remained reduced after long-term weight recovery compared with control participants (d = 0.36). Leptin increase, accompanying short-term weight restoration, mediated the effect of weight gain on volumetric increase in left corticoamygdaloid transition and bilateral medial nuclei. CONCLUSION: Rostral-medially clustered amygdala nuclei show pronounced volumetric increase but incomplete normalization in AN during and after short-term weight restoration. Leptin increase may be relevant for the recovery of specific amygdala nuclei in addition to nutritional rehabilitation, indicating links between amygdala substructure and leptin dynamics of potential pathophysiological and clinical relevance in AN. PLAIN LANGUAGE SUMMARY: The amygdala plays a critical role in processing fearful and rewarding stimuli, and alterations in the amygdala are associated with anorexia nervosa. In this study, the authors measured amygdala nuclei volumes in female patients with acute anorexia nervosa undergoing weight-restoration treatment (n = 110), long-term weight-recovered individuals with anorexia (n = 79), and healthy control participants (n = 271). Structural magnetic resonance imaging revealed that volumes of specific nuclei, clustered in the rostral-medial amygdala, were substantially reduced in acute anorexia nervosa and only partially normalized following weight restoration treatment. Residual reductions in volume persisted even after long-term weight-recovery, compared to healthy control participants. Short-term weight restoration was associated with increases in the neurohormone leptin, and increasing leptin levels were found to mediate the positive impact of weight gain on increased amygdala volume over the treatment course. DIVERSITY & INCLUSION STATEMENT: We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper received support from a program designed to increase minority representation in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Explicating the role of amygdala substructure alterations in the link between hypoleptinemia and rumination in anorexia nervosa.

OBJECTIVE: The amygdaloid complex plays a pivotal role in emotion processing and has been associated with rumination transdiagnostically. In anorexia nervosa (AN), we previously observed differential reductions of amygdala nuclei volumes (rostral-medial cluster substantially affected) and, in another study, elevated food-/weight-related rumination. Both amygdala volumes and rumination frequency correlated with characteristically suppressed leptin levels in AN. Thus, we hypothesized that amygdala nuclei alterations might be associated with AN-related rumination and potentially mediate the leptin-rumination relationship in AN. METHODS: Rumination (food-/weight-related) was assessed using ecological momentary assessment for a 14-day period. We employed frequentist and Bayesian linear mixed effects models in females with AN (n = 51, 12-29 years, majority admitted to inpatient treatment) and age-matched healthy females (n = 51) to investigate associations between rostral-medial amygdala nuclei volume alterations (accessory basal, cortical, medial nuclei, corticoamygdaloid transitions) and rumination. We analyzed mediation effects using multi-level structural equation models. RESULTS: Reduced right accessory basal and cortical nuclei volumes predicted more frequent weight-related rumination in AN; both nuclei fully mediated the effect of leptin on weight-related rumination. In contrast, we found robust evidence for the absence of amygdala nuclei volume effects on rumination in healthy females. CONCLUSION: This study provides first evidence for the relevance of specific amygdala substructure reductions regarding cognitive symptom severity in AN and points toward novel mechanistic insight into the relationship between hypoleptinemia and rumination, which might involve the amygdaloid complex. Our findings in AN may have important clinical value with respect to understanding the beneficial neuropsychiatric effects of leptin (treatment) in AN and potentially other psychiatric conditions such as depression.

The enteric nervous system relays psychological stress to intestinal inflammation.

Mental health profoundly impacts inflammatory responses in the body. This is particularly apparent in inflammatory bowel disease (IBD), in which psychological stress is associated with exacerbated disease flares. Here, we discover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation. We find that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated inflammation via CSF1. Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGF-ß2. We verify the connection between the psychological state, intestinal inflammation, and dysmotility in three cohorts of IBD patients. Together, these findings offer a mechanistic explanation for the impact of the brain on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care.

Serum neurofilament light concentrations are associated with cortical thinning in anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is characterized by severe emaciation and drastic reductions of brain mass, but the underlying mechanisms remain unclear. The present study investigated the putative association between the serum-based protein markers of brain damage neurofilament light (NF-L), tau protein, and glial fibrillary acidic protein (GFAP) and cortical thinning in acute AN. METHODS: Blood samples and magnetic resonance imaging scans were obtained from 52 predominantly adolescent, female patients with AN before and after partial weight restoration (increase in body mass index >14%). The effect of marker levels before weight gain and change in marker levels on cortical thickness (CT) was modeled at each vertex of the cortical surface using linear mixed-effect models. To test whether the observed effects were specific to AN, follow-up analyses exploring a potential general association of marker levels with CT were conducted in a female healthy control (HC) sample (n = 147). RESULTS: In AN, higher baseline levels of NF-L, an established marker of axonal damage, were associated with lower CT in several regions, with the most prominent clusters located in bilateral temporal lobes. Tau protein and GFAP were not associated with CT. In HC, no associations between damage marker levels and CT were detected. CONCLUSIONS: A speculative interpretation would be that cortical thinning in acute AN might be at least partially a result of axonal damage processes. Further studies should thus test the potential of serum NF-L to become a reliable, low-cost and minimally invasive marker of structural brain alterations in AN.

Individual behavioral trajectories shape whole-brain connectivity in mice.

It is widely assumed that our actions shape our brains and that the resulting connections determine who we are. To test this idea in a reductionist setting, in which genes and environment are controlled, we investigated differences in neuroanatomy and structural covariance by ex vivo structural magnetic resonance imaging in mice whose behavioral activity was continuously tracked for 3 months in a large, enriched environment. We confirmed that environmental enrichment increases mouse hippocampal volumes. Stratifying the enriched group according to individual longitudinal behavioral trajectories, however, revealed striking differences in mouse brain structural covariance in continuously highly active mice compared to those whose trajectories showed signs of habituating activity. Network-based statistics identified distinct subnetworks of murine structural covariance underlying these differences in behavioral activity. Together, these results reveal that differentiated behavioral trajectories of mice in an enriched environment are associated with differences in brain connectivity.

An individual's experiences and behavior shape their brain, thereby building and refining a network of connections between neurons. This unique network may affect an individual's brain resilience in the face of aging, injury or disease. Understanding how individual experiences shape brain connections could help scientists develop personalized treatments. It may also have important implications for preventing brain disease. Studying mice can provide a window into some of these brain processes. By using inbred mice, scientists can rule out the role of genetics in brain differences. Scientists can also control the animals' environments and track the activity of individuals to study their behavior. Bogado Lopes et al. show that more active mice living in enriched environments have signs of more complex networks of brain connections. In the experiments, the researchers placed genetically identical mice in either standard laboratory mouse housing or in enriched environments. Mice in the enriched housing had access to multi-level enclosures connected with tubes and supplied with a rotating array of toys. A tiny tracking device was inserted under the skin of the mice to follow their movements. Finally, all mice underwent structural magnetic resonance imaging to assess their brain anatomy and connections. This revealed that the most active and adventurous mice in the enriched enclosures had the most robust signs of increased brain connectivity. However, mice with declining activity levels in the enriched enclosures had fewer brain connections. Brain connection patterns in these creatures of habit were nearly identical to the ones in mice housed in small unenriched enclosures. The results show that how individual mice respond to their environments affects their brain structure. More active behavior patterns lead to more robust networks of brain connections. Larger studies in mice could provide more about lifestyle-dependent brain resilience. It may also help scientists to develop individualized approaches to optimizing brain health.

Differential alterations of amygdala nuclei volumes in acutely ill patients with anorexia nervosa and their associations with leptin levels.

BACKGROUND: The amygdala is a subcortical limbic structure consisting of histologically and functionally distinct subregions. New automated structural magnetic resonance imaging (MRI) segmentation tools facilitate the in vivo study of individual amygdala nuclei in clinical populations such as patients with anorexia nervosa (AN) who show symptoms indicative of limbic dysregulation. This study is the first to investigate amygdala nuclei volumes in AN, their relationships with leptin, a key indicator of AN-related neuroendocrine alterations, and further clinical measures. METHODS: T1-weighted MRI scans were subsegmented and multi-stage quality controlled using FreeSurfer. Left/right hemispheric amygdala nuclei volumes were cross-sectionally compared between females with AN (n = 168, 12-29 years) and age-matched healthy females (n = 168) applying general linear models. Associations with plasma leptin, body mass index (BMI), illness duration, and psychiatric symptoms were analyzed via robust linear regression. RESULTS: Globally, most amygdala nuclei volumes in both hemispheres were reduced in AN v. healthy control participants. Importantly, four specific nuclei (accessory basal, cortical, medial nuclei, corticoamygdaloid transition in the rostral-medial amygdala) showed greater volumetric reduction even relative to reductions of whole amygdala and total subcortical gray matter volumes, whereas basal, lateral, and paralaminar nuclei were less reduced. All rostral-medially clustered nuclei were positively associated with leptin in AN independent of BMI. Amygdala nuclei volumes were not associated with illness duration or psychiatric symptom severity in AN. CONCLUSIONS: In AN, amygdala nuclei are altered to different degrees. Severe volume loss in rostral-medially clustered nuclei, collectively involved in olfactory/food-related reward processing, may represent a structural correlate of AN-related symptoms. Hypoleptinemia might be linked to rostral-medial amygdala alterations.

Environmental perception and control of gastrointestinal immunity by the enteric nervous system.

The enteric nervous system (ENS) forms a versatile sensory system along the gastrointestinal tract that interacts with most cell types in the bowel. Herein, we portray host-environment interactions at the intestinal mucosal surface through the lens of the enteric nervous system. We describe local cellular interactions as well as long-range circuits between the enteric, central, and peripheral nervous systems. Additionally, we discuss recently discovered mechanisms by which enteric neurons and glia respond to biotic and abiotic environmental changes and how they regulate intestinal immunity and inflammation. The enteric nervous system emerges as an integrative sensory system with manifold immunoregulatory functions under both homeostatic and pathophysiological conditions.

Brain Structure in Acutely Underweight and Partially Weight-Restored Individuals With Anorexia Nervosa: A Coordinated Analysis by the ENIGMA Eating Disorders Working Group.

BACKGROUND: The pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in gray matter volume and cortical thickness in acutely underweight patients, others find no differences, or even increases in patients compared with healthy control subjects. Recent weight regain before scanning may explain some of this heterogeneity. To clarify the extent, magnitude, and dependencies of gray matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data. METHODS: We analyzed T1-weighted structural magnetic resonance imaging scans assessed with standardized methods from 685 female patients with AN and 963 female healthy control subjects across 22 sites worldwide. In addition to a case-control comparison, we conducted a 3-group analysis comparing healthy control subjects with acutely underweight AN patients (n = 466) and partially weight-restored patients in treatment (n = 251). RESULTS: In AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area were sizable (Cohen's d up to 0.95), widespread, and colocalized with hub regions. Highlighting the effects of undernutrition, these deficits were associated with lower body mass index in the AN sample and were less pronounced in partially weight-restored patients. CONCLUSIONS: The effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population.

Dynamic Structural Brain Changes in Anorexia Nervosa: A Replication Study, Mega-analysis, and Virtual Histology Approach.

OBJECTIVE: Several, but not all, previous studies of brain structure in anorexia nervosa (AN) have reported reductions in gray matter volume and cortical thickness (CT) in acutely underweight patients, which seem to reverse upon weight gain. The biological mechanisms underlying these dynamic alterations remain unclear. METHOD: In this structural magnetic resonance imaging study, we first replicated and extended previous results in (1) a larger independent sample of 75 acutely underweight adolescent and young adult female patients with AN (acAN; n = 54 rescanned longitudinally after partial weight restoration), 34 weight-recovered individuals with a history of AN (recAN), and 139 healthy controls (HC); and 2) a greater combined sample compiled of both our previous samples and the present replication sample (120 acAN [90 rescanned longitudinally], 68 recAN, and 207 HC). Next, we applied a "virtual histology" approach to the combined data, investigating relations between interregional profiles of differences in CT and profiles of cell-specific gene expression. Finally, we used the ENIGMA toolbox to relate aforementioned CT profiles to normative structural and functional connectomics. RESULTS: We confirmed sizeable and widespread reductions of CT as well as volumes (and, to a lesser extent, surface area) in acAN and rapid increases related to partial weight restoration. No differences were detected between either short- or long-term weight-recovered patients and HC. The virtual histology analysis identified associations between gene expression profiles of S1 pyramidal cells and oligodendrocytes and brain regions with more marked differences in CT, whereas the remaining regions were those with a greater expression of genes specific to CA1 pyramidal, astrocytes, microglia, and ependymal cells. Furthermore, the most affected regions were also more functionally and structurally connected. CONCLUSION: The overall data pattern deviates from findings in other psychiatric disorders. Both virtual histology and connectomics analyses indicated that brain regions most affected in AN are also the most energetically demanding.

Altered White Matter Connectivity in Young Acutely Underweight Patients With Anorexia Nervosa.

OBJECTIVE: Reductions of gray matter volume and cortical thickness in anorexia nervosa (AN) are well documented. However, findings regarding the integrity of white matter (WM) as studied via diffusion weighted imaging (DWI) are remarkably heterogeneous, and WM connectivity has been examined only in small samples using a limited number of regions of interest. The present study investigated whole-brain WM connectivity for the first time in a large sample of acutely underweight patients with AN. METHOD: DWI data from predominantly adolescent patients with acute AN (n = 96, mean age = 16.3 years) and age-matched healthy control participants (n = 96, mean age = 17.2 years) were analyzed. WM connectivity networks were generated from fiber-tractography-derived streamlines connecting 233 cortical/subcortical regions. To identify group differences, network-based statistic was used while taking head motion, WM, and ventricular volume into account. RESULTS: Patients with AN were characterized by 6 WM subnetworks with abnormal architecture, as indicated by increased fractional anisotropy located primarily in parietal-occipital regions and accompanied by reduced radial diffusivity. Group differences based on number of streamlines reached only nominal significance. CONCLUSION: Our study reveals pronounced alterations in the WM connectome in young patients with AN. In contrast to known reductions in gray matter in the acutely underweight state of AN, this pattern does not necessarily indicate a deterioration of the WM network. Future studies using advanced MRI sequences will have to clarify interrelations with axonal packing or myelination, and whether the changes should be considered a consequence of undernutrition or a vulnerability for developing or maintaining AN.

Associations between pituitary-thyroid hormones and depressive symptoms in individuals with anorexia nervosa before and after weight-recovery.

BACKGROUND: There is sound evidence that the hypothalamic-pituitary-thyroid axis plays a role in mood regulation. Alterations in this axis, particularly low triiodothyronine syndrome, are a common neuroendocrine adaptation to semi-starvation in patients with anorexia nervosa (AN), who also frequently suffer from co-existing depressive symptoms. We therefore aimed to investigate the associations between pituitary-thyroid function and psychopathology, in particular depressive symptoms, at different stages of AN using a combined cross-sectional and longitudinal study design. METHODS: Pituitary-thyroid status (FT3, free triiodothyronine; FT4, free thyroxine; conversion ratio FT3/FT4; TSH, thyroid-stimulating hormone) was assessed in 77 young acutely underweight females with AN (acAN) and in 55 long-term weight-recovered individuals with former AN (recAN) in a cross-sectional comparison to 122 healthy controls (HC). Further, pituitary-thyroid status of 48 acAN was reassessed after short-term weight-restoration. We performed correlation analyses of pituitary-thyroid parameters with self-reported measures of psychopathology. RESULTS: AcAN showed significantly lower FT3, FT4, FT3/FT4 ratio, and TSH levels compared to HC. Pituitary-thyroid alterations were partly reversed after short-term weight-restoration. RecAN still had lower FT3 concentrations than HC. Lower FT3 concentrations and FT3/FT4 ratios were associated with more severe depressive symptoms in acAN, occurring prominently in cases of manifest low triiodothyronine syndrome. Longitudinally increasing FT3/FT4 ratios (change scores) were inversely correlated with depressive and general psychiatric symptoms after short-term weight-restoration. CONCLUSIONS: Our results suggest a potential modulation of the severity of depressive symptoms by temporarily decreased FT3 concentrations and inhibited thyroid hormone conversion (FT3/FT4 ratios) in acutely underweight AN. Associations between conversion ratios FT3/FT4 and psychopathology seem to persist across short-term weight-restoration. The findings of our study might have relevant clinical implications, ranging from thyroid monitoring to experimental low-dose thyroid hormone supplementation in certain patients with AN showing severe psychiatric impairment and overt thyroid hormone alterations.

Differential longitudinal changes of neuronal and glial damage markers in anorexia nervosa after partial weight restoration.

Atrophic brain changes in acute anorexia nervosa (AN) are often visible to the naked eye on computed tomography or magnetic resonance imaging scans, but it remains unclear what is driving these effects. In neurological diseases, neurofilament light (NF-L) and tau protein have been linked to axonal damage. Glial fibrillary acidic protein (GFAP) has been associated with astroglial injury. In an attempt to shed new light on factors potentially underlying past findings of structural brain alterations in AN, the current study investigated serum NF-L, tau protein, and GFAP levels longitudinally in AN patients undergoing weight restoration. Blood samples were obtained from 54 acutely underweight, predominantly adolescent female AN patients and 54 age-matched healthy control participants. AN patients were studied in the severely underweight state and again after short-term partial weight restoration. Group comparisons revealed higher levels of NF-L, tau protein, and GFAP in acutely underweight patients with AN compared to healthy control participants. Longitudinally, a decrease in NF-L and GFAP but not in tau protein levels was observed in AN patients upon short-term partial weight restoration. These results may be indicative of ongoing neuronal and astroglial injury during the underweight phase of AN. Normalization of NF-L and GFAP but not tau protein levels may indicate an only partial restoration of neuronal and astroglial integrity upon weight gain after initial AN-associated cell damage processes.

IL10RA modulates crizotinib sensitivity in NPM1-ALK+ anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor-relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance-specific relapse.

Peptide YY3-36 concentration in acute- and long-term recovered anorexia nervosa.

PURPOSE: The gut-brain axis could be a possible key factor in the pathophysiology of anorexia nervosa. The neuropeptide peptide YY3-36, secreted by endocrine L cells of the gastrointestinal tract, is a known regulator of appetite and food intake. The objective of this study was to investigate peptide YY3-36 plasma concentrations at different stages of anorexia nervosa in a combined cross-sectional and longitudinal design to differentiate between effects of acute undernutrition and more enduring characteristics. METHODS: We measured fasting plasma peptide YY3-36 concentrations in young patients with acute anorexia nervosa (n = 47) and long-term recovered patients (n = 35) cross-sectionally in comparison to healthy control participants (n = 58), and longitudinally over the course of inpatient treatment. Physical activity was controlled as it may modulate peptide YY secretion. RESULTS: There was no group difference in peptide YY3-36 concentration among young acutely underweight anorexia nervosa patients, long-term recovered anorexia nervosa patients, and healthy control participants. Longitudinally, there was no change in peptide YY3-36 concentration after short-term weight rehabilitation. For acute anorexia nervosa patients at admission to treatment, there was a negative correlation between peptide YY3-36 concentration and body mass index. CONCLUSIONS: The current study provides additional evidence for a normal basal PYY3-36 concentration in AN. Future studies should study multiple appetite-regulating peptides and their complex interplay and also use research designs including a food challenge.