Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich's ataxia patients.

Transcriptional changes in Friedreich's ataxia (FRDA), a rare and debilitating recessive Mendelian neurodegenerative disorder, have been studied in affected but inaccessible tissues-such as dorsal root ganglia, sensory neurons and cerebellum-in animal models or small patient series. However, transcriptional changes induced by FRDA in peripheral blood, a readily accessible tissue, have not been characterized in a large sample. We used differential expression, association with disability stage, network analysis and enrichment analysis to characterize the peripheral blood transcriptome and identify genes that were differentially expressed in FRDA patients (n = 418) compared with both heterozygous expansion carriers (n = 228) and controls (n = 93 739 individuals in total), or were associated with disease progression, resulting in a disease signature for FRDA. We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression

Rapidly Progressing Neurocognitive Disorder in a Male with FXTAS and Alzheimer's Disease.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that usually begins in the early 60s and affects carriers of premutation expansion (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Additional disorders can co-occur with FXTAS including Alzheimer's disease (AD). Here we discuss a case report of a male with 67 CGG repeats in FMR1 who had mild late-onset FXTAS symptoms followed by neurocognitive disorder symptoms consistent with AD. The patient has developed tremor and ataxia that are the two characteristic symptoms of FXTAS. In addition, he shows rapid cognitive decline, brain atrophy most substantial in the medial temporal lobe, and decreased metabolism in the brain regions that are the characteristic findings of AD. The purpose of this study is to describe a patient profile with both diseases and review the details of an overlap between these two diseases

Neural correlates of early deliberate emotion regulation: Young children\u27s responses to interpersonal scaffolding.

Deliberate emotion regulation, the ability to willfully modulate emotional experiences, is shaped through interpersonal scaffolding and forecasts later functioning in multiple domains. However, nascent deliberate emotion regulation in early childhood is poorly understood due to a paucity of studies that simulate interpersonal scaffolding of this skill and measure its occurrence in multiple modalities. Our goal was to identify neural and behavioral components of early deliberate emotion regulation to identify patterns of competent and deficient responses. A novel probe was developed to assess deliberate emotion regulation in young children. Sixty children (age 4-6 years) were randomly assigned to deliberate emotion regulation or control conditions. Children completed a frustration task while lateral prefrontal cortex (LPFC) activation was recorded via functional near-infrared spectroscopy (fNIRS). Facial expressions were video recorded and children self-rated their emotions. Parents rated their child\u27s temperamental emotion regulation. Deliberate emotion regulation interpersonal scaffolding predicted a significant increase in frustration-related LPFC activation not seen in controls. Better temperamental emotion regulation predicted larger LPFC activation increases post- scaffolding among children who engaged in deliberate emotion regulation interpersonal scaffolding. A capacity to increase LPFC activation in response to interpersonal scaffolding may be a crucial neural correlate of early deliberate emotion regulation

Stability of Satellite Planes in M31 II: Effects of the Dark Subhalo Population

The planar arrangement of nearly half the satellite galaxies of M31 has been a source of mystery and speculation since it was discovered. With a growing number of other host galaxies showing these satellite galaxy planes, their stability and longevity have become central to the debate on whether the presence of satellite planes are a natural consequence of prevailing cosmological models, or represent a challenge. Given the dependence of their stability on host halo shape, we look into how a galaxy plane's dark matter environment influences its longevity. An increased number of dark matter subhalos results in increased interactions that hasten the deterioration of an already-formed plane of satellite galaxies in spherical dark halos. The role of total dark matter mass fraction held in subhalos in dispersing a plane of galaxies present non trivial effects on plane longevity as well. But any misalignments of plane inclines to major axes of flattened dark matter halos lead to their lifetimes being reduced to < 3 Gyrs. Distributing > 40% of total dark mass in subhalos in the overall dark matter distribution results in a plane of satellite galaxies that is prone to change through the 5 Gyr integration time period.Comment: 11 pages, 9 figures, accepted to MNRAS September 22 201

Dyclonine rescues frataxin deficiency in animal models and buccal cells of patients with Friedreich's ataxia.

Inherited deficiency in the mitochondrial protein frataxin (FXN) causes the rare disease Friedreich's ataxia (FA), for which there is no successful treatment. We identified a redox deficiency in FA cells and used this to model the disease. We screened a 1600-compound library to identify existing drugs, which could be of therapeutic benefit. We identified the topical anesthetic dyclonine as protective. Dyclonine increased FXN transcript and FXN protein dose-dependently in FA cells and brains of animal models. Dyclonine also rescued FXN-dependent enzyme deficiencies in the iron-sulfur enzymes, aconitase and succinate dehydrogenase. Dyclonine induces the Nrf2 [nuclear factor (erythroid-derived 2)-like 2] transcription factor, which we show binds an upstream response element in the FXN locus. Additionally, dyclonine also inhibited the activity of histone methyltransferase G9a, known to methylate histone H3K9 to silence FA chromatin. Chronic dosing in a FA mouse model prevented a performance decline in balance beam studies. A human clinical proof-of-concept study was completed in eight FA patients dosed twice daily using a 1% dyclonine rinse for 1 week. Six of the eight patients showed an increase in buccal cell FXN levels, and fold induction was significantly correlated with disease severity. Dyclonine represents a novel therapeutic strategy that can potentially be repurposed for the treatment of FA

Irritability moderates the association between cognitive flexibility task performance and related prefrontal cortex activation in young children

The association between cognitive flexibility and related neural functioning has been inconsistent. This is particularly true in young children, where previous studies have found heterogenous results linking behavior and neural function, raising the possibility of unexplored moderators. The current study explored the moderating role of dimensional irritability in the association between cognitive flexibility task performance and prefrontal activation in young children. A total of 106 3- to 7-year-old children were recruited to complete a custom-designed, child-adapted, cognitive flexibility task, and 98 of them were included in the data analysis. The children\u27s dorsolateral prefrontal cortex activation was monitored using functional near-infrared spectroscopy, and their levels of irritability were reported by parents using the MAP-DB Temper Loss subscale. Results indicated that the mean reaction time of the cognitive flexibility task was negatively correlated with concurrent prefrontal activation. No evidence was found for the association between task accuracy and prefrontal activation. Moreover, irritability moderated the association between the mean reaction time and prefrontal activation. Children high in irritability exhibited a stronger negative association between the mean reaction time and related prefrontal activation than children low in irritability. The moderating model suggested a novel affective-cognitive interaction to investigate the associations between cognitive task performance and their neural underpinnings

Racial Disparities in Time to Huntington Disease Diagnosis in North America: An ENROLL-HD Analysis.

BACKGROUND AND OBJECTIVES: There are well-documented racial and ethnic disparities in access to neurologic care and disease-specific outcomes. Although contemporary clinical and neurogenetic understanding of Huntington disease (HD) is thanks to a decades-long study of a Venezuelan cohort, there are a limited number of studies that have evaluated racial and ethnic disparities in HD. The goal of this study was to evaluate disparities in time from symptom onset to time of diagnosis of HD. METHODS: Using the ENROLL-HD periodic data set 5 (PDS5), we performed sequential multivariate linear regressions to evaluate sociodemographic factors associated with disparities in time to diagnosis (TTD) for gene-positive individuals (CAG repeats 36+) in the North America region. Sensitivity analyses included imputed multivariate regression analysis of individuals with a total motor score (TMS) of 10 or higher and those with 40+ CAG repeats. We also used descriptive statistics to present TTD data in other ENROLL-HD participating regions. RESULTS: Among 4717 gene-positive participants in the North American region, 89.5% identified as White, 3.4% as Hispanic or Latino, and 2.3% as African American/Black. The average TTD in the group was 3.78. When adjusting for clinical and sociodemographic variables, Black participants were diagnosed with HD 1 year later than White participants (p &lt; 0.05). Additional factors associated with a later diagnosis included psychiatric symptoms as initial HD symptom, unemployment during baseline ENROLL visit, and higher educational attainment. Sensitivity analysis of gene-positive (36+ CAG) participants with a TMS of 10 or higher and of those with 40+ CAG repeats yielded similar findings. DISCUSSION: Across multiple statistical models, Black ENROLL-HD participants were diagnosed with HD 1 year later than White participants. Clinical factors suggesting a delay in HD diagnosis included psychiatric symptoms at disease onset and a negative family history of HD. Unemployment during baseline visit and higher educational attainment were sociodemographic factors suggestive of a later diagnosis. Additional multicenter qualitative and quantitative studies are needed to better understand reasons for delays in HD diagnosis among Black individuals, and the role of social and structural determinants of health in obtaining a timely HD diagnosis

Clinical characteristics of patients with spinocerebellar ataxias 1, 2, 3 and 6 in the US; a prospective observational study

Background: All spinocerebellar ataxias (SCAs) are rare diseases. SCA1, 2, 3 and 6 are the four most common SCAs, all caused by expanded polyglutamine-coding CAG repeats. Their pathomechanisms are becoming increasingly clear and well-designed clinical trials will be needed. Methods: To characterize the clinical manifestations of spinocerebellar ataxia (SCA) 1, 2, 3 and 6 and their natural histories in the United States (US), we conducted a prospective multicenter study utilized a protocol identical to the European consortium study, using the Scale for the Assessment and Rating of Ataxia (SARA) score as the primary outcome, with follow-ups every 6 months up to 2 years. Results: We enrolled 345 patients (60 SCA1, 75 SCA2, 138 SCA3 and 72 SCA6) at 12 US centers. SCA6 patients had a significantly later onset, and SCA2 patients showed greater upper-body ataxia than patients with the remaining SCAs. The annual increase of SARA score was greater in SCA1 patients (mean ± SE: 1.61 ± 0.41) than in SCA2 (0.71 ± 0.31), SCA3 (0.65 ± 0.24) and SCA6 (0.87 ± 0.28) patients (p = 0.049). The functional stage also worsened faster in SCA1 than in SCA2, 3 and 6 (p = 0.002). Conclusions: The proportions of different SCA patients in US differ from those in the European consortium study, but as in the European patients, SCA1 progress faster than those with SCA2, 3 and 6. Later onset in SCA6 and greater upper body ataxia in SCA2 were noted. We conclude that progression rates of these SCAs were comparable between US and Europe cohorts, suggesting the feasibility of international collaborative clinical studies

Multimodal examination of emotion processing systems associated with negative affectivity across early childhood

High Temperamental Negative Affectivity in early childhood has been found to predict later emotion dysregulation. While much work has been conducted to separately probe bio-behavioral systems associated with Negative Affectivity, very little work has examined the relations among multiple systems across age. In this study, we use multi-modal methods to index neurobiological systems associated with Negative Affectivity in 53 4-7-year-old children. Prefrontal activation during emotion regulation was measured using functional near-infrared spectroscopy over the lateral prefrontal cortex (PFC) while children played a game designed to elicit frustration in Social (Happy and Angry faces) and Nonsocial contexts. Gaze behaviors while free-viewing Happy and Angry faces were also measured. Finally, Negative Affectivity was indexed using a score composite based on factor analysis of parent-reported temperament. Using mixed-effects linear models, we found an age-dependent association between Negative Affectivity and both PFC activation during frustration and fixation duration on the mouth area of Happy faces, such that older children high in Negative Affectivity spent less time looking at the mouths of Happy faces and had lower PFC activation in response to frustration (ps\u3c0.034). These results provide further insight to how Negative Affectivity may be associated with changes in affective neurobiological systems across early childhood