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.

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.

Autonomic changes in Huntington's disease correlate with altered central autonomic network connectivity.

Autonomic dysfunction has been described in patients with Huntington's disease, but it is unclear if these changes in autonomic tone are related to the central autonomic network. We performed a pilot study to investigate the relationship between the integrity of the central autonomic network and peripheral manifestiations of autonomic dysfunction in premanifest Huntington's disease. We recruited male participants with pre-motor-manifest Huntington's disease and a comparison group consisting of healthy, male participants of approximately the same age. As this was a pilot study, only males were included to reduce confounding. Participants underwent a resting-state functional magnetic resonance imaging study to quantify functional connectivity within the central autonomic network, as well as a resting 3-lead ECG to measure heart rate variability with a particular focus on the parasympathetic time-domain measures of root mean square of successive differences between normal heartbeats. The pre-motor-manifest Huntington's disease participants had significantly decreased root mean square of successive differences between normal heartbeats values compared with the healthy comparison group. The pre-motor-manifest Huntington's disease group had significantly lower functional connectivity within the central autonomic network, which was positively correlated with root mean square of successive differences between normal heartbeats. Patients with pre-motor-manifest Huntington's disease have reduced functional connectivity within the central autonomic network, which is significantly associated with observed changes in autonomic function.

Neonatal leptin administration alters regional brain volumes and blocks neonatal growth restriction-induced behavioral and cardiovascular dysfunction in male mice.

Premature delivery is often complicated by neonatal growth restriction (GR) and neurodevelopmental impairment. Because global overnutrition increases the risk of adult metabolic syndrome, we sought a targeted intervention. Premature delivery and perinatal GR decrease circulating levels of the neurotrophic hormone leptin. We hypothesized that leptin supplementation would normalize the outcomes of mice with incipient neonatal GR. Pups were fostered into litters of 6 or 12 to elicit divergent growth patterns. Pups in each litter received injections of saline or leptin from d 4 to 14. At 4 mo, mice underwent tail cuff blood pressure measurement, behavioral testing, and MRI. Mice fostered in litters of 12 had decreased weanling weights and leptin levels. Neonatal leptin administration normalized plasma leptin levels without influencing neonatal growth. Leptin replacement also normalized the hypertension, stress-linked immobility, conditioned fear, and amygdala enlargement seen in neonatal growth restricted male mice. In control males, neonatal leptin administration led to hypothalamic enlargement, without overt neurocardiovascular alterations. Female mice were less susceptible to the effects of neonatal GR or leptin supplementation. In conclusion, the effects of neonatal leptin administration are modulated by concurrent growth and gender. In growth restricted male mice, physiologic leptin replacement improves adult neurocardiovascular outcomes.

Quantifying the Onset of Unintended Weight Loss in Huntington's Disease: A Retrospective Analysis of Enroll-HD.

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.

Sleep disturbances by disease type and stage in Huntington's disease.

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: There were significant differences between HD participants and non-HD controls in both the disease type and disease stage analyses (p < 0.001). The odds of a sleep disturbance increased with worsening disease stage and was highest in those with juvenile HD. 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. There are also differences based on disease type and stage. This is supplemented by the finding that the onset of sleep disturbances occurs near the time of motor onset of HD.

Autonomic dysregulation as an early pathologic feature of Huntington Disease.

OBJECTIVE: Autonomic nervous system (ANS) dysfunction has been described in adults with motor-manifest Huntington's Disease (HD) or those who are near their predicted motor onset. It is unclear if ANS dysfunction is present years prior to the onset of motor symptoms of HD. To bridge this gap in knowledge, we compared crude markers of ANS function between children with the gene-expansion that causes HD (GE group) who were decades from their predicted motor onset and gene-non-expanded children (GNE group). METHODS: We included participants from the Kids-HD study who were <18 years old. Linear mixed effects regression models were constructed that controlled for sex, age, and BMI, and included a random effect per participant and per family. We compared resting heart rate (rHR), core body temperature (CBT), systolic blood pressure (SBP), and diastolic blood pressure (DBP) between the GE (n = 84) and GNE (n = 238) groups. We then grouped participants from the GE group based on their predicted years to onset (YTO) and compared their vital signs to the GNE group. RESULTS: The GE group had higher rHR (∆ = 3.83, p = 0.0064), SBP (∆ = 2.38, p = 0.032), and CBT (∆ = 0.16, t = 2.92, p = 0.007). The mean rHR and CBT became significantly elevated compared to the GNE group in participants who had 15-25 YTO and those who had <15 YTO. The mean SBP of participants who had 25-35 YTO was significantly elevated compared to the GNE group. CONCLUSION: ANS dysfunction in HD seems to occur approximately 20 years prior to the predicted onset of motor symptoms of HD.

Special Issue: Juvenile Onset Huntington's Disease.

[...].

Autonomic Changes in Juvenile-Onset Huntington's Disease.

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.

The Association between CAG Repeat Length and Age of Onset of Juvenile-Onset Huntington's Disease.

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.

The Neurodevelopmental Hypothesis of Huntington's Disease.

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).

Subcortical T1-Rho MRI Abnormalities in Juvenile-Onset Huntington's Disease.

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.

Abnormal development of cerebellar-striatal circuitry in Huntington disease.

OBJECTIVE: To 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. METHODS: We 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 <36) groups. Seed-to-seed correlations were calculated among 4 regions that provide input signals to the anterior cerebellum: (1) dorsocaudal putamen, (2) globus pallidus externa, (3) subthalamic nucleus, and (4) pontine nuclei; and 2 regions that represented output from the cerebellum: the dentate nucleus to the (1) ventrolateral thalamus and (2) dorsocaudal putamen. Linear mixed effects regression models evaluated differences in developmental trajectories of these connections over time between groups. RESULTS: Four 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. CONCLUSION: These 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.

Comparing Risperidone and Olanzapine to Tetrabenazine for the Management of Chorea in Huntington Disease: An Analysis from the Enroll-HD Database.

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.

Pediatric postoperative cerebellar cognitive affective syndrome follows outflow pathway lesions.

OBJECTIVE: To 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). METHODS: The 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. RESULTS: CCAS 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. CONCLUSION: Lesions 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.