Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia.

Pathogenic variants in the UBQLN2 gene cause X-linked dominant amyotrophic lateral sclerosis and/or frontotemporal dementia characterised by ubiquilin 2 aggregates in neurons of the motor cortex, hippocampus, and spinal cord. However, ubiquilin 2 neuropathology is also seen in sporadic and familial amyotrophic lateral sclerosis and/or frontotemporal dementia cases not caused by UBQLN2 pathogenic variants, particularly C9orf72-linked cases. This makes the mechanistic role of mutant ubiquilin 2 protein and the value of ubiquilin 2 pathology for predicting genotype unclear. Here we examine a cohort of 44 genotypically diverse amyotrophic lateral sclerosis cases with or without frontotemporal dementia, including eight cases with UBQLN2 variants (resulting in p.S222G, p.P497H, p.P506S, p.T487I (two cases), and p.P497L (three cases)). Using multiplexed (5-label) fluorescent immunohistochemistry, we mapped the co-localisation of ubiquilin 2 with phosphorylated TDP-43, dipeptide repeat aggregates, and p62, in the hippocampus of controls (n = 6), or amyotrophic lateral sclerosis with or without frontotemporal dementia in sporadic (n = 20), unknown familial (n = 3), SOD1-linked (n = 1), FUS-linked (n = 1), C9orf72-linked (n = 5), and UBQLN2-linked (n = 8) cases. We differentiate between i) ubiquilin 2 aggregation together with phosphorylated TDP-43 or dipeptide repeat proteins, and ii) ubiquilin 2 self-aggregation promoted by UBQLN2 pathogenic variants that cause amyotrophic lateral sclerosis/and frontotemporal dementia. Overall, we describe a hippocampal protein aggregation signature that fully distinguishes mutant from wildtype ubiquilin 2 in amyotrophic lateral sclerosis with or without frontotemporal dementia, whereby mutant ubiquilin 2 is more prone than wildtype to aggregate independently of driving factors. This neuropathological signature can be used to assess the pathogenicity of UBQLN2 gene variants and to understand the mechanisms of UBQLN2-linked disease.

Latent profile analysis reveals overlapping ARFID and shape/weight motivations for restriction in eating disorders.

BACKGROUND: DSM-5 differentiates avoidant/restrictive food intake disorder (ARFID) from other eating disorders (EDs) by a lack of overvaluation of body weight/shape driving restrictive eating. However, clinical observations and research demonstrate ARFID and shape/weight motivations sometimes co-occur. To inform classification, we: (1) derived profiles underlying restriction motivation and examined their validity and (2) described diagnostic characterizations of individuals in each profile to explore whether findings support current diagnostic schemes. We expected, consistent with DSM-5, that profiles would comprise individuals endorsing solely ARFID or restraint (i.e. trying to eat less to control shape/weight) motivations. METHODS: We applied latent profile analysis to 202 treatment-seeking individuals (ages 10-79 years [M = 26, s.d. = 14], 76% female) with ARFID or a non-ARFID ED, using the Nine-Item ARFID Screen (Picky, Appetite, and Fear subscales) and the Eating Disorder Examination-Questionnaire Restraint subscale as indicators. RESULTS: A 5-profile solution emerged: Restraint/ARFID-Mixed (n = 24; 8% [n = 2] with ARFID diagnosis); ARFID-2 (with Picky/Appetite; n = 56; 82% ARFID); ARFID-3 (with Picky/Appetite/Fear; n = 40; 68% ARFID); Restraint (n = 45; 11% ARFID); and Non-Endorsers (n = 37; 2% ARFID). Two profiles comprised individuals endorsing solely ARFID motivations (ARFID-2, ARFID-3) and one comprising solely restraint motivations (Restraint), consistent with DSM-5. However, Restraint/ARFID-Mixed (92% non-ARFID ED diagnoses, comprising 18% of those with non-ARFID ED diagnoses in the full sample) endorsed ARFID and restraint motivations. CONCLUSIONS: The heterogeneous profiles identified suggest ARFID and restraint motivations for dietary restriction may overlap somewhat and that individuals with non-ARFID EDs can also endorse high ARFID symptoms. Future research should clarify diagnostic boundaries between ARFID and non-ARFID EDs.

Presence and characteristics of disordered eating and orthorexia in irritable bowel syndrome.

INTRODUCTION: Orthorexia, a harmful obsession with eating healthily, may develop from illnesses characterized by dietary restriction, including irritable bowel syndrome (IBS) and eating disorders (ED). Evidence of disordered eating in IBS exists, but orthorexia has not been assessed. This cross-sectional study in adults (≥18 years) assessed presence and characteristics of disordered eating and orthorexia in IBS, compared to control subjects (CS) and ED. METHODS: IBS participants met Rome IV, and ED participants met DSM-5 criteria. Disordered eating was assessed using "sick, control, one-stone, fat, food" (SCOFF, ≥2 indicating disordered eating), and orthorexia by the eating habits questionnaire (EHQ). Secondary measures included stress (PSS); anxiety (HADS-A); food-related quality of life (Fr-QoL), and dietary intake (CNAQ). KEY RESULTS: In 202 IBS (192 female), 34 ED (34 female), and 109 CS (90 female), more IBS (33%) and ED (47%) scored SCOFF≥2 compared to CS (16%, p < 0.001, chi-square). IBS and ED had higher orthorexia symptom severity compared to CS (EHQ IBS 82.9 ± 18.1, ED 90.1 ± 19.6, and CS 73.5 ± 16.9, p < 0.001, one-way ANOVA). IBS and ED did not differ for SCOFF or EHQ (p > 0.05). Those with IBS and disordered eating had higher orthorexia symptom severity (EHQ 78.2 ± 16.6 vs. 92.4 ± 17.5, p < 0.001, independent t-test), worse symptoms (IBS-SSS 211.0 ± 78.4 vs. 244.4 ± 62.5, p = 0.008, Mann-Whitney U test), higher stress (p < 0.001, independent t-test), higher anxiety (p = 0.002, independent t-test), and worse FR-QoL (p < 0.001, independent t-test). CONCLUSIONS AND INFERENCES: Disordered eating and orthorexia symptoms occur frequently in IBS, particularly in those with worse gastrointestinal symptoms, higher stress, and anxiety. Clinicians could consider these characteristics when prescribing dietary therapies.

Avoidant/restrictive food intake disorder symptoms are not as frequent as other eating disorder symptoms when ulcerative colitis is in remission.

BACKGROUND AND AIM: Recent studies have shown that up to 53% of patients with inflammatory bowel disease (IBD) screen positive for avoidant/restrictive food intake disorder (ARFID). There is however concern that ARFID screening rates are over-inflated in patients with active disease. We aimed to evaluate the frequency and characteristics of ARFID symptoms using the Nine Item ARFID Screen (NIAS), and to use another eating disorder measure, the Eating Disorder Examination-Questionnaire 8 (EDE-Q8), to rule-out/characterize other eating disorder cognitive and behavioral symptoms. METHODS: Participants included adults with UC who are enrolled in an in an ongoing cohort study with quiescent UC (SCCAI ≤2 or fecal calprotectin <150 µg/g with corticosteroid-free clinical remission for ≥ 3 months) at baseline. We used self-reported data on demographics, gastrointestinal medications, medical comorbidities, NIAS scores, and other eating disorder symptom scores (8-item Eating Disorder Examination-Questionnaire; EDE-Q-8). RESULTS: We included 101 participants who completed the NIAS at their baseline cohort assessment (age 49.9±16.5 years; 55% female). Eleven participants (11%) screened positively for ARFID on at least one NIAS subscale (n=8 male). Up to thirty participants (30%) screened positive for other eating disorder symptoms (EDE-Q-8 Global ≥2.3). Overall score distributions on the EDE-Q-8 showed that participants scored highest on the Weight Concern and Shape Concern subscales. CONCLUSIONS: Among adults with UC in remission, we found a low rate of ARFID symptoms by the NIAS but a high rate of positive screens for other eating disorder symptoms.

Age, Race, Ethnicity, and Sex of Participants in Clinical Trials Focused on Chronic Pain.

There is limited data on equitable inclusion in chronic pain trials. We aimed to 1) identify the frequency of reporting age, race, ethnicity, and sex in clinical trials targeting chronic pain, and 2) compare sociodemographic representation to the United States (US) population. We examined US-based intervention trials for chronic pain initiated between 2007 and 2021 and registered on ClinicalTrials.gov. We 1) assessed the frequency of reporting each demographic variable, 2) compared representation with US population estimates, and 3) explored change in reporting over time. Of 501 clinical trials, the frequency of reporting was as follows: 36.9% reported older adults, 54.3% reported race, 37.4% reported ethnicity, and 100% reported sex. Rates of race and ethnicity reporting increased, but older adult age reporting decreased over time (ps < .00001). Compared to 2020 US population estimates, there was an equitable representation of older adults, under-representation of individuals identifying as American Indian or Alaska Native (.8% vs .6%), Asian (5.6% vs 2.9%), Black or African American (12.6% vs 12.2%), with more than one race (2.9% vs 1.2%), and Hispanic/Latino (16.9% vs 14.1%). There was an over-representation of individuals identifying as Native Hawaiian or Pacific Islander (.2% vs .5%) or White (70.4% vs 72.9%), and of females (50.8% vs 68.4%). Some representation rates varied by chronic pain condition. Reporting of older adult age, race, and ethnicity was low in chronic pain trials in ClinicalTrials.gov, reinforcing the need for adhering to reporting guidelines. Representation varied across trials compared with US population data, particularly among those identifying as Hispanic/Latino and certain minority racial groups. PERSPECTIVE: Despite initiatives to increase the reporting of demographic information, doing so in clinical pain trials is far from ubiquitous. Moreover, efforts to improve diversity in these trials continue to be insufficient. Indeed, Black, Indigenous, and People of Color (BIPOC) remain under-represented in clinical pain trials.

Avoidant/restrictive food intake disorder prevalence is high in children with gastroparesis and functional dyspepsia.

BACKGROUND: Avoidant/restrictive food intake disorder (ARFID) prevalence in children with gastroparesis (Gp) and/or functional dyspepsia (FD) is unknown. We aimed to identify ARFID prevalence and trajectory over 2 months in children with Gp, FD, and healthy children (HC) using two screening questionnaires. We also explored the frequency of a positive ARFID screen between those with/without delayed gastric emptying or abnormal fundic accommodation. METHODS: In this prospective longitudinal study conducted at an urban tertiary care hospital, patients ages 10-17 years with Gp or FD and age- and gender-matched HC completed two validated ARFID screening tools at baseline and 2-month follow-up: the Nine Item ARFID Screen (NIAS) and the Pica, ARFID, and Rumination Disorder Interview-ARFID Questionnaire (PARDI-AR-Q). Gastric retention and fundic accommodation (for Gp and FD) were determined from gastric emptying scintigraphy. KEY RESULTS: At baseline, the proportion of children screening positive for ARFID on the NIAS versus PARDI-AR-Q was Gp: 48.5% versus 63.6%, FD: 66.7% versus 65.2%, HC: 15.3% versus 9.7%, respectively; p < 0.0001 across groups. Of children who screened positive at baseline and participated in the follow-up, 71.9% and 53.3% were positive 2 months later (NIAS versus PARDI-AR-Q, respectively). A positive ARFID screen in Gp or FD was not related to the presence/absence of delayed gastric retention or abnormal fundic accommodation. CONCLUSIONS & INFERENCES: ARFID detected from screening questionnaires is highly prevalent among children with Gp and FD and persists for at least 2 months in a substantial proportion of children. Children with these disorders should be screened for ARFID.

Gastrointestinal diagnoses in patients with eating disorders: A retrospective cohort study 2010-2020.

BACKGROUND AND AIMS: Gastrointestinal (GI) disorders are common in patients with eating disorders. However, the temporal relationship between GI and eating disorder symptoms has not been explored. We aimed to evaluate GI disorders among patients with eating disorders, their relative timing, and the relationship between GI diagnoses and eating disorder remission. METHODS: We conducted a retrospective analysis of patients with an eating disorder diagnosis who had a GI encounter from 2010 to 2020. GI diagnoses and timing of eating disorder onset were abstracted from chart review. Coders applied DSM-5 criteria for eating disorders at the time of GI consult to determine eating disorder remission status. RESULTS: Of 344 patients with an eating disorder diagnosis and GI consult, the majority (255/344, 74.2%) were diagnosed with an eating disorder prior to GI consult (preexisting eating disorder). GI diagnoses categorized as functional/motility disorders were most common among the cohort (57.3%), particularly in those with preexisting eating disorders (62.5%). 113 (44.3%) patients with preexisting eating disorders were not in remission at GI consult, which was associated with being underweight (OR 0.13, 95% CI 0.04-0.46, p < 0.001) and increasing number of GI diagnoses (OR 0.47 per diagnosis, 95% CI 0.26-0.85, p = 0.01). CONCLUSIONS: Eating disorder symptoms precede GI consult for most patients, particularly in functional/motility disorders. As almost half of eating disorder patients are not in remission at GI consult. GI providers have an important role in screening for eating disorders. Further prospective research is needed to understand the complex relationship between eating disorders and GI symptoms.

Histological Characterisation of a Sheep Model of Mild Traumatic Brain Injury: A Pilot Study.

Large animal models of mild traumatic brain injury (mTBI) are needed to elucidate the pathophysiology of mechanical insult to a gyrencephalic brain. Sheep (ovis aries) are an attractive model for mTBI because of their neuroanatomical similarity to humans; however, few histological studies of sheep mTBI models have been conducted. We previously developed a sheep mTBI model to pilot methods for investigating the mechanical properties of brain tissue after injury. Here, we sought to histologically characterize the cortex under the impact site in this model. Three animals received a closed skull mTBI with unconstrained head motion, delivered with an impact stunner, and 3 sham animals were anesthetized but did not receive an impact. Magnetic resonance imaging (MRI) of the brain was performed before and after the impact and revealed variable degrees of damage to the skull and brain. Fluorescent immunohistochemistry revealed regions of hemorrhage in the cortex underlying the impact site in 2 of 3 mTBI sheep, the amount of which correlated with the degree of damage observed on the post-impact MRI scans. Labeling for microtubule-associated protein 2 and neuronal nuclear protein revealed changes in cellular anatomy, but, unexpectedly, glial fibrillary acidic protein and ionized calcium-binding adaptor molecule 1 labeling were relatively unchanged compared to sham animals. Our findings provide preliminary evidence of vascular and neuronal damage with limited glial reactivity and highlight the need for further in-depth histological assessment of large animal mTBI models.

Latent profile analysis reveals the central role of psychological symptoms in driving disease severity in chronic constipation.

BACKGROUND: Chronic constipation (CC) is defined by symptom criteria reflecting heterogenous physiology. However, many patients with CC have significant psychological comorbidities-an alternative definition using a biopsychosocial classification model could be warranted to inform future treatments. We sought to: (1) empirically derive psychological symptom profiles of patients with CC using latent profile analysis and (2) validate these profiles by comparing them on symptom severity, GI-specific anxiety, body mass index (BMI), and anorectal manometry findings. METHODS: Participants included adults presenting for anorectal manometry for CC (N = 468, 82% female, Mage = 47). Depression/anxiety symptoms and eating disorder (ED) symptoms (EAT-26) were used as indicators (i.e., variables used to derive profiles) representing unique psychological constructs. Constipation symptoms, GI-specific anxiety, BMI, and anorectal manometry results were used as validators (i.e., variables used to examine the clinical utility of the resulting profiles). KEY RESULTS: A 5-profile solution provided the best statistical fit, comprising the following latent profiles (LPs): LP1 termed "high dieting, low bulimia;" LP2 termed "high ED symptoms;" LP3 termed "moderate ED symptoms;" LP4 termed "high anxiety and depression, low ED symptoms;" and LP5 termed "low psychological symptoms." The low psychological symptom profile (61% of the sample) had lower abdominal and overall constipation severity and lower GI-specific anxiety compared to the four profiles characterized by higher psychological symptoms (of any type). Profiles did not significantly differ on BMI or anorectal manometry results. CONCLUSIONS AND INFERENCES: Profiles with high psychological symptoms had increased constipation symptom severity and GI-specific anxiety in adults with CC. Future research should test whether these profiles predict differential treatment outcomes.

Cognitive-behavioral therapy for avoidant/restrictive food intake disorder: A proof-of-concept for mechanisms of change and target engagement.

BACKGROUND: Cognitive-behavioral therapy for avoidant/restrictive food intake disorder (ARFID; CBT-AR) theoretically targets three prototypic motivations (sensory sensitivity, lack of interest/low appetite, fear of aversive consequences), aligned with three modularized interventions. As an exploratory investigation, we: (1) evaluated change in candidate mechanisms in relationship to change in ARFID severity, and (2) tested if assignment (vs. not) to a module resulted in larger improvements in the corresponding mechanism. METHOD: Males and females (N = 42; 10-55 years) participated in an open trial of CBT-AR. RESULTS: Decreases in scaled scores for each candidate mechanism had medium to large correlations with decreases in ARFID severity-sensory sensitivity: -0.7 decrease (r = .42, p = .01); lack of interest/low appetite: -0.3 decrease (r = .60, p < .0001); and fear of aversive consequences: -1.1 decrease (r = .33, p = .05). Linear mixed models revealed significant weekly improvements for each candidate mechanism across the full sample (ps < .0001). There were significant interactions for the sensory and fear of aversive consequences modules-for each, participants who received the corresponding module had significantly larger decreases in the candidate mechanism than those who did not receive the module. DISCUSSION: Sensory sensitivity and fear of aversive consequences improved more if the CBT-AR module was received, but lack of interest/low appetite may improve regardless of receipt of the corresponding module. Future research is needed to test target engagement in CBT-AR with adaptive treatment designs, and to identify valid and sensitive measures of candidate mechanisms. PUBLIC SIGNIFICANCE: The mechanisms through which components of CBT-AR work have yet to be elucidated. We conducted an exploratory investigation to test if assignment (vs. not) to a CBT-AR module resulted in larger improvements in the corresponding prototypic ARFID motivation that the module intended to target. Measures of the sensory sensitivity and the fear of aversive consequences motivations improved more in those who received the corresponding treatment module, whereas the lack of interest/low appetite measure improved regardless of if the corresponding module was received.

Aggregate-prone brain regions in Parkinson's disease are rich in unique N-terminus α-synuclein conformers with high proteolysis susceptibility.

In Parkinson's disease (PD), and other α-synucleinopathies, α-synuclein (α-Syn) aggregates form a myriad of conformational and truncational variants. Most antibodies used to detect and quantify α-Syn in the human brain target epitopes within the C-terminus (residues 96-140) of the 140 amino acid protein and may fail to capture the diversity of α-Syn variants present in PD. We sought to investigate the heterogeneity of α-Syn conformations and aggregation states in the PD human brain by labelling with multiple antibodies that detect epitopes along the entire length of α-Syn. We used multiplex immunohistochemistry to simultaneously immunolabel tissue sections with antibodies mapping the three structural domains of α-Syn. Discrete epitope-specific immunoreactivities were visualised and quantified in the olfactory bulb, medulla, substantia nigra, hippocampus, entorhinal cortex, middle temporal gyrus, and middle frontal gyrus of ten PD cases, and the middle temporal gyrus of 23 PD, and 24 neurologically normal cases. Distinct Lewy neurite and Lewy body aggregate morphologies were detected across all interrogated regions/cases. Lewy neurites were the most prominent in the olfactory bulb and hippocampus, while the substantia nigra, medulla and cortical regions showed a mixture of Lewy neurites and Lewy bodies. Importantly, unique N-terminus immunoreactivity revealed previously uncharacterised populations of (1) perinuclear, (2) glial (microglial and astrocytic), and (3) neuronal lysosomal α-Syn aggregates. These epitope-specific N-terminus immunoreactive aggregate populations were susceptible to proteolysis via time-dependent proteinase K digestion, suggesting a less stable oligomeric aggregation state. Our identification of unique N-terminus immunoreactive α-Syn aggregates adds to the emerging paradigm that α-Syn pathology is more abundant and complex in human brains with PD than previously realised. Our findings highlight that labelling multiple regions of the α-Syn protein is necessary to investigate the full spectrum of α-Syn pathology and prompt further investigation into the functional role of these N-terminus polymorphs.

Validation of a measure of hypervigilance and anxiety about gastrointestinal symptoms for individuals with elevated eating pathology.

Gastrointestinal symptoms are common within eating disorders and gastrointestinal-specific anxiety is a posited maintenance factor. The present study sought to validate a modified version of an existing measure of gastrointestinal-specific anxiety and hypervigilance in a sample with elevated eating pathology. Esophageal-specific terms in the Esophageal Hypervigilance and Anxiety Scale were modified to measure any gastrointestinal symptoms as a general measure of gastrointestinal-specific anxiety and hypervigilance. Three hundred eighty-two undergraduate students (83.5% female, 87.4% White) with elevated eating pathology completed a questionnaire battery that also measured gastrointestinal symptoms, general anxiety sensitivity, and lower gastrointestinal-specific anxiety on two occasions. Analyses were preregistered at Open Science Framework. Confirmatory factor analysis indicated a two-factor solution (anxiety and hypervigilance) fit the data best. Internal consistency and 2-week test-retest reliability were good for subscale scores. Subscale scores exhibited large associations with a measure of lower gastrointestinal-specific anxiety but did not exhibit the hypothesized relationships with general anxiety sensitivity. Subscale scores were at least moderately correlated with measures of gastrointestinal symptoms and somatic symptom severity, with some exceptions (hypervigilance with nausea/vomiting, postprandial fullness/early satiety, bloating). Subscale scores exhibited negligible associations with discriminant validity measures. Results suggest that gastrointestinal-specific anxiety and hypervigilance are separable in samples with elevated eating pathology. The Anxiety and Hypervigilance subscale scores showed good reliability in a sample with elevated eating pathology. Correlations with measures of gastrointestinal symptoms and gastrointestinal-specific anxiety generally demonstrated good convergent and discriminant validity. We recommend researchers use subscale scores, rather than total score, in future research on gastrointestinal symptoms associated with eating pathology. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Relationships among symptoms of gastroparesis to those of avoidant/restrictive food intake disorder in patients with gastroparesis.

BACKGROUND: Patients with symptoms of gastroparesis (Gp) often reduce food intake in attempt to manage their symptoms. Up to 40% of adults with Gp have been reported to have symptoms of a non-body image-based eating disorder, avoidant/restrictive food intake disorder (ARFID). However, whether ARFID symptoms precede or follow the diagnosis of Gp is unknown. METHODS: From January 2021 to January 2022, consecutive adult patients with Gp at an academic center completed self-report surveys for Gp symptom severity (patient assessment of upper gastrointestinal symptoms; PAGI-SYM) and for ARFID (nine-item ARFID screen; NIAS). KEY RESULTS: One hundred and seven patients (age 45.4 ± 17.2 yrs, 84.1% female, BMI 26.4 ± 7.3) with Gp (4-h gastric retention 33.5 ± 21.8%) were included. Eighty-two of the 107 Gp patients (77%) screened positive for ARFID. Positive ARFID screen was most often on the NIAS appetite subscale (84%) and fear subscale (76%), with a lower positive screen rate on the picky subscale (45%). Of the Gp who screened positive for ARFID, 38% reported that eating difficulties came after their Gp diagnosis, whereas 17% reported that eating difficulties preceded their Gp diagnosis, and 15% reported that both began at the same time. CONCLUSIONS: Many (77%) patients with Gp screened positive for ARFID. In Gp patients with ARFID, the Gp diagnosis was more likely to precede the development of eating difficulties. Thus, a subset of patients with Gp may be at risk for developing ARFID. Further longitudinal research is needed to confirm findings and identify risk factors.

Distribution of ubiquilin 2 and TDP-43 aggregates throughout the CNS in UBQLN2 p.T487I-linked amyotrophic lateral sclerosis and frontotemporal dementia.

Mutations in the UBQLN2 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The neuropathology of such UBQLN2-linked cases of ALS/FTD is characterised by aggregates of the ubiquilin 2 protein in addition to aggregates of the transactive response DNA-binding protein of 43 kDa (TDP-43). ALS and FTD without UBQLN2 mutations are also characterised by TDP-43 aggregates, that may or may not colocalise with wildtype ubiquilin 2. Despite this, the relative contributions of TDP-43 and ubiquilin 2 to disease pathogenesis remain largely under-characterised, as does their relative deposition as aggregates across the central nervous system (CNS). Here we conducted multiplex immunohistochemistry of three UBQLN2 p.T487I-linked ALS/FTD cases, three non-UBQLN2-linked (sporadic) ALS cases, and 8 non-neurodegenerative disease controls, covering 40 CNS regions. We then quantified ubiquilin 2 aggregates, TDP-43 aggregates and aggregates containing both proteins in regions of interest to determine how UBQLN2-linked and non-UBQLN2-linked proteinopathy differ. We find that ubiquilin 2 aggregates that are negative for TDP-43 are predominantly small and punctate and are abundant in the hippocampal formation, spinal cord, all tested regions of neocortex, medulla and substantia nigra in UBQLN2-linked ALS/FTD but not sporadic ALS. Curiously, the striatum harboured small punctate ubiquilin 2 aggregates in all cases examined, while large diffuse striatal ubiquilin 2 aggregates were specific to UBQLN2-linked ALS/FTD. Overall, ubiquilin 2 is mainly deposited in clinically unaffected regions throughout the CNS such that symptomology in UBQLN2-linked cases maps best to the aggregation of TDP-43.

Validation of the youth-nine item avoidant/restrictive food intake disorder screen.

OBJECTIVE: This study assessed the factorial, divergent, and criterion-related validity of the Youth-Nine Item Avoidant/Restrictive Food Intake Disorder (ARFID) Screen (Y-NIAS) in a paediatric clinical sample at initial evaluation for an eating disorder (ED). METHOD: Participants included 310 patients (82.9% female, 77.4% White, Age M = 14.65) from a tertiary ED clinic. Confirmatory factor analysis (CFA) evaluated the three-factor of the Y-NIAS. One-way analysis of variance compared Y-NIAS scores across diagnoses. A receiver operating curve analysis assessed the ability of each subscale to identify ARFID presentations from the full sample. Two logistic regressions assessed the criterion-related validity of the obtained Y-NIAS cut-scores. RESULTS: CFA supported the original three-factor structure of the Y-NIAS. Clinically-elevated scores were observed in all diagnostic groups except for binge-eating disorder. Subscales were unable to discriminate ARFID cases from other ED diagnoses. Cut scores were identified for picky eating subscale (10) and Fear subscale (9), but not for Appetite subscale. In combination with the ED Examination Questionnaire (EDE-Q), classification accuracy was moderate for ARFID (62.7%) and other EDs (89.4%). DISCUSSION: The Y-NIAS demonstrated excellent factorial validity and internal consistency. Findings were mixed regarding the utility of the Y-NIAS for identifying clinically-significant ARFID presentations from other ED diagnoses.

Characterization of adult human skeletal cells in different tissues reveals a CD90+CD34+ periosteal stem/progenitor population.

The periosteum plays a crucial role in bone healing and is an important source of skeletal stem and progenitor cells. Recent studies in mice indicate that diverse populations of skeletal progenitors contribute to growth, homeostasis and healing. Information about the in vivo identity and diversity of skeletal stem and progenitor cells in different compartments of the adult human skeleton is limited. In this study, we compared non-hematopoietic populations in matched tissues from the femoral head and neck of 21 human participants using spectral flow cytometry of freshly isolated cells. High-dimensional clustering analysis indicated significant differences in marker distribution between periosteum, articular cartilage, endosteum and bone marrow populations, and identified populations that were highly enriched or unique to specific tissues. Periosteum-enriched markers included CD90 and CD34. Articular cartilage, which has very poor regenerative potential, showed enrichment of multiple markers, including the PDPN+CD73+CD164+CD146- population previously reported to represent human skeletal stem cells. We further characterized periosteal populations by combining CD90 with other strongly expressed markers. CD90+CD34+ cells sorted directly from periosteum showed significant colony-forming unit fibroblasts (CFU-F) enrichment, rapid expansion, and consistent multi-lineage differentiation of clonal populations in vitro. In situ, CD90+CD34+ cells include a perivascular population in the outer layer of the periosteum and non-perivascular cells closer to the bone surface. CD90+ cells are also highly enriched for CFU-F in bone marrow and endosteum, but not articular cartilage. In conclusion, our study indicates considerable diversity in the non-hematopoietic cell populations in different tissue compartments within the adult human skeleton, and suggests that periosteal progenitor cells reside within the CD90+CD34+ population.

Assessing the presence and motivations of orthorexia nervosa among athletes and adults with eating disorders: a cross-sectional study.

PURPOSE: Orthorexia nervosa involves restricting diet based on quality rather than quantity. Although orthorexia is well reported in many at-risk populations, limited data addresses its presence in individuals with eating disorder history (EDs) or athletes. We aimed to identify the presence and potential drivers of orthorexia in adults with EDs and endurance athletes, compared to control subjects. METHODS: Participants ≥ 18y included: people with a diagnosed eating disorder (ED as per DSM-5); endurance athletes (training/competing ≥ 5 h/week); or control subjects. Participants (n = 197) completed an online survey assessing orthorexia (eating habits questionnaire, EHQ), eating motivations (TEMS-B) and compulsive exercise (CET). RESULTS: ED had the highest orthorexia symptom severity (92.0 ± 3.02, n = 32), followed by athletes (76.2 ± 2.74, n = 54) and controls (71.0 ± 1.80, n = 111) (F (2) = 18.2, p < 0.001). A strong positive correlation existed between weight control motives and higher orthorexia symptom severity (r = 0.54, 95% CI [1.35, 2.36], p < 0.001), while a weak negative association existed between Hunger and Pleasure motives and higher orthorexia symptom severity (r = 0.23, 95% CI [- 2.24, - 0.34], p = 0.008; r = 0.26, 95% CI [- 2.11, - 0.47], p = 0.002, respectively). A moderate positive relationship was found between CET and orthorexia symptom severity (95% CI [1.52, 3.12], p < 0.001). CONCLUSION: Adults with ED history and endurance athletes have greater orthorexia symptom severity compared to control. Clinicians working with at-risk populations should screen patients and be aware of red-flags of orthorexic traits, desire to control weight, and compulsive exercise behavior. LEVEL OF EVIDENCE: III: Evidence obtained from cohort studies.

ApoER2-Dab1 disruption as the origin of pTau-associated neurodegeneration in sporadic Alzheimer's disease.

In sporadic Alzheimer's disease (sAD) specific regions, layers and neurons accumulate hyperphosphorylated Tau (pTau) and degenerate early while others remain unaffected even in advanced disease. ApoER2-Dab1 signaling suppresses Tau phosphorylation as part of a four-arm pathway that regulates lipoprotein internalization and the integrity of actin, microtubules, and synapses; however, the role of this pathway in sAD pathogenesis is not fully understood. We previously showed that multiple ApoER2-Dab1 pathway components including ApoE, Reelin, ApoER2, Dab1, pP85αTyr607, pLIMK1Thr508, pTauSer202/Thr205 and pPSD95Thr19 accumulate together within entorhinal-hippocampal terminal zones in sAD, and proposed a unifying hypothesis wherein disruption of this pathway underlies multiple aspects of sAD pathogenesis. However, it is not yet known whether ApoER2-Dab1 disruption can help explain the origin(s) and early progression of pTau pathology in sAD. In the present study, we applied in situ hybridization and immunohistochemistry (IHC) to characterize ApoER2 expression and accumulation of ApoER2-Dab1 pathway components in five regions known to develop early pTau pathology in 64 rapidly autopsied cases spanning the clinicopathological spectrum of sAD. We found that (1) these selectively vulnerable neuron populations strongly express ApoER2; and (2) multiple ApoER2-Dab1 components representing all four arms of this pathway accumulate in abnormal neurons and neuritic plaques in mild cognitive impairment (MCI) and sAD cases and correlate with histological progression and cognitive deficits. Multiplex-IHC revealed that Dab1, pP85αTyr607, pLIMK1Thr508, pTauSer202/Thr205 and pPSD95Thr19 accumulate together within many of the same ApoER2-expressing neurons and in the immediate vicinity of ApoE/ApoJ-enriched extracellular plaques. Collective findings reveal that pTau is only one of many ApoER2-Dab1 pathway components that accumulate in multiple neuroanatomical sites in the earliest stages of sAD and provide support for the concept that ApoER2-Dab1 disruption drives pTau-associated neurodegeneration in human sAD.

Preliminary data that psychological treatment and baseline anxiety are associated with a decrease in postprandial fullness and early satiation for individuals with bulimia nervosa and related other specified feeding or eating disorder.

OBJECTIVE: Gastrointestinal symptoms, particularly postprandial fullness, are frequently reported in eating disorders. Limited data exist evaluating how these symptoms change in response to outpatient psychological treatment. The current study sought to describe the course of postprandial fullness and early satiation across psychological treatment for adults with bulimia nervosa and related other specified feeding or eating disorders and to test if anxiety moderates treatment response. METHODS: Secondary data analysis was conducted on questionnaire data provided by 30 individuals (80% white, M(SD)age = 31.43(13.44) years; 90% female) throughout treatment and six-month follow-up in a pilot trial comparing mindfulness and acceptance-based treatment with cognitive-behavioral therapy for bulimia nervosa. Participants completed items from the Rome IV Diagnostic Questionnaire for Adult Functional Gastrointestinal Disorders and the State Trait Anxiety Inventory. RESULTS: Postprandial fullness and early satiation both significantly decreased over time (ds = 1.23-1.54; p's < .001). Baseline trait anxiety moderated this outcome, such that greater decreases were observed for those with higher baseline anxiety (p = .02). DISCUSSION: Results extend prior work in inpatient samples by providing preliminary data that postprandial fullness and early satiation decrease with outpatient psychological treatment for bulimia nervosa. Baseline anxiety moderated this effect for postprandial fullness. Future work should replicate findings in a larger sample and test anxiety as a mechanism underlying postprandial fullness in eating disorders. PUBLIC SIGNIFICANCE: The current study found that common gastrointestinal symptoms (postprandial fullness and early satiation) decrease over the course of outpatient psychotherapy for adults with full and subthreshold bulimia nervosa. Postprandial fullness decreased more across time for those high in anxiety.

Brief cognitive-behavioral treatment for avoidant/restrictive food intake disorder in the context of functional dyspepsia: Study protocol for a feasibility randomized controlled trial.

BACKGROUND: Avoidant/restrictive food intake disorder (ARFID) symptoms are common (up to 40%) among adults with functional dyspepsia (FD), a disorder of gut-brain interaction characterized by early satiation, post-prandial fullness, epigastric pain, and/or epigastric burning. Using an 8-session exposure-based cognitive-behavioral treatment (CBT) for adults with FD + ARFID compared to usual care (UC) alone, we aim to: (1) determine feasibility, (2) evaluate change in clinical outcomes in, and (3) explore possible mechanisms of action. METHODS: We will randomize adults with FD who meet criteria for ARFID with ≥5% weight loss (N = 50) in a 1:1 ratio to CBT (with continued UC) or to UC alone. A priori primary benchmarks will be: ≥75% eligible participants enroll; ≥75% participants complete assessments; ≥70% participants attend 6/8 sessions; ≥70% of sessions have all content delivered; ≥70% participants rate Client Satisfaction Questionnaire scores above scale midpoint. We will also examine the size of changes in FD symptom severity and related quality of life within and between groups, and explore possible mechanisms of action. CONCLUSIONS: Findings from this trial will inform next steps with treatment development or evaluation-either for further refinement or for next-step efficacy testing with a fully-powered clinical trial.