Evaluating De-Escalation Training for Direct and Indirect Employees Caring for Residents With Huntington's Disease.

INTRODUCTION: Little is known about reducing the challenges for caregivers and patients with Huntington's disease (HD). HD creates behavioral disturbances, cognitive decline, and motor disorder progression over the lifetime requiring some individuals to need long-term facility care. AIMS: There are concerns about safety and confidence of employees caring for residents with HD. METHODS: Nursing staff, administrators, and auxiliary employees were recruited from a long-term care (LTC) facility in rural Iowa, from July 2020 to August 2020. A de-escalation training intervention was delivered. The 1-day intervention included resident behaviors, planning and safety, teamwork, communication, and included role play and simulation. A pre- and post-survey measured confidence and competence in caring for people with HD before and after a training intervention. A resident medical record audit explored challenging behaviors before and after the training intervention. RESULTS: Of 25 participants, six were registered nurses/licensed practical nurses (RNs/LPNs; 24%), four administrators (16%), eight nursing assistants (32%), and seven auxiliary employees (28%). There was improvement in employees perceived safety (33.3%), co-workers enjoyment working with HD residents (54%), understanding symptoms of HD (44.4%), confidence in job abilities (21.0%), and confidence in ability to care for patients with HD (26.3%). A medical record audit showed decreased documentation of resident aggression and care refusal post-intervention. CONCLUSIONS: These findings suggest de-escalation training in LTC facilities increased perception of job safety, co-workers' enjoyment, understanding HD symptoms, confidence in ability to care for patients with HD, and decreased resident agitation and care refusal.

Sex Differences in the Association of Pretransfusion Hemoglobin Levels with Brain Structure and Function in the Preterm Infant.

OBJECTIVE: To assess sex-specific differences in early brain structure and function of preterm infants after red blood cell (RBC) transfusions. STUDY DESIGN: A single-center subset of infants with a birth weight <1000 g and gestational age 22-29 weeks were enrolled from the National Institute of Child Health and Human Development's Neonatal Research Network Transfusion of Prematures Trial. Hemoglobin (Hb) concentration obtained directly before each transfusion (pretransfusion Hb [ptHb]) was obtained longitudinally throughout each infant's neonatal intensive care unit stay and used as a marker of degree of anemia (n = 97). Measures of regional brain volumes using magnetic resonance imaging were obtained at ∼40 weeks postmenstrual age or at hospital discharge, if earlier (n = 29). Measures of brain function were obtained at 12 months corrected age using the Bayley Scales of Infant & Toddler Development, 3rd Edition (n = 34). RESULTS: PtHb was positively correlated with neonatal cerebral white matter volume in males (B = +0.283; P = .006), but not females (B = -0.099; P = .713), resulting in a significant sex interaction (P = .010). Bayley-III gross motor scores and a pooled mean score were significantly lower in association with higher ptHb in females (gross motor score: B = -3.758; P = .013; pooled mean score: B = -1.225; P = .030), but not males (gross motor score: B = +1.758; P = .167; pooled mean score: B = +0.621; P = .359). Higher ptHb was associated with descriptively lower performance on multiple Bayley-III subscales in females, but not in males. CONCLUSIONS: This study demonstrates sex-specific associations between an early marker of anemia and RBC transfusion status (ie, ptHb) with both neonatal white matter volume and early cognitive function at age 12 months in preterm infants.

Age-Related Cognitive Changes as a Function of CAG Repeat in Child and Adolescent Carriers of Mutant Huntingtin.

Limited data exists regarding the disease course of Huntington's Disease (HD) in children and young adults. Here, we evaluate the trajectory of various cognitive skill development as a function of cytosine-adenine-guanine (CAG) repeat length in children and adolescents that carry the mutation that causes HD. We discovered that the development of verbal skills seems to plateau earlier as CAG repeat length increases. These findings increase our understanding of the relationship between neurodegeneration and neurodevelopment and may have far-reaching implications for future gene-therapy treatment strategies. ANN NEUROL 2021;89:1036-1040.

The Cerebellum and Implicit Sequencing: Evidence from Cerebellar Ataxia.

The cerebellum recognizes sequences from prior experiences and uses this information to generate internal models that predict future outcomes in a feedforward manner [Front Hum Neurosci 8: 475, 2014; Cortex 47: 137-44, 2011; Cerebellum 7: 611-5, 2008; J Neurosci 26: 9107-16, 2006]. This process has been well documented in the motor domain, but the cerebellum's role in cognitive sequencing, within the context of implicit versus explicit processes, is not well characterized. In this study, we tested individuals with cerebellar ataxia and healthy controls to clarify the role of the cerebellum sequencing using variations on implicit versus explicit and motor versus cognitive demands across five experiments. Converging results across these studies suggest that cerebellar feedforward mechanisms may be necessary for sequencing in the implicit domain only. In the ataxia group, rhythmic tapping, rate of motor learning, and implicit sequence learning were impaired. However, for cognitive sequencing that could be accomplished using explicit strategies, the cerebellar group performed normally, as though they shifted to extra-cerebellar mechanisms to compensate. For example, when cognitive and motor functions relied on cerebellar function simultaneously, the ataxia group's motor function was unaffected, in contrast to that of controls whose motor performance declined as a function of cognitive load. These findings indicated that the cerebellum is not critical for all forms of sequencing per se. Instead, it plays a fundamental role for sequencing within the implicit domain, whether functions are motor or cognitive. Moreover, individuals with cerebellar ataxia are generally able to compensate for cognitive sequencing when explicit strategies are available in order to preserve resources for motor function.

Hypertension Is Associated With an Earlier Age of Onset of Huntington's Disease.

BACKGROUND AND OBJECTIVE: Hypertension (HTN) is associated with worsening clinical outcomes in neurodegenerative diseases. The relationship between HTN and the age of diagnosis (ADx) of Huntington's disease (HD) is not clear, however. This study sought to determine if the presence of HTN in adult patients with premanifest HD was associated with an earlier ADx compared with normotensive patients with HD. METHODS: Premanifest participants from Enroll-HD were included if they had a cytosine-adenine-guanine greater than or equal to 36, baseline diagnostic confidence level less than 4, baseline total functional capacity score greater than 11, and baseline motor score less than 21. There were 3020 premanifest participants with HD, and 293 reported a diagnosis of HTN. HTN was transformed into a time-dependent variable, and a Cox proportional hazard survival model determine if the presence of HTN affected the time to motor conversion. Baseline cytosine-adenine-guanine-age product score, cytosine-adenine-guanine repeat length, baseline age, sex, baseline body mass index, smoking history, and region were included as covariates. RESULTS: Participants with HTN had an increased annualized hazard of motor conversion compared to normotensive participants with HD (hazard ratio, 1.29; 95% confidence interval, 1.02-1.64; P = 0.034). CONCLUSIONS: A previous study reported a protective effect of HTN in HD, but did not account for the fact that the prevalence of HTN increases with age. By controlling for this confounder, we more accurately outline the association between the ADx of HD to demonstrate that a diagnosis of HTN may be associated with an earlier ADx of HD. These results represent an association, however, and further investigation is warranted. © 2020 International Parkinson and Movement Disorder Society.

Statin use and delayed onset of Huntington's disease.

BACKGROUND: There is evidence to suggest that 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) may be beneficial in Huntington's disease (HD). OBJECTIVE: This study aimed to determine if statin use was associated with delayed motor diagnosis in participants with premotor HD. METHODS: Among premotor HD participants from the Enroll-HD database, statin users were propensity score matched with statin nonusers based on cytosine-adenine-guanine-age product score, cytosine-adenine-guanine repeat length, baseline age, sex, and region. A Cox regression survival analysis compared the annualized hazard ratio (HR) of receiving a motor diagnosis between the 2 groups. RESULTS: The annualized HR of progressing to an HD motor diagnosis was lower in the statin users (n = 89) when compared with the statin nonusers (n = 89; HR = 0.27 [95% CI 0.18-0.50], P < .0001). CONCLUSIONS: In patients with premotor HD, statin use was associated with a delayed motor diagnosis of HD. Further studies are warranted to investigate if statins would be an effective disease-modifying therapy for HD. © 2018 International Parkinson and Movement Disorder Society.

Sex-specific alterations in preterm brain.

BACKGROUND: The literature on brain imaging in premature infants is mostly made up of studies that evaluate neonates, yet the most dynamic time of brain development happens from birth to 1 year of age. This study was designed to obtain quantitative brain measures from magnetic resonance imaging scans of infants born prematurely at 12 months of age. METHODS: The subject group was designed to capture a wide range of gestational age (GA) from premature to full-term infants. An age-specific atlas generated quantitative brain measures. A regression model was used to predict effects of GA and sex on brain measures. RESULTS: There was a primary effect of sex on: (1) intracranial volume, males > females; (2) proportional cerebral cortical gray matter (females > males), and (3) cerebral white matter (males > females). GA predicted cerebral volume and cerebral spinal fluid. GA also predicted cortical gray matter in a sex-specific manner with GA having a significant effect on cortical volume in the males, but not in females. CONCLUSIONS AND RELEVANCE: Sex differences in brain structure are large early in life. GA had sex-specific effects highlighting the importance evaluating sex effects in neurodevelopmental outcomes of premature infants.

Correction: Sex-specific alterations in preterm brain.

In the original article, the legend within Fig. 3 incorrectly read as '*p < 0.10, **p < 0.05, ***p > 0.01'. This has now been changed to '*p < 0.10, **p < 0.05, ***p < 0.01'. This has been corrected in both the PDF and HTML versions of the Article. The authors would like to apologise for this error.

Sex-specific effects of the Huntington gene on normal neurodevelopment.

Huntington disease is a neurodegenerative disorder caused by a gene (HTT) with a unique feature of trinucleotide repeats ranging from 10 to 35 in healthy people; when expanded beyond 39 repeats, Huntington disease develops. Animal models demonstrate that HTT is vital to brain development; however, this has not been studied in humans. Moreover, evidence suggests that triplet repeat genes may have been vital in evolution of the human brain. Here we evaluate brain structure using magnetic resonance imaging and brain function using cognitive tests in a sample of school-aged children ages 6 to 18 years old. DNA samples were processed to quantify the number of CAG repeats within HTT. We find that the number of repeats in HTT, below disease threshold, confers advantageous changes in brain structure and general intelligence (IQ): the higher the number of repeats, the greater the change in brain structure, and the higher the IQ. The pattern of structural brain changes associated with HTT is strikingly different between males and females. HTT may confer an advantage or a disadvantage depending on the repeat length, playing a key role in either the evolution of a superior human brain or development of a uniquely human brain disease. © 2016 Wiley Periodicals, Inc.

Regionally selective atrophy of subcortical structures in prodromal HD as revealed by statistical shape analysis.

Huntington disease (HD) is a neurodegenerative disorder that involves preferential atrophy in the striatal complex and related subcortical nuclei. In this article, which is based on a dataset extracted from the PREDICT-HD study, we use statistical shape analysis with deformation markers obtained through "Large Deformation Diffeomorphic Metric Mapping" of cortical surfaces to highlight specific atrophy patterns in the caudate, putamen, and globus pallidus, at different prodromal stages of the disease. On the basis of the relation to cortico-basal ganglia circuitry, we propose that statistical shape analysis, along with other structural and functional imaging studies, may help expand our understanding of the brain circuitry affected and other aspects of the neurobiology of HD, and also guide the most effective strategies for intervention.

Regional brain morphometric characteristics of nonsyndromic cleft lip and palate.

Nonsyndromic cleft lip and palate (NSCLP) encompasses a group of orofacial abnormalities. Emerging evidence has revealed the presence of structural brain abnormalities in affected individuals. Previous studies have performed structure-based volumetric analysis of the brain assessing gross lobular subdivisions of the cerebral cortex and white matter which may have only vague relationships to the functional subregions implicated in behavioral and cognitive deficits observed in NSCLP patients. High-resolution magnetic resonance imaging structural data were acquired to provide a detailed characterization of the brain with respect to both regional cortical volume and thickness in 26 children with NSCLP and 26 age- and demographically matched typically developing children. Children with NSCLP exhibited abnormally large cerebral cortex grey matter volumes with decreased volumes of subcortical grey matter and cerebral white matter structures. Hemisphere-specific patterns of cortical volume and thickness abnormalities were identified. This study is the first to examine cortical thickness abnormalities in NSCLP. Overall, these findings suggest that the brains of children with NSCLP are less mature than those of their age-matched peers. Gender-specific comparisons reveal that NSCLP females were more immature compared to their typically developing peers compared to NSCLP males.

Haploinsufficiency of interferon regulatory factor 6 alters brain morphology in the mouse.

Orofacial clefts are among the commonest birth defects. Among many genetic contributors to orofacial clefting, Interferon Regulatory Factor 6 (IRF6) is unique since mutations in this gene cause Van der Woude (VWS), the most common clefting syndrome. Furthermore, variants in IRF6 contribute to increased risk for non-syndromic cleft lip and/or palate (NSCL/P). Our previous work shows that individuals with either VWS or NSCL/P may have cerebral anomalies (larger anterior, smaller posterior regions), and a smaller cerebellum. The objective of this study was to test the hypothesis that disrupting Irf6 in the mouse will result in quantitative brain changes similar to those reported for humans with VWS and NSCL/P. Male mice heterozygous for Irf6 (Irf6(gt1/+); n = 9) and wild-type (Irf6(+/+) ; n = 6) mice at comparable age underwent a 4.7-T MRI scan to obtain quantitative measures of cortical and subcortical brain structures. There was no difference in total brain volume between groups. However, the frontal cortex was enlarged in the Irf6(gt1/+) mice compared to that of wild types (P = 0.028) while the posterior cortex did not differ. In addition, the volume of the cerebellum of Irf6(gt1/+) mice was decreased (P = 0.004). Mice that were heterozygous for Irf6 showed a similar pattern of brain anomalies previously reported in humans with VWS and NSCL/P. These structural differences were present in the absence of overt oral clefts. These results support a role for IRF6 in brain morphometry and provide evidence for a potential genetic link to abnormal brain development in orofacial clefting.

Sex differences in the association of pretransfusion haemoglobin and cognition in preterm infants.

OBJECTIVES: To assess sex-specific differences in the association between pre-transfusion haemoglobin values and early neurodevelopmental function. DESIGN: Observational follow-up of infants with birth weights <1000 g and gestational ages 22-28 weeks who were enrolled in the NICHD Neonatal Research Network Transfusion of Prematures (TOP) Trial at 19 U.S. sites, 2012-2017. MAIN OUTCOME MEASURES: Pretransfusion haemoglobin values were obtained longitudinally through 36 weeks' postmenstrual age. The infant's mean pretransfusion haemoglobin was used as a marker of degree of anaemia (n=1655 measures). Measures of brain function were obtained at 22-26 months' corrected age using the Bayley Scales of Infant & Toddler Development, third edition (BSID-III) (n=1290 BSID-III scores). Sex-specific estimates for the linear relation between pretransfusion haemoglobin and BSID-III scores were obtained from repeated-measures regression analysis, adjusted for gestational age, birth weight, study site, clinical characteristics, and demographic covariates. RESULTS: The relation of pretransfusion haemoglobin with 24-month BSID-III scores showed significant, independent interactions with both (1) sex (p=0.046) and (2) retinopathy of prematurity (ROP; p=0.004). In 614 males, BSID-III scores were higher by 1.07 points per g/dL (95% CI 1.58 to 4.33; p=0.008), not differing significantly among the three subscales (cognitive, language and motor; p=0.94). In 247 infants with ROP, BSID-III scores were higher by 2.95 points per g/dL (95% CI 0.28 to 1.87; p<0.0001), uniformly across subscales (p=0.73). These associations were non-significant in 676 females (p=0.96) and 1043 infants without ROP (p=0.81). CONCLUSIONS: This study demonstrates sex-specific associations between mean pretransfusion haemoglobin (a marker of the severity of anaemia throughout the neonatal intensive care unit [NICU] hospitalisation) and early neurodevelopmental function at 22-26 months' corrected age.

Abnormal cerebellar structure is dependent on phenotype of isolated cleft of the lip and/or palate.

Isolated cleft lip and/or palate (ICLP) is one of the most common congenital birth defects in the USA, affecting roughly 1 in 600 births annually. Along with the facial deformity, this population has been found to have abnormal neurodevelopment and gross structural abnormalities in the brain, particularly within the cerebellum. The current study examined cerebellar structure within the two primary subtypes of ICLP: cleft lip with/without cleft palate (CL/P) and cleft palate alone (CPO). A large sample of 107 subjects aged 7 to 27 years with ICLP was compared to 127 healthy controls. Samples were separated by sex. Brain structure was obtained via magnetic resonance imaging. For males, after controlling for intracranial volume, cerebellum volume was significantly lower in the ICLP group (F = 12.351, p = 0.001). Regionally in the cerebellum, males with ICLP had proportionally larger anterior lobes (F = 4.022, p = 0.047) and smaller superior posterior lobes (F = 5.686, p = 0.019). CL/P males showed only a reduction in overall cerebellum volume, with no regional changes. CPO males showed only regional changes, with no reduction in overall volume. Females with ICLP showed no overall or regional cerebellar abnormalities. However, females with CPO did have significantly lower cerebellum volumes than controls. The results reveal both global and regional cerebellar abnormalities within subjects with ICLP. They also establish the existence of abnormal cerebellar morphologies that are dependent on cleft subtype as well as sex. This lends further support to the claim that CL/P and CPO are distinct conditions.

Corpus callosum shape is altered in individuals with nonsyndromic cleft lip and palate.

Individuals with nonsyndromic cleft lip with or without cleft palate (CL/P) have altered brain structure compared with healthy controls. Preliminary evidence suggests that the corpus callosum may be dysmorphic in orofacial clefting; however, this midline brain structure has not been systematically assessed in this population. The goal of the present study was to carry out a morphometric assessment of the corpus callosum and its relationship to cognitive performance in a well-characterized patient cohort with orofacial cleft. Midline brain images were obtained from previously collected MRI scans of 24 CL/P subjects and 40-adult-male controls. Eight landmarks on the corpus callosum were digitized on each image and their x,y coordinate locations saved. A geometric morphometrics analysis was applied to the landmark coordinate data to test for shape differences across groups. The relationship between corpus callosum shape and IQ was explored with nonparametric correlation coefficients. Results revealed significant differences in mean corpus callosum shape between CL/P cases and controls (P = 0.029). The CL/P corpus callosum was characterized by increased overall convexity resulting from a superior and posterior displacement. Within CL/P cases, increased corpus callosum shape dysmorphology was moderately correlated with reduced performance IQ (r = 0.546). These results provide additional evidence that midline brain changes may be an important part of the orofacial cleft phenotype.

Height, BMI, and pituitary volume in individuals with and without isolated cleft lip and/or palate.

INTRODUCTION: Individuals with isolated cleft lip and/or palate (ICLP) are often reported to be of shorter stature relative to peers, and the objective of this study was to explore the role of the pituitary in relationship to growth. METHODS: Fifty-five males and 32 females with ICLP were compared to 121 healthy males and 158 healthy females with respect to height and BMI. Magnetic resonance imaging (MRI) scans were obtained from all ICLP participants and 47% of healthy group participants. RESULTS: Males with ICLP were shorter than healthy males and had lower BMI. However, the trajectories for height and BMI did not differ between groups. Analyses in a separate sample of adult males suggested that height normalizes in males with ICLP in their early 30s. There were no differences in mean pituitary volume and pituitary trajectories between male groups. Females with ICLP were shorter than healthy females and also had slower growth rates. They did not differ in mean BMI or BMI trajectories. Furthermore, there were no differences in mean pituitary volume, or in pituitary trajectories. DISCUSSION: Our findings suggest that there are no gross morphological differences in pituitary volume in individuals with ICLP, although more subtle differences may exist.

Neuropsychological, behavioral, and academic sequelae of cleft: early developmental, school age, and adolescent/young adult outcomes.

This article reviews behavioral, neuropsychological, and academic outcomes of individuals with cleft across three age levels: (1) infancy/early development, (2) school age, and (3) adolescence/young adulthood. The review points out that attachment, neurocognitive functioning, academic performance/learning, and adjustment outcomes are the result of a complex interaction between biological and environmental factors and vary with developmental level, sex, and craniofacial anomaly diagnosis. The degree to which associated genetic or neurodevelopmental conditions may explain inconsistent findings is unknown and suggests the need for caution in generalizing from group data on cleft.