Julie Eisengart

Learning words and rules: Abstract knowledge of word order in early sentence comprehension

Children quickly acquire basic grammatical facts about their native language. Does this early syntactic knowledge involve knowledge of words or rules? According to lexical accounts of acquisition, abstract syntactic and semantic categories are not primitive to the language-acquisition system; thus, early language comprehension and production are based on verb-specific knowledge. The present experiments challenge this account: We probed the abstractness of young childrens knowledge of syntax by testing whether 25- and 21-month-olds extend their knowledge of English word order to new verbs. In four experiments, children used word order appropriately to interpret transitive sentences containing novel verbs. These findings demonstrate that although toddlers have much to learn about their native languages, they represent language experience in terms of an abstract mental vocabulary. These abstract representations allow children to rapidly detect general patterns in their native language, and thus to learn rules as well as words from the start.

Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report

Cerebral adrenoleukodystrophy (cALD) remains a devastating neurodegenerative disease; only allogeneic hematopoietic cell transplantation (HCT) has been shown to provide long-term disease stabilization and survival. Sixty boys undergoing HCT for cALD from 2000 to 2009 were analyzed. The median age at HCT was 8.7 years; conditioning regimens and allograft sources varied. At HCT, 50% demonstrated a Loes radiographic severity score ≥ 10, and 62% showed clinical evidence of neurologic dysfunction. A total of 78% (n = 47) are alive at a median 3.7 years after HCT. The estimate of 5-year survival for boys with Loes score < 10 at HCT was 89%, whereas that for boys with Loes score ≥ 10 was 60% (P = .03). The 5-year survival estimate for boys absent of clinical cerebral disease at HCT was 91%, whereas that for boys with neurologic dysfunction was 66% (P = .08). The cumulative incidence of transplantation-related mortality at day 100 was 8%. Post-transplantation progression of neurologic dysfunction depended significantly on the pre-HCT Loes score and clinical neurologic status. We describe the largest single-institution analysis of survival and neurologic function outcomes after HCT in cALD. These trials were registered at www.clinicaltrials.gov as #NCT00176904, #NCT00668564, and #NCT00383448.

Systematic evaluation of Axis-I DSM diagnoses in delayed sleep phase disorder and evening-type circadian preference.

BACKGROUND Alterations in circadian rhythms can have profound effects on mental health. High co-morbidity for psychiatric disorders has been observed in patients with circadian rhythm disorders, such as delayed sleep phase disorder (DSPD), and in those with an evening-type circadian preference. The aim of this study was to systematically determine the prevalence and type of Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM IV) Axis-I disorders in those with DSPD compared to evening-type controls. METHODS Forty-eight DSPD and 25 evening-type participants took part in this study. Sleep and wake parameters were assessed with actigraphy, diary and questionnaires (Pittsburgh Sleep Quality Index (PSQI) and Functional Outcomes of Sleep Questionnaire (FOSQ). Evening-type preference was defined by the Horne-Ostberg questionnaire. DSPD was determined by an interview according to International Classification of Sleep Disorders criteria. Current and past diagnoses of psychiatric disorders were assessed with a Structured Clinical Interview for DSM-IV disorders. RESULTS DSPD was associated with a later wake time, longer sleep time, higher PSQI score and lower Horne-Ostberg and FOSQ scores compared to evening-types. There were no significant differences in the prevalence or type of Axis-I disorders between those with DSPD or evening-type preference. Over 70% of participants met criteria for at least one past Axis-I disorder. Approximately 40% of both the DSPD and evening-types met criteria for a past diagnosis of mood, anxiety (most frequently phobia) or substance-use disorders. Evening types were more likely to have a past diagnosis of more than one Axis-I disorder. CONCLUSIONS These results highlight the important link between circadian rhythms and mental disorders. Specifically, an evening circadian chronotype regardless of DSPD status is associated with a risk for anxiety, depressive or substance-use disorders.

Enzyme replacement is associated with better cognitive outcomes after transplant in Hurler syndrome

OBJECTIVE To investigate whether intravenous enzyme replacement therapy (ERT) benefits cognitive function in patients with mucopolysaccharidosis type IH (Hurler syndrome) undergoing hematopoietic cell transplantation (HCT). STUDY DESIGN Data were obtained for 9 children treated with HCT + ERT (ERT group) and 10 children treated with HCT only (no-ERT group) from neuropsychologic evaluations before HCT and at 1-year and 2-year post-HCT follow-up. RESULTS At 2 years after HCT, children in the ERT group lost 9.19 fewer IQ points per year compared with children in the no-ERT group (P = .031). Furthermore, the ERT group improved in nonverbal problem solving and processing, whereas the no-ERT group declined, resulting in a difference of 9.44 points per year between the 2 groups (P < .001). CONCLUSION ERT in association with HCT enhances cognitive outcomes, providing new evidence that ERT is a valuable addition to the standard transplantation protocol. Although the mechanism responsible for this improved outcome is unknown, both direct benefits and indirect effects must be considered.

Neurocognition across the spectrum of mucopolysaccharidosis type I: Age, severity, and treatment.

OBJECTIVES Precise characterization of cognitive outcomes and factors that contribute to cognitive variability will enable better understanding of disease progression and treatment effects in mucopolysaccharidosis type I (MPS I). We examined the effects on cognition of phenotype, genotype, age at evaluation and first treatment, and somatic disease burden. METHODS Sixty patients with severe MPS IH (Hurler syndrome treated with hematopoietic cell transplant and 29 with attenuated MPS I treated with enzyme replacement therapy), were studied with IQ measures, medical history, genotypes. Sixty-seven patients had volumetric MRI. Subjects were grouped by age and phenotype and MRI and compared to 96 normal controls. RESULTS Prior to hematopoietic cell transplant, MPS IH patients were all cognitively average, but post-transplant, 59% were below average, but stable. Genotype and age at HCT were associated with cognitive ability. In attenuated MPS I, 40% were below average with genotype and somatic disease burden predicting their cognitive ability. White matter volumes were associated with IQ for controls, but not for MPS I. Gray matter volumes were positively associated with IQ in controls and attenuated MPS I patients, but negatively associated in MPS IH. CONCLUSIONS Cognitive impairment, a major difficulty for many MPS I patients, is associated with genotype, age at treatment and somatic disease burden. IQ association with white matter differed from controls. Many attenuated MPS patients have significant physical and/or cognitive problems and receive insufficient support services. Results provide direction for future clinical trials and better disease management.

Neurocognitive trajectory of boys who received a hematopoietic stem cell transplant at an early stage of childhood cerebral adrenoleukodystrophy

Importance Untreated childhood cerebral adrenoleukodystrophy (cALD) is a fatal disease associated with progressive cerebral demyelination and rapid, devastating neurologic decline. The standard of care to enhance long-term survival and stabilize cerebral disease is a hematopoietic stem cell transplant (HSCT). Neurologic outcomes are better when HSCT occurs at an earlier stage of cALD, yet there is limited understanding of the neurocognitive trajectory of patients who undergo HSCT. Objectives To characterize neurocognitive outcomes of boys with cALD and early-stage cerebral disease who were treated with an allogeneic HSCT and to identify disease- and treatment-related factors associated with long-term functioning. Design, Setting, and Participants Baseline and follow-up neurocognitive test performance was analyzed for all boys with cALD who received an HSCT at the University of Minnesota between January 1, 1991, and October 20, 2014, and who had a pretransplant magnetic resonance imaging (MRI) severity score of less than 10 (scale range, 0-34; higher scores indicate greater severity). Main Outcomes and Measures Longitudinal neurocognitive test performance in 4 domains (verbal comprehension, perceptual [visual] reasoning, working memory, and processing speed) were the primary outcome measures. Secondary analysis at the most recent evaluation also included measures of sustained attention, verbal memory, visual-motor integration, and fine motor function. Results Among the 62 boys in this study (mean [SD] age at transplant, 8.37 [2.80] years; range, 4-16 years), there was a significant association of pretransplant MRI severity and baseline verbal comprehension (r = –0.340; P = .008), perceptual reasoning (r = –0.419; P = .001), and processing speed (r = –0.285; P = .03) scores. Higher pretransplant MRI severity scores were also associated with a steeper decline in neurocognitive functioning during the 5-year follow-up period. Twenty-two of 33 patients (67%) with available long-term follow-up neurocognitive testing had severe impairment in at least 1 neurocognitive domain at the most recent evaluation. Conclusions and Relevance Boys with cALD who have greater than minimal cerebral disease detected on MRI scans at the time of an HSCT are at risk for severe, persistent neurocognitive deficits. These findings motivate further exploration of methods of detecting cerebral disease prior to development of lesions observable on MRI scans, an endeavor that may be facilitated by newborn screening for adrenoleukodystrophy. These findings may serve a benchmark role in evaluating the efficacy of novel interventions for cALD.

Childhood Cerebral X-Linked Adrenoleukodystrophy: Diffusion Tensor Imaging Measurements for Prediction of Clinical Outcome after Hematopoietic Stem Cell Transplantation

BACKGROUND AND PURPOSE: DTI in cerebral X-linked adrenoleukodystrophy may demonstrate abnormalities in both affected and nonaffected WM; these values have not been studied serially after hematopoietic stem cell transplantation. The purpose of this study was to study pretransplant and posttransplant DTI parameters serially and ultimately to determine the ability of pretransplant DTI parameters to predict clinical outcome after HSCT in children with ALD. MATERIALS AND METHODS: Eight patients with posterior-pattern cerebral ALD underwent DTI at 3T before HSCT (T0), at 30–60 days (T1), 90–120 days (T2), 180 days (T3), and 1 year (T4) after HSCT. FA and MD were serially measured in 19 regions, and these measurements were compared with those in control patients. MR imaging severity (Loes) scores were recorded. Correlations were performed between DTI parameters and Loes scores, neurologic function scores, and several neuropsychologic scores. RESULTS: Both FA and MD in subjects differed significantly from that in controls at nearly every time point within cerebellar WM, callosal splenium, and parieto-occipital WM; FA alone was significantly different at each time point within the optic radiations, lateral geniculate, and the Meyer loop (P < .05). Loes scores at T0 correlated strongly with each clinical score at T4 (r = 0.771–0.986, P < .05). The only significant DTI correlation at T0 with a clinical score at T4 was callosal body FA with adaptive function (r = 0.976, P < .001). Correlating the change in DTI values with change in NFS (change between T0 and T4) showed that only ΔMD within the optic radiations correlated strongly with ΔNFS (r = 0.903, P < .05). CONCLUSIONS: DTI values at T0 were generally poor predictors of outcome at 1 year, whereas Loes scores were generally good predictors. ΔMD within the optic radiations strongly correlates with ΔNFS over that year. In addition, certain normal-appearing regions, such as cerebellar WM, may have DTI abnormalities before HSCT that persist after HSCT.

A longitudinal study of emotional adjustment, quality of life and adaptive function in attenuated MPS II

Objectives The behavioral, adaptive and quality of life characteristics of attenuated mucopolysaccharidosis type II (MPS II) have not been well studied. Understanding changes over time in the attenuated phenotype may assist in helping achieve better outcomes in long-term function. This longitudinal study investigates these outcomes in relation to age, somatic disease burden, and IQ. Specifically, somatic disease burden is a major challenge for these patients, even with treatment with enzyme replacement therapy. Methods 15 patients, 10 between ages 6 and < 12 and 5 between ages ≥ 12 and 18, were selected who had at least 2 yearly visits. The occurrence of physical signs, the Physical Symptom Score, and IQ in these two groups was studied as well as the longitudinal association of age with standardized measures of quality of life, adaptive function, and behavioral symptoms as rated by parents and the childs self-report. Slopes by age across and within patients were calculated for these measures. Results All but one child had hearing loss, most had joint contractures and short stature. Somatic disease burden increased with age. IQ, although normal for most, also improved with age in those under 12 years of age. Physical quality of life decreased while psychosocial quality of life increased with age. Although other adaptive skills were in the broad average range, daily living skills were low at baseline relative to normative data and decreased over time. Behavior ratings indicated improvement in attention and hyperactivity over time. No patient had severe psychopathology, but older children reported an increasing sense of inadequacy and low self-esteem on self-report, presumably due to increasing awareness of differences from peers over time. Conclusions Attenuated MPS II patients have increasing somatic disease burden and poor physical quality of life as they develop as well as decreasing self-esteem and sense of adequacy. Psychosocial quality of life, adaptive skills, and attention improve. Recognition of and intervention around these issues will be beneficial to MPS II attenuated patients who have the resources to use such assistance to improve their long-term outcomes.

Discharge due to running away from residential treatment: Youth and setting effects

ABSTRACT Running away from residential treatment is a relatively common and dangerous outcome for youth. Both clinical and program factors have been associated with the risk of running away. The present study directly compared the relative importance of youth-specific and program-specific predictors in a large sample across 52 treatment sites. Data from a state-wide outcomes management system for residential treatment were used to study youth who were discharged because of running away. A sample of 2,114 treatment episodes was analyzed. Consistent with prior research, youth-specific variables such as gender and substance use were associated with risk of discharge due to running away. However, program was an equally powerful predictor of who runs from treatment. While some youth are at greater risk of running from treatment than others, it also appears to be the case that some programs are better at preventing running, even among high risk youth.

Childhood Cerebral Adrenoleukodystrophy: MR Perfusion Measurements and Their Use in Predicting Clinical Outcome after Hematopoietic Stem Cell Transplantation.

BACKGROUND AND PURPOSE: MR perfusion has shown abnormalities of affected WM in cerebral X-linked adrenoleukodystrophy, but serial data is needed to explore the import of such findings after hematopoietic stem cell transplantation. Our aim was to prospectively measure MR perfusion parameters in patients with cerebral adrenoleukodystrophy pre- and post-hematopoietic stem cell transplantation, and to correlate those measurements with clinical outcome. MATERIALS AND METHODS: Ten patients with cerebral adrenoleukodystrophy prospectively underwent DSC–MR perfusion imaging at <45 days pre- (baseline), 30–60 days post-, and 1 year post-hematopoietic stem cell transplantation. MR perfusion measurements in the 10 patients and 8 controls were obtained from the parieto-occipital WM, splenium of the corpus callosum, leading enhancing edge, and normal-appearing frontal white matter. MR imaging severity scores and clinical neurologic function and neurocognitive scores were also obtained. MR perfusion values were analyzed in the patients with cerebral adrenoleukodystrophy at each time point and compared with those in controls. Correlations were calculated between the pre-hematopoietic stem cell transplantation MR perfusion values and 1-year clinical scores, with P value adjustment for multiple comparisons. RESULTS: At baseline in patients with cerebral adrenoleukodystrophy, both relative CBV and relative CBF within the splenium of the corpus callosum and parieto-occipital WM significantly differed from those in controls (P = .005–.031) and remained so 1 year post-hematopoietic stem cell transplantation (P = .003–.005). Meanwhile, no MR perfusion parameter within the leading enhancing edge differed significantly from that in controls at baseline or at 1 year (P = .074–.999) or significantly changed by 1 year post-hematopoietic stem cell transplantation (P = .142–.887). Baseline Loes scores correlated with 1-year clinical neurologic function (r = 0.813, P < .0001), while splenium of the corpus callosum relative CBV also significantly correlated with 1-year neurologic function scale and the neurocognitive full-scale intelligence quotient and performance intelligence quotient scores (r = −0.730–0.815, P = .007–.038). CONCLUSIONS: Leading enhancing edge measurements likely remain normal post-hematopoietic stem cell transplantation in cerebral adrenoleukodystrophy, suggesting local disease stabilization. Meanwhile, parieto-occipital WM and splenium of the corpus callosum relative CBV and relative CBF values worsened; this change signified irreversible injury. Baseline splenium of the corpus callosum relative CBV may predict clinical outcomes following hematopoietic stem cell transplantation.