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Background: Unintended weight loss and decreased body mass indexes (BMIs) are common symptoms of individuals with manifest HD. It is unknown at what point during disease progression weight loss starts to accelerate relative to a healthy individual’s weight and when recommended interventions should be initiated to have the strongest impact on patient care. Objective: The objective of this study was to identify a point in time relative to age at motor onset when the decline in weight in HD starts to accelerate relative to a non-HD population. The relationship between initiation of weight loss interventions and changes in weight loss was also explored. Methods: Participants from the fifth version of the Enroll-HD study were identified for this research. Linear mixed-effects piecewise regression models were used to estimate the point in time relative to the reported age of motor onset in which BMI started to decline in participants with HD compared to healthy non-HD controls. A post-hoc descriptive analysis was performed to look at when nutritional supplements and swallow therapy were initiated in participants with HD relative to motor onset. Results: BMI decline in the HD group began to accelerate compared to controls approximately 5.7 years after the reported age of motor onset (95% CI: 4.7–6.9). The average initiation times of swallow therapy and nutritional supplements were 7.7 years (SD = 5.5 years) and 6.7 years (SD = 6.5 years) after motor onset, respectively. Conclusion: Our findings suggest a potential point for intervention of nutrition programs or therapies used to prevent future weight loss.

INTRODUCTION: Sleep disturbances are a common symptom in patients with Huntington’s disease (HD). However, it is unclear when in the disease course of HD sleep disturbances become more frequent compared to the general population. This study investigated the frequency and odds of developing sleep disturbances between adults with HD or at-risk for HD and non-HD controls. METHODS: Participants from the Enroll-HD study were split by both disease type and disease severity using CAG length, diagnostic confidence level, and total functional capacity score. Multivariate logistic regression was used to calculate odds ratios adjusted for age, sex, tobacco and alcohol use, depression and psychosis scores, and cognition to compare HD groups to non-HD controls. Cox proportional hazards models and Kaplan Meier curves were used to determine differences in probabilities of developing sleep disturbances and how sleep disturbances are related to age at motor onset. RESULTS: The odds of sleep disturbance was greater in HD participants than non-HD controls (OR: 1.93, p < 0.001). Additionally, those with juvenile HD and late-stage disease had the greatest odds of sleep disturbance development. The development of a sleep disorder in manifest HD participants was observed to be around the time of disease onset. CONCLUSIONS: Sleep disturbances are more frequent in HD patients than those without HD. The frequency is also greater in those with juvenile HD and increases as the disease progresses. This is supplemented by the finding that the onset of sleep disturbances occurs near the time of motor onset of HD.

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.

Background: The gene (Huntingtin or HTT) causing Huntington’s disease (HD) is vital for development and is expressed throughout the brain and body lifelong. The mutant form (mHTT) may influence growth and development. Objective: To determine the impact of mHTT on human measures of growth, including height, weight, and body mass index (BMI), between child and adolescent carriers of mHTT and control peers. Methods: Children ages 6–18 years of age (n = 186) at risk for HD were enrolled in the KidsHD study. For research purposes only, genetic testing was performed to classify participants as Gene-Expanded (GE = 78) or as Gene Non-Expanded (GNE = 108). Outcome measures included height, weight, and body mass index (BMI). Mixed models were used to determine if non-linear age trends differed between groups for BMI, height, and weight. Results: Differences were seen in the trajectory of BMI in which the GE group reached a plateau in late adolescence with no further increase, compared with a nearly linear increase in the GNE group. There was a significant sex interaction pattern where GE males were taller than GNE males in adolescence, in the presence of similar weight. In contrast, GE females weighed significantly less than their GNE counterparts in adolescence, in the presence of similar height. Conclusion: Measures of growth are abnormal in child and adolescent carriers of mHTT, decades before HD onset. Although further studies are needed for replication, the current findings suggest that developmental aberrations may be systemic and a vital part of disease pathology.

The current dogma of HD pathoetiology posits it is a degenerative disease affecting primarily the striatum, caused by a gain of function (toxicity) of the mutant mHTT that kills neurons. However, a growing body of evidence supports an alternative theory in which loss of function may also influence the pathology.This theory is predicated on the notion that HTT is known to be a vital gene for brain development. mHTT is expressed throughout life and could conceivably have deleterious effects on brain development. The end event in the disease is, of course, neurodegeneration; however the process by which that occurs may be rooted in the pathophysiology of aberrant development. To date, there have been multiple studies evaluating molecular and cellular mechanisms of abnormal development in HD, as well as studies investigating abnormal brain development in HD animal models. However, direct study of how mHTT could affect neurodevelopment in humans has not been approached until recent years. The current review will focus on the most recent findings of a unique study of children at-risk for HD, the Kids-HD study. This study evaluates brain structure and function in children ages 6–18 years old who are at risk for HD (have a parent or grand-parent with HD).

ObjectiveTo assess brain morphometry in a sample of patients with juvenile-onset Huntington disease (JOHD) and several mouse models of Huntington disease (HD) that likely represent the human JOHD phenotype.MethodsDespite sharing the mutation in the Huntingtin gene, adult-onset HD characteristically presents as a hyperkinetic motor disorder, while JOHD typically presents as a hypokinetic motor disease. The University of Iowa Kids-JHD program enrolls individuals 5 to 25 years of age who have already received the clinical diagnosis. A total of 19 children with juvenile HD (JHD) (mean CAG = 72) were studied. Patients with JHD were compared to healthy controls (n = 234) using a cross-sectional study design. Volumetric data from structural MRI was compared between groups. In addition, we used the same procedure to evaluate brain morphology of R6/2, zQ175, HdhQ250 HD mice models.ResultsParticipants with JHD had substantially reduced intracranial volumes. After controlling for the small intracranial volume size, the volumes of subcortical regions (caudate, putamen, globus pallidus, and thalamus) and of cortical white matter were significantly decreased in patients with JHD. However, the cerebellum was proportionately enlarged in the JHD sample. The cerebral cortex was largely unaffected. Likewise, HD mice had a lower volume of striatum and a higher volume of cerebellum, mirroring the human MRI results.ConclusionsThe primary pathology of JOHD extends beyond changes in the striatal volume. Brain morphology in both mice and human patients with JHD shows proportional cerebellar enlargement. This pattern of brain changes may explain the unique picture of hypokinetic motor symptoms in JHD, which is not seen in the hyperkinetic chorea-like phenotype of adult-onset HD.

To assess sex-specific differences in early brain structure and function of preterm infants after red blood cell (RBC) transfusions.A single-center subset of infants with a birth weight1000 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 InfantToddler Development, 3rd Edition (n = 34).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.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.

Reports of behavioral disturbance in Juvenile-Onset Huntington&rsquo, s Disease (JOHD) have been based primarily on qualitative caregiver reports or retrospective medical record reviews. This study aims to quantify differences in behavior in patients with JOHD using informant- and self-report questionnaires. Informants of 21 children/young adults (12 female) with JOHD and 115 children/young adults (64 female) with a family history of Huntington&rsquo, s Disease, but who did not inherit the disease themselves (Gene-Non-Expanded, GNE) completed the Behavior Rating Inventory of Executive Function (BRIEF) and the Pediatric Behavior Scale (PBS). Mixed linear regression models (age/sex adjusted) were conducted to assess group differences on these measures. The JOHD group had significantly higher scores, indicating more problems, than the GNE group on all BRIEF subscales, and measures of Aggression/Opposition and Hyperactivity/Inattention of the PBS (all p &lt, 0.05). There were no group differences in Depression/Anxiety. Inhibit, Plan/Organize, Initiate, and Aggression/Opposition had significant negative correlations with Cytosine-Adenine-Guanine (CAG) repeat length (all p &lt, 0.05) meaning that individuals with higher CAG repeats scored lower on these measures. There was greater discrepancy between higher informant-vs. lower self-reported scores in the JOHD group, supporting the notion of lack of insight for the JOHD-affected group. These results provide quantitative evidence of behavioral characteristics of JOHD.

Patients with adult-onset Huntington’s Disease (AOHD) have been found to have dysfunction of the autonomic nervous system that is thought to be secondary to neurodegeneration causing dysfunction of the brain–heart axis. However, this relationship has not been investigated in patients with juvenile-onset HD (JOHD). The aim of this study was to compare simple physiologic measures between patients with JOHD (n = 27 participants with 64 visits) and participants without the gene expansion that causes HD (GNE group; n = 259 participants with 395 visits). Using data from the Kids-JOHD study, we compared mean resting heart rate (rHR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) between the JOHD and GNE groups. We also divided the JOHD group into those with childhood-onset JOHD (motor diagnosis received before the age of 13, [n = 16]) and those with adolescent-onset JOHD (motor diagnosis received at or after the age of 13 [n = 11]). We used linear mixed-effects models to compare the group means while controlling for age, sex, and parental socioeconomic status and including a random effect per participant and family. For the primary analysis, we found that the JOHD group had significant increases in their rHR compared to the GNE group. Conversely, the JOHD group had significantly lower SBP compared to the GNE group. The JOHD group also had lower DBP compared to the GNE group, but the results did not reach significance. SBP and DBP decreased as disease duration of JOHD increased, but rHR did not continue to increase. Resting heart rate is more sensitive to changes in autonomic function as compared to SBP. Therefore, these results seem to indicate that early neurodegenerative changes of the central autonomic network likely lead to an increase in rHR while later progression of JOHD leads to changes in blood pressure. We hypothesize that these later changes in blood pressure are secondary to neurodegeneration in brainstem regions such as the medulla.

Huntington’s disease (HD) is a fatal neurodegenerative disease caused by the expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene. An increased CAG repeat length is associated with an earlier disease onset. About 5% of HD cases occur under the age of 21 years, which are classified as juvenile-onset Huntington’s disease (JOHD). Our study aims to measure subcortical metabolic abnormalities in JOHD participants. T1-Rho (T1ρ) MRI was used to compare brain regions of 13 JOHD participants and 39 controls. Region-of-interest analyses were used to assess differences in quantitative T1ρ relaxation times. We found that the mean relaxation times in the caudate (p < 0.001), putamen (p < 0.001), globus pallidus (p < 0.001), and thalamus (p < 0.001) were increased in JOHD participants compared to controls. Furthermore, increased T1ρ relaxation times in these areas were significantly associated with lower volumes amongst participants in the JOHD group. These findings suggest metabolic abnormalities in brain regions previously shown to degenerate in JOHD. We also analyzed the relationships between mean regional T1ρ relaxation times and Universal Huntington’s Disease Rating Scale (UHDRS) scores. UHDRS was used to evaluate participants’ motor function, cognitive function, behavior, and functional capacity. Mean T1ρ relaxation times in the caudate (p = 0.003), putamen (p = 0.005), globus pallidus (p = 0.009), and thalamus (p = 0.015) were directly proportional to the UHDRS score. This suggests that the T1ρ relaxation time may also predict HD-related motor deficits. Our findings suggest that subcortical metabolic abnormalities drive the unique hypokinetic symptoms in JOHD.

ObjectiveTo test the hypothesis that the trajectory of functional connections over time of the striatum and the cerebellum differs between presymptomatic patients with the Huntington disease (HD) gene expansion (GE) and patients with a family history of HD but without the GE (GNE), we evaluated functional MRI data from the Kids-HD study.MethodsWe utilized resting-state, functional MRI data from participants in the Kids-HD study between 6 and 18 years old. Participants were divided into GE (CAG 36–59) and GNE (CAG ResultsFour of the six striatal–cerebellum correlations showed significantly different trajectories between groups. All showed a pattern where in the early age ranges (6–12 years) there was hyperconnectivity in the GE compared to the GNE, with those trajectories showing linear decline in the latter half of the age range.ConclusionThese results parallel previous findings showing striatal hypertrophy in children with GE as early as age 6. These findings support the notion of developmentally higher connectivity between the striatum and cerebellum early in the life of the child with HD GE, possibly setting the stage for cerebellar compensatory mechanisms.

Introduction Huntington's chorea (HC) is commonly managed with neuroleptic medications, though there is little evidence to support their use. This study aimed to perform a real-world comparison of the efficacy of risperidone and olanzapine to tetrabenazine (TBZ) for HC. Methods The Enroll-HD database was used to perform a propensity score-matched comparison of risperidone and olanzapine to TBZ, regarding their efficacy in controlling chorea. Participants with motor manifest Huntington's disease (HD) were grouped according to their use of risperidone, olanzapine, or TBZ. For the three groups, independent propensity score matching was performed on participants' baseline total functional score (TFC), baseline total motor score (TMS), disease burden score, CAG repeat length, baseline age, region, sex, and body mass index. Independent samples t test was used to calculate the differences between the groups in the annual rate of change of the TMS from the baseline to the second available visit. Results The risperidone (n = 72) and olanzapine groups (n = 77) had annualized increases (worsening) in the TMS of only 1.47 points and 3.20 points, respectively, compared to 5.70 points in the two matched TBZ groups (n = 72) (P = 0.019) and (n = 77) (P = 0.143), respectively. Conclusions In the absence of prospective data, this analysis of the Enroll-HD database found that the neuroleptics risperidone and olanzapine seemed to at least be comparable to TBZ at controlling HC. These results demonstrate that neuroleptics may have comparable efficacy to TBZ for the treatment of HC. Further prospective studies are needed to confirm these findings.

ObjectiveTo determine whether tetrabenazine (TBZ) use is associated with an increased incidence of depression and/or suicidal ideation.MethodsIn this retrospective cross-sectional study of the Enroll-HD database, we used multiple logistic regression analyses to determine whether TBZ use is associated with an increased incidence of depression and/or suicidal ideation. For both dependent variables (depression and suicidality), separate analyses were conducted on (1) all participants, (2) only participants with a history of depression, and (3) only participants with no history of depression. Adjustments were made for CAG repeat length, total motor score, total functional capacity, Symbol Digit Modalities Test score, sex, disease duration, history of depression (when applicable), antipsychotic use, and antidepressant use.ResultsCompared to participants who were not using TBZ (n = 3,548), TBZ users (n = 543) did not have an increased risk of depression (odds ratio [OR] = 0.78, p = 0.064). Participants taking TBZ actually had a relatively lower risk of suicidality (OR = 0.61, p = 0.043). Among only participants with a history of depression, those using TBZ had a lower incidence of depression (OR = 0.71, p = 0.016) and suicidal ideation (OR = 0.57, p = 0.028) compared to those not using TBZ. Finally, among only participants with no history of depression, TBZ use was not associated with a higher incidence of depression (OR = 1.59, p = 0.18) or suicidality (OR = 1.43, p = 0.66) compared to those who were not using TBZ.ConclusionsTBZ use was not associated with an increased incidence of depression or suicidality. These findings suggest that TBZ may be safe to use in patients with Huntington disease who have a history of depression.

Background Huntington's Disease (HD) is caused by an abnormality in the HTT gene. This gene includes trinucleotide repeats ranging from 10 to 35, and when expanded beyond 39, causes HD. We previously reported that CAG repeats in the normal range had a direct and beneficial effect on brain development with higher repeats being associated with higher cognitive function. The current study now expands this line of inquiry to evaluate the effects of CAG repeat throughout the entire spectrum of repeats from 15 to 58. Methods We evaluated brain function in children ages 6–18 years old. DNA samples were processed to quantify the number of CAG repeats within HTT. Linear regression was used to determine if number of CAG repeats predicted measures of brain function. Findings The number of repeats in HTT, had a non-linear effect on a measure of general intelligence with an inverted U shape pattern. Increasing repeat length was associated with higher GAI scores up until roughly 40–41 repeats. After this peak, increasing repeat length was associated with declining GAI scores. Interpretation HTT may confer an advantage or a disadvantage depending upon the repeat length, playing a key role in the determination of intelligence, or causing a uniquely human brain disease., Highlights • The HTT gene includes trinucleotide repeats ranging from 10 to 35 in the normal population. • Huntington’s disease is caused when the trinucleotide repeats in the HTT gene expand beyond the normal range. • The gene is vital for brain growth in which each repeat contributes to the development of brain function, measured as intelligence. • Increasing repeats are beneficial to a certain point, then becomes detrimental to intelligence, forming an inverted U relationship. A Faustian Bargain: Could the key to the evolution of the human brain be found in a dreadful disease? Huntington's Disease is a fatal progressive brain disease caused by a single gene. Results from the current study show that the same gene is important for brain development and intelligence. Therefore, this gene may have a simultaneous advantage and disadvantage: a role in the evolution of a superior human brain, yet the disadvantage of a uniquely human brain disease.

Aim: The symptoms of Huntington's disease are well known, yet the symptoms of juvenile Huntington's disease (JHD) are less established due to its rarity. The study examined a cluster of symptoms considered to be common, but under-recognized in JHD: pain, itching, sleeping difficulties, psychosis and tics. Materials & methods: A symptom survey was constructed using the online tool Qualtrics and dispersed to JHD caregivers through websites. Results: A total of 33 surveys were completed. Disrupted sleep was the most prevalent symptom (87%), followed by tics (78%), pain (69%), itching (60%) and psychosis (39%). Conclusion: Despite limitations, the study supports that there are symptoms in the JHD population that are not considered classic, however, are common and significant for patients and caregivers.

OBJECTIVE The current study examined whether the arithmetical calculation skills of children, adolescents, and young adults with isolated cleft of the lip and/or palate (iCL/P) differ significantly from unaffected control participants. Comparisons of potential neuropsychological predictors of arithmetical calculation were also conducted to determine whether these variables differ significantly for participants with iCL/P. METHOD Participants (N = 176; 93 iCL/P and 83 Control) ranged in age from 7 to 26 years old. A standardized battery of achievement and neuropsychological skills was administered. Between group differences on math achievement was assessed through a univariate analysis of covariance. Relationships between neuropsychological measures and math achievement were analyzed separately for participants with iCL/P and controls through hierarchical linear regressions. RESULTS Arithmetical calculation was significantly lower for the iCL/P group. Rapid naming, sustained attention, and visual-spatial organization were significant predictors for the iCL/P group; rapid naming was the lone variable that was significantly more predictive of arithmetical calculation for the iCL/P group than for control participants. CONCLUSIONS These results suggest that inefficient verbal label retrieval related to short-term memory (STM) deficits underlie the calculation difficulties of individuals with iCL/P. These findings have implications for approaches to remediation, as well as future research. (PsycINFO Database Record

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.

ObjectiveTo evaluate lesion location after pediatric cerebellar tumor resection in relation to the development of severe cognitive and affective disturbances, or cerebellar cognitive affective syndrome (CCAS).MethodsThe postsurgical lesion location of 195 pediatric patients with cerebellar tumors was mapped onto a template brain. Individuals with CCAS were matched to 2 participants without CCAS by sex, age, and lesion volume. Lesion analyses included both a hypothesis-driven evaluation of the cerebellar outflow pathway (deep nuclei and superior cerebellar peduncles) and data-driven multivariate lesion symptom mapping. Lesion-associated networks were evaluated by comparing connectivity patterns between the lesion location of cases with and those without CCAS with resting-state functional connectivity MRI data from large normative adult and pediatric cohorts.ResultsCCAS was present in 48 of 195 participants (24.6%) and was strongly associated with cerebellar outflow tract lesions (p < 0.0001). Lesion symptom mapping also highlighted the cerebellar outflow pathway, with peak findings in the fastigial nuclei extending into the inferior vermis. Lesion network mapping revealed that the cerebellar region most associated with CCAS was functionally connected to the thalamic mediodorsal nucleus, among other sites, and that higher connectivity between lesion location and the mediodorsal nucleus predicts CCAS occurrence (p < 0.01). A secondary analysis of 27 participants with mutism revealed similar localization of lesions and lesion-associated networks.ConclusionLesions of the cerebellar outflow pathway and inferior vermis are associated with major cognitive and affective disturbances after pediatric cerebellar tumor resection, and disrupted communication between the cerebellum and the thalamic mediodorsal nucleus may be important.

We thank Sampaio et al. for the comment on our article.1 The Enroll-HD dataset does not contain information regarding why participants abandoned a particular therapy.2 Therefore, making the assumption that abandonment of tetrabenazine (TBZ) therapy occurs secondary to depression/suicidality could falsely induce a spurious positive association between TBZ and depression/suicidality that is equally dangerous. Furthermore, participants who abandoned TBZ prior to their baseline visit were included in the TBZ nonuser group.1 If the assumptions being made by Sampaio et al. are accurate, then it is reasonable to assume that an increased percentage of participants in the TBZ nonuser group have a history of depression. However, the percentage of participants with a history of depression is nearly identical between the 2 groups,1 indicating that few participants discontinued TBZ due to depression/suicidality.

Purpose of review: Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit.\ud \ud Recent findings: The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations.\ud \ud Summary: The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments.\ud \ud Described as “one of the more variable diseases found in medicine,” myotonic dystrophy type 1 (DM1) is an autosomal dominant, triplet-repeat expansion disorder that affects somewhere between 1:3,000 and 1:8,000 individuals worldwide.1 There is a modest association between increased repeat expansion and disease severity, as evidenced by the average age of onset and overall morbidity of the condition. An expansion of over 35 repeats typically indicates an unstable and expanding mutation. An expansion of 50 repeats or higher is consistent with a diagnosis of DM1. DM1 is a multisystem and heterogeneous disease characterized by distal weakness, atrophy, and myotonia, as well as symptoms in the heart, brain, gastrointestinal tract, endocrine, and respiratory systems. Symptoms may occur at any age. The severity of the condition varies widely among affected individuals, even among members of the same family.\ud \ud Comprehensive evidence-based guidelines do not currently exist to guide the treatment of DM1 patients. As a result, the international patient community reports varied levels of care and care quality, and difficulty accessing care adequate to manage their symptoms, unless they have access to multidisciplinary neuromuscular clinics.\ud \ud Consensus-based care recommendations can help standardize and improve the quality of care received by DM1 patients and assist clinicians who may not be familiar with the significant variability, range of symptoms, and severity of the disease. Care recommendations can also improve the landscape for clinical trial success by eliminating some of the inconsistencies in patient care to allow more accurate understanding of the benefit of potential therapies.

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.

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There is a known negative association between cytosine–adenine–guanine (CAG) repeat length and the age of motor onset (AMO) in adult-onset Huntington’s Disease (AOHD). This relationship is less clear in patients with juvenile-onset Huntington’s disease (JOHD), however, given the rarity of this patient population. The aim of this study was to investigate this relationship amongst a relatively large group of patients with JOHD using data from the Kids-JOHD study. Additionally, we analyzed data from the Enroll-HD platform and the Predict-HD study to compare the relationship between CAG repeat length and AMO amongst patients with AOHD to that amongst patients with JOHD using linear regression models. In line with previous reports, the variance in AMO that was predicted by CAG repeat length was 59% (p < 0.0001) in the Predict-HD study and 57% from the Enroll-HD platform (p < 0.0001). However, CAG repeat length predicted 84% of the variance in AMO amongst participants from the Kids-JOHD study (p < 0.0001). These results indicate that there may be a stronger relationship between CAG repeat length and AMO in patients with JOHD as compared to patients with AOHD. These results provide additional information that may help to model disease progression of JOHD, which is beneficial for the planning and implementation of future clinical trials.

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 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.

Background Huntington Disease (HD) and human immunodeficiency virus (HIV) are both associated with neurodegeneration in the cerebral cortex and striatum. The rate of striatal degeneration is a known predictor of symptom onset in HD indicating a potential neurobiological link between HD and HIV. Objective To determine if the presence of pre-existing HIV infection would trigger a significantly earlier age of symptom onset (ASO) in HD-mutation carriers when compared to non-infected HD subjects. Methods This was a retrospective analysis of the Enroll-HD database that included participants with a CAG repeat of at least 36. Participants with HD and a comorbidity of HIV that was diagnosed prior to their reported ASO were identified and compared to participants with HD who did not have HIV. An ANCOVA analysis was performed to investigate the differences in ASO between the HIV and non-HIV groups. Sex, drug use, and CAG repeat number were used as covariates. Results The average ASO of HD subjects with previous HIV infection (n = 8) was 9.1 years earlier than non-HIV infected HD subjects (n = 3259) [F (1, 3267) =10.05, p = 0.002]. Despite low numbers of participants in the HIV group, the calculated effect size of this difference was 1.07. Conclusion The known neurobiological changes caused by HIV seem to hasten the ASO in patients with HD. These results may enhance our understanding of the neuropathology of HD in a way that will help with the identification of novel targets for future therapies.

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 one year of age. This study was designed to obtain quantitative brain measures from Magnetic Resonance Imaging (MRI) 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 gestational age, sex, on brain measures. Results: There was a primary effect of sex on: 1) intracranial volume (ICV), 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 (CSF). 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.

Previous research has shown sex differences in brain morphology ( De Bellis et al., 2001 ). However, these studies have not taken gender into account. Gender is a phenotype that describes behavior. In this study, we examined the relationship between gender, sex, and brain volumes in children. One hundred and eight children ages 7 to 17 were administered the Children's Sex Role Inventory ( Boldizar, 1991 ) and obtained volumetric brain data via magnetic resonance imaging (MRI). We found that, in the frontal lobe, higher masculinity predicted greater volumes of white matter. Also, in the temporal lobe, higher femininity predicted greater volumes of gray matter.

In Huntington’s disease (HD) mutant HTT is ubiquitously expressed yet the striatum undergoes profound early degeneration. Cell culture studies suggest that a striatal-enriched protein, Rhes, may account for this vulnerability. We investigated the therapeutic potential of silencing Rhes in vivo using inhibitory RNAs (miRhes). While Rhes suppression was tolerated in wildtype mice, it failed to improve rotarod function in two distinct HD mouse models. Additionally, miRhes treated HD mice had increased anxiety-like behaviors and enhanced striatal atrophy as measured by longitudinal MRI when compared to control treated mice. These findings raise caution regarding the long-term implementation of inhibiting Rhes as a therapy for HD.

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.

Research extending back 50 years has documented a strong occurrence of language disorders (LD) among children with non-syndromic cleft of the lip and/or palate (NSCL/P; Conrad, Richman, Nopoulos, & Dailey, 2009; Goldstein et al., 2007; Hentges et al., 2011; Lamb, Wilson, & Leeper, 1972; Nopoulos, Berg, VanDemark, et al., 2002; Roberts, Mathias, & Wheaton, 2012). This is most often reflected in a high occurrence of Dyslexia in children with NSCL/P (Broder, Richman, & Matheson, 1998; Chapman, 2011; Collett, Stott-Miller, Kapp-Simon, Cunningham, & Speltz, 2010; Richman, Eliason, & Lindgren, 1988; Richman & Ryan, 2003; Richman, Wilgenbusch, & Hall, 2005). For some subgroups this appears to be a developmental lag where reading skills improve in adolescence, though others continue to demonstrate a deficit into adulthood (Richman, et al., 1988). Early on, it was hypothesized that the high rates of Dyslexia and LD were due either to poor articulation resulting from the abnormal oral cavity or hearing loss secondary to frequent episodes of Otitis Media (Amaral, Martins, & Santos, 2010; Chapman, 2011; Collett, Stott-Miller, et al., 2010). These disruptions to sensory input at critical developmental times were hypothesized to impair phonological awareness, a key skill required for reading (Ramus, 2003). Research supporting this theory has found correlations between early speech issues (Chapman, 2011), poor hearing (Boscariol, Andre, & Feniman, 2009; Collett, Stott-Miller, et al., 2010) and reading outcomes. However, there have been some criticisms of this theory. Research within the general population has shown normal phonological development in persons with severe speech disabilities (Ramus, Pidgeon, & Frith, 2003), which suggests that phonological representations are not solely a product of speech articulation (Ramus et al., 2003). Second, there are studies among people with NSCL/P that demonstrate no relationship between articulation, hearing, and reading or language outcome (Ceponiene, Haapanen, Ranta, Naatanen, & Hukki, 2002; Hentges, et al., 2011; Lamb, et al., 1972; Shriver, Canady, Richman, Andreasen, & Nopoulos, 2006). These findings suggest that there may be something more than disrupted speech or hearing influencing language and reading skills among people with NSCL/P. In order to better understand the neurological underpinnings of these outcomes, some research has evaluated neuropsychological skills associated with reading (i.e., phonological awareness, rapid labeling, and auditory/visual memory). Studies have shown related deficiencies in rapid labeling and auditory/visual memory compared to controls (Brennan & Cullinan, 1974; Ceponiene, et al., 2002; Ceponiene et al., 1999; Nopoulos, Berg, VanDemark, et al., 2002; Richman & Ryan, 2003; Richman, et al., 2005; Smith & McWilliams, 1968). Although, there has been some research that has found no differences in reading or these related skills (Chapman, 2011; Collett, Leroux, & Speltz, 2010; Smith & McWilliams, 1968). In support of a theory of neuropsychological deficits, our laboratory has documented abnormal brain structure in both children (Nopoulos, Langbehn, Canady, Magnotta, & Richman, 2007) and adults with NSCL/P (Nopoulos, Berg, Canady, et al., 2002; Nopoulos et al., 2005). These changes in brain structure are hypothesized to be due to abnormal brain development that occurs in parallel with the abnormality in facial development. Establishing a relationship between reading performance and specific language-based neuropsychological skills would support the notion that the reading disabilities may be rooted in abnormal brain structure and function, rather than a secondary effect from deprivation of sensory input. One weakness in this body of literature is that the majority of recent research evaluating language and reading skills are focused on younger subjects (maximum age around 8 years old), in whom reading skills are just starting to develop. A close evaluation of articulation, hearing, neuropsychological skill, and reading among an older sample, where reading skill is stronger or more established, is lacking. The purpose of this study was to obtain measures of word reading, neuropsychological skill, speech production, and history of hearing in children, adolescents, and young adults with NSCL/P. Key questions for evaluation included: 1) What is the effect of sex, age and group membership on reading outcome for subjects with and without cleft? 2) What is the relationship of reading skill to measures of neuropsychological skill, speech, and hearing? It was hypothesized that reading skill would increase with age for all subjects; however, there may be a group-by-age interaction where reading for subjects with NSCL/P is discrepant at younger ages and “catches-up” in young adulthood. It was also expected that neuropsychological skill would be associated to reading outcome, but results for speech and hearing were not predicted.

This study evaluated the relationship between exposure to anesthesia and previously identified differences in cognitive functioning, growth, and volumetric brain measures among a sample of children, adolescents, and young adults with isolated oral clefts. Data from a cross-sectional study were combined with a retrospective chart review. Data were obtained for 87 participants with isolated cleft lip and/or palate (55% male), ranging from 7.5 to 27 years old (mean = 15.78, standard deviation = 4.58). Measures of interest included cognitive functioning, growth measures, and brain volumes. Number of surgeries and time under anesthesia were obtained through systematic medical record review. Potential sex and cleft type differences in exposure as well as relationships between anesthesia exposure and outcome measures were evaluated. Participants with isolated cleft lip and palate had more surgeries and were under anesthesia longer. For participants with isolated cleft lip only, more surgeries were correlated to lower verbal IQ and higher frontal lobe volume.

Objective Juvenile Huntington's Disease (JHD) is an extremely rare autosomal dominant neurodegenerative disease with onset in childhood or teenage years. Although there are many similarities with the adult form of the disease, JHD has a clinically distinct presentation. Some common symptoms include behavioral problems and cognitive decline. However, given the rarity of juvenile presentations, limited research exists regarding sex difference performances on executive and intellectual functioning in a JHD population. Thus, exploratory research was conducted to investigate such findings. Method Data from the Kids HD research study was analyzed (N = 58; mean age = 15.5, 50.8% female). Preliminary bivariate partial correlations, independent t-tests, and one way ANOVA tests were used to examine differences in executive and intellectual functioning between male and female participants. Results Performance significantly differed on several aspects of executive and intellectual functioning between sexes, including shifting attention (p = 0.007), verbal intellect (p = 0.019), and general ability intellect (p = 0.041). Significant differences were also observed regarding inhibition (p = 0.003), verbal categorical fluency (p = 0.021), and sorting (p = < 0.001). Conclusions Results suggest that there are significant differences in executive and intellectual functioning between sexes. In particular, males had more difficulty shifting attention, despite higher verbal intellect and higher general ability intellect. Females demonstrated greater inhibition, while males demonstrated stronger verbal categorical fluency and abstract reasoning. Between sexes, results indicate evidence of performance differences across tasks of executive and intellectual functioning. Such findings are consistent with a subcortical neurodegenerative process, such as HD.

In the original article, the legend within Fig. 3 incorrectly read as ‘*p 0.01’. This has now been changed to ‘*p

Social isolation is common among individuals with isolated cleft lip and palate (ICLP), but the available data on why this may be are mixed. We present a novel theory relating to reduced social motivation in ICLP, called the social abulia hypothesis. Based on this hypothesis, we predicted that reduced social motivation would lead to reduced responsiveness to negative social feedback, in terms of both explicit responses and noncontrolled, psychophysiological responses. Twenty males with ICLP and 20 normal comparison males between 13 and 25 years old participated in the study. Social motivation was examined by measuring participants' response to negative social feedback (social exclusion). Additionally, psychophysiological reactivity to positive and negative social stimuli was measured. In order to rule out other potential contributors to social isolation, we tested basic social perception, emotion recognition, and social anxiety. In line with the social abulia hypothesis, we show that negative social feedback had less of an effect on males with ICLP than on healthy male peers, which was evident in explicit responses and noncontrolled, psychophysiological responses to negative social feedback. Our results could not be attributed to problems in social perception, a lack of understanding facial expressions, or increased social anxiety, as groups did not differ on these constructs. This study suggests that current views on social isolation in ICLP may need to be reconsidered to include the possibility that isolation in this population may be the direct result of reduced social motivation.

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.

The goal of this project was to develop two age appropriate atlases (neonatal and one year old) that account for the rapid growth and maturational changes that occur during early development. Tissue maps from this age group were initially created by manually correcting the resulting tissue maps after applying an expectation maximization (EM) algorithm and an adult atlas to pediatric subjects. The EM algorithm classified each voxel into one of ten possible tissue types including several subcortical structures. This was followed by a novel level set segmentation designed to improve differentiation between distal cortical gray matter and white matter. To minimize the req uired manual corrections, the adult atlas was registered to the pediatric scans using high -dimensional, symmetric image normalization (SyN) registration. The subject images were then mapped to an age specific atlas space, again using SyN registration, and the resulting transformation applied to the manually corrected tissue maps. The individual maps were averaged in the age specific atlas space and blurred to generate the age appropriate anatomical priors. The resulting anatomical priors were then used by the EM algorithm to re-segment the initial training set as well as an independent testing set. The results from the adult and age-specific anatomical priors were compared to the manually corrected results. The age appropriate atlas provided superior results as compared to the adult atlas. The image analysis pipeline used in this work was built using the open source software package BRAINSTools.

Advances in medical image applications have led to mounting expectations in regard to their impact on neuroscience studies. In light of this fact, a comprehensive application is needed to move neuroimaging data into clinical research discoveries in a way that maximizes collected data utilization and minimizes the development costs. We introduce BRAINS AutoWorkup, a Nipype based open source MRI analysis application distributed with BRAINSTools suite (http://brainsia.github.io/BRAINSTools/). This work describes the use of efficient and extensible automated brain MRI analysis workflow for large-scale multi-center longitudinal studies. We first explain benefits of our extensible workflow development using Nipype, including fast integration and validation of recently introduced tools with heterogeneous software infrastructures. Based on this workflow development, we also discuss our recent advancements to the workflow for reliable and accurate analysis of multi-center longitudinal data. In addition to Nipype providing a unified workflow, its support for High Performance Computing (HPC) resources leads to a further increased time efficiency of our workflow. We show our success on a few selected large-scale studies, and discuss future direction of this translation research in medical imaging applications.

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.

Structural magnetic resonance imaging studies provide evidence for sex differences in the human brain. Differences in surface area and the proportion of gray to white matter volume are observed, in particular in the parietal lobe. To our knowledge, no studies have examined sex differences in parietal lobe structure in younger populations or in the context of development. The present study evaluated sex differences in the structure of the parietal lobe in children aged 7 to 17 years. In addition, by adding a cohort of previously studied adults aged 18 to 50 years, sex differences in parietal lobe structure were examined across the age span of 7 to 50 years. Compared with the adult sample, the younger sample showed that the ratio of parietal lobe cortex to white matter was greater in female brains, but no sex differences in surface area. When examining the effects of age, surface area exhibited a significant sex-age interaction. In male brains, there was essentially no decrease in surfaces area over time, whereas in female brains, there was a significant decrease in surface area over time. These findings support the notion of structural sex differences in the parietal lobe, not only in the context of cross-sectional assessment but also in terms of differences in developmental trajectories.

Environmental factors may contribute as much as one-third of the variance in Huntington disease (HD) age of onset. Substance abuse is a risk factor for other neurodegenerative disorders; however, whether substance abuse influences HD age of onset is not well established. This study investigated the relationships between alcohol, drug, and tobacco abuse and HD age of onset in 136 participants with symptomatic HD. CAG repeat length was used as a covariate in all analyses, as it represents the most significant determinant of HD age of onset. The relationship between substance abuse, HD age of onset, and sex was also examined, as women may experience greater medical harm from substance abuse. Lifetime alcohol abuse and lifetime drug abuse were associated with earlier age of HD onset; a similar trend was seen for current tobacco abuse. For women, lifetime alcohol abuse was associated with earlier onset of HD, with a similar trend for lifetime drug abuse. However, alcohol, drug, and tobacco abuse were not significantly associated with age of onset in men. Further work is needed to determine whether substance abuse is a causative risk factor for earlier onset of HD, and why the environmental factors associated with age of onset vary by sex.