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To report long-term ophthalmic findings in Wolfram syndrome, including rates of visual decline, macular thinning, retinal nerve fiber layer (RNFL) thinning, and outer plexiform layer (OPL) lamination.Single-center, cohort study.A total of 38 participants were studied, who underwent a complete ophthalmic examination as well as optical coherence tomography imaging of the macula and nerve on an annual basis. Linear mixed-effects models for longitudinal data were used to examine both fixed and random effects related to visual acuity and optic nerve quadrants of RNFL and macula thickness.Participants completed a mean of 6.44 years of follow-up (range 2-10 years). Visual acuity declined over time in all participants, with a mean slope of 0.059 logMAR/y (95% CI = 0.07-0.05 logMAR/y), although nearly 25% of participants experienced more rapid visual decline. RNFL thickness decreased in superior, inferior, and nasal quadrants (β = -0.5 µm/y, -0.98 µm/y, -0.28 µm/y, respectively). OPL lamination was noted in 3 study participants, 2 of whom had autosomal dominant mutations.Our study describes the longest and largest natural history study of visual acuity decline and retinal morphometry in Wolfram syndrome to date. Results suggest that there are slower and faster progressing subgroups and that OPL lamination is present in some individuals with this disease.

To characterize the association between environmental (residential air) manganese (Mn) exposure and cognitive performance, focusing on cognitive control, in a Black African population.We administered the Go-No-Go, Digit Span, and Matrix Reasoning tests to population-based samples age ≥40 from a high Mn (smelter) exposed community, Meyerton (N = 629), and a demographically comparable low (background levels) non-exposed community, Ethembalethu, (N = 96) in Gauteng province, South Africa. We investigated the associations between community and performance on the cognitive tests, using linear regression. We adjusted a priori for age and sex, and examined the effect of adjustment for education, nonverbal IQ, smoking, and alcohol consumption. We measured airborne PMCompared to Ethembalethu residents, Meyerton residents' test scores were lower (poorer) for all tests: 0.55 (95 % confidence interval [CI] 0.08, 1.03) lower scores for Matrix Reasoning, 0.34 (95 % CI -0.07, 0.75) lower for Digit Span, and 0.15 (95 % CI 0.09, 0.21) lower for Go-No-Go (high frequency discriminability index [probability]). The latter represented the most marked difference in terms of z-scores (0.50, 95 % CI 0.30, 0.71 standard deviations lower). The mean of the z-score of each of the three tests was also lower (0.34, 95 % CI 0.18, 0.50 standard deviations lower). These associations were similar in men and women, but attenuated with adjustment for education. Differences for Matrix Reasoning and Digit Span between the two communities were observed only among those who had lived in Meyerton ≥10 years, whereas for Go-No-Go, differences were also apparent among those who had lived in Meyerton10 years. Mean PMResidence in a community near a high Mn emission source is associated with cognitive dysfunction, including aspects of cognitive control as assessed by the Go-No-Go test.

Background Wolfram Syndrome is a rare genetic disorder usually resulting from pathogenic variation in the WFS1 gene, which leads to an exaggerated endoplasmic reticulum (ER) stress response. The disorder is typically characterized by diabetes insipidus, diabetes mellitus, optic nerve atrophy, hearing loss, and neurodegenerative features. Existing literature suggests it may also have psychiatric manifestations. Objective To examine lifetime psychiatric diagnoses and medication history in Wolfram Syndrome. Method Child, adolescent, and young adult Wolfram Syndrome participants (n=39) were assessed by a child & adolescent psychiatrist to determine best estimate DSM-5 lifetime psychiatric diagnoses as well as psychoactive medication history. In addition, the Child & Adolescent Symptom Inventory-5 (CASI-5) Parent Checklist was used to determine likely psychiatric diagnoses based on symptom counts in Wolfram Syndrome patients (n=33), type 1 diabetes (n=15), and healthy comparison (n=18) groups. Results Study participants with Wolfram Syndrome had high lifetime rates of anxiety disorders (77%). Also, 31% had an obsessive-compulsive spectrum disorder, 33% had a mood disorder, 31% had a neurodevelopmental or disruptive behavior disorder, and 31% had a sleep-wake disorder. More than half of Wolfram Syndrome participants had taken at least one psychoactive medication, and one third had taken at least one selective serotonin reuptake inhibitor (SSRI). Some individuals reported poor response to sertraline but better response after switching to another SSRI (fluoxetine or citalopram). In general, people with Wolfram Syndrome often reported benefit from psychotherapy and/or commonly used psychoactive medications appropriate for their psychiatric diagnoses. Conclusions Wolfram Syndrome may be associated with elevated risk for anxiety and obsessive-compulsive spectrum disorders, which seem generally responsive to usual treatments for these disorders.

ImportanceBoth neighborhood and household socioeconomic disadvantage relate to negative health outcomes and altered brain structure in children. It is unclear whether such findings extend to white matter development, and via what mechanisms socioeconomic status (SES) influences the brain.ObjectiveTo test independent associations between neighborhood and household SES indicators and white matter microstructure in children, and examine whether body mass index and cognitive function (a proxy of environmental cognitive/sensory stimulation) may plausibly mediate these associations.DesignThis cross-sectional study used baseline data from the Adolescent Brain Cognitive Development (ABCD) Study, an ongoing 10-year cohort study tracking child health.SettingSchool-based recruitment at 21 U.S. sites.ParticipantsChildren aged 9 to 11 years and their parents/caregivers completed baseline assessments between October 1st, 2016 and October 31st, 2018. Data analysis was conducted from July to December 2022.ExposuresNeighborhood disadvantage was derived from area deprivation indices at primary residence. Household SES indicators were total income and the highest parental education attainment.Main Outcomes and MeasuresThirty-one major white matter tracts were segmented from diffusion-weighted images. The Restriction Spectrum Imaging (RSI) model was implemented to measure restricted normalized directional (RND; reflecting oriented myelin organization) and isotropic (RNI; reflecting glial/neuronal cell bodies) diffusion in each tract. Obesity-related measures were body mass index (BMI), BMIz-scores, and waist circumference, and cognitive performance was assessed using the NIH Toolbox Cognition Battery. Linear mixed-effects models tested the associations between SES indicators and scanner-harmonized RSI metrics. Structural equation models examined indirect effects of obesity and cognitive performance in the significant associations between SES and white mater microstructure summary principal components. Analyses were adjusted for age, sex, pubertal development stage, intracranial volume, and head motion.ResultsThe analytical sample included 8842 children (4299 [48.6%] girls; mean age [SD], 9.9 [0.7] years). Greater neighborhood disadvantage and lower parental education were independently associated with lower RSI-RND in forceps major and corticospinal/pyramidal tracts, and had overlapping associations in the superior longitudinal fasciculus. Lower cognition scores and greater obesity-related measures partially accounted for these SES associations with RSI-RND. Lower household income was related to higher RSI-RNI in almost every tract, and greater neighborhood disadvantage had similar effects in primarily frontolimbic tracts. Lower parental education was uniquely linked to higher RSI-RNI in forceps major. Greater obesity-related measures partially accounted for these SES associations with RSI-RNI. Findings were robust in sensitivity analyses and mostly corroborated using traditional diffusion tensor imaging (DTI).Conclusions and RelevanceThese cross-sectional results demonstrate that both neighborhood and household contexts are relevant to white matter development in children, and suggest cognitive performance and obesity as possible pathways of influence. Interventions targeting obesity reduction and improving cognition from multiple socioeconomic angles may ameliorate brain health in low-SES children.Key PointsQuestionAre neighborhood and household socioeconomic levels associated with children’s brain white matter microstructure, and if so, do obesity and cognitive performance (reflecting environmental stimulation) mediate the associations?FindingsIn a cohort of 8842 children, higher neighborhood disadvantage, lower household income, and lower parental education had independent and overlapping associations with lower restricted directional diffusion and greater restricted isotropic diffusion in white matter. Greater body mass index and poorer cognitive performance partially mediated these associations.MeaningBoth neighborhood and household poverty may contribute to altered white matter development in children. These effects may be partially explained by obesity incidence and poorer cognitive performance.

Wolfram syndrome is a rare disease characterized by diabetes, neurodegeneration, loss of vision, and audition. We recently found, in a young sample of participants (mean age 15 years), that Wolfram syndrome was associated with impairment in smell identification with normal smell sensitivity and whole-mouth taste function. However, these senses were assessed separately, and it is unknown whether smell–taste interactions are altered in Wolfram syndrome, which was the focus of this study. Participants with Wolfram syndrome (n = 36; 18.2 ± 6.8 years) and sex–age-equivalent healthy controls (n = 34) were assessed with a battery of sensory tests. Using sip-and-spit methods, participants tasted solutions containing gustatory and olfactory stimuli (sucrose with strawberry extract, citric acid with lemon extract, sodium chloride in vegetable broth, and coffee) with and without nose clips, and rated perceived taste and retronasal smell intensities using the generalized Labeled Magnitude Scale. Participants also completed n-butanol detection thresholds and the University of Pennsylvania Smell Identification Test (UPSIT). Retronasal smell increased taste intensity of sucrose, sodium chloride, and coffee solutions similarly in both groups (P values

OBJECTIVE 1) Describe the progression of diabetes mellitus over time in an observational study of Wolfram syndrome, a rare, genetic, neurodegenerative disorder which often includes diabetes mellitus and is typically diagnosed during childhood or adolescence. 2) Determine whether C-peptide could be used as a marker of diabetes progression in interventional trials for Wolfram syndrome. METHODS N=44 (25F/19M) participants with genetically-confirmed Wolfram syndrome attended the Washington University Wolfram Research Clinic annually from 2010-2019. Medical history, physical examinations, blood sampling, and questionnaires were used to collect data about diabetes mellitus and other components of Wolfram syndrome. Beta-cell function was assessed by determination of C-peptide during a mixed meal tolerance test. Random coefficients models evaluated the rate of progression of C-peptide over time, and power analyses were used to estimate the number of subjects needed to detect a change in C-peptide decline during an intervention trial. RESULTS 93.2% of patients had diabetes mellitus. Mean HbA1c across all study visits was 7.9%. C-peptide significantly decreased with increasing duration of diabetes mellitus (p

Background: Obesity is related to quantitative neuroimaging abnormalities including reduced gray matter volumes and impaired white matter microstructural integrity, although the underlying mechanisms are not well understood. Objective: We assessed influence of obesity on neuroinflammation imaging that may mediate brain morphometric changes. Establishing the role of neuroinflammation in obesity will enhance understanding of this modifiable disorder as a risk factor for Alzheimer’s disease (AD) dementia. Methods: We analyzed brain MRIs from 104 cognitively normal participants (CDR = 0) and biomarker negativity for CSF amyloid or tau. We classified body mass index (BMI) as normal (BMI

OBJECTIVE To assess whether previously observed brain and cognitive differences between children with type 1 diabetes and control subjects without diabetes persist, worsen, or improve as children grow into puberty and whether differences are associated with hyperglycemia. RESEARCH DESIGN AND METHODS One hundred forty-four children with type 1 diabetes and 72 age-matched control subjects without diabetes (mean ± SD age at baseline 7.0 ± 1.7 years, 46% female) had unsedated MRI and cognitive testing up to four times over 6.4 ± 0.4 (range 5.3–7.8) years; HbA1c and continuous glucose monitoring were done quarterly. FreeSurfer-derived brain volumes and cognitive metrics assessed longitudinally were compared between groups using mixed-effects models at 6, 8, 10, and 12 years. Correlations with glycemia were performed. RESULTS Total brain, gray, and white matter volumes and full-scale and verbal intelligence quotients (IQs) were lower in the diabetes group at 6, 8, 10, and 12 years, with estimated group differences in full-scale IQ of −4.15, −3.81, −3.46, and −3.11, respectively (P < 0.05), and total brain volume differences of −15,410, −21,159, −25,548, and −28,577 mm3 at 6, 8, 10, and 12 years, respectively (P < 0.05). Differences at baseline persisted or increased over time, and brain volumes and cognitive scores negatively correlated with a life-long HbA1c index and higher sensor glucose in diabetes. CONCLUSIONS Detectable changes in brain volumes and cognitive scores persist over time in children with early-onset type 1 diabetes followed longitudinally; these differences are associated with metrics of hyperglycemia. Whether these changes can be reversed with scrupulous diabetes control requires further study. These longitudinal data support the hypothesis that the brain is a target of diabetes complications in young children.

Background Deep brain stimulation of the subthalamic nucleus is a widely used adjunctive therapy for motor symptoms of Parkinson's disease, but with variable motor response. Predicting motor response remains difficult, and novel approaches may improve surgical outcomes as well as the understanding of pathophysiological mechanisms. The objective of this study was to determine whether preoperative resting-state functional connectivity MRI predicts motor response from deep brain stimulation of the subthalamic nucleus. Methods We collected preoperative resting-state functional MRI from 70 participants undergoing subthalamic nucleus deep brain stimulation. For this cohort, we analyzed the strength of STN functional connectivity with seeds determined by stimulation-induced (ON/OFF) 15 O H2 O PET regional cerebral blood flow differences in a partially overlapping group (n = 42). We correlated STN-seed functional connectivity strength with postoperative motor outcomes and applied linear regression to predict motor outcomes. Results Preoperative functional connectivity between the left subthalamic nucleus and the ipsilateral internal globus pallidus correlated with postsurgical motor outcomes (r = -0.39, P = 0.0007), with stronger preoperative functional connectivity relating to greater improvement. Left pallidal-subthalamic nucleus connectivity also predicted motor response to DBS after controlling for covariates. Discussion Preoperative pallidal-subthalamic nucleus resting-state functional connectivity predicts motor benefit from deep brain stimulation, although this should be validated prospectively before clinical application. These observations suggest that integrity of pallidal-subthalamic nucleus circuits may be critical to motor benefits from deep brain stimulation. © 2020 International Parkinson and Movement Disorder Society.

BACKGROUND AND PURPOSE: Wolfram syndrome is a rare genetic disease with characteristic brain involvement. We reviewed the brain MR images of patients with Wolfram syndrome to determine the frequency and characteristics of common neuroradiologic findings. MATERIALS AND METHODS: We retrospectively reviewed the imaging data of patients with genetically-confirmed Wolfram syndrome who had been recruited to the Washington University Wolfram Syndrome Research Clinic. These patients were evaluated between 2010 and 2019 with annual MRIs, along with other measures. MR images were assessed for clinical neuroradiologic signs at each individual’s first and last follow-up visits to characterize the frequency, rate of progression, and clinical correlations of these signs. RESULTS: We included 30 patients (13 males/17 females; average age at first visit, 14 years; average age at last visit, 19 years). The median duration of follow-up was 5 years (range, 2–9 years). The most common findings were an absent or diminished posterior pituitary bright spot (first, 53%; last, 70%), T1/T2 pons signal abnormalities (first, 53%; last, 67%), optic nerve atrophy (first, 30%; last, 80%), white matter T2 hyperintensities (first, 27%; last, 35%), and cerebellar atrophy (first, 23%; last, 70%). CONCLUSIONS: Patients with Wolfram syndrome present characteristic neuroradiologic findings that involve the posterior pituitary gland, optic nerves, white matter, brain stem, and cerebellum. These abnormal findings appear at an early age and tend to increase in frequency with time. However, the neurologic significance and neuropathologic mechanisms of each sign require more investigation. Neuroradiologists should be aware of the pattern of these features in Wolfram syndrome.

Wolfram syndrome is a rare disease caused by pathogenic variants in the WFS1 gene with progressive neurodegeneration. As an easily accessible biomarker of progression of neurodegeneration has not yet been found, accurate tracking of the neurodegenerative process over time requires assessment by costly and time-consuming clinical measures and brain magnetic resonance imaging (MRI). A blood-based measure of neurodegeneration, neurofilament light chain (NfL), is relatively inexpensive and can be repeatedly measured at remote sites, standardized, and measured in individuals with MRI contraindications. To determine whether NfL levels may be of use in disease monitoring and reflect disease activity in Wolfram syndrome, plasma NfL levels were compared between children and young adults with Wolfram syndrome (n = 38) and controls composed of their siblings and parents (n = 35) and related to clinical severity and selected brain region volumes within the Wolfram group. NfL levels were higher in the Wolfram group [median (interquartile range) NfL = 11.3 (7.8–13.9) pg/mL] relative to controls [5.6 (4.5–7.4) pg/mL]. Within the Wolfram group, higher NfL levels related to worse visual acuity, color vision and smell identification, smaller brainstem and thalamic volumes, and faster annual rate of decrease in thalamic volume over time. Our findings suggest that plasma NfL levels can be a powerful tool to non-invasively assess underlying neurodegenerative processes in children, adolescents and young adults with Wolfram syndrome.

OBJECTIVE: To determine whether striatal dopamine (DA) release is affected by food ingestion and whether the DA response to high-calorie food images is greater in the fasted than fed state in people with obesity. METHODS: Striatal DA release was evaluated in 10 people with obesity and prediabetes after participants consumed a meal to satiation and after they fasted overnight, and in response to viewing images of high-calorie compared with low-calorie foods after consuming a meal to satiation or fasting overnight, by using positron emission tomography with [(11)C]raclopride injection. RESULTS: Striatal DA D2/D3 receptor availability was not different during fasted and fed conditions. Viewing images of high-calorie foods induced striatal DA release relative to viewing images of low-calorie foods (p

BACKGROUND AND PURPOSE: The hippocampus is a frequent focus of quantitative neuroimaging research, and structural hippocampal alterations are related to multiple neurocognitive disorders. An increasing number of neuroimaging studies are focusing on hippocampal subfield regional involvement in these disorders using various automated segmentation approaches. Direct comparisons among these approaches are limited. The purpose of this study was to compare the agreement between two automated hippocampal segmentation algorithms in an adult population. MATERIALS AND METHODS: We compared the results of 2 automated segmentation algorithms for hippocampal subfields (FreeSurfer v6.0 and volBrain) within a single imaging data set from adults (n = 176, 89 women) across a wide age range (20–79 years). Brain MR imaging was acquired on a single 3T scanner as part of the IXI Brain Development Dataset and included T1- and T2-weighted MR images. We also examined subfield volumetric differences related to age and sex and the impact of different intracranial volume and total hippocampal volume normalization methods. RESULTS: Estimated intracranial volume and total hippocampal volume of both protocols were strongly correlated (r = 0.93 and 0.9, respectively; both P < .001). Hippocampal subfield volumes were correlated (ranging from r = 0.42 for the subiculum to r = 0.78 for the cornu ammonis [CA]1, all P < .001). However, absolute volumes were significantly different between protocols. volBrain produced larger CA1 and CA4-dentate gyrus and smaller CA2-CA3 and subiculum volumes compared with FreeSurfer v6.0. Regional age- and sex-related differences in subfield volumes were qualitatively and quantitatively different depending on segmentation protocol and intracranial volume/total hippocampal volume normalization method. CONCLUSIONS: The hippocampal subfield volume relationship to demographic factors and disease states should undergo nuanced interpretation, especially when considering different segmentation protocols.

Objective To characterize the association between residential environmental manganese (Mn) exposure and depression and anxiety, given prior associations among occupationally-exposed workers. Methods We administered the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI) to 697 study participants in their preferred languages. These participants represented a population-based sample of residents aged ≥40 from two predominantly Black African communities in Gauteng province, South Africa: 605 in Meyerton, adjacent to a large Mn smelter, and 92 in Ethembalethu, a comparable non-exposed community. We investigated the associations between community (Meyerton vs. Ethembalethu) and severity of depression and anxiety, using linear regression, adjusting for age and sex. To document community-level differences in Mn exposure, we measured airborne PM2.5-Mn. Results Meyerton residents had BDI scores 5.63 points (95 % CI 3.07, 8.20) higher than Ethembalethu residents, with all questions contributing to this significant difference. STAI-state scores were marginally higher in Meyerton than Ethembalethu residents [2.12 (95 % CI -0.17, 4.41)], whereas STAI-trait scores were more similar between the communities [1.26 (95 % CI -0.82, 3.35)]. Mean PM2.5-Mn concentration was 203 ng/m3 at a long-term fixed site in Meyerton and 10 ng/m3 in Ethembalethu. Conclusion Residence near Mn emission sources may be associated with greater depression symptomatology, and possibly current, but not lifetime, anxiety.

OBJECTIVE: Basal ganglia regions are part of the brain’s reward-processing networks and are implicated in the neurobiology of obesity and eating disorders. This study examines basal ganglia microstructural properties in adults with and without obesity. METHODS: Diffusion basis spectrum imaging (DBSI) images were analyzed to obtain putative imaging markers of neuroinflammation. Relationships between basal ganglia DBSI metrics and reward sensitivity and eating behaviors were also explored. RESULTS: A total of 46 participants (25 people with obesity; aged 20–40 years; 37 women) were included. Relative to the people in the normal-weight group, people with obesity had smaller caudate and larger nucleus accumbens (NAcc) volumes (p < 0.05) and lower DBSI fiber fraction (reflecting apparent axonal/dendrite density) in NAcc and putamen, higher DBSI nonrestricted fraction (reflecting tissue edema) in NAcc and caudate, and higher DBSI restricted fraction (reflecting tissue cellularity) in putamen (p ≤ 0.01, all). Increased emotional and reward eating behaviors were related to lower NAcc axonal/dendrite density and greater tissue edema (p ≤ 0.002). The relationships between emotional eating and adiposity measures were mediated by NAcc microstructure. CONCLUSIONS: These findings provide evidence that microstructural alterations in basal ganglia relate to obesity and insights linking NAcc microstructure and eating behavior in adults.

Objective: To assess whether previously observed brain and cognitive differences between children with type 1 diabetes and non-diabetic controls persist, worsen or improve as children grow into puberty, and whether differences are associated with hyperglycemia. Research Design & Methods: 144 children with type 1 diabetes and 72 non-diabetic age-matched controls, mean±SD age 7.0±1.7 years at baseline, 46% female, had unsedated magnetic resonance imaging and cognitive testing up to 4 times over 6.4±0.4 years (5.3-7.8); HbA1C and continuous glucose monitoring were done quarterly. FreeSurfer-derived brain volumes and cognitive metrics assessed longitudinally were compared between groups using mixed effects models at 6, 8, 10 and 12 years. Correlations with glycemia were performed. Results: Total brain, gray and white matter volumes, full-scale and verbal IQ were lower in the diabetes group [at 6, 8, 10 and 12 years estimate group differences in full-scale IQ respectively: -4.15, -3.81, -3.46, -3.11, p 3x103, -21159, -25548, -28577, p C index and higher sensor glucose in diabetes. Conclusions: Detectable changes in brain volumes and cognitive scores persist over time in children with early-onset type 1 diabetes followed longitudinally; these differences are associated with metrics of hyperglycemia. Whether these changes can be reversed with scrupulous diabetes control requires further study. These longitudinal data support the hypothesis that the brain is a target of diabetes complications in young children.

UNSTRUCTURED Type 1 diabetes (T1D) is one of the most common chronic childhood diseases, and its prevalence is rapidly increasing. The management of glucose in T1D is challenging, as youth must consider a myriad of factors when making diabetes care decisions. This task often leads to significant hyperglycemia, hypoglycemia, and glucose variability throughout the day, which have been associated with short- and long-term medical complications. At present, most of what is known about each of these complications and the health behaviors that may lead to them have been uncovered in the clinical setting or in laboratory-based research. However, the tools often used in these settings are limited in their ability to capture the dynamic behaviors, feelings, and physiological changes associated with T1D that fluctuate from moment to moment throughout the day. A better understanding of T1D in daily life could potentially aid in the development of interventions to improve diabetes care and mitigate the negative medical consequences associated with it. Therefore, there is a need to measure repeated, real-time, and real-world features of this disease in youth. This approach is known as ecological momentary assessment (EMA), and it has considerable advantages to in-lab research. Thus, this viewpoint aims to describe EMA tools that have been used to collect data in the daily lives of youth with T1D and discuss studies that explored the nuances of T1D in daily life using these methods. This viewpoint focuses on the following EMA methods: continuous glucose monitoring, actigraphy, ambulatory blood pressure monitoring, personal digital assistants, smartphones, and phone-based systems. The viewpoint also discusses the benefits of using EMA methods to collect important data that might not otherwise be collected in the laboratory and the limitations of each tool, future directions of the field, and possible clinical implications for their use.

BACKGROUND Wolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial. METHODS Based on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions. RESULTS Dantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects. CONCLUSION This study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02829268 FUNDING NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.

BackgroundWolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, may be beneficial.MethodsBased on the results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, our group put together the first-ever clinical trial in pediatric and adult patients with Wolfram syndrome. An open-label phase 1b/2a trial design was chosen. The primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric patients with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β-cell functions, visual acuity, quality of life measures related to vision, and neurological functions.ResultsThe results indicate that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in β-cell function, which might correlate with a positive trend in other outcome measures, including visual acuity and neurological functions.ConclusionThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome.Trial registrationClinicalTrials.gov Identifier NCT02829268Key PointsQuestionIs dantrolene sodium safe and effective for the treatment of adult and pediatric patients with Wolfram syndrome?FindingsThe results of this open-label clinical trial show that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in β-cell function, which might correlate with a positive trend in other outcome measures, including visual acuity and neurological functions.MeaningDantrolene sodium is well tolerated by patients with Wolfram syndrome. Some patients may experience an increase in β cell function when taking dantrolene.ImportanceWolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, is an emerging therapeutic strategy.ObjectiveThe primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric subjects with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β-cell functions, visual acuity, quality of life measures related to vision, and neurological functions.DesignOpen-label phase 1b/2a trial of dantrolene sodium over a 6-month treatment period.SettingSingle site, academic medical center.ParticipantsAdult and pediatric subjects with a genetically confirmed diagnosis of Wolfram syndrome.InterventionsAll subjects received increasing doses of dantrolene sodium.Main Outcomes and MeasuresThe safety and tolerability of dantrolene sodium administered orally at the upper end of therapeutic dose range for 6 months, and the efficacy of dantrolene sodium on residual pancreatic β-cell functions using a mixed-meal tolerance test, visual acuity using LogMar scores, quality of life measures related to vision using Visual Functioning Questionnaire – 25, and neurological functions using the Wolfram Unified Rating Scale (WURS) and standard neurological assessments.ResultsThe results indicate that dantrolene sodium is well tolerated by subjects with Wolfram syndrome. Although the study was small, a select few subjects seemed to have improvements in β-cell function, which might be correlated with a positive trend in visual acuity.Conclusions and RelevanceThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome.Trial RegistrationRegistered with clinicaltrials.gov, NCT02829268, (https://clinicaltrials.gov/ct2/show/NCT02829268?term=NCT02829268&draw=2&rank=1)

Background/AimsAge-related cognitive decline is a pervasive problem in our aging population. To date, no pharmacological treatments to halt or reverse cognitive decline are available. Behavioral interventions, such as physical exercise and Mindfulness-Based Stress Reduction, may reduce or reverse cognitive decline, but rigorously designed randomized controlled trials are needed to test the efficacy of such interventions.MethodsHere, we describe the design of the Mindfulness, Education, and Exercise study, an 18-month randomized controlled trial that will assess the effect of two interventions—mindfulness training plus moderate-to-vigorous intensity exercise or moderate-to-vigorous intensity exercise alone—compared with a health education control group on cognitive function in older adults. An extensive battery of biobehavioral assessments will be used to understand the mechanisms of cognitive remediation, by using structural and resting state functional magnetic resonance imaging, insulin sensitivity, inflammation, and metabolic and behavioral assessments.ResultsWe provide the results from a preliminary study (n = 29) of non-randomized pilot participants who received both the exercise and Mindfulness-Based Stress Reduction interventions. We also provide details on the recruitment and baseline characteristics of the randomized controlled trial sample (n = 585).ConclusionWhen complete, the Mindfulness, Education, and Exercise study will inform the research community on the efficacy of these widely available interventions improve cognitive functioning in older adults.

BACKGROUND: Remote limb ischemic conditioning (RLIC) is a technique in which tissues distant from the target organ are exposed to brief, sub-lethal bouts of ischemia. The effects of remotely applied ischemic conditioning are systemically transferred to the target organ, and typically manifested as protection from subsequent ischemic injury. Previous studies in our lab have found and confirmed that RLIC enhances learning and retention during motor training on a balance task. The current study tested the effect of RLIC dose (number of cycles) on learning enhancement in young, healthy adults. METHODS: Forty healthy participants age 18–40 years were randomized to receive 5 cycles of sham conditioning (n = 9), 3 cycles of RLIC (n = 11), 4 cycles of RLIC (n = 10), or 5 cycles of RLIC (n = 10) using a blood pressure cuff around the upper arm once a day for 7 consecutive weekdays (Days 1 – 7). Participants concurrently trained on a balance task, bi-manual cup stacking task, and a discrete sequence production task on Days 3 – 7. Change in performance on each of the three tasks was compared across groups. RESULTS: Participants in all four groups improved their performance on each of the three tasks over time. However, RLIC at any dose did not enhance learning on any of the three tasks. CONCLUSIONS: While RLIC is safe, inexpensive, and clinically-feasible, reproducibility may be challenged by unidentified factors, raising critical challenges to the straightforward translation of RLIC for improving rehabilitation outcomes in individuals recovering from neurological injury.

Endoplasmic reticulum (ER) stress in beta cells is an important pathogenic component of both type 1 and type 2 diabetes mellitus, as well as genetic forms of diabetes, especially Wolfram syndrome. However, there are currently no convenient ways to assess ER stress in beta cells, raising the need for circulating ER stress markers indicative of beta cell health. Here we show that pancreatic stone protein/regenerating protein (PSP/reg) is a potential biomarker for ER stressed beta cells. PSP/reg levels are elevated in cell culture and mouse models of Wolfram syndrome, a prototype of ER stress-induced diabetes. Moreover, PSP/reg expression is induced by the canonical chemical inducers of ER stress, tunicamycin and thapsigargin. Circulating PSP/reg levels are also increased in some patients with Wolfram syndrome. Our results therefore reveal PSP/reg as a potential biomarker for beta cells under chronic ER stress, as is the case in Wolfram syndrome.

Wolfram Syndrome (WFS) is a rare, genetic, neurodegenerative disorder with associated features of diabetes mellitus (DM), diabetes insipidus, deafness, and optic atrophy. In order to design intervention studies, concrete markers of disease progression are required. DM in WFS is believed to be due to endoplasmic reticulum stress-induced failure of insulin secretion. Therefore, progressive loss of insulin production may be a viable marker of disease progression. The purpose of this study was to examine progression of DM, measured by beta-cell function, in WFS patients over time. N=44 (25F/19M) participants with genetically confirmed WFS attended the Washington University Wolfram Research Clinic from 2010-2019. A mixed meal tolerance test was administered to assess beta cell function (i.e., C-peptide). A hierarchical random coefficients model was used to relate C-peptide as a function of DM duration. Most patients (91%) had DM at time of study enrollment (N=39) or developed DM during the study (N=1). There was a significant association between C-peptide and DM duration, such that C-peptide decreased over time (F= 39.44, p= Disclosure M. Ray: None. T. Hershey: None. L. Chen: None. N.H. White: None. B.A. Marshall: None. Funding Washington University (HD070855, U54HD087011); Clinical and Translational Science Award (UL1RR024992); National Institute on Drug Abuse (5T32DA007261-27); Diabetes Research Center (DK020579); Snow Foundation, George Decker and Julio V. Santiago Pediatric Diabetes Research Fund; Mallinckrodt Institute of Radiology; McDonnell Center for Systems Neuroscience

Background: Reward behaviors including those related to eating are influenced by output from the ventral striatum (VS), dorsal striatal [caudate(Cau) and putamen(Put)]and hypothalamus (HTH). We hypothesized that weight loss would induce modifications in activation in these regions of interest (ROI) during a consummatory reward task. Methods: We recruited metabolic abnormal obese (MAO) from the VA St.Louis Health Care System and Washington University in St.Louis (WUSTL). MAO was screened for by fasting insulin and plasma glucose, 2 hour 75 gram OGTT, and hemoglobin A1c. MAO was defined as prediabetes by ADA criteria and/ or elevated HOMA-IR. Functional magnetic resonance imaging (fMRI) scanning sessions were completed at the WUSTL Center for Clinical Imaging Research. A rapid event-related design was used to randomly deliver taste of chocolate milk (choc) or tasteless water (wat). Each taste receipt was proceeded by a cue of corresponding image of chocolate milk or a glass of water. A total of 5 runs, each with 24 trials were completed. Imaging analyses included preprocessing with fMRIprep including censoring excessive motion ≥ 0.5mm. Single subject GLM analyses were completed in AFNI. ROIs were designated bilaterally (lt and rt) except for HTH. A canonical HRF was applied to the food cue event and the AFNI tent function over 9 TRs was applied to the taste receipt event. To evaluate for an effect of weight loss (WL) on food cue and taste receipt-induced activation, repeated measures ANOVA for each region was completed with condition (choc or wat) as a covariate. Also in the model for taste receipt, repetition time (TR) was included as a covariate. Results reported as F(sign.). Results: Ten participants achieved at least 7% WL, (range 7-15%), 44±8 years, BMI 38±4kg/m2, f/m 4/6, fasting pg 105±11, 2 hour OGTT pg 132 ±49 mg/dL, HOMA-IR 3.9±1.8. One participant fulfilled criteria for T2D. For taste receipt several significant effects were found for WL: Cau_lt WL 5.9(0.02) and WL*TR 4.9(0.03), Cau_rt WL 8.6(0.004) and WL*TR 8(0.005), Put_lt WL 8.5(0.004), HTH WL*condition 5.4(0.02) and a trend for WL 3.3(0.07). All other comparisons were non-significant including all in the VS and all for food cue. Conclusions: Moderate weight loss in MAO modified taste receipt-induced activation in the Cau, Put, and HTH but not in the VS.

OBJECTIVE This study examined whether a history of diabetic ketoacidosis (DKA) is associated with changes in longitudinal cognitive and brain development in young children with type 1 diabetes. RESEARCH DESIGN AND METHODS Cognitive and brain imaging data were analyzed from 144 children with type 1 diabetes, ages 4 to RESULTS In 48 of 51 subjects, the DKA event occurred at the time of onset, at an average of 2.9 years before study entry. The moderate/severe DKA group gained more total and regional white and gray matter volume over the observed 18 months compared with the none/mild group. When matched by age at time of enrollment and average HbA1c during the 18-month interval, participants who had a history of moderate/severe DKA compared with none/mild DKA were observed to have significantly lower Full Scale Intelligence Quotient scores and cognitive performance on the Detectability and Commission subtests of the Conners’ Continuous Performance Test II and the Dot Locations subtest of the Children’s Memory Scale. CONCLUSIONS A single episode of moderate/severe DKA in young children at diagnosis is associated with lower cognitive scores and altered brain growth. Further studies are needed to assess whether earlier diagnosis of type 1 diabetes and prevention of DKA may reduce the long-term effect of ketoacidosis on the developing brain.

Purpose: Wolfram syndrome is a neurodegenerative disorder characterized by childhood onset diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing impairment, and commonly bladder and bowel dysfunction. We hypothesized that there is an association between a smaller pons, which contains the pontine micturition center, and abnormal lower urinary tract function.Materials and Methods: Patients with genetically confirmed Wolfram syndrome attended an annual multidisciplinary research clinic. Subjects underwent noninvasive urodynamic testing and brain magnetic resonance imaging, and completed validated patient reported outcome measures. Bowel and bladder diaries were completed before visits. Age and gender corrected linear and logistic mixed effects models were used to correlate pons volume, corrected for whole brain size, to urodynamic and patient reported outcomes.Results: A total of 36 patients attended 142 visits between 2010 and 2016. Mean age was 16.9 years (range 7 to 30) and 64% of patients w...

BackgroundWe sought to define the radiologic features that differentiate neoplastic from non-neoplastic T2 hyperintensities (T2Hs) in neurofibromatosis type 1 (NF1) and identify those lesions most likely to require oncologic surveillance.MethodsWe conducted a single-center retrospective review of all available brain MRIs from 68 children with NF1 (n = 190) and 46 healthy pediatric controls (n = 104). All T2Hs identified on MRI were characterized based on location, border, shape, degree of T1 hypointensity, and presence of mass effect or contrast enhancement, and subsequently classified using newly established radiologic criteria as either unidentified bright objects (UBOs) or probable tumors. Lesion classification was pathologically confirmed in 10 NF1 cases.ResultsT2Hs were a highly sensitive (94.4%; 95% confidence interval [CI] 86.4%–98.5%) and specific (100.0%; 95% CI 92.3%–100.0%) marker for the diagnosis of NF1. UBOs constituted the majority of T2Hs (82%) and were most frequently located in cerebellar white matter, medial temporal lobe, and thalamus, where they were more likely than probable tumors to be bilateral (p < 0.001) and have nondiscrete borders (p < 0.001). Surprisingly, 57% of children with T2Hs harbored lesions classified as probable tumors, and 28% of children with probable tumors received treatment. In contrast to UBOs, probable tumors were most frequently located within the globus pallidus and medulla, and rarely occurred prior to 3 years of age.ConclusionsWith the implementation of standardized radiologic criteria, a high prevalence of brain tumors was identified in this at-risk population of children, of which nearly one-third required treatment, emphasizing the need for appropriate oncologic surveillance for patients with NF1 harboring nonoptic pathway brain tumors.

The inclusion of milk in school feeding is accepted as good nutritional practice, but specific benefits remain uncertain.The objective was to determine whether consumption of 8.8 g milk protein/d given as milk powder with a multiple micronutrient-enriched porridge resulted in greater increases in linear growth and Cambridge Neuropsychological Test Automated Battery (CANTAB) scores in Ghanaian schoolchildren when compared with 1 of 3 control groups.A randomized, double-blind, placebo-controlled clinical trial in healthy children aged 6-9 y was conducted comparing 8.8 g milk protein/d with 4.4 g milk protein/d or 4.4 g milk protein + 4.4 g rice protein/d (isonitrogenous, half of the protein from milk and half from rice) or a non-nitrogenous placebo. Primary outcomes were changes in length after 9 mo and CANTAB scores after 4.5 mo; secondary outcomes were body-composition measures. Supplements were added to porridge each school day and consumed for 9 mo. Anthropometric and body-composition measures and CANTAB tests were completed upon enrollment and after 4.5 and 9 mo. Group results were compared by using ANCOVA for anthropometric measures and the Kruskal-Wallis test for CANTAB scores.Children receiving 8.8 g milk protein/d showed greater increases on percentage correct in Pattern Recognition Memory (mean ± SD: 5.5% ± 16.8%; P 0.05) and Intra/Extradimensional Set Shift completed stages compared with all other food groups (0.6 ± 2.3; P 0.05). No differences were seen in linear growth between the groups. The children receiving either 4.4 or 8.8 g milk protein/d had a higher fat-free body mass index than those who received no milk, with an effect size of 0.34 kg/m2.Among schoolchildren, the consumption of 8.8 g milk protein/d improved executive cognitive function compared with other supplements and led to the accretion of more lean body mass, but not more linear growth. This trial was registered at www.clinicaltrials.gov"www.clinicaltrials.gov as NCT02757508.