Longitudinal Clinical and Biological Characteristics in Juvenile-Onset Huntington's Disease.

BACKGROUND: Juvenile-onset Huntington's disease (JOHD) is a rare form of Huntington's disease (HD) characterized by symptom onset before the age of 21 years. Observational data in this cohort is lacking. OBJECTIVES: Quantify measures of disease progression for use in clinical trials of patients with JOHD. METHODS: Participants who received a motor diagnosis of HD before the age of 21 were included in the Kids-JOHD study. The comparator group consisted of children and young adults who were at-risk for inheriting the genetic mutation that causes HD, but who were found to have a CAG repeat in the non-expanded range (gene non-expanded [GNE]). RESULTS: Data were obtained between March 17, 2006, and February 13, 2020. There were 26 JOHD participants and 78 GNE participants who were comparable on age (16.03 vs. 14.43, respectively) and sex (53.8% female vs. 57.7% female, respectively). The mean annualized decrease in striatal volume in the JOHD group was -3.99% compared to -0.06% in the GNE (mean difference [MD], -3.93%; 95% confidence intervals [CI], [-4.98 to -2.80], FDR < 0.0001). The mean increase in the Unified Huntington's Disease Rating Scale Total Motor Score per year in the JOHD group was 7.29 points compared to a mean decrease of -0.21 point in the GNE (MD, 7.5; 95% CI, [5.71-9.28], FDR < 0·0001). CONCLUSIONS: These findings demonstrate that structural brain imaging and clinical measures in JOHD may be potential biomarkers of disease progression for use in clinical trials. Collaborative efforts are required to validate these results in a larger cohort of patients with JOHD. © 2022 International Parkinson and Movement Disorder Society.

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.

Neurofilament Light Protein as a Potential Blood Biomarker for Huntington's Disease in Children.

BACKGROUND: Juvenile-onset Huntington's disease (JOHD) is a rare and particularly devastating form of Huntington's disease (HD) for which clinical diagnosis is challenging and robust outcome measures are lacking. Neurofilament light protein (NfL) in plasma has emerged as a prognostic biomarker for adult-onset HD. METHODS: We performed a retrospective analysis of samples and data collected between 2009 and 2020 from the Kids-HD and Kids-JHD studies. Plasma samples from children and young adults with JOHD, premanifest HD (preHD) mutation carriers, and age-matched controls were used to quantify plasma NfL concentrations using ultrasensitive immunoassay. RESULTS: We report elevated plasma NfL concentrations in JOHD and premanifest HD mutation-carrying children. In pediatric HD mutation carriers who were within 20 years of their predicted onset and patients with JOHD, plasma NfL level was associated with caudate and putamen volumes. CONCLUSIONS: Quantifying plasma NfL concentration may assist clinical diagnosis and therapeutic trial design in the pediatric population. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Associations between neurofilament light-chain protein, brain structure, and chronic kidney disease.

BACKGROUND: Neurofilament light-chain (NfL) protein is a blood-based marker of neuroaxonal injury. We sought to (1) compare plasma NfL levels in children with chronic kidney disease (CKD) and healthy peers, (2) characterize the relationship between NfL level and kidney function, and (3) evaluate NfL as a predictor of abnormal brain structure in CKD. METHODS: Sixteen children with CKD due to congenital kidney anomalies and 23 typically developing peers were included. Plasma NfL was quantified using single-molecule array immunoassay. Participants underwent structural magnetic resonance imaging. Multiple linear regression models were used to evaluate the association between plasma NfL levels, kidney function, and brain structure. RESULTS: An age × group interaction was identified whereby NfL levels increased with age in the CKD group only (estimate = 0.65; confidence interval (CI) = 0.08-1.22; p = 0.026). Decreased kidney function was associated with higher NfL levels (estimate = -0.10; CI = -0.16 to -0.04; p = 0.003). Lower cerebellar gray matter volume predicted increased plasma NfL levels (estimate = -0.00024; CI = -0.00039 to 0.00009; p = 0.004) within the CKD group. CONCLUSIONS: Children with CKD show accelerated age-related increases in NfL levels. NfL level is associated with lower kidney function and abnormal brain structure in CKD. IMPACT: NfL is a component of the neuronal cytoskeleton providing structural axonal support. Elevated NfL has been described in relation to gray and white matter brain volume loss. We have previously described the abnormal cerebellar gray matter in CKD. We explored the relationship between NfL, CKD, and brain volume. There is an accelerated, age-related increase in NfL level in CKD. Within the CKD sample, NfL level is associated with abnormal kidney function and brain structure. Decreased kidney function may be linked to abnormal neuronal integrity in pediatric CKD.

Melatonin may slow disease progression in amyotrophic lateral sclerosis: Findings from the Pooled Resource Open-Access ALS Clinic Trials database.

INTRODUCTION: We utilized the Pooled Resource Open-Access Clinical Trials (PRO-ACT) database to investigate whether melatonin use among patients with amyotrophic lateral sclerosis (ALS) was associated with slower disease progression and prolonged survival. METHODS: This retrospective analysis of the PRO-ACT database addresses the impact of melatonin on progression and overall survival of ALS. A Cox proportional hazards ratio model was performed to investigate the effect that melatonin had on time to death. For secondary outcome measures, linear mixed effects regression models were used to ascertain the effect of melatonin on change in standardized ALS Functional Rating Scale (sALSFRS) and percentage predicted forced vital capacity (FVC) scores. RESULTS: Melatonin users had a significantly decreased annualized hazard death rate compared with the non-melatonin users (hazard ratio, 0.241; 95% confidence interval, 0.088-0.659; P = .0056). The melatonin users also had a slower rate of decline in sALSFRS score (t = 2.71; P = .0069) and change in percent predicted FVC score (t = 2.94; P = .0035) compared with the non-melatonin users. DISCUSSION: Our findings suggest that melatonin may be beneficial for patients with ALS. Due to the nature of this database, our results are solely intended to be hypothesis-generating and no strong associations can be made. Given the low cost and favorable safety profile of melatonin, the hypotheses generated warrant further investigation.

Early pediatric chronic kidney disease is associated with brain volumetric gray matter abnormalities.

BACKGROUND: The impact of pediatric chronic kidney disease (pCKD) on the brain remains poorly defined. The objective of this study was to compare brain morphometry between children with early-stage pCKD and typically developing peers using structural magnetic resonance imaging (MRI). METHODS: The sample age range was 6-16 years. A total of 18 children with a diagnosis of pCKD (CKD stages 1-3) due to congenital anomalies of the kidney and urinary tract and 24 typically developing peers were included. Volumetric data from MRI and neurocognitive testing were compared using linear models including pCKD status, age, maternal education level, and socioeconomic status. RESULTS: Cerebellar gray matter volume was significantly smaller in pCKD, t(38) = -2.71, p = 0.01. In contrast, cerebral gray matter volume was increased in pCKD, t(38) = 2.08, p = 0.04. Reduced cerebellum gray matter volume was associated with disease severity, operationalized as estimated glomerular filtration rate (eGFR), t(14) = 2.21, p = 0.04 and predicted lower verbal fluency scores in the pCKD sample. Enlarged cerebral gray matter in the pCKD sample predicted lower scores on mathematics assessment. CONCLUSIONS: This study provides preliminary evidence for a morphometric underpinning to the cognitive deficits observed in pCKD. IMPACT: The impact of pediatric chronic kidney disease (CKD) on the brain remains poorly defined, with no data linking brain morphometry and observed cognitive deficits noted in this population. We explored the relationship between brain morphometry (using structural magnetic resonance imaging), cognition, and markers of CKD. Cerebellar and cerebral gray matter volumes are different in early CKD. Volumetric decreases in cerebellar gray matter are predicted by lower eGFR, suggesting a link between disease and brain morphometry. Reduced cerebellar gray matter predicted lower verbal fluency for those with pCKD. Enlarged cerebral gray matter in the pCKD sample predicted lower mathematics performance.

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.

Evaluating motor progression of juvenile-onset Huntington's Disease: An Enroll-HD analysis.

INTRODUCTION: Juvenile-onset Huntington's disease (JOHD) is characterized by a unique motor phenotype relative to patients with adult-onset Huntington's Disease (AOHD). This study characterized motor progression of JOHD to propose improved outcome measures for this group. METHODS: We used linear mixed effect regression models to compare progression of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS) and the chorea score between patients with JOHD and AOHD. We then evaluated all 31 subscales that make up the UHDRS over time within patients with JOHD to identify measures that may be used to track motor progression most reliably. RESULTS: The JOHD cohort had faster TMS progression compared to AOHD (p = 0.006) but no group difference in the rate of change of chorea. Patients with JOHD did not show significant change in any of the chorea subscales. The subscales that changed most reliably over time amongst patients with JOHD were dysarthria, upper extremity dystonia, tandem walking, gait, bilateral pronate/supinate, bilateral finger-tapping, and tongue protrusion. When these subscales were summed, they progressed at a faster rate (7.07%, 95% CI [5.96-8.18]) than the TMS (4.92%, 95% CI [3.95-5.89]). CONCLUSION: While the TMS changes at a significant rate in JOHD subjects, not all subscales that make up the TMS accurately represent the unique motor features of JOHD. A JOHD-specific scale performed better at tracking motor progression relative to the TMS. This scale may improve clinical care for patients with JOHD and allow for the development of more efficient clinical trials.

A pilot dose-finding study of Terazosin in humans.

Background: Parkinson's disease (PD) is a prevalent neurodegenerative disorder where progressive neuron loss is driven by impaired brain bioenergetics, particularly mitochondrial dysfunction and disrupted cellular respiration. Terazosin (TZ), an α-1 adrenergic receptor antagonist with a known efficacy in treating benign prostatic hypertrophy and hypertension, has shown potential in addressing energy metabolism deficits associated with PD due to its action on phosphoglycerate kinase 1 (PGK1). This study aimed to investigate the safety, tolerability, bioenergetic target engagement, and optimal dose of TZ in neurologically healthy subjects. Methods: Eighteen healthy men and women (60 - 85 years old) were stratified into two cohorts based on maximum TZ dosages (5 mg and 10 mg daily). Methods included plasma and cerebrospinal fluid TZ concentration measurements, whole blood ATP levels, 31 Phosphorous magnetic resonance spectroscopy for brain ATP levels, 18 F-FDG PET imaging for cerebral metabolic activity, and plasma metabolomics. Results: Our results indicated that a 5 mg/day dose of TZ significantly increased whole blood ATP levels and reduced global cerebral 18 F-FDG PET uptake without significant side effects or orthostatic hypotension. These effects were consistent across sexes. Higher doses did not result in additional benefits and showed a potential biphasic dose-response. Conclusions: TZ at a dosage of 5 mg/day engages its metabolic targets effectively in both sexes without inducing significant adverse effects and provides a promising therapeutic avenue for mitigating energetic deficiencies. Further investigation via clinical trials to validate TZ's efficacy and safety in neurodegenerative (i.e., PD) contexts is warranted.

Memantine Use and Cognitive Decline in Huntington's Disease: An Enroll-HD Study.

Background: Memantine is an N-methyl-d-aspartate (NMDA) receptor antagonist that is used to treat moderate to severe Alzheimer's Dementia (AD) and has been speculated to provide clinical benefits in Huntington's disease (HD). Objective: To assess the effectiveness of memantine on the trajectory of cognitive decline in individuals with manifest HD. Methods: Using participants from the Enroll-HD study, the primary analysis compared trajectories in cognition over a 5-year period using linear mixed effect models of prevalent and incident memantine users who were propensity-score-matched with non-users on measures of disease progression and demographics. Results: In the primary analysis there were no significant differences in the trajectories between memantine users and non-users on any primary outcomes of interest. Conclusions: Memantine use was not associated with any clinical benefit for individuals with manifest HD. Further studies are warranted to assess the impact of memantine on clinical outcomes in HD.

The effects of antidepressants on depressive symptoms in manifest Huntington's disease.

OBJECTIVE: Currently there is little evidence to guide the treatment of depression in Huntington's disease (HD). The primary objective was to determine the effectiveness of antidepressant medications on lowering depressive symptom scores in patients with manifest HD. The secondary objective was to determine the effect of antidepressant use on measures of disease progression. METHODS: After retrospectively identifying motor-manifest HD participants with at least borderline depressive symptoms from the Enroll-HD database, 86 new users of antidepressant medication were exact matched with non-users on depression score, and matched on propensity scores developed using age, sex, CAG repeat length, anxiety scores, and disease progression measures. Linear mixed effect models were used to assess the change in depression scores, anxiety scores, and disease progression measures based on antidepressant use between two visits approximately one-year apart. RESULTS: There was no significant difference in the change in depression score between antidepressant users and non-users (p = 0.46). There were also no significant differences in the change in total motor score (p = 0.88), total functional capacity score (p = 0.16), number correct on the symbol digit modality test (p = 0.49), or anxiety score (p = 0.68). CONCLUSIONS: Initiation of antidepressant medication was not associated with a greater reduction in depressive symptoms or changes in other symptoms when compared to non-use. The findings of this study support further research on the effectiveness of antidepressants in Huntington's disease patients. Clinical trials or studies with a larger sample of new antidepressant users should be used to assess the causal effects of antidepressant medications on depressive symptoms.

A pilot to assess target engagement of terazosin in Parkinson's disease.

BACKGROUND: Impaired brain energy metabolism is a key feature of Parkinson's disease (PD). Terazosin (TZ) binds phosphoglycerate kinase 1 and stimulates its activity, which enhances glycolysis and increases ATP levels. Preclinical and epidemiologic data suggest that TZ may be neuroprotective in PD. We aimed to assess target engagement and safety of TZ in people with PD. METHODS: We performed a 12-week pilot study in people with PD. Participants were randomized to receive 5 mg TZ or placebo. Participants and study personnel were blinded. We assessed TZ target engagement by measuring brain ATP with 31P-magnetic resonance spectroscopy (MRS) and whole blood ATP with a luminescence assay. Robust linear regression models compared changes between groups controlling for baseline brain and blood ATP levels, respectively. We also assessed clinical measures of PD and adverse events. RESULTS: Thirteen participants were randomized. Mild dizziness/lightheadedness was more common in the TZ group, and three participants taking TZ dropped out because of dizziness and/or orthostatic hypotension. Compared to the placebo group, the TZ group had a significant increase in the ratio of ßATP to inorganic phosphate in the brain. The TZ group also had a significant increase in blood ATP levels compared to the placebo group (p < 0.01). CONCLUSIONS: This pilot study suggests that TZ may engage its target and change ATP levels in the brain and blood of people with PD. Further studies may be warranted to test the disease-modifying potential of TZ.

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.

Behavioral features in child and adolescent huntingtin gene-mutation carriers.

INTRODUCTION: We compared neuropsychiatric symptoms between child and adolescent huntingtin gene-mutation carriers and noncarriers. Given previous evidence of atypical striatal development in carriers, we also assessed the relationship between neuropsychiatric traits and striatal development. METHODS: Participants between 6 and 18 years old were recruited from families affected by Huntington's disease and tested for the huntingtin gene expansion. Neuropsychiatric traits were assessed using the Pediatric Behavior Scale and the Behavior Rating Inventory of Executive Function. Striatal volumes were extracted from 3T neuro-anatomical images. Multivariable linear regression models were conducted to evaluate the impact of group (i.e., gene nonexpanded [GNE] or gene expanded [GE]), age, and trajectory of striatal growth on neuropsychiatric symptoms. RESULTS: There were no group differences in any behavioral measure with the exception of depression/anxiety score, which was higher in the GNE group compared to the GE group (estimate = 4.58, t(129) = 2.52, FDR = 0.051). The growth trajectory of striatal volume predicted depression scores (estimate = 0.429, 95% CI 0.15:0.71, p = .0029), where a negative slope of striatal volume over time was associated with lower depression/anxiety. CONCLUSIONS: The current findings show that GE children may have lower depression/anxiety compared to their peers. Previously, we observed a unique pattern of early striatal hypertrophy and continued decrement in volume over time among GE children and adolescents. In contrast, GNE individuals largely show striatal volume growth. These findings suggest that the lower scores of depression and anxiety seen in GE children and adolescents may be associated with differential growth of the striatum.